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The transcription factor STAT3 drives the expression of genes promoting cellular proliferation, survival, and pluripotency. The description of STAT3 mutations and their clinical correlates in myeloid neoplasms, such as acute myeloid leukemia and myelodysplastic syndromes, raises new insights into both the pathogenesis and the targeted therapy of these diseases.
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AIM: Illicitly manufactured fentanyl and its analogs are the primary drivers of opioid overdose deaths in the United States (U.S.). People who use drugs may be exposed to fentanyl or its analogs intentionally or unintentionally. This study sought to identify strategies used by rural people who use drugs to reduce harms associated with unintentional fentanyl exposure. METHODS: This analysis focused on 349 semi-structured qualitative interviews across 10 states and 58 rural counties in the U.S conducted between 2018 and 2020. Interview guides were collaboratively standardized across sites and included questions about drug use history (including drugs currently used, frequency of use, mode of administration) and questions specific to fentanyl. Deductive coding was used to code all data, then inductive coding of overdose and fentanyl codes was conducted by an interdisciplinary writing team. RESULTS: Participants described being concerned that fentanyl had saturated the drug market, in both stimulant and opioid supplies. Participants utilized strategies including: (1) avoiding drugs that were perceived to contain fentanyl, (2) buying drugs from trusted sources, (3) using fentanyl test strips, 4) using small doses and non-injection routes, (5) using with other people, (6) tasting, smelling, and looking at drugs before use, and (7) carrying and using naloxone. Most people who used drugs used a combination of these strategies as there was an overwhelming fear of fatal overdose. CONCLUSION: People who use drugs living in rural areas of the U.S. are aware that fentanyl is in their drug supply and use several strategies to prevent associated harms, including fatal overdose. Increasing access to harm reduction tools (e.g., fentanyl test strips, naloxone) and services (e.g., community drug checking, syringe services programs, overdose prevention centers) should be prioritized to address the polysubstance-involved overdose crisis. These efforts should target persons who use opioids and other drugs that may contain fentanyl.
Subject(s)
Analgesics, Opioid , Fentanyl , Harm Reduction , Rural Population , Humans , Fentanyl/poisoning , Female , United States/epidemiology , Adult , Male , Analgesics, Opioid/poisoning , Analgesics, Opioid/adverse effects , Middle Aged , Opioid-Related Disorders/prevention & control , Drug Overdose/prevention & control , Drug Overdose/epidemiology , Opiate Overdose/prevention & control , Opiate Overdose/epidemiology , Young Adult , Qualitative Research , Naloxone/therapeutic useABSTRACT
T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.
Subject(s)
Chromatin , Genomics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Single-Cell Analysis , Humans , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Child , Chromatin/genetics , Chromatin/metabolism , Enhancer Elements, Genetic/genetics , Genome, Human/genetics , Male , Transcriptome/genetics , Female , Epigenomics , Gene Expression Regulation, LeukemicABSTRACT
BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder associated with cardiovascular risks. This study aimed to assess the prevalence of probable OSA and its relationship with cardiovascular risks and diseases focusing on age-stratified young adults (20-40 years) and older (>40 years). METHODS AND RESULTS: The study used a cross-sectional design, analyzing data from the National Health and Nutrition Examination Survey conducted between 2013 and 2018, comprising 9887 community-dwelling adults aged ≥20 years. Probable OSA was determined on the basis of self-report of OSA-related symptoms (eg, snoring, gasping/breath cessation while sleeping). Cardiovascular risk factors, including hypertension, diabetes, hyperlipidemia, and metabolic syndrome, were evaluated according to established guidelines. Cardiovascular diseases (CVDs) included self-reported heart conditions, including congestive heart failure, coronary heart disease, angina, heart attacks, and strokes. Individuals with probable OSA showed a significantly higher prevalence of health conditions, including hypertension (adjusted prevalence ratio [aPR], 1.19; P<0.001), diabetes (aPR, 1.17; P: 0.01), metabolic syndrome (aPR, 1.14; P<0.001), heart attack (aPR, 1.63; P<0.01), stroke (aPR, 1.41; P: 0.03), and any CVD event (aPR, 1.36; P: 0.01) after adjusting for relevant factors. Young adults with probable OSA showed higher prevalence rates of any CVD events (aPR, 3.44; P<0.001), hypertension (aPR, 1.45; P<0.001), metabolic syndrome (aPR, 1.25; P<0.001), and angina (aPR, 10.39; P<0.001). CONCLUSIONS: The study suggests early identification and management of OSA in individuals at risk for CVD. While cross-sectional, it emphasizes that health care providers should recognize OSA as significantly associated with CVDs and its precursor risks in young adults, stressing proactive care and screening to reduce CVD risk in this population.
