new AHA News: New Report Details What to Know About Cardiovascular Disease Symptoms By www.medicinenet.com Published On :: Fri, 19 Aug 2022 00:00:00 PDT Title: AHA News: New Report Details What to Know About Cardiovascular Disease SymptomsCategory: Health NewsCreated: 8/18/2022 12:00:00 AMLast Editorial Review: 8/19/2022 12:00:00 AM Full Article
new AHA News: Newborn Was 'Very Sick Little Boy' Despite Several Normal Prenatal Ultrasounds By www.medicinenet.com Published On :: Thu, 25 Aug 2022 00:00:00 PDT Title: AHA News: Newborn Was 'Very Sick Little Boy' Despite Several Normal Prenatal UltrasoundsCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
new AHA News: People With Dementia May Be Less Likely to Receive an Advanced Treatment For Stroke By www.medicinenet.com Published On :: Wed, 24 Aug 2022 00:00:00 PDT Title: AHA News: People With Dementia May Be Less Likely to Receive an Advanced Treatment For StrokeCategory: Health NewsCreated: 8/24/2022 12:00:00 AMLast Editorial Review: 8/24/2022 12:00:00 AM Full Article
new 'News Addiction' Is Common and Can Harm Your Mental Health By www.medicinenet.com Published On :: Thu, 25 Aug 2022 00:00:00 PDT Title: 'News Addiction' Is Common and Can Harm Your Mental HealthCategory: Health NewsCreated: 8/24/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
new Poliovirus Discovered in New York Wastewater By www.medicinenet.com Published On :: Mon, 15 Aug 2022 00:00:00 PDT Title: Poliovirus Discovered in New York WastewaterCategory: Health NewsCreated: 8/12/2022 12:00:00 AMLast Editorial Review: 8/15/2022 12:00:00 AM Full Article
new New Reports on Polio: How Worried Should We Be? By www.medicinenet.com Published On :: Tue, 16 Aug 2022 00:00:00 PDT Title: New Reports on Polio: How Worried Should We Be?Category: Health NewsCreated: 8/15/2022 12:00:00 AMLast Editorial Review: 8/16/2022 12:00:00 AM Full Article
new Here's How New Federal Legislation Might Cut Your Drug Costs By www.medicinenet.com Published On :: Mon, 15 Aug 2022 00:00:00 PDT Title: Here's How New Federal Legislation Might Cut Your Drug CostsCategory: Health NewsCreated: 8/12/2022 12:00:00 AMLast Editorial Review: 8/15/2022 12:00:00 AM Full Article
new New Approach Cuts Odds for Anal Cancer in People With HIV By www.medicinenet.com Published On :: Thu, 16 Jun 2022 00:00:00 PDT Title: New Approach Cuts Odds for Anal Cancer in People With HIVCategory: Health NewsCreated: 6/16/2022 12:00:00 AMLast Editorial Review: 6/16/2022 12:00:00 AM Full Article
new There's More MS in Northern Countries. Now, Researchers Find New Reason Why By www.medicinenet.com Published On :: Thu, 25 Aug 2022 00:00:00 PDT Title: There's More MS in Northern Countries. Now, Researchers Find New Reason WhyCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/25/2022 12:00:00 AM Full Article
new New Multiple Sclerosis Treatment Shows Promise in Trial By www.medicinenet.com Published On :: Fri, 26 Aug 2022 00:00:00 PDT Title: New Multiple Sclerosis Treatment Shows Promise in TrialCategory: Health NewsCreated: 8/25/2022 12:00:00 AMLast Editorial Review: 8/26/2022 12:00:00 AM Full Article
new AHA News: How You Feel About Aging Could Affect Health. Here's How to Keep the Right Attitude. By www.medicinenet.com Published On :: Fri, 19 Aug 2022 00:00:00 PDT Title: AHA News: How You Feel About Aging Could Affect Health. Here's How to Keep the Right Attitude.Category: Health NewsCreated: 8/19/2022 12:00:00 AMLast Editorial Review: 8/19/2022 12:00:00 AM Full Article
new You Could Live 9 Years Longer in Hawaii Than in Mississippi, New Data Shows By www.medicinenet.com Published On :: Tue, 23 Aug 2022 00:00:00 PDT Title: You Could Live 9 Years Longer in Hawaii Than in Mississippi, New Data ShowsCategory: Health NewsCreated: 8/23/2022 12:00:00 AMLast Editorial Review: 8/23/2022 12:00:00 AM Full Article
new Organ From Live Donor Best When Child Needs New Kidney By www.medicinenet.com Published On :: Thu, 18 Aug 2022 00:00:00 PDT Title: Organ From Live Donor Best When Child Needs New KidneyCategory: Health NewsCreated: 8/17/2022 12:00:00 AMLast Editorial Review: 8/18/2022 12:00:00 AM Full Article
new CDC Panel Urges Seniors to Get New, More Potent Flu Shot This Fall By www.medicinenet.com Published On :: Thu, 23 Jun 2022 00:00:00 PDT Title: CDC Panel Urges Seniors to Get New, More Potent Flu Shot This FallCategory: Health NewsCreated: 6/23/2022 12:00:00 AMLast Editorial Review: 6/23/2022 12:00:00 AM Full Article
