Mackenzie Cottrell, PharmD
Assistant Professor
Co-Director of the UNC CFAR Clinical Pharmacology and Analytical Chemistry Core
Division of Pharmacotherapy and Experimental Therapeutics
University of North Carolina at Chapel Hill
West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and LucanixH. Jack West
This document summarizes information about three cancer vaccines - MAGE-A3, Stimuvax (L-BLP25, Tecemotide), and Lucanix (Belagenpumatucel-L). It discusses past and ongoing clinical trials of these vaccines in non-small cell lung cancer (NSCLC), including trial designs, results, and potential efficacy in patient subgroups. Key information presented includes Phase 3 trial results for Stimuvax showing a possible survival benefit in patients receiving concurrent chemotherapy and radiation, and evidence that Belagenpumatucel-L may benefit certain NSCLC patient subgroups based on retrospective analyses.
The document discusses the classification and labelling of glyphosate. It summarizes glyphosate's toxicological profile based on numerous studies. For human health, it finds glyphosate unlikely to cause cancer, genetic damage, or reproductive toxicity. It proposes classification as STOT RE 2 (H373) based on repeated dose toxicity. For the environment, it finds glyphosate toxic to aquatic life with long-lasting effects based on acute and chronic toxicity values, proposing classification as Aquatic Chronic 2 (H411). The document concludes by comparing the classification approaches of different regulatory agencies.
This case report describes a 74-year-old male nursing home resident admitted for left lower lung pneumonia. His medical history includes right medulla infarction with left hemiparesis, subglottic stenosis post tracheostomy, diabetes, hypertension, and hyperlipidemia. Laboratory tests and imaging show bilateral lower lung pneumonia with acute respiratory failure requiring mechanical ventilation. Sputum cultures grow Acinetobacter baumannii and Pseudomonas aeruginosa resistant to many antibiotics. The patient is treated with a combination of intravenous antibiotics including ceftazidime, azithromycin, imipenem, and nebulized colistin, with resolution of symptoms and pneumonia.
This document summarizes recent cancer assessments of glyphosate and epidemiological studies and animal carcinogenicity studies on glyphosate. It notes that IARC and Portier et al. classified glyphosate as a probable human carcinogen while EFSA, FAO/WHO JMPR, and draft EPA assessments found it unlikely to pose a carcinogenic risk. Meta-analyses of epidemiological studies found a statistically significant increased risk of non-Hodgkin lymphoma. Animal studies found increased incidences of renal tumors, malignant lymphomas, and hemangiosarcomas in male mice, with statistical significance. Rat studies had mixed or inadequate findings.
Dr. David Mooney - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
This document summarizes a presentation given by Dr. Mark Martens on behalf of the Glyphosate Task Force regarding the hazard assessment of glyphosate related to carcinogenicity and reproductive toxicity. The presentation covered genotoxicity studies, carcinogenicity studies in mice and rats, epidemiological evidence, and conclusions. Over 80 genotoxicity studies were evaluated, including a weight-of-evidence analysis concluding glyphosate is not genotoxic. Carcinogenicity studies in mice and rats were also reviewed, finding a lack of statistical significance and dose-response relationship for reported tumors. The largest epidemiological study found no association between glyphosate and non-Hodgkin's lymphoma.
West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and LucanixH. Jack West
This document summarizes information about three cancer vaccines - MAGE-A3, Stimuvax (L-BLP25, Tecemotide), and Lucanix (Belagenpumatucel-L). It discusses past and ongoing clinical trials of these vaccines in non-small cell lung cancer (NSCLC), including trial designs, results, and potential efficacy in patient subgroups. Key information presented includes Phase 3 trial results for Stimuvax showing a possible survival benefit in patients receiving concurrent chemotherapy and radiation, and evidence that Belagenpumatucel-L may benefit certain NSCLC patient subgroups based on retrospective analyses.
The document discusses the classification and labelling of glyphosate. It summarizes glyphosate's toxicological profile based on numerous studies. For human health, it finds glyphosate unlikely to cause cancer, genetic damage, or reproductive toxicity. It proposes classification as STOT RE 2 (H373) based on repeated dose toxicity. For the environment, it finds glyphosate toxic to aquatic life with long-lasting effects based on acute and chronic toxicity values, proposing classification as Aquatic Chronic 2 (H411). The document concludes by comparing the classification approaches of different regulatory agencies.
This case report describes a 74-year-old male nursing home resident admitted for left lower lung pneumonia. His medical history includes right medulla infarction with left hemiparesis, subglottic stenosis post tracheostomy, diabetes, hypertension, and hyperlipidemia. Laboratory tests and imaging show bilateral lower lung pneumonia with acute respiratory failure requiring mechanical ventilation. Sputum cultures grow Acinetobacter baumannii and Pseudomonas aeruginosa resistant to many antibiotics. The patient is treated with a combination of intravenous antibiotics including ceftazidime, azithromycin, imipenem, and nebulized colistin, with resolution of symptoms and pneumonia.
This document summarizes recent cancer assessments of glyphosate and epidemiological studies and animal carcinogenicity studies on glyphosate. It notes that IARC and Portier et al. classified glyphosate as a probable human carcinogen while EFSA, FAO/WHO JMPR, and draft EPA assessments found it unlikely to pose a carcinogenic risk. Meta-analyses of epidemiological studies found a statistically significant increased risk of non-Hodgkin lymphoma. Animal studies found increased incidences of renal tumors, malignant lymphomas, and hemangiosarcomas in male mice, with statistical significance. Rat studies had mixed or inadequate findings.
Dr. David Mooney - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
This document summarizes a presentation given by Dr. Mark Martens on behalf of the Glyphosate Task Force regarding the hazard assessment of glyphosate related to carcinogenicity and reproductive toxicity. The presentation covered genotoxicity studies, carcinogenicity studies in mice and rats, epidemiological evidence, and conclusions. Over 80 genotoxicity studies were evaluated, including a weight-of-evidence analysis concluding glyphosate is not genotoxic. Carcinogenicity studies in mice and rats were also reviewed, finding a lack of statistical significance and dose-response relationship for reported tumors. The largest epidemiological study found no association between glyphosate and non-Hodgkin's lymphoma.