Subject(s)
Cardiovascular Diseases , Nutrition Surveys , Sleep Apnea, Obstructive , Humans , Male , Adult , Female , Sleep Apnea, Obstructive/epidemiology , Sleep Apnea, Obstructive/diagnosis , Cross-Sectional Studies , United States/epidemiology , Prevalence , Young Adult , Middle Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/diagnosis , Age Factors , Aged , Risk Factors , Risk Assessment , Heart Disease Risk FactorsABSTRACT
BACKGROUND: Left ventricular diastolic dysfunction indicated by elevated pulmonary capillary wedge pressure (ePCWP) may worsen cardiorespiratory status in bronchopulmonary dysplasia (BPD), but the scope of ePCWP by cardiac catheterization is not well described. METHODS: This single-center retrospective cohort study included infants with BPD without congenital heart disease, significant intracardiac shunts, or pulmonary vein stenosis who underwent cardiac catheterization from 2010 to 2021. ePCWP was defined as >10 mmHg. Quantitative measures of ventricular systolic and diastolic function were performed on existing echocardiograms. Patients with and without ePCWP were compared using the Chi-squared or Wilcoxon rank-sum tests. Associations between catheterization hemodynamics and echocardiographic parameters were assessed by simple linear regression. RESULTS: Seventy-one infants (93% Grade 2 or 3 BPD) met inclusion criteria, and 30 (42%) had ePCWP. Patients with ePCWP were older at catheterization (6.7 vs. 4.5 months, p < 0.001), more commonly underwent tracheostomy (66.7% vs. 29.3%, p = 0.003), and had higher mean systemic blood pressure [64.5 (56.0, 75.0) vs. 47.0 (43.0, 55.0) mm Hg, p < 0.001], higher systemic vascular resistance [11.9 (10.4, 15.6) vs. 8.7 (6.7, 11.2) WU*m2, p < 0.001), and lower cardiac index [3.9 (3.8, 4.9) vs. 4.7 (4.0, 6.3) L/min/m2, p = 0.03] at catheterization. Mean pulmonary artery pressure, pulmonary vascular resistance, and mortality were similar between the groups. Echocardiographic indices of left ventricular diastolic dysfunction did not correlate with PCWP. CONCLUSIONS: ePCWP was common in infants with severe BPD who underwent cardiac catheterization in this cohort. The association between ePCWP and higher systemic blood pressure supports further study of afterload reduction in this population.
Subject(s)
Bronchopulmonary Dysplasia , Cardiac Catheterization , Pulmonary Wedge Pressure , Humans , Retrospective Studies , Male , Female , Bronchopulmonary Dysplasia/physiopathology , Bronchopulmonary Dysplasia/diagnosis , Pulmonary Wedge Pressure/physiology , Infant , Blood Pressure/physiology , Cohort Studies , Infant, Newborn , Echocardiography/methodsABSTRACT
PURPOSE: This study explores the relationship between depression and cardiovascular disease (CVD) in the US adult population, focusing on sex differences. DESIGN: Cross-sectional study. SETTING: National Health and Nutrition Examination Survey data (2013-2018). PARTICIPANTS: A total of 14 699 community-dwelling adults (≥20 years). MEASURE: The Patient Health Questionnaire (PHQ-9) depression screening tool assessed depressive symptoms. CVD events included heart failure, coronary heart disease, angina, heart attack, or stroke. ANALYSIS: Adjusted prevalence ratios were estimated using a Poisson regression model. RESULTS: The study finds a positive association between CVD incidents and both mild to moderate depressive symptoms (aPR:1.42, P = .002) and moderately severe to severe depression (aPR:1.72, P = .024). Overall, females exhibit a 47% lower likelihood of CVD incidents compared to males. However, in a subgroup analysis, increased depressive symptoms correlate with higher CVD incidents in females (aPRs range: 2.09 to 3.43, P < .001) compared to males (aPRs range: 1.45 to 1.77, P < .001). CONCLUSION: Depression is associated with increased cardiovascular disease (CVD) risk. Females generally have a lower CVD risk than males, but more severe depressive symptoms elevate CVD risk in females. These findings emphasize the significance of considering sex differences. Further research is needed to understand the underlying mechanisms.
