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‘Coming into their own’: FDA approval of liquid biopsy tests puts early, less invasive cancer detection in broader reach – USA TODAY

Posted: September 5, 2020 at 12:54 am

In the past, in order to get tumor cells from a patient, a doctor had to do surgery or biopsy. Now a nurse draws blood from the arm, like what happens in a routine blood test. (Sept. 2017) Video Elephant

Cancer patients often have to endure months of anxiety and side effects before they can schedule a scan or painful biopsy to learn if their treatment is working.

Liquid biopsy tests, which have won federal approval in recent weeks, could make that process faster and less miserable.

The Food and Drug Administration approved Guardant360 CDxin early August for use in a range of solid tumors; Foundation Medicine's FoundationOne Liquid CDx, became available for widespread use as of late last month.

The tests aren't brand new, but the federal approvals will make them more accessible, as Medicare and more insurance companies cover the costs, which can run as much as $6,000.

"I think that liquid biopsies now are coming into their own," said Dr. Matthew Freedman, an oncologist and researcher at the Dana-Farber Cancer Institute in Boston.

The newly approved liquid biopsies can identify the genetic signature of tumors, which then can be used to match patients to treatments or research trials with experimental therapies.

Lung cancer patients who have certain genetic mutations in their tumors, for instance, can double or triple their life expectancy when given a drug targeted to those mutations.

Doctors can also use liquid biopsies a few weeks after starting treatment to see how a tumor is evolving, and perhaps gain insights into why a treatment isn't working, said Helmy Eltoukhy, CEO of Guardant Health, of Redwood City, California, which makes Guardant360 CDx.

"It's better care for patients at lower cost if you test appropriately," he said.

Today, many cancer patients, particularly those with hard-to-reach tumors, get one biopsy with all future treatment decisions based on that one sample. But tumors change over time. "There's almost no other area of medicine where you'd use an old clinical specimen to decide treatment," Eltoukhy said.

Because blood is so easy to access, a liquid biopsy can be done several times to see how the tumor evolves, he said. And patients who live far from an academic medical center can still get cutting-edge recommendations without traveling.

So-called liquid biopsies, recently approved by the FDA, may make it easier for oncologists to track their patients' cancers.(Photo: Guardant Health)

Liquid biopsies are generally seen as not as precise as more typical biopsies, where a needle is inserted directly into a solid tumor. "If one had a choice, the choice would be to look at the biopsies," said Dr. Bert Vogelstein, who has spent years developing liquid biopsy tests as a professor at Johns Hopkins University in Baltimore.

But with some cancers, it's not easy to access the tumor, or there's very little cancerous material that can be withdrawn or seen.

As a tumor begins to spread its tentacles,it's initially invisible on scans. And after successful surgery, there may be no obvious tumor, but residual disease could still be lurking.

Liquid biopsies can fill those crucial gaps.

Scientific advances in recent years have made it possible to identify cancer DNA in the bloodstream tiny needles in the haystack of the bloodstream.

This opens up a lot of possibilities for treatment and diagnosis, Vogelstein said.

Guardant Health is one of two companies that recently received approval for its liquid biopsy tests, intended to make it easier to track cancers.(Photo: Guardant Health)

In colon cancer, for instance, roughly half of Stage 3 patients who otherwise would die can be cured with so-called adjuvant therapy, Vogelstein said. But nearly everyone who has enough metastatic cancer to be visible on an X-ray will die from their disease. "You cure close to 0% with adjuvant therapy," he said.

Adjuvant therapy is terribly toxic, though, so doctors don't want to use it unless they believe the patient is likely to have metastatic disease.

"So, this is a decision that virtually every patient goes through: Should I undergo adjuvant therapy?" said Vogelstein.

Until now, they've only beenable to guess and play the odds. But early research suggests using liquid biopsy to identify if there's residual diseasecan help make that decision easier, Vogelstein said.

Although studies proving the clinical usefulness of liquid biopsies have yet to be completed, he added, "Patients with positive liquid biopsies after surgery nearly always recur, and many that don't have positive liquid biopsy tests don't recur."

Dr. Neal Shore, medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, said he uses liquid biopsies to help him find clinical trials for patients with advanced cancer.

One patient, who only wanted to be identified by his first name, Joel, has been on a clinical trial of a double-drug therapy for two years, after a liquid biopsy identified a genetic mutation in his advanced prostate cancer.

"He looks great," Shore said on a call with Joel and his wife Tracey. "He's done exceptionally well."

Joel said the treatment has been challenging at times. He has trouble swallowing some days, suffers from back pain, and the hormone therapy he still takes gives him hot flashes.

But his wife said his issues are largely manageable with Tylenol and heating pads. "For the most part, he feels pretty good," she said.

Shore, who treats patients with kidney, bladder and prostate cancers, said liquid biopsies are particularly useful when a tissue sample is old or unusable.

"It expands our treatment armamentarium," he said. "This is really exciting for me as a urologist."

The next step, said Cindy Perettie, CEO of Cambridge, Massachusetts-based Foundation Medicine, will be to use liquid biopsies early in the course of someone's treatment.

"We're really focused on taking it from the metastatic setting and moving it to the early setting," she said. "That's where we're going to have the opportunity to really impact (patients)."

Breast cancer patients on maintenance therapy with tamoxifen, for instance, usually have to wait five years to know if their cancer has advanced, she said, but a liquid biopsy could let them know much faster and more often.

"We can look every six months whether they've progressed or not," Perettie said.

Even further into the future, the real potential for liquid biopsies lies in early detection.

For kidney cancer, as well as many other tumors, the earlier the diagnosis, the better the chance of survival, said Freedman of Dana-Farber. He, along with colleagues including Dr. Toni Choueiri, showed in a paper published earlier this summerthey could identify kidney cancer cells in urine at all stages of disease.

If such tumors could be identified when they're just beginning, the prognosis for kidney cancer would vastly improve.

"You want to cure cancer. You don't cure it with third-line chemo. You want to cure it before it happens," Choueiri said.

Today, about 20% of cancers are diagnosed via screening tools like mammography, colonoscopies or stool-based tests. Add liquid biopsies and that figure could jump to 75%. "I think that will be possible within five years or so," said Vogelstein, who is involved in a company, Thrive Earlier Detection, based in Cambridge, Massachusetts, that is working on such a test.

The challenge: the smaller the tumor, the less DNA released from the cancer cells, so the harder it is to detect.

Metastatic cancers that have spread throughout the body might account for 5-10% of the DNA floating in the bloodstream; but DNA from very early tumors may make up just 1-in-10,000 or 1-in-100,000 DNA molecules in blood, Vogelstein said.

Studies have shown it's feasible to find these few needles in a haystackbut not whether it's useful to doctors or patients.

There is also a risk to using liquid biopsies as a screening tool for early tumors, Vogelstein warned. False positives telling people they have cancer when they don't could do a lot of harm.

And a liquid biopsy can only say there's a high likelihood someone has cancer somewhere and that further testing is warranted, he said. Sometimes, something might look like cancer on a CT scan, but it isn't.

"It is essential," he said, "to show that the benefits of early detection outweigh the risks."

Contact Karen Weintraub at kweintraub@usatoday.com

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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'Coming into their own': FDA approval of liquid biopsy tests puts early, less invasive cancer detection in broader reach - USA TODAY

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Liquid biopsies to disrupt the oncology testing market – Medical Device Network

Posted: September 5, 2020 at 12:54 am

Obtaining sufficient tumour tissue for oncology testing can be challenging, particularly when there is an insufficient biopsy sample, and invasive procedures pose a health risk to the patients. This is especially true for non-small cell lung carcinoma (NSCLC), where 27%31% of patients are unable to provide a suitable specimen upon diagnosis. One area of active research in oncology testing has been the evaluation of alternative sources of testing material. Liquid biopsy refers to the analysis of any tumour-derived material, circulating in the blood or any other body fluid. The detection of mutations via circulating tumour DNA (ctDNA) found in plasma has been rising in popularity due to its minimal invasiveness.

On 7 August, Guardant Health announced the Food and Drug Administration (FDA) approval of its novel liquid biopsy comprehensive tumour mutation profiling test across all solid cancers. This is a landmark approval for cancer testing as Guardant Healths liquid biopsy is the first of its kind to genetically profile tumours anywhere in the body from a single blood draw. The FDA approval of this test includes its approval as a companion diagnostic for identifying patients with metastatic NSCLC based on the presence of mutations in the EGFR gene. Lung cancer is the current leading cause of cancer-related deaths worldwide with NSCLC comprising 80%90% of all lung cancers. As such, the need for this test is very high.

On 27 August, Foundation Medicine, a Roche company, received FDA approval for its FoundationOne Liquid CDx, a multi-cancer comprehensive liquid biopsy test. Foundation Medicines test is broader than Guardant Healths, covering more than 300 cancer-related genes. In addition to single-gene alterations, Foundation Medicines test also reports on the presence of multi-gene signatures namely microsatellite instability and blood tumour mutational burden, which can help guide the use of cancer immunotherapies.

The genomic analysis of ctDNA has the potential to offer insight across multiple metastatic sites. This is particularly valuable in settings with increased genomic heterogeneity such as in patients with treatment resistance. Some key opinion leaders (KOLs) interviewed by GlobalData have indicated that despite the fact that the test has some sensitivity issues, liquid biopsies are a cheaper alternative and the minimally invasive aspect of the technique improves patient satisfaction. Other KOLs noted the potential for liquid biopsies to integrate the overall cancer burden in patients with numerous metastases in different locations. GlobalData predicts an increased usage of liquid biopsies in the future due to the benefits they offer patients with metastatic recurrence.

Liquid biopsy is revolutionising cancer tests as it is non-invasive, precise and provides faster turnaround time for results compared to traditional solid tumour biopsy. While DNA sequencing methods such as Sanger sequencing have been considered the gold standard for detecting many genetic mutations associated with cancer, these techniques have lower sensitivity, and thus, require samples with a higher percentage of mutated DNA. As such, the use of ctDNA will be important for detecting cancerous mutations where tumours are hard to resect. Furthermore, the use of highly sensitive assays such as next-generation sequencing (NGS) will aid in the detection of cancerous mutations. As sequencing technology like NGS becomes more developed and its costs decrease, GlobalData expects these techniques to be more frequently used to test for mutations in cancer.

GlobalData is this websites parent business intelligence company.

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Genentech Announces FDA Approval of Gavreto (pralsetinib) for the Treatment of Adults With Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer -…

Posted: September 5, 2020 at 12:54 am

Sept. 4, 2020 23:00 UTC

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, Inc., a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has approved Gavreto (pralsetinib) for the treatment of adults with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. This indication was approved under the FDAs accelerated approval program based on data from the Phase I/II ARROW study. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations.