new Wonca Europe 2023 Definition of General Practice/Family Medicine: New Needs New Content By www.jabfm.org Published On :: 2024-10-25T09:26:14-07:00 Full Article
new Roles of the ABCG2 Transporter in Protoporphyrin IX Distribution and Toxicity [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II-Minireview] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy. SIGNIFICANCE STATEMENT This review summarized the roles of ABCG2 in modulating PPIX distribution and highlighted the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated toxicity. Full Article
new Assessing Trends in Cytokine-CYP Drug Interactions and Relevance to Drug Dosing [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II-Minireview] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ –58% to ~35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ~six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine–CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine–CYP drug interactions in drug discovery and development. SIGNIFICANCE STATEMENT There has been significant progress in understanding cytokine-mediated drug interactions for CYP-sensitive substrates. This article provides an overview of the progress in this field, including a trend analysis of systemic exposures of CYP-sensitive substrates coadministered with anti-interleukin therapeutics. In addition, the review also provides a perspective of current methods used to assess these drug interactions during drug development and a focus on individualized medicine, particularly in acute care settings. Full Article
new Pharmacometabolomics in Drug Disposition, Toxicity, and Precision Medicine [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II-Minireview] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy. SIGNIFICANCE STATEMENT Pharmacometabolomics has emerged as an approach to identify metabolites that allow for implementation of precision medicine approaches to pharmacotherapy. This review article provides an overview of pharmacometabolomics including highlights of important examples. Full Article
new Characterizing the Distribution of a Stimulator of Interferon Genes Agonist and Its Metabolites in Mouse Liver by Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry [Special Section on New and Emerging Areas and Technologies in Drug Met By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments. SIGNIFICANCE STATEMENT An integrated imaging approach utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) complemented with immunohistochemistry (IHC) and histology was used to address the question of target exposure at the cellular level. Localized quantification of the parent drug in the target organ and identification of potential metabolites in the context of tissue histology were also achieved in one experimental suite to support characterization of pharmacokinetic properties of the drug in the early discovery stage.: Full Article
new Evaluating Drug-Drug Interaction Risk Associated with Peptide Analogs Using advanced In Vitro Systems [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Drug–drug interaction (DDI) assessment of therapeutic peptides is an evolving area. The industry generally follows DDI guidelines for small molecules, but the translation of data generated with commonly used in vitro systems to in vivo is sparse. In the current study, we investigated the ability of advanced human hepatocyte in vitro systems, namely HepatoPac, spheroids, and Liver-on-a-chip, to assess potential changes in regulation of CYP1A2, CYP2B6, CYP3A4, SLCO1B1, and ABCC2 in the presence of selected therapeutic peptides, proteins, and small molecules. The peptide NN1177, a glucagon and GLP-1 receptor co-agonist, did not suppress mRNA expression or activity of CYP1A2, CYP2B6, and CYP3A4 in HepatoPac, spheroids, or Liver-on-a-chip; these findings were in contrast to the data obtained in sandwich cultured hepatocytes. No effect of NN1177 on SLCO1B1 and ABCC2 mRNA was observed in any of the complex systems. The induction magnitude differed across the systems (e.g., rifampicin induction of CYP3A4 mRNA ranged from 2.8-fold in spheroids to 81.2-fold in Liver-on-a-chip). Small molecules, obeticholic acid and