The Pesticides Peer Review evaluated the toxicological properties of glyphosate. They concluded glyphosate is unlikely to be genotoxic or carcinogenic based on animal and human studies. Some studies reported increased tumors in rats and mice, but the peer review determined these were not toxicologically relevant. Regarding developmental toxicity in rabbits, some studies reported effects like cardiac malformations, but these occurred at maternally toxic doses. The majority view was glyphosate does not require classification for developmental toxicity. The peer review set the acceptable daily intake and reference dose for glyphosate based on developmental toxicity observed in rabbits.
1) The study investigated the role of the long non-coding RNA NNT-AS1 in progesterone resistance in endometrial cancer.
2) The researchers found that NNT-AS1 and survivin expression were increased, while miR-542-3p expression was decreased, in progesterone-resistant endometrial cancer cells.
3) Experiments showed that NNT-AS1 regulates progesterone resistance in endometrial cancer by functioning as a competing endogenous RNA for miR-542-3p, thereby regulating survivin expression.
academic / small company collaborations for rare and neglected diseasesv2Sean Ekins
This document discusses academic and small company collaborations for rare and neglected diseases. It provides background on rare diseases, noting they affect 6-7% of the population in the US and less than 1 in 2000 people in Europe. Many rare diseases have a genetic origin. The document then focuses on specific rare diseases, including Sanfilippo Syndrome, a lysosomal storage disorder caused by deficiencies in certain enzymes. Potential treatment approaches for Sanfilippo Syndrome are discussed such as enzyme replacement therapy, gene therapy, and substrate reduction therapy. The document also discusses machine learning models to identify potential drug candidates for other rare and neglected tropical diseases such as tuberculosis, Chagas disease, and Ebola virus.
Shifting paradigms in vaccinology immune modulation and sex differences explo...WAidid
Even there are very limited immunological studies to date, Professor Flanagan explains the new paradigms in vaccinology exploring sex differences:
- Vaccines have non-targeted heterologous effects on innate and adaptive immunity
- These can alter susceptibility to non-vaccine targeted infectious diseases and can alter all cause mortality
- Females are more susceptible
Professor Flanagan concludes the slideset with the need to understand mechanisms in order to exploit beneficial and avoid harmful effects.
The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) re-evaluated the toxicity of glyphosate residues in food, particularly related to genotoxic and carcinogenic risks. They concluded that glyphosate is unlikely to pose a carcinogenic risk to humans through diet based on the absence of carcinogenicity in rodents at human-relevant doses and absence of genotoxicity by oral route in mammals. They found some evidence of positive association between glyphosate exposure and non-Hodgkin lymphoma in case-control studies but not in the large, high-quality Agricultural Health Study cohort. The JMPR determined glyphosate does not interact with hormone receptors and has no gen
The document summarizes information about HIV, its life cycle, approved antiretroviral drugs, adverse effects of antiretrovirals, lipodystrophy, drug interactions, and guidelines for initiating antiretroviral therapy in special populations. It provides details on the classes of antiretrovirals including nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists. It discusses the rationale for combination antiretroviral therapy and boosted protease inhibitors.
1) EGFR mutations are found in 10-30% of NSCLC cases and are associated with response to EGFR TKIs as first-line treatment.
2) Several studies including IPASS, EURTAC and LUX-Lung 3 have shown superior PFS for first-generation EGFR TKIs like gefitinib and erlotinib and the second-generation TKI afatinib compared to platinum-based chemotherapy as first-line treatment for EGFR mutation-positive NSCLC.
3) Meta-analyses of these studies demonstrate improved PFS for EGFR TKIs compared to chemotherapy in EGFR mutation-positive NSCLC, though OS is generally similar between the treatments
This document summarizes current treatments for lupus nephritis and emerging therapies. Standard treatment is corticosteroids plus cyclophosphamide for severe cases, though mycophenolate mofetil is now widely used as well for induction and maintenance. Emerging options include calcineurin inhibitors, biologics, and targeted therapies, though more research is still needed to define their roles and long term safety. Overall, treatment outcomes have improved but corticosteroid use remains high and new options are still evaluated.
Compound A inhibits bladder cancer growth through multiple mechanisms:
1) It functions as both a glucocorticoid receptor agonist and androgen receptor antagonist, inhibiting proliferation and inducing apoptosis in bladder cancer cells expressing both receptors.
2) It promotes interactions between the glucocorticoid receptor and nuclear factor-κB, inducing glucocorticoid receptor-mediated transrepression of genes related to invasion, migration and inflammation.
3) In mouse models, Compound A more strongly suppresses tumor growth than dexamethasone or hydroxyflutamide alone, indicating its dual receptor effects are more beneficial than targeting individual receptors.
This document summarizes research on identifying genetic factors associated with traumatic brain injury (TBI) outcomes. It notes that the ApoE4 allele has been associated with worse outcomes, but replication has been limited. Larger collaborative studies are needed using quantitative measures as "endophenotypes" to better detect genetic effects. Lessons from Alzheimer's disease research show that genome-wide association studies with thousands of patients are needed to reliably identify genetic risk factors for complex diseases like TBI.
My Prostate Cancer Story by Paul SchellhammerTony Crispino
With permission of Dr. Schellhammer this slide deck should be interesting to any PCa patient. Dr. Schellhammer is a former president of the American Urological Association and a leading authority on prostate cancer. He has fought i long battle. He and his colleague, Paul Lange operated on each other and had vastly different results.
This study identified risk factors for fluoroquinolone resistance in nosocomial urinary tract infections caused by gram-negative bacilli. Recent exposure to fluoroquinolones, cotrimoxazole, and metronidazole were independent risk factors. Residence in a long-term care facility and prior hospitalization were also risk factors, suggesting resistance may spread across healthcare facilities. The study analyzed 251 cases of infections from two hospitals between 2003-2005.