The FDA approval of Gavreto for RET fusion-positive non-small cell lung cancer is an important step towards our goal of providing an effective treatment option for every person diagnosed with lung cancer, no matter how rare or hard-to-treat their type of disease, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. We remain committed to finding personalized treatment options for people with cancer based on specific genomic or molecular alterations, and we look forward to partnering with Blueprint Medicines to further explore the potential of Gavreto across multiple RET-altered tumor types.

RET-activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and medullary thyroid cancer (MTC), and treatment options that selectively target these genetic alterations are limited. In NSCLC, RET fusions represent approximately 1-2% of patients. Biomarker testing for these fusions is the most effective way to identify people who are eligible for treatment with Gavreto.

The approval is based on the results from the Phase I/II ARROW study, in which Gavreto produced durable clinical responses in people with RET fusion-positive NSCLC with or without prior therapy, and regardless of RET fusion partner or central nervous system involvement. Gavreto demonstrated an overall response rate (ORR) of 57% (95% CI: 46%, 68%) and complete response (CR) rate of 5.7% in the 87 people with NSCLC previously treated with platinum-based chemotherapy, and the median duration of response (DoR) was not reached (95% CI: 15.2 months, not reached). In the 27 people with treatment-nave NSCLC, the ORR was 70% (95% CI: 50%, 86%) with an 11% CR rate. The most common adverse reactions (25%) were fatigue, constipation, musculoskeletal pain and increased blood pressure (hypertension).

Gavreto is now the sixth FDA-approved medicine in Genentechs portfolio of treatments for lung cancer. The FDA granted Breakthrough Therapy Designation to Gavreto for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy and for RET mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments.

The FDA has also granted Priority Review to Gavreto for the treatment of people with advanced or metastatic RET-mutant MTC and RET fusion-positive thyroid cancer, and is expected to make a decision on approval by February 28, 2021. This New Drug Application (NDA) was accepted for review under the FDAs Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.

For those who qualify, Blueprint Medicines will offer patient assistance programs for people prescribed Gavreto by their doctor through YourBlueprint . Please visit http://www.yourblueprint.com or contact 1-888-BLUPRNT for more information.

About the ARROW study

ARROW (NCT03037385) is a Phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability and efficacy of Gavreto, administered orally in people with rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancer and other RET-altered solid tumors. The trial consists of two parts: a dose escalation portion, which is complete, and an expansion portion in people treated with 400 mg of Gavreto, once-daily. ARROW is being conducted at multiple sites across the United States, European Union and Asia.

About lung cancer

According to the American Cancer Society, it is estimated that more than 228,000 Americans will be diagnosed with lung cancer in 2020, and NSCLC accounts for 80-85% of all lung cancers. It is estimated that approximately 85% of lung cancer diagnoses in the United States are made when the disease is in the advanced stages. In NSCLC, RET fusions represent approximately 1-2% of patients.

About Gavreto

Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations, regardless of the tissue of origin. Preclinical data have shown that Gavreto inhibits primary RET fusions and mutations that cause cancer in subsets of patients, as well as secondary RET mutations predicted to drive resistance to treatment. Blueprint Medicines and Genentech are also co-developing Gavreto for the treatment of patients with various types of RET-altered thyroid cancers and other solid tumors.

Gavreto U.S. Indication

Gavreto (pralsetinib) is indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

Gavreto may cause serious side effects, including:

Lung problems (pneumonitis) occurred in 10% of patients who received Gavreto, including 2.7% with Grade 3/4, and 0.5% with fatal reactions. Monitor for pulmonary symptoms indicative of interstitial lung disease (ILD)/pneumonitis. Withhold Gavreto and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue Gavreto based on severity of confirmed ILD.

Increased blood pressure (hypertension) occurred in 29% of patients, including Grade 3 hypertension in 14% of patients. Overall, 7% had their dose interrupted and 3.2% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Gavreto in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Gavreto. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Gavreto based on the severity.

Liver problems (hepatotoxicity): Serious hepatic adverse reactions occurred in 2.1% of patients treated with Gavreto. Increased AST occurred in 69% of patients, including Grade 3/4 in 5.4% and increased ALT occurred in 46% of patients, including Grade 3/4 in 6%. The median time to first onset for increased AST was 15 days (range: 5 days to 1.5 years) and increased ALT was 22 days (range: 7 days to 1.7 years). Monitor AST and ALT prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Gavreto based on severity.

Grade 3 bleeding (hemorrhagic events) occurred in 2.5% of patients treated with Gavreto including one patient with a fatal hemorrhagic event. Permanently discontinue Gavreto in patients with severe or life-threatening hemorrhage.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Gavreto has the potential to adversely affect wound healing. Withhold Gavreto for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Gavreto after resolution of wound healing complications has not been established.

Based on findings from animal studies and its mechanism of action, Gavreto can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Gavreto and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Gavreto and for 1 week after the final dose. Advise women not to breastfeed during treatment with Gavreto and for 1 week after the final dose.

Common adverse reactions (25%) were fatigue, constipation, musculoskeletal pain, and hypertension. Common Grade 3-4 laboratory abnormalities (2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium (corrected) and increased alanine aminotransferase (ALT).

Avoid coadministration with strong CYP3A inhibitors. Avoid coadministration of Gavreto with combined P-gp and strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the Gavreto dose. Avoid coadministration of Gavreto with strong CYP3A inducers. If coadministration cannot be avoided, increase the Gavreto dose.

Please click here to see the full Prescribing Information for Gavreto.

Gavreto, Blueprint Medicines, YourBlueprint and associated logos are trademarks of Blueprint Medicines Corporation.

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have six approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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Genomic analysis reveals insights on virulent, emerging foodborne pathogen – UB Now: News and views for UB faculty and staff – University at Buffalo…

Posted: September 5, 2020 at 12:54 am

Foodborne pathogens are very common and usually benign, but certain virulent strains of pathogens can result in severe disease and even death. Distinguishing specific strains of pathogens can help scientists better understand them and develop biomarkers to help detect them in patients, expediting diagnosis and treatment.

UB researchers have now completed the genomic analysis of a specific strain of Shiga-toxin E. coli (STEC) that can cause severe disease outbreaks and is increasingly common. The research could play a role in expanding the understanding of STEC infections and, potentially, in developing vaccines against them.

According to the Centers for Disease Control and Prevention, STEC are estimated to cause more than 265,000 infections per yearin the U.S., and are associated with more than 3,600 hospitalizations and approximately 30 deaths.

Published in BMC Genomics last month, the paper describes the genomic analysis completed on a unique STEC strain isolated from an otherwise healthy 2 -year-old child living in Davidson County, Tennessee. The pathogen caused severe illness, including hemolytic uremic syndrome, a condition that destroys red blood cells, lowers platelets and blocks blood vessels in kidneys, resulting in anemia and kidney damage.

The child survived but was hospitalized for a month and sustained severe complications affecting multiple organ systems, including her lungs, heart, kidney, brain, circulatory system and gastrointestinal tract.

The Shiga-toxin producing E. coli she was infected with is a non-0157 STEC. While the pathogens classified as 0157 STEC infections generally are more common and result in more severe disease, the number of emerging, non-0157 STEC pathogens has been on the increase. Some lead to severe disease, creating a growing public health concern, according to the UB researchers.

The paper states that there are more than 400 of these non-0157 STEC strains, and more than a quarter are reported to cause gastrointestinal disease, often presenting first as bloody diarrhea with hemolytic uremic syndrome and if untreated, in rare cases, death.

The specific pathogen the child was infected with was a STEC 0145:H25. Since genomic studies on emerging non-0157 STEC are limited, our studies are significant because they reveal the genetic makeup of emergent STEC 0145:H25 in comparison with other STEC strains, says Oscar G. Gmez-Duarte, corresponding author on the paper, associate professor and chief of the Division of Pediatric Infectious Diseases in the Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences at UB, and a pediatrician with UBMD Pediatrics.

The findings reveal how this emerging STEC causes severe disease and that it may be as virulent, or even more virulent, than more common STEC strains, leading to severe and even deadly disease in susceptible hosts, he says. It also provides information on how this potentially preventable infection continues to affect vulnerable individuals.

A key finding of the study, he says, was that this 0145:H25 serotype leads to particularly severe infection. Moreover, in addition to carrying virulence genes present in 0157 STEC, it has additional genes and new potential virulence genes as compared to other non-0157 strains that have been studied. These findings deserve further analysis to understand the pathogenesis of these emergent STEC infections, Gmez-Duarte says.

The analysis was conducted through a collaboration between the Department of Pediatrics researchers and colleagues at UBs New York State Center of Excellence in Bioinformatics and LifeSciences, whose expertise in bioinformatics and whole genome sequencing analysis allowed the team to uncover the genetic information critical to understanding where these strains are derived from and how they may be traced to unique reservoirs, such as contaminated food products or infected livestock.

Gmez-Duarte is an expert in infectious gastrointestinal diseases and diarrhea in children. He established a global health research program, the International Enteric Vaccines Research Program (IEVRP), dedicated to studying the epidemiology, pathogenesis and vaccine development of childhood gastrointestinal infections within the U.S. and abroad. He has also conducted vaccine development research for pediatric infectious diseases.

UB co-authors are Julio Guerra of the Department of Pediatrics and Jonathan E. Bard and Donald Yergeau of the Genomics and Bioinformatics Core of UBs NYS Center of Excellence in Bioinformatics and Life Sciences. Chengxian Zhang and Natasha Halasa of Vanderbilt University are also co-authors.

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Existing Class of Drugs May Improve Neurological Function in Patients with Rare, Aggressive Genetic Disorder – Newswise

Posted: September 5, 2020 at 12:54 am

Philadelphia, September 3, 2020 New findings from Childrens Hospital of Philadelphia (CHOP) show that some patients with a rare and aggressive form of leukodystrophy may benefit from receiving treatment with a class of targeted therapy drugs that could improve their neurological function. A correspondence about these findings was published today in the New England Journal of Medicine.

Aicardi-Goutires syndrome (AGS) is a rare genetic disorder and type of leukodystrophy that affects the brain and immune system. In patients with AGS, the bodys immune system turns on itself in a destructive way, targeting the brains white matter, causing most children with the disorder to experience mild to severe intellectual or physical impairments. Most children with AGS are unable to walk or talk and have multisystemic complications, including skin inflammation.