abemaciclib, showed varying responses in HepatoPac, spheroids, and Liver-on-a-chip, indicating a need for EC50 determinations to fully assess translatability data. HepatoPac, the most extensively investigated in this study (3 donors), showed high potential to investigate DDIs associated with CYP regulation by therapeutic peptides. Spheroids and Liver-on-a-chip were only assessed in one hepatocyte donor and further evaluations are required to confirm their potential. This study establishes an excellent foundation toward the establishment of more clinically-relevant in vitro tools for evaluation of potential DDIs with therapeutic peptides. SIGNIFICANT STATEMENT At present, there are no guidelines for drug–drug interaction (DDI) assessment of therapeutic peptides. Existing in vitro methods recommended for assessing small molecule DDIs do not appear to translate well for peptide drugs, complicating drug development for these moieties. Here, we establish evidence that complex cellular systems have potential to be used as more clinically-relevant tools for the in vitro DDI evaluation of therapeutic peptides. Full Article
new Exogenous Pregnane X Receptor Does Not Undergo Liquid-Liquid Phase Separation in Nucleus under Cell-Based In Vitro Conditions [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiologic and pathologic conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biologic functions. Until now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithm tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation. Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, cytochrome P450 3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells. SIGNIFICANCE STATEMENT PXR plays a critical role in hepatic physiological and pathological processes. The present study clearly demonstrated that exogenous PXR does not undergo phase separation after activation by agonist or under hyperosmotic stress in nucleus. These findings may help understand PXR biology. Full Article
new Differential Tissue Abundance of Membrane-Bound Drug Metabolizing Enzymes and Transporter Proteins by Global Proteomics [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs. SIGNIFICANCE STATEMENT This study quantified the abundance and compositions of drug-metabolizing enzymes and transporters in pooled human liver, intestine, and kidney microsomes as well as individual intestinal microsomes using an optimized global proteomics approach. The data revealed large intertissue differences in the abundance of these proteins and high intestinal interindividual variability in the levels of cytochrome P450s (e.g., CYP3A4 and CYP3A5), uridine diphosphate-glucuronosyltransferase 2B17, carboxylesterase 2, and microsomal glutathione S-transferase 2. These data are applicable for the prediction of first-pass metabolism and tissue-specific drug clearance. Full Article
new Regulation of Human Hydrolases and Its Implications in Pharmacokinetics and Pharmacodynamics [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including carboxylesterase (CES)-1 CES2, arylacetamide deacetylase (AADAC), paraoxonase (PON)-1 PON3, and cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared with other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases. SIGNIFICANCE STATEMENT Hydrolases play a crucial role in the metabolism of numerous clinically important medications. Genetic polymorphisms and nongenetic regulators can affect hydrolases’ expression and activity, consequently influencing the exposure and clinical outcomes of hydrolase substrate drugs. A comprehensive understanding of hydrolase regulation can refine therapeutic regimens, ultimately enhancing the efficacy and safety of drugs metabolized by the enzymes. Full Article
new 50th Anniversary Celebration Collection Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II--Editorial [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Full Article