This study assessed the effects of compound A (CpdA) on bladder cancer cell growth. CpdA functions as both a glucocorticoid receptor (GR) modulator and androgen receptor (AR) antagonist. In GR/AR-positive bladder cancer cells, CpdA strongly inhibited cell proliferation, colony formation, migration and invasion. CpdA decreased the viability of control cells more than GR or AR silencing cells. In mouse xenograft models, CpdA more strongly suppressed tumor growth than dexamethasone or hydroxyflutamide. CpdA likely inhibits bladder cancer growth predominantly by inducing GR transrepression and partially through the AR pathway.
Whole genome microbiology for Salmonella public health microbiologyPhilip Ashton
This document discusses how Public Health England is implementing whole genome sequencing (WGS) as the routine method for Salmonella reference microbiology. Salmonella causes many cases of foodborne illness in the UK each year. WGS provides higher resolution typing than previous methods and allows for global data sharing. PHE has invested in the infrastructure and bioinformatics capabilities needed for large-scale Salmonella WGS. WGS was used to investigate an international Salmonella Enteritidis outbreak. Analysis of outbreak strains identified multiple clusters corresponding to different outbreaks. WGS also determines antimicrobial resistance profiles and allows characterization of bacterial strains. PHE aims to continue improving Salmonella analysis methods using WGS.
1) The study investigated how Gram-negative bacterial lipopolysaccharide (LPS), a component of bacteria like Chlamydia and Neisseria that cause STIs, affects expression of HIV receptors in cervical epithelial cells.
2) The results showed that LPS increased expression of the CCR5 HIV co-receptor and other alternative receptors in cervical cells through activation of EGFR, ERK1/2, and COX-2 signaling pathways.
3) This suggests that STIs have the potential to enhance susceptibility to HIV infection in women by regulating expression of HIV receptors in cervical epithelial cells through an inflammatory response.
A systematic, data driven approach to the combined analysis of microarray and...Laurence Dawkins-Hall
The use of gene expression data from Micro arrays coupled with WT QTL's linked to Tryp resistance phenotypes in Cattle to elucidate pertinent genetic changes underpinning phenotype in putative candidate genes
1) Aspirin inhibited constitutive NF-κB activity and Cox-2 expression in human pancreatic carcinoma cell lines in a dose-dependent manner.
2) Aspirin did not significantly inhibit the in vitro growth of pancreatic carcinoma cell lines.
3) In an orthotopic mouse model, none of the mice injected with NF-κB inhibited pancreatic carcinoma cells developed tumors, whereas all mice injected with non-inhibited cells developed tumors. Mice receiving prophylactic aspirin treatment showed a significantly lower tumor incidence than mice receiving later aspirin treatment or no treatment.
Pre and Post Exposure Prophylaxis and HIV Prevention presented by Dr. Ken Mayer, Research Director of the Fenway Health Center at the Fenway Health Center community education conference: An End To AIDS - How A State Bill Can Change Everything hosted by SearchForACure.org, the Fenway Health Center, and the MA Dept. of Public Health
Aidsrounds121412morris 121214115641-phpapp01Lucas Brown
The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians and researchers to provide the most current research, clinical practices, and trends in HIV and other infectious diseases. The slides from an AIDS Clinical Rounds presentation are intended for educational purposes of the audience and may not be used without the presenter's permission. The presentation provides an update on PrEP (pre-exposure prophylaxis) for HIV, including data on efficacy from recent studies, pharmacology, adverse events, and guidance for its use.
The Pesticides Peer Review evaluated the toxicological properties of glyphosate. They concluded glyphosate is unlikely to be genotoxic or carcinogenic based on animal and human studies. Some studies reported increased tumors in rats and mice, but the peer review determined these were not toxicologically relevant. Regarding developmental toxicity in rabbits, some studies reported effects like cardiac malformations, but these occurred at maternally toxic doses. The majority view was glyphosate does not require classification for developmental toxicity. The peer review set the acceptable daily intake and reference dose for glyphosate based on developmental toxicity observed in rabbits.
1) The study investigated the role of the long non-coding RNA NNT-AS1 in progesterone resistance in endometrial cancer.
2) The researchers found that NNT-AS1 and survivin expression were increased, while miR-542-3p expression was decreased, in progesterone-resistant endometrial cancer cells.
3) Experiments showed that NNT-AS1 regulates progesterone resistance in endometrial cancer by functioning as a competing endogenous RNA for miR-542-3p, thereby regulating survivin expression.
academic / small company collaborations for rare and neglected diseasesv2Sean Ekins
This document discusses academic and small company collaborations for rare and neglected diseases. It provides background on rare diseases, noting they affect 6-7% of the population in the US and less than 1 in 2000 people in Europe. Many rare diseases have a genetic origin. The document then focuses on specific rare diseases, including Sanfilippo Syndrome, a lysosomal storage disorder caused by deficiencies in certain enzymes. Potential treatment approaches for Sanfilippo Syndrome are discussed such as enzyme replacement therapy, gene therapy, and substrate reduction therapy. The document also discusses machine learning models to identify potential drug candidates for other rare and neglected tropical diseases such as tuberculosis, Chagas disease, and Ebola virus.
Shifting paradigms in vaccinology immune modulation and sex differences explo...WAidid
Even there are very limited immunological studies to date, Professor Flanagan explains the new paradigms in vaccinology exploring sex differences:
- Vaccines have non-targeted heterologous effects on innate and adaptive immunity
- These can alter susceptibility to non-vaccine targeted infectious diseases and can alter all cause mortality
- Females are more susceptible
Professor Flanagan concludes the slideset with the need to understand mechanisms in order to exploit beneficial and avoid harmful effects.
The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) re-evaluated the toxicity of glyphosate residues in food, particularly related to genotoxic and carcinogenic risks. They concluded that glyphosate is unlikely to pose a carcinogenic risk to humans through diet based on the absence of carcinogenicity in rodents at human-relevant doses and absence of genotoxicity by oral route in mammals. They found some evidence of positive association between glyphosate exposure and non-Hodgkin lymphoma in case-control studies but not in the large, high-quality Agricultural Health Study cohort. The JMPR determined glyphosate does not interact with hormone receptors and has no gen
The document summarizes information about HIV, its life cycle, approved antiretroviral drugs, adverse effects of antiretrovirals, lipodystrophy, drug interactions, and guidelines for initiating antiretroviral therapy in special populations. It provides details on the classes of antiretrovirals including nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists. It discusses the rationale for combination antiretroviral therapy and boosted protease inhibitors.