Prior studies have linked the activation of interferons signaling proteins that respond to various immune disruptions to exacerbated symptoms in AGS. Researchers at CHOP wanted to explore whether a class of small molecule inhibitor drugs called janus kinase (JAK) inhibitors could be used to block interferon activation in a way that helped these patients.

Because treatment options for AGS are limited and the symptoms that these patients experience are so severe, there is a need to explore a wide variety of options, said senior author Adeline Vanderver, MD, an attending physician in the Division of Neurology, Program Director of the Leukodystrophy Center, and Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at CHOP.

The study was conducted at CHOP with 35 international patients with genetically confirmed AGS. These patients received baricitinib, an oral JAK1 and JAK2 inhibitor, with doses based on each patients renal function, age and symptoms. Patients had their developmental histories evaluated from the onset of the disease to the end of the study, which ranged from 7.4 months to 41.5 months. The study team analyzed a variety of developmental milestones, including head control, sitting, rolling, smiling, babbling, and the use of single words and word combinations.

Before the patients in this study received treatment, 26 of the 35 had stable or declining neurologic function, and 9 of the 35 patients gained one or two of these developmental skills after disease onset. However, during the study, 20 patients met new milestones, and 12 patients gained between two to seven new skills. The improvements were typically observed within three months into the study and persisted. Children who received higher doses of the therapy appeared to achieve more of these milestones.

Some of the AGS patients who received baricitinib were at risk for developing thrombocytosis, leukopenia, and infection and therefore should be monitored closely while taking the drug.

Measuring neurologic improvements in these patients is a complex process, but the results of this study are encouraging, especially because we observed improvements even in patients with severe and long-standing disease, Vanderver said.

Eli Lilly provided the medication for the study and performed the safety laboratory tests. This work was supported by grants NINDS U01 NS106845 and NICHD U01HD082806 and the State of Pennsylvania, Commonwealth Universal Research Enhancement Program, the J.A. Kamens Chair in Translational Neurotherapeutics from CHOP; grant KL2TR001879 from the National Center for Advancing Translational Sciences of the NIH, K23NS114113 the National Institute of Neurological Disorders and Stroke of the NIH, and K08-HL140129 from the Parker B. Francis Foundation; and funding from the Department of Pediatrics at CHOP.

Vanderver et al, Janus Kinase Inhibition in the AicardiGoutires Syndrome. N Engl J Med, online September 3, 2020. DOI: 10.1056/NEJMc2001362.

About Childrens Hospital of Philadelphia: Childrens Hospital of Philadelphia was founded in 1855 as the nations first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Childrens Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

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NUS team’s map sheds light on heart diseases – The Straits Times

Posted: September 5, 2020 at 12:54 am

Researchers have developed a coherent map of genes in the heart and looked at how they may cause heart diseases, which could pave the way for new treatments for these illnesses.

Heart diseases are a complex set of diseases influenced by different genes, and it is challenging to understand which genes are responsible for a particular disease, say experts.

To help scientists unravel the complex web of genes and how they interact, researchers from the National University of Singapore Yong Loo Lin School of Medicine (NUS Medicine) and the National University Hospital created what they said is the first map of the heart's genes and the "switches" between them that control how the genes behave and contribute to heart diseases.

Genes code for specific traits, and the switches are the non-coding portions of DNA between the genes.

Each gene has more than one switch and the switches may be far away from the genes that they control, making it tricky for scientists to match the switches to the genes.

The genetic heart map locates the genes and their switches so that scientists can eventually study them to create targeted treatments, such as gene therapy.

"If we understand how these genes are controlled, then we may find ways to control heart failure itself... and identify new disease-causing genes," said Professor Roger Foo from the university's department of medicine, who led the research team.

Heart diseases, which eventually lead to heart failure, cause one-third of all deaths in Singapore annually.

The researchers are part of the Cardiovascular Disease Translational Research Programme, one of nine new strategic research focus areas that were established at NUS Medicine in July.

The new focus areas, which also include infectious diseases, healthy longevity and precision medicine, aim to create greater synergy and collaboration between basic and clinical scientists within the National University Health System, and to deliver research outcomes that address current clinical and national healthcare issues.

Professor Chng Wee Joo, vice-dean of research at NUS Medicine, said: "We hope that these nine programmes will deliver not just outstanding research, but over the next five to 10 years, make some real impact on how we treat our patients and on the population's health."

BETTER UNDERSTANDING

If we understand how these genes are controlled, then we may find ways to control heart failure itself... and identify new disease-causing genes.

PROFESSOR ROGER FOO, from the National University of Singapore's department of medicine, who led the team that developed the map of genes in the heart.

The development of the gene map was published as two companion publications in the journals Circulation Research and Circulation last month and this month respectively.

The map took about five years to develop, and the researchers studied tissues from 36 healthy hearts and 34 failing hearts to map out the genes and switches.

Prof Foo said some scientists from Singapore and abroad have reached out to them to find out more about various genes from the map.

He also noted that none of the drugs currently used in treating heart disease targets genes, and cardiovascular research is not as well funded compared with other health conditions.

"The place where a lot of gene targeting is happening, I feel, is in cancer. Looking at the progress that cancer treatment has seen in recent years with targeted therapy, this is our dream for cardiovascular disease also, now that we have mapped out all these specific processes," he added.

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New HIV Gene Therapy, CAR-T Treatments Could be on the Horizon for Patients – BioSpace

Posted: September 5, 2020 at 12:54 am

Could gene therapy provide a solution to HIV? A new research project aims to find out.

The National Institutes of Health(NIH) has backed researchers at the University of Southern California and the Fred Hutchison Cancer Center with a five-year, $14.6 million grant to develop a gene therapy that could potentially control HIV without the need for daily medications. Most HIV patients take a well-regimented cocktail of medications each day to control the virus. This therapy could change that. According to an announcement from the Keck School of Medicine at USC, the goal will be to develop a therapy that prepares patients for a stem cell transplantation using their own cells with little to no toxicity, engineers their own stem cells to fight HIV and stimulates those cells to quickly produce new and engineered immune cells once they're reintroduced into the patient. The hematopoietic stem cell transplants, also known as bone marrow transplants, have been used to treat some blood cancers. The idea is to infuse an HIV patient withhealthy donor blood stem cells that can grow into any type of blood or immune cell.

The gene therapy strategy has been inspired by three cases where leukemia patients who also had HIV received blood stem cell transplants from donors who also carried a mutation that confers immunity to HIV. The mutation was in the CCR5 gene, which encodes a receptor that HIV uses to infect immune cells and is present in about 1 percent of the population, USC said.

The program will engineer blood cells to remove CCR5 from a patient's own stem cells.That will be combined with other genetic changes so that the progeny of engineered stem cells will release antibodies and antibody-like molecules that block HIV.

In addition to the potential gene therapy treatment, researchers are also assessing whether or not CAR-T treatments will benefit HIV patients. Researchers from Harvard University developed a Dual CAR T-cell immunotherapy that can potentially help fight HIV infection. First reported by Drug Target Review, the HIV-specific CAR-T cell is being developed to not only target and eliminated HIV-infected cells, but also reproduce in vivo to enable the patients to fight off the infection. HIVs primary target it T cells, which are part of the bodys natural immune response.

Todd Allen, a professor of Medicine at Harvard Medical School, said the Dual CAR-T cell immunotherapy has so far provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself.

According to the report, theDual CAR T cell was developed through the engineering of two CARs into a single T cell. Each of the CARs contained a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. As DTR reported, the first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

To protect the CAR-T cells from HIV, the team added the protein C34-CXCR4, which prevents HIV from attaching to and infecting cells. When that was added, the researchers found in animal models that the treatment was long-lived, replicated in response to HIV infection, killed infected cells effectively and was partially resistant to HIV infection.

Still, other researchers are looking to those rare individuals who are infected with HIV but somehow on their own are able to suppress the virus without the need for any treatment. Researchers have sought to replicate what this small percentage of patients can naturally do in other patients who require those daily regimens of medications. Through the sequencing of the genetic material of those rare individuals, researchers made an interesting discovery.

The team discovered large numbers of intact viral sequences in the elite controllers chromosomes. But in this group, the genetic material was restricted to inactive regions, where DNA is not transcribed into RNA to make proteins, MedNewsToday reported.

Now the race is on to determine how this can be replicated and used to treat the nearly 38 million people across the globe who have been diagnosed with HIV.

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The Honorable Dr. Dale Layman, Founder of Robowatch, LLC, is Recognized as the 2020 Humanitarian of the Year by Top 100 Registry, Inc. – IT News…

Posted: September 4, 2020 at 1:56 am

PR.com2020-09-03

Joliet, IL, September 03, 2020 --(PR.com)-- The Honorable Dr. Dale Pierre Layman, A.S., B.S., M.S., Ed.S., Ph.D. #1, Ph.D. #2, Grand Ph.D. in Medicine, MOIF, FABI, DG, DDG, LPIBA, IOM, AdVMed, AGE, is the Founder and President of Robowatch, L.L.C. (www.robowatch.info.) Robowatch is an international non-profit group aiming to keep a watchful human eye on the fast-moving developments occurring in the fields of robotics, computing, and Artificial Intelligence (A.I.) industries. As the first person in his family to attend college in 1968, he earned an Associate of Science (A.S.) in Life Science from Lake Michigan College. The same year, he won a Michigan Public Junior College Transfer Scholarship to the University of Michigan in Ann Arbor. In 1971, he received an Interdepartmental B.S. with Distinction, in Anthropology - Zoology, from the University of Michigan. From 1971 to 1972, Dr. Layman served as a Histological Technician in the Department of Neuropathology at the University of Michigan Medical School. From 1972 to 1974, he attended the U of M Medical School, Physiology department, and was a Teaching Fellow of Human Physiology. He completed his M.S. in Physiology from the University of Michigan in 1974.

From 1974 to 1975, Dr. Layman served as an Instructor in the Biology Department at Lake Superior State College. In 1975, he became a full-time, permanent Instructor in the Natural Science Department of Joliet Junior College (J.J.C.) and taught Human Anatomy, Physiology, and Medical Terminology to Nursing & Allied Health students. Appointed to the Governing Board of Text & Academic Authors, he authored several textbooks, including but not limited to the Terminology of Anatomy & Physiology and Anatomy Demystified. In 2003, Dr. Layman wrote the Foreword to the Concise Encyclopedia of Robotics, Stan Gibilisco.