new Learnings From an Innovative Model to Expand Access to a New and Underutilized Nonhormonal Contraceptive Diaphragm By ghspjournal.org Published On :: 2024-10-29T12:28:39-07:00 ABSTRACTWe document the effort over the last 30 years to respond to the call by women advocates at the International Conference on Population and Development for more woman-initiated single or dual-purpose contraceptive methods by developing the Caya contoured diaphragm, an innovative diaphragm designed to meet the needs of women and their partners and expand options for nonhormonal barrier contraception. We describe the complex and interrelated set of activities undertaken to develop the product using a human-centered design process and how we are working to create a corollary sustainable market. This review includes the evidence generated around improved acceptability among couples in low- and middle-income countries and depicts challenges and practical actions on how to dispel misconceptions about diaphragm use. Importantly, we share programmatic lessons learned on increasing universal access to this new sexual and reproductive health technology. Following our new model for increasing access to new and underutilized methods, Caya is now registered and being marketed in nearly 40 countries worldwide. Full Article
new National Politics’ Role in Developing Primary Health Care Policy for Maternal Health in Papua New Guinea: A Qualitative Document Analysis By ghspjournal.org Published On :: 2024-10-29T12:28:39-07:00 ABSTRACTPolitics is one of the critical factors that influence health policy agendas. However, scholarly efforts, especially in low- and middle-income countries, rarely focus on how politics influence health policy agenda-setting. We conducted a qualitative document review to examine the factors that led to developing the free primary health care policy for maternal health in Papua New Guinea. We also discuss mechanisms through which national politics, as an overriding factor, influenced the development of the policy. The review draws on Kingdon’s multiple-stream model for agenda-setting and incorporates theoretical insights from Fox and Reich’s framework for analyzing the politics of health reform for universal health coverage in low- and middle-income countries. Full Article
new The Dawning of a New Age of Preclinical Analgesic Drug Screening [Viewpoint] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 Full Article
new Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities [75th Anniversary Celebration Collection Special Section] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. Significance Statement Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurologic and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. This review endeavors to describe these processes in detail.: Full Article
new New Tools Take Whole-Person Approach to Obesity Care [Family Medicine Updates] By www.annfammed.org Published On :: 2024-09-23T14:00:14-07:00 Full Article
new Deep End Kawasaki/Yokohama: A New Challenge for GPs in Deprived Areas in Japan [Innovations in Primary Care] By www.annfammed.org Published On :: 2024-09-23T14:00:14-07:00 Full Article
new [PERSPECTIVES] New Paradigms in the Clinical Management of Li-Fraumeni Syndrome By perspectivesinmedicine.cshlp.org Published On :: 2024-11-01T07:17:20-07:00 Approximately 8.5%–16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant—a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li–Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning–based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention. Full Article
new The History Behind Andor Season 2’s New TIE Fighter By gizmodo.com Published On :: Tue, 12 Nov 2024 21:40:23 +0000 Cassian's on a new mission to steal a familiar ship in the next season of his self-titled Star Wars show. Full Article Television Andor Explainer LUCASFILM Star Wars
new News Wrap: Dozens missing after deadly Mogadishu truck bombing By www.pbs.org Published On :: Mon, 16 Oct 2017 22:45:17 +0000 Watch Video | Listen to the AudioJUDY WOODRUFF: And in the day’s other news: More than 300 people are now confirmed dead after Saturday’s massive truck bombing in Somalia, one of the world’s worst attacks in years. Nearly 400 more were wounded. The government blamed the al-Qaida-linked Al-Shabaab group. Rescue crews today searched for survivors at the scene of the bombing, a crowded street in the capital, Mogadishu. With dozens still missing, officials say they expect the death toll to rise. OSMAN LIBAH IBRAHIM, Deputy Minister for Natural Resources, Somalia (through interpreter): More bodies are gradually being found and removed from the rubble. There are other people who are under the rubble. We have