1) EGFR mutations are found in 10-30% of NSCLC cases and are associated with response to EGFR TKIs as first-line treatment.
2) Several studies including IPASS, EURTAC and LUX-Lung 3 have shown superior PFS for first-generation EGFR TKIs like gefitinib and erlotinib and the second-generation TKI afatinib compared to platinum-based chemotherapy as first-line treatment for EGFR mutation-positive NSCLC.
3) Meta-analyses of these studies demonstrate improved PFS for EGFR TKIs compared to chemotherapy in EGFR mutation-positive NSCLC, though OS is generally similar between the treatments
This document summarizes current treatments for lupus nephritis and emerging therapies. Standard treatment is corticosteroids plus cyclophosphamide for severe cases, though mycophenolate mofetil is now widely used as well for induction and maintenance. Emerging options include calcineurin inhibitors, biologics, and targeted therapies, though more research is still needed to define their roles and long term safety. Overall, treatment outcomes have improved but corticosteroid use remains high and new options are still evaluated.
Compound A inhibits bladder cancer growth through multiple mechanisms:
1) It functions as both a glucocorticoid receptor agonist and androgen receptor antagonist, inhibiting proliferation and inducing apoptosis in bladder cancer cells expressing both receptors.
2) It promotes interactions between the glucocorticoid receptor and nuclear factor-κB, inducing glucocorticoid receptor-mediated transrepression of genes related to invasion, migration and inflammation.
3) In mouse models, Compound A more strongly suppresses tumor growth than dexamethasone or hydroxyflutamide alone, indicating its dual receptor effects are more beneficial than targeting individual receptors.
This document summarizes research on identifying genetic factors associated with traumatic brain injury (TBI) outcomes. It notes that the ApoE4 allele has been associated with worse outcomes, but replication has been limited. Larger collaborative studies are needed using quantitative measures as "endophenotypes" to better detect genetic effects. Lessons from Alzheimer's disease research show that genome-wide association studies with thousands of patients are needed to reliably identify genetic risk factors for complex diseases like TBI.
My Prostate Cancer Story by Paul SchellhammerTony Crispino
With permission of Dr. Schellhammer this slide deck should be interesting to any PCa patient. Dr. Schellhammer is a former president of the American Urological Association and a leading authority on prostate cancer. He has fought i long battle. He and his colleague, Paul Lange operated on each other and had vastly different results.
This study identified risk factors for fluoroquinolone resistance in nosocomial urinary tract infections caused by gram-negative bacilli. Recent exposure to fluoroquinolones, cotrimoxazole, and metronidazole were independent risk factors. Residence in a long-term care facility and prior hospitalization were also risk factors, suggesting resistance may spread across healthcare facilities. The study analyzed 251 cases of infections from two hospitals between 2003-2005.
This study assessed the effects of compound A (CpdA) on bladder cancer cell growth. CpdA functions as both a glucocorticoid receptor (GR) modulator and androgen receptor (AR) antagonist. In GR/AR-positive bladder cancer cells, CpdA strongly inhibited cell proliferation, colony formation, migration and invasion. CpdA decreased the viability of control cells more than GR or AR silencing cells. In mouse xenograft models, CpdA more strongly suppressed tumor growth than dexamethasone or hydroxyflutamide. CpdA likely inhibits bladder cancer growth predominantly by inducing GR transrepression and partially through the AR pathway.
Whole genome microbiology for Salmonella public health microbiologyPhilip Ashton
This document discusses how Public Health England is implementing whole genome sequencing (WGS) as the routine method for Salmonella reference microbiology. Salmonella causes many cases of foodborne illness in the UK each year. WGS provides higher resolution typing than previous methods and allows for global data sharing. PHE has invested in the infrastructure and bioinformatics capabilities needed for large-scale Salmonella WGS. WGS was used to investigate an international Salmonella Enteritidis outbreak. Analysis of outbreak strains identified multiple clusters corresponding to different outbreaks. WGS also determines antimicrobial resistance profiles and allows characterization of bacterial strains. PHE aims to continue improving Salmonella analysis methods using WGS.
1) The study investigated how Gram-negative bacterial lipopolysaccharide (LPS), a component of bacteria like Chlamydia and Neisseria that cause STIs, affects expression of HIV receptors in cervical epithelial cells.
2) The results showed that LPS increased expression of the CCR5 HIV co-receptor and other alternative receptors in cervical cells through activation of EGFR, ERK1/2, and COX-2 signaling pathways.
3) This suggests that STIs have the potential to enhance susceptibility to HIV infection in women by regulating expression of HIV receptors in cervical epithelial cells through an inflammatory response.
A systematic, data driven approach to the combined analysis of microarray and...Laurence Dawkins-Hall
The use of gene expression data from Micro arrays coupled with WT QTL's linked to Tryp resistance phenotypes in Cattle to elucidate pertinent genetic changes underpinning phenotype in putative candidate genes
1) Aspirin inhibited constitutive NF-κB activity and Cox-2 expression in human pancreatic carcinoma cell lines in a dose-dependent manner.
2) Aspirin did not significantly inhibit the in vitro growth of pancreatic carcinoma cell lines.
3) In an orthotopic mouse model, none of the mice injected with NF-κB inhibited pancreatic carcinoma cells developed tumors, whereas all mice injected with non-inhibited cells developed tumors. Mice receiving prophylactic aspirin treatment showed a significantly lower tumor incidence than mice receiving later aspirin treatment or no treatment.
Pre and Post Exposure Prophylaxis and HIV Prevention presented by Dr. Ken Mayer, Research Director of the Fenway Health Center at the Fenway Health Center community education conference: An End To AIDS - How A State Bill Can Change Everything hosted by SearchForACure.org, the Fenway Health Center, and the MA Dept. of Public Health
Aidsrounds121412morris 121214115641-phpapp01Lucas Brown
The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians and researchers to provide the most current research, clinical practices, and trends in HIV and other infectious diseases. The slides from an AIDS Clinical Rounds presentation are intended for educational purposes of the audience and may not be used without the presenter's permission. The presentation provides an update on PrEP (pre-exposure prophylaxis) for HIV, including data on efficacy from recent studies, pharmacology, adverse events, and guidance for its use.