As a renowned scholar and book author, Dr. Layman proposed The Faculty Ranking Initiative in the State of Illinois to increase the credibility of faculty members in the States two-year colleges, which will help with research grants or publications. In 1994, the State of Illinois accepted this proposal. J.J.C. adapted the change in 2000, and Dr. Layman taught full-time from 1975 until his retirement in 2007. He returned and taught part-time from 2008 to 2010. Dr. Layman received an Ed.S. (Educational Specialist) in Physiology and Health Science from Ball State University in 1979. Then, in 1986, Dr. Layman received his first Ph.D. from the University of Illinois, in Health and Safety Studies. In 2003, Dr. Layman received a second Ph.D. and a Grand Ph.D. in Medicine, from the Academie Europeenne D Informatisation (A.E.I.) and the World Information Distributed University (WIDU). He is the first American to receive the Grand Doctor of Philosophy in Medicine.

In 1999, Dr. Layman delivered a groundbreaking speech at the National Convention of Text and Academic Authors, Park City, Utah. Here, he first publicly explained his unique concept: Compu-Think, a contraction for computer-like modes or ways of human thinking. This reflects the dire need for humans to develop more computer-like modes or ways of Natural Human thinking. This concept has important practical applications to Human Health and Well-being. In 2000, Dr. Layman gave several major talks and received top-level awards. In May of 2000, he participated in a two-week faculty exchange program with Professor Harrie van Liebergen of the Health Care Division of Koning Willem I College, Netherlands.

In 2001, after attending an open lecture on neural implants at the University of Reading, England, Dr. Layman created Robowatch. The London Diplomatic Academy published several articles about his work, such as Robowatch (2001) and Robowatch 2002: Mankind at the Brink (2002). The article Half-human and half-computer, Andrej Kikelj (2003) discussed the far-flung implications of Dr. Laymans work. Using the base of half-human, half-computer, Dr. Layman coined the name of a new disease, Psychosomatic Technophilic, which translates as an abnormal love or attraction for technology [that replaces] the body and mind. Notably, Dr. Layman was cited several times in the article Transhumanism, (Wikipedia, 2009). Further in 2009, several debates about Transhumanism were published in Wikipedia, and they identified Dr. Layman as an anti-transhumanist who first coined the phrase, Terminator argument.

In 2018, Dr. Layman was featured in the cover of Pro-Files Magazine, 8th Edition, by Marquis Whos Who. He was the Executive Spotlight in Robotics, Computers and Artificial Intelligence, in the 2018 Edition of the Top 101 Industry Experts, by Worldwide Publishing. He also appeared on the cover of the July 2018 issue of T.I.P. (Top Industry Professionals) magazine, the International Association of Top Professionals. Dr. Layman was also the recipient of the prestigious Albert Nelson Marquis Lifetime Achievement Award (2017-2018). Ever a Lifelong Student and taking classes for the past few years at J.J.C., Dr. Layman was recently inducted (2019) to his second formal induction into the worlds largest honor society for community college students, Phi Theta Kappa.

Contact Information:

Top 100 Registry Inc.

David Lerner

855-785-2514

Contact via Email

http://www.top100registry.com

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‘Were not your slaves’: Alternative health providers bristle at warning letters about their coronavirus treatments – USA TODAY

Posted: September 4, 2020 at 1:55 am

The Bill and Melinda Gates Foundation have invested $350 million to fund treatment and vaccine research to fight coronavirus. USA TODAY

Operation Quack Hack, the federal governments initiative to clamp down on fake coronavirus medications and cures, has exposed a health underground in America brimming with distrust not only of mainstream medicinebut the government itself.

Its a Tea Party for COVID-times.

Its members are angry at government warning letters that many perceive as an infringement on their right to free speech, free trade and people's control over their health care and some are ready to fight back.

A common refrain: How can we trust the same government that signed off onopioids?

The most radical believe that wealthy globalists including Bill Gates and Anthony Fauci created the coronavirus, unleashed it from Wuhan, China, along with immune-system-weakening 5G wireless technology; and intend to install digital ID chips in our bodies at the same time they give us the vaccine.

For them, the two agencies behind Operation Quack Hack the Food and Drug Administration and the Federal Trade Commission are sinister organizations. Their objective is to force everyone to take the vaccine, and the only way to do that is to convince ustheres no other choice.

Were not your slaves, were not in your cult, right-wing talk show host Alex Jones shouted in June at an anti-mask rally in Austin. If you want war, you'd better believe you got war.

Info Wars founder Alex Jones joins nearly 150 anti-mask protesters.(Photo: RICARDO B. BRAZZIELL/AMERICAN-STATESMAN)

False claims: Fact check: 'Plandemic' sequel makes false claims about Bill Gates

COVID-5G: https://www.mcgill.ca/oss/article/covid-19-pseudoscience-technology/how-distrust-and-coinc

Jones got in trouble with the FDA in April for peddling a line of silver products, including silver-laced toothpaste, as a COVID-19 cure.

The majority of alternative health providers that received warning letters are less extreme, but many still think the FDA and FTC are out to get them. The goal as they see it? To protect Big Pharma from competition as their market share grows.

The healthcare system in this country is rigged against inexpensive, safe, and effective natural remedies in favor of expensive pharmaceutical drugs, saidClark Hansen, anaturopathic medical doctor in Arizona,in an email message to USA TODAY. "The US medical system is ignoring any treatment that is not patentable and therefore cannot provide a multi-billion profit for some giant healthcare company.

The FTC warned Hansenin May to stop implying that a combination of elderberry, echinacea and the herb andrographis could prevent coronavirus infection.

In an email to USA TODAY, the FDA said its goalactually isto protect consumers from scammers and products that harm them. The agency added that it doesnt want consumers wasting their time on remedies that may lead to delays in getting proper diagnosis and medical care for COVID-19 and other potentially serious diseases and conditions.

Its sister agency was more succinct.

The FTC has taken aggressive action against marketers who want to take advantage of the anxiety caused by the current health crisis, the agency said in an email.We have done so to prevent consumer injury.There is no other motivation.

Under the law, supplement suppliers are not allowed to use some words "cure," "treat," "prevent," "mitigate" or "diagnose" in promotional materials.

Though many providers openly declare their products wont cure COVID-19, the mention of treat or prevent in the same sentence as "coronavirus" has been enough to trigger a letter from the FTC and FDA.

Recognizing the power of these agencies, mostof the more than 300 companies and individuals that got warning letters have responded by removing or changingmarketing materials on their websites, then they've quietly gotten back to the business of addressing customer ailments.

Theres plenty of money to be made in the herbal remedies and alternative health care market even without a pandemic. Revenueis expected to reach nearly $18 billion in the United States this year, according to IBISWorld, a global economic research firm.

Nevertheless, frustration lies just beneath the surface.

Kate Tietje, who runs the Modern Alternative Mama website and ran afoul of the government for touting Elderberry Elixir, vitamin C and vitamin D as remedies for the coronavirus, had this to say about government regulators in a post she later removed from her website:

Seeing that the FDA allows approved drugs to harm and even kill millions of people, while badgering natural companies that have fewer than 10 reports of unproven adverse effect claims, shows us definitively that its not about keeping people healthy.

Since the onset of the pandemic seven months ago, the FDA and the FTC have sent out an average of 13letters a weekwarning companies and individualsto stop making false claims about their ability to prevent or cure COVID-19.

Many of the recipients have a history of fraud and malfeasance.

They include televangelist JimBakker, who spent five years in prison for defrauding his own ministry back in the 1980s;Gordon Pedersen, who wears a lab coat and stethoscope and calls himself a doctor even though he holds no medical degree; and Matthew Martinez, who agreed to give up his chiropractor'slicense in 2016 after being accused of having sex with clients and suggesting that a patient with multiple sclerosis could be cured by drinking breast milk.

Both Bakker and Pedersen told their followers that Silver Solution was the antidote to COVID-19 and were sued by the government for failing to address allegedly false claims outlined in warning letters.

If the government does not receive an adequate response to its warning letter it can file suit, seek arestraining order to shutdown the company's web sites and operations, commandit to recall and destroy its products and raw materials and refund its customers.

Pedersen refused to participate in court proceedings and could not be reached for comment. Bakker battled back, claiming religious exemption. Court documents filed on his behalf state that his product is a sacrament, as important to his ministry as solicitingdonations and preaching the second coming of Christ.

As for Martinez, the FTC faulted him for claiming that high doses of vitamin C "havea significant impacton treating coronavirus" and that stem cells helpin the healing process.After receiving his warning letter from the FTC, he also boasted that the ultraviolet light in his companys octagon-shaped Blue Room provided virus-killing benefits.

Another warning letter recipient with a history of breaking the law was Richard Marschall. A naturopathic physician, he got busted twice between 2011 and 2017 for introducing misbranded drugs into interstate commerce and spent 60 days in jail. That didnt stop him from marketing a product called the dynamic duo that he said could crush 30 different viral infections including those in the Corona family.

On Aug. 5, Marschall was indicted for the third time on the same charge: introducing misbranded drugs into interstate commerce.

An insistence to keep selling supposed coronavirus cures after being told not to is also what got Marc White Eagle Travalino in trouble.

A self-proclaimed medicine man and shaman who runs website and folksy trading post in Fort Davis, Texas, Travalino got nabbed by the FDA for saying his Kolon Kleen, Maska Miakoda and Shar Mar products were proven to work and destroy the coronavirus. Instead of ceasing his marketing activities after receiving his warning letter, he tried to sell more treatments this time to an undercover agent.

The government responded by shutting down all Travalinos operations, both online and brick-and-mortar.

Some coronavirus treatments exposed by Operation Quack Hack were more outlandish.

Face Vital LLC swore by a battery-powered silicon brush used for cleaning facial pores. Mypurmist argued that its hand-held steam machine was the answer. BioElectric Shield offered a golf-ball-sized pendant to block immune-system-sapping 5G electromagnetic waves.

5G appears to be the straw that broke the camels back when it comes to the spread of the Coronavirus, the company said on its website.An extremely intense rollout of 5G was launched initially in Wuhan City, China.

Is it a coincidence that this is also where the coronavirus outbreak started? the company asked. "We are urging you to get protection from EMF radiation."

At least four makers of electric pulse machines, used by chiropractors to reduce muscle tension, stated online that their devices boost the immune system. Electric pulse therapy is like a power up for your cells akin to giving your cells a cup of coffee to energize and speed up their job, said BioBalance, a Maryland-based company.

Three morecompanies suggested sound waves or music could defeat the virus. Musical Medicine, headed by Dr. Suzanne Jonas, advertised new music "designed to boost your immune system. Spooky2 Scalar, a New York company headed by Matt Forrest, said its new sounds would protect you and your family, andBioenergy Wellness in Miami said it had found a COVID-attacking frequency and that sound frequencies were better at penetrating cells than chemicals.