heard them as they scream for help. My biggest worry is that even the wounded are succumbing to their injuries. JUDY WOODRUFF: The attack happened two days after Somalia’s defense minister and army chief resigned for undisclosed reasons. There’s been yet another shift to the right in European politics; 31-year-old conservative Sebastian Kurz, Austria’s foreign minister, is set to become that country’s next leader. But he’s short of a majority in Parliament and will likely form a coalition with the far-right Freedom Party. It was founded by ex-Nazis in the 1950s. Kurz has called for the European Union to focus more on internal trade and securing borders. He celebrated in Vienna. SEBASTIAN KURZ, Austrian People’s Party (through interpreter): I have a big request for you. Use today to celebrate. You all have earned it through hard work and dedication. At the same time, I need to tell you that tomorrow the work starts. We didn’t just run to win the elections. We did so to bring Austria back to the top. We ran in this election to achieve real change. JUDY WOODRUFF: A final result in the election is likely to be decided on Thursday. Wildfires that broke out over the weekend in Portugal have killed at least 35 people, including a one-month-old infant. Today, more than 5,300 firefighters with some 1,600 vehicles were battling the fires, some of which officials say were started by arsonists. Wildfires have also left at least four people dead in neighboring Spain. Army Sergeant Bowe Bergdahl pleaded guilty today to desertion and misbehavior before the enemy. He was captured by the Taliban in 2009, after leaving his post in Afghanistan. It prompted an intense search and a prisoner swap. Bergdahl appeared before a military judge in Fort Bragg, North Carolina, today. The 31-year-old could be sentenced to life in prison. He said his actions were very inexcusable, adding he didn’t — quote — “think there’d be any reason to pull off a crucial mission to look for one guy.” The truck driver in deadly immigrant smuggling run has pleaded guilty in court. San Antonio police found at least 39 immigrants, 10 of whom died, packed into a sweltering semi-trailer last year and died. The driver, James Matthew Bradley Jr., pleaded to conspiracy and transporting immigrants, resulting in death. He faces now up to life in prison. A New Jersey man has been convicted of planting two pressure-cooker bombs on New York City streets last year. Ahmed Khan Rahimi faces a maximum sentence of life in prison for charges including using a weapon of mass destruction. One of the bombs exploded in Manhattan’s Chelsea neighborhood, wounding 30. The second didn’t detonate. Officials said Rahimi was inspired by ISIS and al-Qaida. JOHN MILLER, Deputy Commissioner, NYPD Intelligence & Counterterrorism: Ahmed Khan Rahimi learned a lesson which we keep reminding people of. This is the wrong place to try and carry out an act of terrorism. Witnesses will come forward, evidence will be developed, arrests will be made, prosecutions will be brought forth, and they will be successful. JUDY WOODRUFF: Prosecutors said Rahimi also planted a pipe bomb in Seaside Heights, New Jersey, but no one was injured. Colin Kaepernick has filed a grievance against the national football league. The former San Francisco 49ers quarterback says that he remains unsigned due to collusion by team owners over his national anthem protests. Kaepernick sparked a debate when he kneeled during the anthem last year, protesting police mistreatment of African-Americans. On Wall Street today, the Dow Jones industrial average gained 85 points to close at 22957. The Nasdaq rose 18. And the S&P 500 added four. It was a milestone day in the world of astronomy. For the first time, researchers say they have detected gravitational waves with a flash of light from the same cosmic event. The dual observation supports Albert Einstein’s general theory of relativity. The ripples in space and the light burst were caused by the collision of two neutron stars. They were first detected in August. The post News Wrap: Dozens missing after deadly Mogadishu truck bombing appeared first on PBS NewsHour. Full Article al-Shabab Austria Mogadishu Sebastian Kurz