Новые данные с конференции по ВИЧ-инфекции CROI 2017/Clinical Impact of New D...hivlifeinfo
Clinical Impact of New Data From CROI 2017
Expert faculty members Joel E. Gallant, MD, MPH, and Charles B. Hicks, MD, summarize key studies from this important annual conference.
Format: Microsoft PowerPoint (.ppt)
File size: 1.25 MB
Date posted: 3/3/2017
Contemporary Management of HIV. New Data From AIDS 2018hivlifeinfo
This document summarizes key findings from the AIDS 2018 conference regarding contemporary management of HIV. It describes studies showing:
1) No linked HIV transmissions occurred in over 77,000 condomless sex acts when the HIV+ partner had an undetectable viral load in the PARTNER2 study.
2) On-demand PrEP was highly effective at preventing HIV in several studies when adherence was high.
3) Early results from the ANRS Prevenir study found no difference in HIV incidence between daily and on-demand PrEP, with high adherence in both groups.
The 18th International AIDS Conference (AIDS 2010)Abhishek Shah
The document summarizes key findings from the 18th International AIDS Conference held in Vienna, Austria in July 2010. Some of the main topics discussed include:
- The Vienna Declaration calling for decriminalization of drug use and scaling up HIV prevention and treatment services.
- Studies showing reduced HIV risk with male circumcision and use of tenofovir gel.
- Ongoing PrEP trials evaluating daily oral tenofovir for HIV prevention.
- Modeling suggesting universal HIV testing and treatment could reduce new infections and deaths in South Africa over 40 years.
Dr. Manuel Hidalgo - Simposio Internacional ' Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
A protocol presentation I created during my training at KEMH. Disease was ulcerative colitis. Suggestions made by expert evaluating this have not been incorporated.
Современное лечение ВИЧ: лечение ВИЧ у женщин.2017/Contemporary Management of...hivlifeinfo
In this downloadable slideset, Kathleen E. Squires, MD, and Program Director Joseph J. Eron, Jr., MD, review key data and optimal strategies in caring for HIV-infected women, including ART safety and efficacy in women, reproductive health management, ART and pregnancy, and preventing HIV infection in women.
Format: Microsoft PowerPoint (.ppt)
File size: 1.59 MB
Date posted: 4/25/2017
This document summarizes research on Tuberous Sclerosis Complex (TSC), including key facts about the disease, progress that has been made in understanding the genetics and molecular mechanisms, development of treatments like Everolimus, and ongoing areas of research focus like clinical trials of new drugs and studying disease mechanisms using cellular and animal models.
Cовременное лечение ВИЧ : новые данные с конференции CROI 2017/ Contemporary...hivlifeinfo
Cовременное лечение ВИЧ : новые данные с конференции CROI 2017/ Contemporary Management of HIV. New Data From CROI 2017
In this downloadable slideset, Charles B. Hicks, MD, and Program Director Joseph J. Eron, Jr., MD, review key new HIV data presented at the Seattle 2017 meeting.
Topics include:
-Prevention
-New data on currently available ART
-Switch/simplification strategies for virologically suppressed patients
-Investigational ARV agents
-Treatment complications and comorbidities
This document summarizes information about hepatitis B and C co-infection with HIV. It notes that co-infection leads to faster progression of liver disease and higher rates of liver cancer and mortality. Treatment for both viruses is important, with newer regimens like tenofovir alafenamide having comparable efficacy to tenofovir disoproxil fumarate but being more tolerable with less bone and kidney toxicity. Achieving a sustained virologic response reduces complications of liver disease and improves overall health outcomes.
Colorectal Cancer Research & Treatment News - recap from the May 2014 ASCO co...Fight Colorectal Cancer
This document summarizes key findings from the PRIME trial evaluating the addition of panitumumab to FOLFOX4 as first-line treatment for metastatic colorectal cancer. Biomarker analysis found that KRAS exon 2 wild-type tumors derived greater benefit from the addition of panitumumab, with a progression-free survival advantage compared to FOLFOX4 alone. Further biomarker testing found mutations in other RAS isoforms or BRAF reduced likelihood of benefit from panitumumab. The results support use of RAS/BRAF mutation testing to select patients for first-line anti-EGFR therapy in combination with chemotherapy.
Lupus Nephritis Dilemma - Prof. Mohsen El KosiMNDU net
This document discusses Lupus Nephritis (LN), a common complication of Systemic Lupus Erythematosus (SLE) that affects the kidneys. It covers the epidemiology and diagnostic criteria of SLE, outlines current treatment options for LN including steroids, immunosuppressants, and biologics, and discusses ongoing clinical trials. It also examines challenges in LN management such as variability in histological classification systems and lack of consensus on treatment protocols. Overall, the document provides an overview of LN as a complex condition with ongoing efforts to improve diagnosis and outcomes.
The document summarizes a presentation on supportive care in oncology. It discusses the use of granulocyte colony-stimulating factors (G-CSF) to prevent febrile neutropenia, optimal antiemetic regimens, and approaches to managing bone health in cancer patients. The presentation covers guidelines for using pegfilgrastim or filgrastim prophylaxis in chemotherapy, and the recommended use of aprepitant, palonosetron, and dexamethasone for acute and delayed nausea and vomiting. It also reviews data on using bisphosphonates or denosumab in patients with breast cancer receiving aromatase inhibitors to prevent treatment-related bone loss.
The document summarizes a supportive care session that took place on April 3, 2011 from 15:00-16:30. It discusses fatigue management, antiemetics, growth factors, and bone health. Specifically, it covers the use of granulocyte colony-stimulating factors to prevent febrile neutropenia, updated antiemetic guidelines for preventing chemotherapy-induced nausea and vomiting, and the role of bisphosphonates and denosumab in maintaining bone health for cancer patients.