These treatments and others subject to the warning letters have no ability to help anyone with COVID-19, said professor Arthur Caplan, who heads the medical ethics division at the NYU School of Medicine.

Arthur L. Caplan Ph.D. of New York University's Langone Medical Center.(Photo: John Abbott Photography)

Theyre just emptying our pockets for their own gain and greed, he said.

Caplan added that if companies receiving warning letters had any real virus fighting abilities, Dr. Fauci,director of the National Institute of Allergy and Infectious Diseases, would be talking about them on TV.

If Im going to bet on the future, Caplan said. Im still betting on the infectious disease guys over the vitamin purveyors to work our way out of this,

Peddling potions, balmsand tinctures for ailments asvaried as erectile disfunction and Parkinson's disease, alternative health providers targeted by Operation Quack Hack do most of their business over the Internet.

About four in 10 also operate naturopathic, holistic, acupuncture or chiropractic clinics where practitioners meet with clients to help with pain management or plan healthy alternatives for living on an increasingly toxic planet.

For nearly a third, go-to products for fighting coronavirus virus have been simple the kind of thing any mother might suggest to ward off the flu: vitamin C, vitamin D and zinc. Another 26% offered some mixture of herbs or essential oils that might include elderberries, echinacea, ginger, garlic, licorice, turmeric, peppermint, astragalus root, reishi mushrooms, blackseed oil, olive leaf, dandelion.

In a nod to the New Testament, some even recommend frankincense and myrrh.

Corey Basch, associate professor in the Department of Public Health at William Paterson University in Wayne, N.J., said that vitamins, minerals and other micronutrients are a needed element for maintaining health, including immune function.

But its not always clear for whom these supplements will work and under what circumstances.To Basch and others, that alone justifies the government clamping down on those thatmake a definitive statement about the a cure or treatment forCOVID-19.

They need to have competent scientific evidence that something works and no one has that, said Mitchell Katz, spokesman for the FTC.

Alternative health care providers say that doesnt mean they should be silenced. Thats where Dr. David Brownstein, who believes in the basic mission of the FDA and FTC, says the two agencies have gone too far.

Dr. David Brownstein, of West Bloomfield MI, a AARM member.(Photo: Steven M. Herppich)

A medical doctor who got interested in holistic medicine nearly 30 years ago when his father was suffering from heart disease, Brownstein said he found a new way of looking at health care less centered on medications than on treatments that support the immune system.

Brownstein said one of his patients gave him a book on nutrition, which led him to wean his father off nitroglycerin pills in favor of natural supplements. Within 30 days, he said, his fathers cholesterol fell from 300 to 200, his 20-year history of angina endedand his skin turned from pasty gray to pink.

That led Brownstein to seek out natural therapies for his patients, including an anti-viral strategy that he regularly turns to during flu season. The regimen involves high doses of vitamins A, C, D and iodine for four days, followed, if necessary, by nebulizer treatments of hydrogen peroxide and iodine, then intravenous treatments of hydrogen peroxide, vitamin C and ozone.

Brownstein said he used the same regimen every year for more than 20 yearsand on more than 100 COVID-19 patients during the outbreak in the Detroit suburbs in March and April.

Dr. Brownstein administering viral treatment to patients in April.(Photo: Courtesy)

My partners, nurses and I were going out to see patients in their cars in the parking lot in 30-degree weather in March, Brownstein said. We were giving them IVs in their cars, and as soon as we started treating them they got better. We saw 107 patients. Only one was hospitalized. No one died and no one had to be ventilated.

Instead of drawing praise, Brownstein said he got in trouble with the FTC for posting the results of his 107-person study on his website and including YouTube testimonials from patients who recovered. Brownstein said the FTC faulted his study because it wasnt randomized, meaning he had no untreated control group.

I just couldnt sleep at night if I did that, he said. How could I not have people receive a therapy that I thought could help them?

Dr. Brownstein administering to patients during the onset of the pandemic in April.(Photo: Courtesy)

Brownsteins study was peer-reviewed by three medical doctors and an academicand contained more than 90 citations to scholarly articles and texts. But the FTC still made him pull it off his website. The cost of doing that, he said, is that the general public and fellow doctors around the world didnt get the benefit of what he saw on the front lines of the crisis.

It sends a chill out that you cant report anything about COVID thats positive, Brownstein said. You cant report anything that doesnt fit the narrative that all you can do is wear a mask, social-distance and wait for a vaccine.

The pushback against the governments orders is that they represent an unnecessary overstep against alternative health companies that are doing no harmand may even be providing peace of mind at a difficult time.

Rosalee De la Foret, a best-selling author and herbalist, acknowledged that regulators had a legal right to cite her for mentioning the forbidden word "prevent" in promotional materials about herbal products. But she believes the FDA and FTC are too heavy-handed in applying the law.

Best selling author and herbalist Rosalee De la Foret(Photo: Courtesy)

De la Foret, who mentioned the benefits of an herb called astragalus in one of her articles, maintained that she was very careful to point out that the root was not a cure forCOVID-19 or anything else.

I was trying to be open and honest, De la Foret said. But they were saying that I was wink wink implying that the product could be used to cure the virus.

That interpretation, De la Foret said, prevents people from discussing remedies that might be useful.

Heaven forbid that something in nature might be more effective than a drug, agreedHansen, the Arizona naturopathic doctor.

Ralph Fucetola, a retired lawyer and co-trustee of the Natural Solutions Foundation, also echoed that sentiment.

This Deep State attack on good medicine is particularly outrageous because during a declared pandemic it is ethical, according to the (World Health Organization), to use even unapproved remedies that may offer help, Fucetola said in an article posted in April on OpenSourceTruth.com, a website that pushesback against the mass media. Once again, the Federal authorities are putting themselves squarely against common sense in order to maintain the fiction that the government is here to help.

Ralph Fucetola(Photo: Courtesy)

Fucetola told USA TODAY that theres a distinction between treatment ofa disease, which drug companies provide, and therapies that may benefit a patient, which alternative health companies offer.

Theyre trying to subject us to the treatment of disease standard, Fucetola said. People in the health freedom world, in the natural remedies world, are not trying to treat diseases, were trying to help people achieve a healthy status.

Fucetola said he still hopes to reach an understanding with the FDA and FTC regarding what can be said about Nano Silver, a nutrient he says supports a healthy immune system.

Like most other alternative health providers, he has taken down all allegedly offending documents from his website.Even Jones, the founder of Info Wars, has taken steps to comply.

But some letter recipients, including televangelist JimBakker, silver solution salesman Gordon Pederson non-religious church founder Mark Grenon,and investigative journalist Maryam Henein, are defiant.

Investigative journalist Maryam Henein, who edited the movie "Vanishing of the bees."(Photo: Courtesy)

Henein, who directed the filmVanishing of the Beesand foundedHoneyColony.com, a natural-remedies website, said she drew a warning letter by suggesting that the best coronavirus treatment is prevention and recommending that customers take chelated silver, vitamin C and magnesium.

I know in my heart I did not do anything wrong Henein told USA TODAY. The FDA and FTC are using the coronavirus to attack natural remedies. Theres a reason we call them the medical mafia.

So far, the FDA and FTC have ignored Henein because she made required changes to her website, but they went after Pedersen and Grenon when bothmen refused to play by the rules.

Sued in late April and accused of tryingto defraud consumers by claiming his liquid silver product will destroy all forms of viruses, Pedersen declined to accept any mail from the U.S. attorneys office andchose to represent himself as a sovereign citizen.

He declared that the court had no jurisdiction over him as a private living, flesh and blood man.

U.S.attorneys swiftly responded by persuading the court to impose a restraining order and then shut down Pedersons websites. That, in turn, persuaded Pedersens partners to push him out of his company and agree to reimburse any customers who believed they had been defrauded.

Grenon, who declined to talk to USA TODAY, deployed similar tactics, refusing to recognize the authority of the U.S. government over Genesis II Church of Health and Healing, which offered church members Miracle Mineral Solution a bleach-like substance as a sacrament, in return for donations.

Mark Grenon(Photo: YouTube)

He went further, too, threatening the government and the judge presiding over his case.

In July, law enforcement officials raided his familys headquarters and distribution facility in Bradenton, Florida. They arrested two of his sons, Jonathan and Jordan, who are still being held without bail. They seized cash and goldfrom the company safeand carted off all the companys computers, electronic equipment, files and documents. They also confiscated all raw materials used to make MMS.

Grenon, who was at his familys compound in Colombia at the time of the raid, said in a Youtube video interview with Henein that hes determined to face his accusers. He's certain he will prevail.

Experts say his legal position is not enviable. Its not a good idea to get in a fight with the FDA and the FTC, they say, no matter how righteous you think your cause.

Theyre like the IRS, said Caplan, the NYU medical ethics professor. Flout them, challenge them, dont cooperate and they come down hard.

Read or Share this story: https://www.usatoday.com/story/news/investigations/2020/09/03/government-coronavirus-crackdown-angers-alternative-health-providers/5660997002/

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Neogene precipitation, vegetation, and elevation history of the Central Andean Plateau – Science Advances

Posted: September 4, 2020 at 1:55 am

Abstract

Andean uplift played a fundamental role in shaping South American climate and species distribution, but the relationship between the rise of the Andes, plant composition, and local climatic evolution is poorly known. We investigated the fossil record (pollen, leaves, and wood) from the Neogene of the Central Andean Plateau and documented the earliest evidence of a puna-like ecosystem in the Pliocene and a montane ecosystem without modern analogs in the Miocene. In contrast to regional climate model simulations, our climate inferences based on fossil data suggest wetter than modern precipitation conditions during the Pliocene, when the area was near modern elevations, and even wetter conditions during the Miocene, when the cordillera was around ~1700 meters above sea level. Our empirical data highlight the importance of the plant fossil record in studying past, present, and future climates and underscore the dynamic nature of high elevation ecosystems.

A major uncertainty in climate modeling is how future precipitation will change over the Central Andean Plateau (CAP) and Amazon Basin (1). While some model outputs suggest feedbacks that will lead to massive drying (2, 3), others suggest wetter-than-modern conditions (46). Ongoing changes in temperature and atmospheric CO2 concentration (pCO2) will, by the end of this century, provide similar conditions to those found in the late Miocene and early Pliocene (7). Between ca. 10 million years ago (Ma) (late Miocene) and 5 Ma (early Pliocene), the northernmost part of the CAP (NCAP) doubled in elevation (8, 9). Mechanistic models (e.g., RegCM3 and ECHAM) project that this uplift increased precipitation over the CAP, creating essentially modern climate patterns (Fig. 1) (5, 911). The CAP paleobotanical record provides physical evidence that can be used to reconstruct paleoprecipitation, providing elements for testing the validity of climate models of the geologic past and for refining predictions of future climates. Here, we provide both Miocene and Pliocene paleobotanical evidence to document the effects that uplift of the NCAP had on regional ecosystems and climates.