new WATCH: Trump and Greek prime minister hold joint news conference By www.pbs.org Published On :: Tue, 17 Oct 2017 16:28:24 +0000 Watch President Donald Trump and the Greek prime minister’s joint news conference in the player above. WASHINGTON — President Donald Trump says the U.S. stands with Greece as they recover from their economic crisis. He is speaking with Prime Minister Alexis Tsipras at the White House in a joint news conference. The U.S. president says the two leaders have discussed defense, energy, commerce and trade. Trump is praising Greece for its defense spending under NATO and is noting a potential sale to Greece to upgrade its F-16 aircraft, which he says would be worth up to $2.4 billion and generate thousands of U.S. jobs. Tsipras says his country has made economic strides and is “leaving behind the economic model that led to the crisis.” He says Greece’s relationship with the U.S. is “more important than ever.” The post WATCH: Trump and Greek prime minister hold joint news conference appeared first on PBS NewsHour. Full Article Alexis Tsipras Donald Trump Greece
new Lealiifano has new focus By www.theaustralian.com.au Published On :: Tue, 14 Jun 2016 14:00:00 GMT Christian Lealiifano will draw inspiration from his newborn son in the second Test in Melbourne this Saturday. Full Article
new Two runners saved by the same public defibrillator back new appeal By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 06:30:00 +0000 Two runners saved by the same public defibrillator appeal for all the life-saving devices to be publicly available. Tens of thousands of defibs are unregistered so ‘invisible’ in an emergency. Full Article
new New research to better understand the biological factors of suicidal behaviour By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 06:30:00 +0000 New research to better understand the biological factors of suicidal behaviour Researchers at the University of Glasgow are embarking on two new PhD projects to better understand the impact that biological factors may have on suicidal behaviour. Full Article
new First new homes on Scottish town's high street 'in living memory' By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 04:30:00 +0000 The flats are described as the first new homes on the Scottish town's High Street 'in living memory' Full Article
new Accountancy firm opens new office in Scottish town By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 04:33:00 +0000 The accountancy firm has opened a new office in the Scottish town Full Article
new Housebuilder completes 'one of the largest' new Highland homes projects since 1970s By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 04:35:00 +0000 A rural housing project branded as ‘truly transformative’ has been completed Full Article
new New direct rail service to link Edinburgh and Wales for the first time By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 10:36:29 +0000 A rail service linking Scotland, Wales and England with one train journey is to start running for the first time. Full Article
new Fire chiefs hail £30m investment in ‘whole new level’ 999 emergency system By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 11:48:39 +0000 The technology will deliver enhanced day-to-day and major incident response capability Full Article
new Scottish family-owned distillery launches new ‘dining destination’ By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 13:02:10 +0000 A Scottish distillery has hailed the opening of a new 'dining destination' amid an expansion push. Full Article
new Famous Doddie Weir trousers worn to promote charity's new Balmoral partnership By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 16:33:56 +0000 The concierge team at The Balmoral have helped raise awareness for a special event to raise money for charity in memory of Scotland legend Doddie Weir. Full Article
new RPG Cast – Episode 613: “Nancy New Year” By rpgamer.com Published On :: Sat, 08 Jan 2022 19:53:37 +0000 Chris gets caught up on Columbo while queueing for FFXIV. Eclipse steals the show from Kelley by opening the Chrome dev tools. And Josh sells all his Spoony Bard NFTs. The post RPG Cast – Episode 613: “Nancy New Year” appeared first on RPGamer. Full Article News Podcasts RPG Cast Astria Ascending Final Fantasy V Final Fantasy XIV: Shadowbringers Marvel's Guardians of the Galaxy Persona 5 Strikers Pokémon Brilliant Diamond / Shining Pearl