This 3-sentence summary provides the essential information from the document:
The document outlines a conference program from June 30 - July 3, 2013 in Kuala Lumpur, Malaysia called IAS 2013, which covered highlights and official coverage of HIV pathogenesis, treatment, and prevention. It includes slides on antiretroviral therapy guidelines, clinical trials of new drugs and regimens, and investigational long-acting antiretroviral agents. The
Her2Neu positive breast cancer is comprises of about 15-20% of all breast cancer. Among them quite a few number of patients present as de novo metastasis . In this presentation you ll find a guide how to manage it with relevant evidences. Presentation is meant for Oncology trainees.
This lecture was part of an educational course performed by the IATTGI group this August in Buenos Aires and describes novel targets and novel drugs in hepatocellular carcinoma.
Estado actual de terapia sistémica en cáncer renal metastásicoMauricio Lema
This document discusses the current management of metastatic renal cell carcinoma (mRCC). It provides an overview of targeted therapies for mRCC including tyrosine kinase inhibitors (TKIs) such as sunitinib, pazopanib, and cabozantinib that target the VEGF pathway. Clinical trial results are presented comparing TKIs in first-line mRCC. Active surveillance is also discussed as a treatment option for select asymptomatic or minimally symptomatic mRCC patients. Toxicities of TKIs like fatigue, diarrhea and hand-foot syndrome are reviewed along with their negative impact on quality of life.
Similar to 07.17.20 | Precision HIV PrEP – Tailoring the Prescription for the User (20)
Katherine Promer Flores, MD (she/her)
Staff Physician
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California San Diego
Daniel Lee, MD
Clinical Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
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Division of Infectious Diseases & Global Public Health
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Division of Infectious Diseases & Global Public Health
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University of California, San Diego
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Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
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Richard Garfein, PhD, MPH
Professor
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Adjunct Professor
Division of Infectious Disease and Global Public Health
Department of Medicine
University of California, San Diego
Este documento fornece informações sobre uma sessão de treinamento virtual sobre HIV/AIDS para militares internacionais. A agenda inclui atualizações sobre a vacina COVID-19 e sua implementação na Nigéria, com discussões sobre implicações para pessoas vivendo com HIV. A sessão é conduzida pelo programa MIHTP-ECHO com o objetivo de melhorar o atendimento e prevenção de HIV em militares em todo o mundo.
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Laura Bamford, MD, MSCE
Associate Professor of Medicine
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Division of Infectious Diseases and Global Public Health
Department of Medicine
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Davey Smith, MD, MAS
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Chief, Division of Infectious Diseases and Global Public Health
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Associate Program Director, Infectious Diseases Fellowship
Division of Infectious Diseases & Global Public Health
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1. HIV & Global Health Rounds
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease and global public health clinicians,
physicians, and researchers. The goal of these presentations is to
provide the most current research, clinical practices, and trends in HIV,
HBV, HCV, TB, and other infectious diseases of global significance.
The slides from the HIV & Global Health Rounds presentation that you
are about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
2. Precision HIV PrEP: Tailoring
the Prescription for the User
17July2020
Mackenzie Cottrell, PharmD, MS
mlcottre@email.unc.edu
4. Disparities in PrEP Efficacy
Biological or Behavioral?
Daily Oral PrEP
RCT Population Treatment Outcome
TDF2 Heterosexual high risk men and women F/TDF Inconclusive
Partners PrEP Serodiscordant heterosexual couples F/TDF Protective
Partners PrEP Serodiscordant heterosexual couples TDF Protective
iPrEx MSM and Transgender women F/TDF Protective
Discover MSM and Transgender women F/TDF Protective
Discover MSM and Transgender women F/TAF Protective
FEM-PrEP Heterosexual high risk women F/TDF Futile
VOICE Heterosexual high risk women F/TDF Futile
VOICE Heterosexual high risk women TDF Futile
Plot adapted from Landovitz R. PrEP for HIV Prevention: What We Know and What We Still Need to Know for Implementation. CROI 2015.
% Adherence by Objective Assessment Measure
20 30 40 50 60 70 80 90 100
%Effectiveness
-60
-40
-20
0
20
40
60
80
100
Female Only
Male and Female
Male and Transgender Woman
*
*Discover % effectiveness calculated compared to background
incidence and adherence estimated based on CASI, pill count, and DBS.
F/TDF F/TAF
%Efficacy
5. PrEP Effectiveness May Differ by User
Corneli A et al. JAIDS 2014;66:324-331Grant et al. Lanced ID 2014;14(9):820-829
80% HIV risk reduction
with ≥2 doses/week
But 45-60% taking ≥ 2
doses/week in FEM-PrEP
iPrEx OLE Overall 51% Risk FEM-PrEP Overall Futile
6. PrEP Effectiveness May Differ by User
2015 HIV Diagnoses Among Heterosexual Subpopulations in U.S.
0 1000 2000 3000 4000 5000
BlackHispanic/LatinoWhite
Male
Female
CDC. HIV Surveillance Report 2016;27:22; Bush et al. Racial characteristics of FTC/TDF for pre-exposure prophylaxis users in the U.S. Paper presented at:
2016 ASM Microbe; June 16-20, 2016; Boston. Session 371.
Overall, only 20.7% of those initiating PrEP were women, and from 2012
to 2015 the percentage of women starting PrEP decreased by 37.1%.
7. Intracellular: Inside the Nucleus
Extracellular: Blood and Tissue Intracellular: Blood and Tissue
PrEP Pharmacology & Mechanism of Action
T -PPP
PharmacokineticsPharmacodynamics
A
U
CG
U
CG
C
A
U
HIV RNA
HIV ssDNA
A -PPPA -PPP
A -PPP
Phosphatases Deactivate
Kinases Activate
TFV
-PPP
FTC
-PPP
TFV
-PP
FTC
-PP
FTC
-P
Transport into CellFTC
TDF TFV
-PEsterase Transport into Cell
TFV
-P
TAF Transport into Cell Cathepsin-A
Reverse
TranscriptaseT
8. PrEP Blood PK Scales with Dose
PBMC TFVdp Concentration (Median +/- IQR) Versus Time After a
Single 5mg, 10mg, or 25mg Dose of Tenofovir Alafenamide Over 14 Days
Time (h)
TFVdp(fmol/millioncells) 0.1
1
10
100
1000
25mg TAF; 18% BLQ
10mg TAF; 27% BLQ
LLOQ
5mg TAF; 38% BLQ
Time (h)
0 1 3 7 10
TFVdp(fmol/millioncells)
1
10
100
Adapted from Cottrell ML et al. J Infect Dis. 2016 Jul;214(1):55-64; Cottrell et al. JAC 2017 Jun;72(6):1731–1740.