Geographic location of the CAP, summary of paleoprecipitation estimates from previous studies. (A) Topographic map showing the location of the CAP and the location of the Descanso-Yauri Basin (black triangle) in the Peruvian Andes. Gray triangles indicate the geographic location of sites from the modern palynological dataset and their environmental distribution (elevation and mean annual precipitation). m.a.s.l., meters above sea level. (B) Simulated precipitation based on the ECHAM model when the CAP had 100% (600 to 700 mm/year) and 40% (100 to 200 mm/year) of its current elevation [figure taken from (9)].

The modern NCAP sits at ~4000 m of elevation and has a mean annual temperature (MAT) ~8 to 9C and a mean annual precipitation (MAP) ~500 to 800 mm. The CAP is characterized by cold and strong winds throughout the year, and it experiences extreme diurnal and nocturnal temperature changes reaching up to 30C (12). Most precipitation in the CAP falls during the austral summer as a result of easterly winds bringing moisture from the Atlantic Ocean via Amazonia (13). The modern high-elevation vegetation types of the NCAP are grasslands and shrublands, known locally as puna.

Here, we studied the Neogene paleobotanical record from the NCAP (Fig. 1) aiming to (i) estimate regional paleoelevation and paleoprecipitation and (ii) reconstruct its paleovegetation. The plant fossil material was collected in the Descanso Formation, Descanso-Yauri Basin, southern Peru. This basin has an approximate area of 2000 km2. We studied two members (or lithostratigraphic units) from the Descanso Formation that were previously dated using radiometric methods: Member B, dated to ca. 18.7 to 9.1 Ma (middle to late Miocene) (8, 14), and Member C, dated to ca. 4.8 to 3.9 Ma [Fig. 2; early Pliocene; (8)]. Exposed along most of the basin, Member B is the thickest unit of the Descanso Formation and was deposited in a braided-river environment (8). There is an angular unconformity (time gap) between members B and C of approximately 4 Ma during which an uplift of ca. 2500 m has been inferred on the basis of isotopic data (8). Member C is a thin unit deposited in a fluvial-lacustrine system at a similar elevation as it is found today (8, 15).

(A) Geologic map for the Descanso-Yauri Basin, showing where the samples were collected [modified from (8)]. (B) Stratigraphic column for El Descanso Formation, including members A, B, and C [modified from (8)]. Bars next to the samples correspond to the uncertainty in the stratigraphic depth for the sample or group of samples. Undulating line represents the unconformity between members B and C. (C) Photographs of some of the macro- and microfossils collected for this study. From top to bottom: Fossil log with 7 m of length, legume fossil wood anatomy (scale bar, 1 mm), Ribes sp. leaf (scale bar, 10 mm), and Podocarpus sp. pollen (scale bar, 10 m). Photo credits: First and second rows: C. Martnez, Cornell University and Smithsonian Tropical Research Institute (STRI); third row: A. Aliaga, Museo de Historia Natural de Lima; fourth row: J. E. Moreno, STRI.

The plant fossil record from the Descanso-Yauri Basin studied here included palynological (pollen and spores) and macrofossil samples (permineralized wood and compressions and impressions of leaves and fruits) of Neogene age (Fig. 2). The age of the fossiliferous localities was determined using previously published stratigraphic information (8), together with new zircon U-Pb geochronologic analyses of two tuff samples from the Member B that yielded ages of 10.03 0.16/0.18 Ma and 12.07 0.73/0.74 Ma (fig. S1 and the Supplementary Materials). A total of 187 paleobotanical samples were collected from 88 localities from members B and C. Seventy-five palynological samples were analyzed, containing 168 palynomorph taxa in 5389 individual occurrences (table S1 and the Supplementary Materials for raw counts). From those, 154 palynomorphs were described (see the Supplementary Materials for descriptions and plates for each palynomorph). Thirteen samples of permineralized wood were assigned to four morphotypes. Ninety-nine samples consisted of macrofossil compressions and impressions of leaves and fruits and were assigned to eight morphotypes (see the Supplementary Materials for descriptions and plates for each macrofossil morphotype).

Wood samples were preserved as silica permineralizations and were only found at the top of Member B (Fig. 2). Eight specimens had taxonomic affinities with Fabaceae and one with the fossil genus Anacardioxylon (Anacardiaceae). Within Fabaceae, two samples were identified within the Tribe Ingeae, five samples within the mimosoid clade, and one as the fossil genus Andiroxylon sp. (see the Supplementary Materials). Tree height was estimated for the Andiroxylon sp. sample based on its diameter, and estimates ranged from 29.8 to 34.6 m. In tropical high-elevation ecosystems, plant growth is dependent on the number of hours of freezing per day (16). A correlation between tree height and elevation across six modern Andean elevation transects shows that trees taller than 30 m are not found above ~1100 m of elevation in the Andean region (17). Nevertheless, assuming that plants shift their distribution upward when the temperature increases (18), a temperature correction for the late Miocene would produce higher estimates. On the basis of these observations, we infer that trees of the size found in Member B would not be found above ~1750 m during the late Miocene. This provides a maximum likely paleoelevation for Member B at the time of deposition.

The traits of woody plants found in Member B are consistent with a warm and wet setting. All wood samples had simple perforation plates. Twelve of the 13 samples collected had diffuse porous wood and nondistinct growth rings. Six of the seven samples identified had large vessel diameters (>150 and up to 270 m) and high proportions of axial parenchyma cells. Diffuse porosity, nondistinct growth rings, vessels of large diameter, simple perforation plates, and a large proportion of axial parenchyma cells were dominant wood anatomical characters in our fossil assemblage. That combination of characters is commonly found in trees of large size, having lowland affinities, and growing in sites with high MAP regimes and low seasonality (19, 20).

Leaves were found in both members; Member B only had palm leaf fragments (Arecaceae), whereas Member C had leaves with taxonomic affinities to five genera and one family that are today present in the Puna: Ribes (Grossulariaceae), Berberis (Berberidaceae), Polylepis (Rosaceae), Polystichum (Dryopteridaceae), Equisetum (Equisetaceae), and Juncaceae (see the Supplementary Materials for descriptions and photographs of each morphotype). The palynological record shows that the floristic composition of Member B is dominated (>50 counts) by the families: Podocarpaceae, Cyatheaceae, Polygonaceae, Poaceae, Polypodiaceae, Chenopodiaceae, Chloranthaceae, Malvaceae, Asteraceae, Lycopodiceae, Araceae, Solanaceae and Caryophyllaceae, while Member C is dominated by Poaceae and Cyatheaceae (table S3). Studies across modern Andean transects have shown that altitudinal vegetation gradients are accurately reflected by modern pollen rain data and thus that fossil palynological assemblages can be used to reconstruct aspects of past Andean ecosystems (21).

Taking the sum of the paleobotanical data, we developed a new quantitative coexistence analysis to reconstruct paleoprecipitation and paleoelevation. This coexistence analysis uses climate and elevation information associated with the nearest living relatives of the identified palynomorphs and macrofossil taxa to estimate a mutual climate and altitudinal range (table S3). Although climate tolerances of species could have shifted since the Miocene, no substantial changes seem likely to have occurred given physiological uniformitarianism (22). Two distribution datasets (palynological and macrofossil) were described through bivariate probability density distributions of modern taxon occurrence along elevation and precipitation gradients. Global temperatures during both, middle to late Miocene and early Pliocene times, were warmer than preindustrial temperatures. Therefore, we performed a correction of temperature estimates that resulted in average displacements of the elevation by ~650 and 440 m for members B and C, respectively, using modern lapse rate for the Central Andes (fig. S3) (23). Each distribution dataset (palynological and macrofossil) was first analyzed independently, and later after a mixture sensitivity analysis was applied (fig. S4), final estimations were weighted equally for precipitation and for the elevation of Member C (1 = 2 = 0.5). However, an unequal weight was assigned for elevation estimates for Member B due to the high sensitivity found in our analysis depending on the dataset used (1 = 0.615). For Member B, the median elevation based on the mixture model (palynological and macrofossil data) was 1636 m (interquartile range, 971 to 2850 m), whereas for Member C, the median estimated elevation was 3780 m (interquartile range, 3340 to 4140 m). These corrected elevation estimates are congruent with previous paleoelevation estimates based on isotopic data for the NCAP (fig. S5) (8). Median annual precipitation for Member B based on the mixture model was 1671 mm/year. (interquartile range, 1265 to 2077 mm/year), whereas for Member C, it was 862 mm/year (interquartile range, 620 to 1121 mm/year; Fig. 3). These estimates of environmental space show a trend that progressed in time toward ascending elevation and decreasing precipitation (Fig. 3). An additional comparison with environmental space from Holocene records from the CAP shows that changes in the environmental space from Miocene to Pliocene were much greater than those transitioning from Pliocene to Holocene (Fig. 3). It is worth noting that nonanalog assemblages can still be used to provide quantitative paleoclimate reconstructions. Analogs rely on the co-occurrence of species in their realized niche space, but the fundamental niche (sensu Hutchinson, 1957) (24) of species is broader than their observed realized niche. By using the range tolerance of the genera, probabilities can be generated for overlapping environmental characteristics, even if the genera do not co-occur today (25).

Estimated environmental space for the middle to late Miocene (Member B; gray), the early Pliocene (Member C; red), and the Holocene (blue) at Descanso-Yauri Basin, showing probability density functions for precipitation (right) and elevation (bottom). These estimations are based on a mixture of micro- and macrofossil sets.

Our reconstructions for the middle to late Miocene indicate that when the southern Peruvian Andes were at half of their modern elevation (~1600 m), MAP was about three times higher (~1700 mm/year) than today. In contrast, regional climate models (ECHAM, GENESIS, PLASIM, and RegCM3) predict that half-modern CAP elevations would lead to much-drier-than-modern conditions (3, 5, 10, 11, 26, 27). For example, the global ECHAM model indicates that when the Andes were at 40% of their modern elevation, MAP was 100 to 200 mm, or about ~80% drier than today (Fig. 1B) (9). Previous paleobotanical studies also suggest that, during the middle to late Miocene, the CAP had a paleoelevation between 1200 and 2000 m, a MAT of ~20 to 22C, and a MAP ranging from 550 to 1500 mm (fig. S5) (28, 29). Although other MAP estimates based on paleobotanical data from other CAP localities suggest lower precipitation ranges for the Miocene (30, 31), these values are never lower than modern records. The incongruence between the paleobotanical evidence from the middle to late Miocene and climate models for the CAP is a major question that needs to be addressed to predict the impact of future climate change in South America.