new RPG Cast – Episode 615: “The New Dialga Looks Like My Brother’s Broken Vacuum Cleaner” By rpgamer.com Published On :: Sat, 22 Jan 2022 20:40:16 +0000 Kelley ruins Warcraft by including Conker. Chris mortgages his Xbox. Josh's cat won't let him control his Xbox. And Microsoft has announced their new Candy Crush themed Windows 12. The post RPG Cast – Episode 615: “The New Dialga Looks Like My Brother’s Broken Vacuum Cleaner” appeared first on RPGamer. Full Article News Podcasts RPG Cast Final Fantasy Legend II Final Fantasy V Final Fantasy XIV: Shadowbringers Gyromancer Nobody Saves the World Scarlet Nexus
new RPG Cast – Episode 624: “Kirby Is the New Elden Ring” By rpgamer.com Published On :: Sat, 26 Mar 2022 20:27:45 +0000 Chris wants an OP fox with mods. Matt wears a turnip and marries a twelve year old. And Josh goes off to read the new J.R.R. Martin time loop book. The post RPG Cast – Episode 624: “Kirby Is the New Elden Ring” appeared first on RPGamer. Full Article News Podcasts RPG Cast Elden Ring Final Fantasy VI Kirby Pokémon Legends Arceus Rune Factory 5 The Legend of Heroes: Trails of Cold Steel III Triangle Strategy
new RPG Cast – Episode 639: “Can We Just Kill This Guy and Get a New Hero” By rpgamer.com Published On :: Sat, 23 Jul 2022 21:21:22 +0000 Kelley thinks like a cat. Chris experiments with broccoli. Josh sells weed with Snoop Dogg. Don't tempt the mouse. The post RPG Cast – Episode 639: “Can We Just Kill This Guy and Get a New Hero” appeared first on RPGamer. Full Article News Podcasts RPG Cast Breath of Fire Final Fantasy VI Monster Hunter Rise
new Dragon Age: The Veilguard Debuts in 2nd on the New Zealand Charts By www.vgchartz.com Published On :: Fri, 08 Nov 2024 22:45:49 GMT Call of Duty: Black Ops 6 has remained in first place on the New Zealand charts, according to IGEA for the week ending November 3, 2024. There were two new releases in the top 10 this week with Dragon Age: The Veilguard debuting in second place and Horizon Zero Dawn Remastered in fourth place. Hogwarts Legacy is down one spot to third place, Grand Theft Auto V is up three spots to fifth place, and NBA 2K25 climbed from ninth to sixth place. Red Dead Redemption is in seventh place, Borderlands 3 is in eight place, Battlefield 2042 is in ninth place, and EA Sports FC 25 rounds out the top 10. Here are the top 10 best-selling titles in New Zealand for the week: Call of Duty: Black Ops 6 Dragon Age: The Veilguard - NEW Hogwarts Legacy Horizon Zero Dawn Remastered - NEW Grand Theft Auto V NBA 2K25 Red Dead Redemption Borderlands 3 Battlefield 2042 EA Sports FC 25 A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.Full Article - https://www.vgchartz.com/article/463029/dragon-age-the-veilguard-debuts-in-2nd-on-the-new-zealand-charts/ Full Article Analysis Charts Industry
new Hideaki Itsuno to Lead New AAA Developer LightSpeed Japan Studio By www.vgchartz.com Published On :: Tue, 12 Nov 2024 03:37:22 GMT Tencent Games subsidiary LightSpeed Studios has announced Hideaki Itsuno, who recently left Capcom after 30 years working for the company, will be leading a new video game studio called LightSpeed Japan Studio. LightSpeed Japan Studio will have two locations in Tokyo and Osaka and is focused on developing original AAA games. "Joining LightSpeed Studios is an exciting new chapter for me," said Hideaki Itsuno. "With LightSpeed’s strong development capability and global network, I look forward to creating original AAA action game titles together with the amazing team and building aesthetic and innovative experiences for the global player community. We welcome all talented and passionate game creators from the world over to join our vision." LightSpeed Studios president Jerry Chen added, "It is our great honor to have Hideaki Itsuno join LightSpeed Studios. The establishment of LightSpeed Japan Studio is a significant step in LightSpeed Studios’ expansion and demonstrates our commitment to bringing the best possible games to our players." Itsuno directed entries in the Rival Schools, Power Stone, Capcom VS. SNK, Devil May Cry, and Dragon’s Dogma franchises. A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.Full Article - https://www.vgchartz.com/article/463041/hideaki-itsuno-to-lead-new-aaa-developer-lightspeed-japan-studio/ Full Article Analysis Charts Industry