Nominal Time (hr)
0 10 20 30 40 50
FTC-TPConcentration(fmol/10
6
cells)
100
1000
10000
100mg Emtricitabine Solution
200mg Emtricitabine Solution
400mg Emtricitabine Solution
Nominal Time (hr)
0 10 20 30 40 50
TFV-DPConcentration(fmol/10
6
cells)
1
10
100
150mg Tenofovir-DF
300mg Tenofovir-DF
600mg Tenofovir-DF
9. PrEP Blood PK Scales with Frequency
Hendrix et al. AIDS Res Hum Retroviruses. 2016 Jan;32(1):32-43.
10. Tissue:BloodPlasmaRatio
0.1
1
10
100
Tenofovir
Emtricitabine
Cervix/Vagina Male Rectum
PrEP PK Differs by Transmission Site
TFV Exposure in Female Genital
Tract vs Male Rectum
TFVdp Exposure in Female Genital
Tract vs Female Rectum
Patterson KB Sci Transl Med. 2011 Dec 7;3(112):112re4.
TFV TFV-dp FTC FTC-tp
AUC0-48(ngorfmol*hr*mg
-1
)
1
10
100
1000
10000
Rectal tissue
FGT tissue
Adapted from Cottrell ML et al. J Infect Dis. 2016 Jul 1;214(1):55-64.
14. TAF Results in Higher TFVdp in Lymph Node MNCs
Fletcher et al. Clin Pharmacol Ther 2020 May 8. [Ahead of print]
15. FTCtp Generally High in Lymph Node MNCs
Fletcher et al. Clin Pharmacol Ther 2020 May 8. [Ahead of print]
16. PK/PD: How much is enough?
Time (hours)
0 20 40 60 80 100 120
NaturalLogConcentration
SS Cmax
SS Trough
SS PK Principles
1. In=Out
2. Achieved by ~5 T1/2
3. Time to SS independent of:
• Dose
• Dose frequency
• Concentration
Trough
17. PrEP Time to Steady State Differs by Compartment
Compartment
TFVdp t1/2
(hrs)
TFVdp 90% Tss
(days)
Blood Plasma 17 3
Blood derived
CD4+ cells
112
(100, 118)
16.3
(14.6, 17.2)
Colon CD4+
cells
60
(52, 72)
8.8
(7.6, 10.5)
FGT CD4+ cells
139
(121, 167)
20.3
(17.6, 24.4)
Louissaint, et al. AIDS Res Hum Retrovir 2013; Wang, et al. AIDS Res Hum Retrovir. 2004; 20: 1173-1182.
Day after initiating daily dosing
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30Concentration
1
10
100
Below assay limits of quantification
17 hour half-life
120 hour half-life
17 hour half-life
139 hour half-life
18. Dose vs Response Relationship
Drug Concentration
1 10 100 1000 10000 100000
PercentInhibition
0
10
20
30
40
50
60
70
80
90
100
EC50→
EC90→
EC99→
PK/PD: How much is enough?
19. PBMC TFVdp Correlated with PrEP Efficacy
Anderson PL et al. Sci Transl Med 2012; 4(151)
EC90 = 16fmol/million vPBMC
20. Endogenous Nucleotides Mediate Potency
Adapted from: García-Lerma J G et al. J. Virol. 2011;85:6610-6617
Lower TFVdp:dATP associated with
infection in 4/6 macaques dosed with
tenofovir PrEP
Molar TFVdp:dATP ratio of ≥1
associated with 100% reverse
transcriptase inhibition
%RTInhibition
dATP, mM
Treated with 0.005 mM TFVdp
00.10.010.0010.0001
100
80
60
40
20
0
1000
100
10
1
TFVdp:dATPratios
Weeks
21. Metabolite:Nucleotide Correlates with in vitro Inhibition
▲CD4+
○ TZM-bl
Cell EC50 (±SE) Hill (±SE) EC90
TZM-bl 0.01 (±0.001) 1.02 (±0.11) 0.086
CD4+ 0.086 (±0.011) 1.81 (±0.39) 0.29
Cell EC50 (±SE) Hill (±SE) EC90
TZM-bl 0.059 (±0.004) 1.42 (±0.11) 0.27
CD4+ 0.022 (±0.005) 1.86 (±0.67) 0.07
▲CD4+
○ TZM-bl
Cottrell ML et al. J Infect Dis. 2016 Feb 24 [Epub ahead of print].
%Protection
%Protection
TFVdp:dATP (Molar Ratio) FTCtp:dCTP (Molar Ratio)
22. TFVdp and FTCtp Inhibit HIV Synergistically
Ψ=0.632 (±0.074; p<0.001)Chakraborty A and Jusko W. J Pharm Sci. 2002;91(5):1334-1342.
23. v v
PK/PD Modeling can Predict Effective Dosing
Doses of TDF/FTC PrEP per Week%PopulationAchievingTargetExposure
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 1 2 3 4 5 6 7
100% 100%
Female Genital Tract Lower GI Tract
Adapted from Cottrell ML et al. J Infect Dis. 2016 Jul 1;214(1):55-64.
Female Genital Tract vs Lower GI Tract
Time (hr)
0 48 96 144 192 240 288 336
%PopulationAchievingTargetExposure
0
10
20
30
40
50
60
70
80
90
100
Sex
24. Female Sex Hormones May Mediate PK/PD
Median (IQR) Estradiol in 16 TGW starting FHT
Baseline 6 months
29 (16) pg/ml 258 (812) pg/ml
Deutsch et al. Obstet Gynecol 2015; 125 (3): 605-610
Estradiol and progesterone mediate ADME pathways
Absorption
gastric pH
gastric emptying
intestinal motility
Delayed drug absorption –
SR formulations particularly
impacted
Decreased absorption for
acid dependent drugs
Distribution
intravascular volume
sodium and water
retention
Altered plasma
concentrations of
hydrophilic and lipophilic
drugs
25. Female Sex Hormones May Mediate PK/PD
Shieh et al. Oral abstract OA23.03. R4P 2018; Shen Z et al. PLoS One. 2013 Jul 25;8(7):e69854; Shen Z et al. PLoS One. 2014 Jun 30;9(6):e100863.