Our early Pliocene reconstructions indicate that, around 4.8 Ma, the NCAP had already attained near-modern elevations (~3800 m) and had a MAP slightly higher than modern (~850 mm). This higher-than-modern MAP is also supported by the fossil lacustrine biota (diatoms and ostracods) (15), stratigraphic (15), and isotopic data (8, 32). Given that ferns have higher water requirements than angiosperms (33), the high proportion of fern taxa present in Member C of the Descanso Basin compared with the modern puna (fig. S6B) offers additional evidence to support the high MAP estimations for the early Pliocene. The time spanned by Member C overlaps with the early Pliocene warm period (4.6 to 3.1 Ma). Our inferred wetter conditions for the NCAP during the early Pliocene contradict some global climate models that report permanent El Niolike conditions during the early Pliocene warm periodwhich implies lower-than-modern precipitation for the CAP(34, 35). However, whether these wetter conditions correspond to a large scale or a permanent state for the Altiplano during the Pliocene is unknown as numerous high-magnitude regional sea surface temperature (SST) excursions (36) and short-term climate perturbations (37) have also been reported for the Pliocene.

Separately, when comparing Pleistocene with Pliocene climate data, evidence from Pleistocene cores in the Altiplano suggest that glacial (interglacial) periods were wetter (drier) than modern (3840). Considering that SSTs for the Peru margin show that the early Pliocene was 3.3C warmer than the late Pleistocene (36) and that the elevation of the CAP has not changed substantially since the early Pliocene, paleoprecipitation would be expected to follow the interglacial pattern with drier regional conditions. However, our wetter CAP estimates for the early Pliocene suggest that this time period does not represent an extended interglacial period.

To address the similarities of paleofloras in members B and C to modern ecosystems, we used the Chaos dissimilarity index (CDI). We first calculate CDI for all extant sites in four elevation ranges (lowlands, lower montane, upper montane, and puna) to estimate the overall heterogeneity of the ecosystem, and then we compared the extant sites with the fossil palynological record from each member (Table 1). For Member B, the median CDI between palynoflora and extant lower montane sites was 0.8. This value is considerably higher than the median CDI of 0.3 obtained by all pairs of extant lower montane modern sites, suggesting high dissimilarity (Fig. 4A and Table 1). The median CDI between the Member B palynoflora and all extant upper montane sites was 0.7. This value differs substantially from the median CDI of 0.17 obtained by all pairs of extant upper montane modern sites, also suggesting high dissimilarity (Fig. 4B and Table 1). Thus, our results suggest that the palynoflora of Member B is not similar to extant Andean montane sites. This Miocene palynoflora is composed of common montane forest indicators such as Podocarpus, Hedyosmum, Bocconia, Mutisia, and Cyatheaceae, as well as higher elevation taxa such as Calamagrostis, Polylepis, and Valeriana. However, the oddity of this flora is emphasized by the co-occurrence of plants with traits of lowland ecosystems (e.g., 30-m legume trees and palms). Therefore, we propose that the Member B paleoflora does not have a modern analog and that it was more heterogeneous than modern montane ecosystems.

Floristic comparison of pollen records from members B and C and modern pollen records from sites located along the Central and Northern Andes (Fig. 1A). The altitudinal gradient includes sites from lowland, lower montane, upper montane, and puna ecosystems. The comparison was done using the CDI (0 = least dissimilar; 1 = most dissimilar).

Comparison of palynofloras from members B and C with extant pollen data from South America. The density plots show the probability distribution of the CDI (0 = least dissimilar; 1 = most dissimilar). Green curves represent CDI for within-biome comparison for modern altitudinal ranges (lower montane, upper montane, and puna). (A) Comparison for lower montane sites: Gray curve represents CDI between the fossil assemblage from the Miocene Member B and the modern lower montane sites. (B) Comparison for upper montane sites: Gray curve represents CDI between the fossil assemblage from the Miocene Member B and the modern upper montane sites. (C) Comparison for puna sites: Red curve represents CDI between the fossil assemblage from the Pliocene Member C and the modern puna sites.

For Member C, the median CDI between the palynoflora and all extant sites from the Puna was 0.2. This value was similar to the mean CDI of 0.16 obtained by all pairs of puna modern sites, suggesting low dissimilarity (Fig. 4C and Table 1). The macrofossil record of Member C also indicates a puna biome by the combined presence of Polylepis, Berberis, Ribes, and Polystichum. The Member C flora, therefore, represents the earliest record of the Puna, appearing shortly after the landscape is inferred to have reached near-modern elevations. This early puna differs from the modern puna by having a higher diversity and abundance of ferns (fig. S6B).

Late Miocene uplift shaped modern ecology: The rise of the Tibetan Plateau gave rise to the Asiatic monsoon system (41), while the uplift of the Andes created the South American Summer Monsoon (6). Moisture-laden winds flowing across Amazonia started to be deflected southward by the rising Andes between the Miocene and the Pliocene, drying out the highlands. This Andean uplift created new Neotropical niches for highland and dryland (Peruvian coastal rain shadow) species, while markedly reducing the area available to mid-montane species. Our data indicate that there would also have been a substantial reduction in potential biomass as forests supporting large trees were replaced by grasslands. The fact that current climate models underestimate Miocene precipitation so severely leads to underestimates of carbon storage and overestimates of the grasslands available to Miocene megafauna. Capturing the topographic effects of the Andes on atmospheric circulation accurately is essential to modeling both past and future climate change.

The coexistence approach proposed here offers a novel way to analyze macrofossil and palynological data and improves reconstructions of past climates and ecosystems. Our paleoelevation estimations calculated on the basis of the Neogene plant fossil record of the NCAP support evidence from previous studies based on isotopic data (8, 9) that proposed rapid surface uplift of approximately 2500 m in elevation between ~9.1 and 4.8 Ma. In contrast, our paleoprecipitation estimations strongly differ from those predicted by regional and global precipitation simulations for the Miocene and Pliocene [e.g., (3, 5, 29, 38)], revealing a marked precipitation decrease over the NCAP with the Andean uplift. Understanding the origin of these discrepancies can help reveal the driving forces controlling the climate of the Altiplano and ultimately the overall climate of South America. The uplift of the CAP shaped the biome distribution and climate of the region: Our reconstructions of a montane forest ecosystem without modern analogs in the Miocene and of a puna-like ecosystem in the early Pliocene highlight the dynamic nature of high elevation ecosystems and how these can change and evolve as a response to extreme modifications in elevation and climate.

Fieldwork. The Descanso-Yauri Basin, southern Peru, was explored during three field trips done during the dry season of years 2014, 2015, and 2016. We collected as many samples as possible during those field trips. All the samples were collected from members B and C. During the collection process, we kept a stratigraphic control by visiting the localities previously described by Kar et al. (8) and then by correlating stratigraphically the new localities found. We collected palynological samples, tuffs, and compressions and impressions of fossil leaves and fertile parts and permineralized wood. To correlate stratigraphically two of the new localities, we used radiometric dating of volcanic horizons (tuffs) present near the fossiliferous region.

Zircon U-Pb geochronology methods. Two tuff samples with abundant pumaceous fragments were collected to correlate two wood localities of the Colpamayo and San Miguel regions using U-Pb geochronology (Fig. 2). The sample from the Colpamayo region (STRI-MUSM 44449) was collected from a 60-cm conglomerate rich in pumaceous fragments, and the sample from the San Miguel region (STRI-MUSM 44448) was collected from a 50-cm-thick ashfall tuff. Zircon separates were performed by standard magnetic and gravity-based methods at the University of Rochester using a Frantz LB-1 separator and methylene iodide. Before U-Pb analysis by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), zircons were mounted in 1 epoxy plugs and characterized by cathodoluminescence (CL) imaging using a JEOL JSM-7100 electron microscope equipped with a field-emission gun and a Deben Centaurus CL detector at the Mackay Microbeam Laboratory, University of Nevada, Reno. All U-Pb isotopic measurements were performed by LA-ICP-MS at the Arizona Laserchron Center, University of Arizona using a Photon Machines Analyte-G2 Excimer laser system coupled to a Thermo Finnigan Element2 single collector ICP-MS. Analytical methods for the U-Pb analyses are outlined in Ibez-Mejia et al. (42) and Pullen et al. (43) (see the Supplementary Materials for detailed methods and reference material).

Palynological data. Palynological sample preparation included digestion of 10 g of rock in hydrochloric acid for 12 hours, addition of water, and decantation after 12 hours, followed by digestion in hydrofluoric acid for at least 24 hours, addition of water, and decantation of the acid solution after 24 hours. Sieving of the dissolved mineral fraction was initially done with a 250-m mesh to eliminate the thick fraction, followed by sieving through to 10-m mesh. Panning of the >10-m fraction was done in an ultrasonic equipment for recovery of the less dense organic matter fraction. This residue was cleaned in the ultrasonic equipment for some seconds, and the organic residue was concentrated by centrifugation, followed by mounting of a first cover slide in a solution of polyvinyl alcohol. Mounting of a second cover slide was done after oxidation with nitric acid, sealing with Canada balsam. Samples were processed at the laboratory of Paleoflora, Bucaramanga, Colombia. Palynomorphs were counted aiming for a minimum of 300 specimens per slide. Transects of all slides were made at 40 magnification using an Olympus BH-2 binocular scope to identify all pollen types. Bright-field microphotographs were obtained at 100 magnification using a Pixera Camera System attached to the Olympus scope.

All the taxonomic affinities proposed for the palynomorphs are reported in alphabetical order by family and then by genus (file S5). The proposed botanical affinities at the family, genus, and species level were proposed by comparing the fossil taxa with pollen atlases of extant taxa of the region and the pollen reference collection of A. Graham at the Center for Tropical Paleoecology and Archaeology, from the Smithsonian Tropical Research Institute, Panama (see the Supplementary Materials for reference material). The taxonomic status of botanical names was updated consulting the Tropicos database. Some associated organisms and those undetermined palynomorphs are included as assemblage of possible indicators of environmental conditions.