FGT Cells treated with Estradiol
1. Gender affirming-FSH do not
alter kinase expression in
PBMCs or colon tissue
2. In vitro FSH nucleotidase
activity in epithelial cells
3. In vitro FSH TFVdp in FGT
derived CD4+ cells
FGT Derived CD4+s Blood Derived CD4+s
26. PrEP Effectiveness in Transgender Women
Deutsch et al. Lancet HIV 2015 Dec;2(12):e512-e519
Lower TFVdp in DBS amongst TGW
27. Gender Affirming FHT May Systemic PrEP in TGW
Shieh et al. J Int AIDS Soc. 2019 Nov;22(11):e25405Cirrincione et al. JAC 2020 Jan [Epub ahead of print]
PlasmaTFV(ng/m)
PlasmaTFV(μg/m)
Time (hours) Time (hours)
CG adults (n=17)
TGW (n=15)
CGM (n=8)
TGW (n=8)
27% AUC
20% Ctrough*
24% AUC*
11% Ctrough
Plasma TFV and FTC in TGW vs CGM Plasma TFV in TGW vs Cisadults
* p<0.05
28. Gender Affirming FHT May PrEP in Tissues
Trend towards TFVdp/FTCtp in
TransWomen vs CisMen in Colon Cells
TFVdp in TransWomen vs CisMen
and Women in Rectal Tissues
Active
Metabolite
Ctau PBMC Colon Cells
TFVdp
% Reduction 16% 36%
P value 0.3 0.44
FTCtp
% Reduction -1% 44%
P value 0.98 0.38
Cottrell et al. Clin Infect Dis. 2019 Apr 9. pii: ciz290.
Shieh et al. Oral abstract OA23.03. R4P 2018
7-fold lower
TFVdp FTCtp
PBMCsRectalTissues
29. How Can We Monitor PrEP Dose Taking Behavior?
State of the Evidence for PrEP in 2011
RCT Population Treatment Outcome
Partners
PrEP
Serodiscordant
heterosexual couples
TDF/FTC Protective
Partners
PrEP
Serodiscordant
heterosexual couples
TDF Protective
iPrEx
MSM and Transgender
women
TDF/FTC Protective
TDF2
Heterosexual high risk
men and women
TDF/FTC Inconclusive
FEM-PrEP
Heterosexual high risk
women
TDF/FTC Futile
VOICE
Heterosexual high risk
women
TDF/FTC Futile
VOICE
Heterosexual high risk
women
TDF Futile
Plot adapted from Landovitz R. PrEP for HIV Prevention: What We Know and What We Still Need to Know for Implementation. CROI 2015. Statistics: Pearson
correlation of extracted data using PlotDigitizer v2.6.8.
% Adherence by Objective Assessment Measure
20 40 60 80 100 120%Effectiveness
-60
-40
-20
0
20
40
60
80
100
FEM-PrEP (TDF/FTC)
PartnersPrEP (TDF)
PartnersPrEP (TDF/FTC)
TDF2 (TDF/FTC)
VOICE (TDF)
VOICE (TDF/FTC)
iPrEx (TDF/FTC)
Pill Count
r=0.60, p=0.2
% Detectable Drug Concentration
r=0.89, p=0.006
30. Day after initiating daily dosing
2 4 6 8 10 12 14 16 18 20
Concentration
1
10
100
Below assay limits of quantification
17 hour half-life
Short Term Adherence Measures
• Concentrations of short half-
life compounds in urine and
plasma overlap for single and
multiple doses
• No overlap for long half-life
compounds in cells or hair
Concerns: White Coat Adherence
Day after initiating daily dosing
2 4 6 8 10 12 14 16 18 20
Concentration
1
10
100
Below assay limits of quantification
17 hour half-life
120 hour half-life
No overlap between Dose 2 and 20 concentrations
Overlap between Dose 2 and 20 concentrations
31. Day after initiating daily dosing
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Concentration
1
10
100
Below assay limits of quantification
17 hour half-life
120 hour half-life
Long term Adherence Measures
• Long time to steady state
increases risk of
misinterpretation following
recent changes in behavior
• Concentrations of 0 doses for
>1 week similar to those after
recently initiating daily dosing
Concerns: Misclassification Following Recent Changes
32. Long Term Adherence Measures
RBCs: DOT of 100, 67, 33% TDF doses per week (N= 48)
Anderson PL et al. AAC 2017;62(1):1710-17
Steady-state exposure by 8 week
Daily dosing misclassified up to 1
month on therapy
700 fmol/punch = 4+ doses/week
1 month after discontinuing therapy
33. Long term Adherence Measures
RBCs (DOT of 100, 67, and 33% of TAF doses/week (N=36)
Yager J. TFVdp in DBS Following Escalating TAF/FTC Dosing (Abstract 463 CROI 2019).
TAF #2
7mm
TDF #1
3mm
Week
1-12
Week
24-36
TDF=518
TDF=946
TDF=1542
Steady-state exposure by week 12?
34. Long Term Adherence Measures
Hair (HPLC-MS/MS)
Liu A et al. PLOSone 2014;9(1) Koss et al. CID 2018;66(2):213-9
2 Doses/Week
0.01 (0.008-0.02)
7 Doses/Week
0.04 (0.02-0.05)
Median (Range)
35. Summary
• PK studies and PK/PD modeling indicate PrEP pharmacology
differs between HIV transmission sites for TDF and TAF
• TFVdp and FTCtp in FGT vs GI tissues
• Based on modeling higher levels of adherence are required to achieve
PrEP target exposure in female genital tract
• Gender Affirming FHT may Systemic and Rectal PrEP exposure
by enhancing phosphatase activity
• Pharmacologic measures of PrEP (i.e. DBS and hair) correlate with
PrEP effectiveness and may more accurately indicate adherence
than subjective measures