Macrofossil data. Macrofossil compressions and impressions were studied at the Paleontological Collection of the Museo de Historia Natural de la Universidad Nacional Mayor de San Marcos, Lima, Peru (DPV-MHN-UNMSM). Sediment was carefully removed using an air scriber to expose possible attachments and the maximum number of features. Specimens were observed using a Leica EZ4 HD coupled to an integrated camera of 5.0-megapixel with a complementary metal-oxide semiconductor sensor. Photographs were taken with varied low-angle light. Each leaf morphotype was described following the terminology of the Manual of Leaf Architecture (44). Comparisons with extant taxa were made with herbarium material from the San Marcos Herbarium (MHN-UNMSM, Lima, Peru), and virtual collections were accessed through the JSTOR Global Plants database and literature.

Permineralized wood was initially cut with diamond saws at the Museum of Natural History of Universidad de San Marcos of Lima (MUSM). Thin sections were prepared following the standard techniques described in detail by Boonchai (45). The anatomy of the samples was described following the International Association of Wood Anatomists (IAWA) list of microscopic features for hardwood identification (46). Preliminary comparisons with modern and fossil wood were done using the InsideWood database (47), and additional comparisons were done on the basis of literature.

Using linear regression models that account for the allometric relation between stem diameter and tree height in modern trees, we estimated the approximate height of one complete fossil sample (48, 49). Four different regression models were used for the calculation, one that uses a global dataset (48), while the other three used large tropical datasets from west Amazonia, tropical South America, and the pantropical region (49).

Macrofossil compressions and impressions and permineralized wood were organized and described by morphotypes following the method described by Peppe et al. (50). Each morphotype has a three-letter prefix (DSB or DSC) based on the name of the formation and the member from which they belong to, plus a number starting from one. A systematic affinity was proposed for each morphotype. Species names were not proposed for any of the morphotypes described because this required extensive research into the nomenclature of the taxon, previous fossil descriptions, and phylogenetic relationships (50), which were topics out of the scope of this paper.

A new coexistence method was developed here to estimate paleoelevation and paleoprecipitation using the macrofossil and palynological data collected in this study. Climate and elevation information associated with the nearest living relatives of the identified palynomorphs and macrofossil taxa was used to estimate a mutual climate and altitudinal range. Two distribution datasets (palynological and macrofossil) were described through bivariate probability density distributions of modern taxon occurrence both of our variables of interest.

Given that palynological counts were uneven because of differential preservation of samples and also aiming to make palynology and macrofossil estimates comparable, palynological relative abundance was not considered representative of environmental conditions, and the dataset was therefore transformed to presence-absence. Palynological samples were filtered to consider only samples that met the following criteria: (i) The sample was composed of taxa that were represented in the modern pollen and spore dataset, (ii) at least three taxa were represented in the sample, and (iii) at least one of the taxa present in the sample was identified at the genus level. For macrofossil material, taxonomic identifications at the family and genus level were used for the paleoclimatic analysis, and in instances of taxonomic uncertainty in the identifications, the probability density distributions were based on the modern distribution of multiple taxa that were phylogenetically related.

The distribution of taxa found in the fossil datasets (palynology and macrofossils) was described through bivariate probability density distributions (PDD) of modern taxon occurrence along elevation and precipitation gradients. These distributions were described through a bivariate Gaussian kernel density estimator (51) defined byf(x;H)=1ni=1nKH(xXi)where f(x;H) defines the probability density at a point x = (x1, x2)T; Xi = (Xi1, Xi2)T is the vector of realizations at points i = 1,2, , n, for variables X1 (elevation) and X2 (precipitation).

H=|h100h2| is a matrix of bandwidths; in our case, h1 = h2 = 250.

K(x)=12e12xTx is the Gaussian kernel smoother.

Georeferenced occurrences of the nearest living relatives of both palynological and macrofossil records were extracted from the BIEN R package (52) and were described in terms of the elevation and MAP at the occurrence points (data from WordClim) (53). Thus, two reference libraries of bivariate environmental distributions were built: one for palynology (PDFpaly) and one for macrofossils (PDFmacro). In instances of taxonomic uncertainty in the identification of macrofossils, PDFmacro was based on the modern distribution of multiple taxa that were phylogenetically related. The paleoenvironmental reconstruction for a given fossil palynology sample consisted of PDFfossil palyj derived from a nonweighted finite mixture (54) of the modern PDFpaly of sj pollen and spore taxa present in the fossil sample j. Individual sample estimates from the same stratigraphic member (T) were, in turn, mixed to obtain a PDFTPDFfossil palyj=k=1sjPDFpalykleadsPDFT=j=1nTPDFfossil palyjwhere PDFfossil palyj is the probability density function (PDF) of sample j composed of sj pollen taxa; PDFpalyk is the PDF of modern pollen taxon k with k = 1,2, , s.; PDFT is the PDF of stratigraphic member T, represented by nT samples.

The paleoenvironmental reconstruction based on macrofossils consisted of a single PDF for each stratigraphic member (PDFmacroB and PDFmacroC), as followsPDFmacro=i=1sPDFmacrokwhere PDFmacrok is the PDF of modern pollen taxon k with k = 1,2, , s. PDFpaly and PDFmacro of each sample represent the probability distribution of data pairs of precipitation and elevation conditioned to the presence of a given set of taxa s. The credible environmental area within each PDF was obtained by trimming the margins of the bivariate surface, keeping the area of the distribution associated with a cumulative probability higher than 0.5. On the basis of the probability densities of this area, the marginal distribution of elevation and precipitation for each sample was extracted, obtaining one macrofossil-based marginal distribution per variable per stratigraphic member and nB and nC palynology-based marginal distributions per variable. For summarizing palynology-based estimates, marginal distributions were subsequently mixed.

Marginal distributions of elevation estimates based on palynology and macrofossils were corrected taking into account the global temperature within the estimated age range for each stratigraphic member between 12.87 and 8.4 Ma for Member B and 5.3 and 4.3 Ma for Member C, global temperature anomaly data from Hansen et al. (55). Observed global temperature anomalies within the time period of each stratigraphic member were randomly sampled, converted to elevation using a lapse rate of 0.6C (56), and added to our estimates (global temperature was warmer).

Final estimates of both elevation and precipitation per stratigraphic member resulted from mixing palynology- and macrofossil-based marginal distributions. Modern estimates were based on mixing palynology-based, cross-validated estimates with distributions of modern climatic data (this latter step was necessary because of the lack of macrofossils for the Holocene). Such mixture resulted from an addition of individual densities weighted by a proportion factor, as followsMDparameter=1*MDpaly+2*MDmacrowhere MDparameter is the marginal distribution of temperature or precipitation; MDpaly is the pollen-based marginal distribution of temperature or precipitation; MDmacro is the macrofossil-based marginal distribution of temperature or precipitation; 1 and 2 are the representation factors for palynology and macrofossil data, respectively, with 1 + 2 = 1.

This mixture model was developed to evaluate the proportion or weight that each proxy (palynological versus macrofossil) should be given to better estimate paleoclimatic conditions because this information was unknown from the literature. 1 was set to vary from zero (estimation based exclusively on macrofossils) to one (estimation based exclusively on palynology) aiming to evaluate the stability of estimates. When estimates varied monotonically with , we selected a solution based on a completely proportional mixture (i.e., 2= 1= 0.5), whereas when the estimation was notoriously affected by the selection of , the inflection point was preferred. The environmental space for each time period was represented as the conjunction of the interquartile range of elevation and precipitation.

Fossil palynological data from members B and C were used for a comparison with modern pollen data. The modern pollen dataset consisted of palynological counts grouped by family from South American sites that span an elevation gradient from 100 to 4700 m. We used the CDI (57) to estimate similarities between modern data and modern versus fossil palynological data. The parameters used to estimate the CDI here were the asymmetric Sorensen-type using probability estimations and taxa abundance data. This analysis was implemented in R using the CommEcol package (58).

Because the modern pollen dataset did not include spore counts, we also did a comparison of the proportion of angiosperms and ferns present in the palynological record from Member C and modern data from the Global Biodiversity Information Facility (59) using relative abundances. Modern data were extracted from a polygon that included the Altiplano region and the eastern and western flanks of the Andes. The polygon was between 17 and 11 of latitude and 74 and 69 of longitude. Within the analysis, a quaternary sample that was collected in the Espinar region was also included in the comparison. Last, the inferred habit from the taxa represented in the fossil palynological samples was also compared to evaluate changes in the ecosystems.

Acknowledgments: We thank R. Salas-Gismondi, J. Tejada, and M. Arakaki for providing help in the field and space at the Museum of Natural History of Lima, Peru; G. Umasi for valuable help in the field and the Espinar community for welcoming us; D. Caballero for help with a palynological analysis; N. Jud for helpful discussions about the wood samples; T. Jordan, M. A. Gandolfo, and K. Nixon for providing guidance and reviewing the manuscript multiple times; N. Kar for providing geological information for the region; J. Houston for providing photo rights for the cover photo; and C. Hoorn and an anonymous reviewer for insightful comments on this manuscript. Funding: C.M. thanks the Fulbright-Colciencias Doctoral Fellowship, from Colombia; the College of Agriculture and Life Sciences, the Plant Biology Section, the Harold E. Moore, Jr. Memorial and Endowment Funds, and the Cornell Graduate School Research Travel Grant, Cornell University, USA, for providing facilities, travel and research support. C.J. was funded by the Smithsonian Institution, the National Geographic Society (NGS 2014 9537-14), the Anders Foundation, the 1923 Fund, and the Gregory D. and Jennifer Walston Johnson. A.C.-M. was supported by Programa de Apoyos para la Superacin del Personal Acadmico de la UNAM (PASPA, DGAPA). M.I.-M. acknowledges funding by NSF-EAR 1926124. Author contributions: C.M. and C.J. led the writing and had significant contributions from W.C., M.B.B., and M.I.-M. C.M., and C.J., designed the study and organized and conducted fieldwork. W.C. contributed to project design. A.C.-M. and C.M. contributed to the paleoprecipitation and paleoelevation analyses. C.M. described and analyzed wood fossil samples. J.E.M. and C.J. contributed to palynological analyses. F.M., C.J., and C.M. contributed to the stratigraphic analyses and fieldwork. A.A. and C.M. prepared and described the leaf macrofossils. M.I.-M. and F.M. conducted the zircon U-Pb geochronologic analyses. M.B., A.C.-M., C.M., and C.J. contributed to the comparison with modern pollen. C.J and C.M. provided financial support. All authors contributed to the manuscript and figure preparation. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested to the authors.

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Neogene precipitation, vegetation, and elevation history of the Central Andean Plateau - Science Advances

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