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Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.
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Alveologenesis, the final stage in lung development, substantially remodels the distal lung, expanding the alveolar surface area for efficient gas exchange. Secondary crest myofibroblasts (SCMF) exist transiently in the neonatal distal lung and are crucial for alveologenesis. However, the pathways that regulate SCMF function, proliferation and temporal identity remain poorly understood. To address this, we purified SCMFs from reporter mice, performed bulk RNA-seq and found dynamic changes in Hippo-signaling components during alveologenesis. We deleted the Hippo effectors Yap/Taz from Acta2-expressing cells at the onset of alveologenesis, causing a significant arrest in alveolar development. Using single cell RNA-seq, we identified a distinct cluster of cells in mutant lungs with altered expression of marker genes associated with proximal mesenchymal cell types, airway smooth muscle and alveolar duct myofibroblasts. In vitro studies confirmed that Yap/Taz regulates myofibroblast-associated gene signature and contractility. Together, our findings show that Yap/Taz is essential for maintaining functional myofibroblast identity during postnatal alveologenesis.
Subject(s)
Cell Differentiation , Hippo Signaling Pathway , Morphogenesis , Myofibroblasts , Protein Serine-Threonine Kinases , Pulmonary Alveoli , Signal Transduction , YAP-Signaling Proteins , Animals , Mice , Myofibroblasts/metabolism , Myofibroblasts/cytology , YAP-Signaling Proteins/metabolism , YAP-Signaling Proteins/genetics , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/cytology , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Morphogenesis/genetics , Mesoderm/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Lung/metabolism , Organogenesis/genetics , Gene Expression Regulation, DevelopmentalABSTRACT
Individuals with a body mass index (BMI)≥25 kg/m2 are less likely to initiate and continue breastfeeding than are those with BMIs<25. Given the intergenerational health benefits of breastfeeding, it is important to understand breastfeeding behaviors and their correlates among individuals with BMIs≥25. Thus, in an observational cohort with BMI≥25 (N = 237), we aimed to characterize longitudinal relationships among breastfeeding planning, initiation, and duration and their sociodemographic/clinical correlates and determine if pre-pregnancy BMI predicts breastfeeding planning, initiation, and duration. Breastfeeding behaviors, weight/BMI, and sociodemographic/clinical characteristics were assessed in early, mid, and late pregnancy, and at six-months postpartum. Most participants planned to (84%) and initiated (81%) breastfeeding, of which 37% breastfed for ≥6 months. Participants who were married, first-time parents, higher in education/income, and had never smoked tobacco were more likely to plan, initiate, and achieve ≥6 months of breastfeeding. Higher pre-pregnancy BMI was not associated with breastfeeding planning or initiation but was associated with lower adjusted odds of breastfeeding for ≥6 months relative to <6 months. Findings suggest that support aimed at extending breastfeeding among those with elevated pre-pregnancy BMI may be warranted. Future interventions should also address sociodemographic and clinical inequities in breastfeeding.
Subject(s)
Breast Feeding , Overweight , Female , Humans , Pregnancy , Body Mass Index , Mothers , Obesity/complications , Overweight/epidemiology , Overweight/complications , Postpartum PeriodABSTRACT
Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage tracing and modeling studies demonstrated that HPS AT2 cells were primed to persist in a Krt8+ reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are novel mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.
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BACKGROUND: Pharmacies are critical healthcare partners in community efforts to eliminate bloodborne illnesses. Pharmacy sale of sterile syringes is central to this effort. METHODS: A mixed methods "secret shopper" syringe purchase study was conducted in the fall of 2022 with 38 community pharmacies in Maricopa and Pima Counties, Arizona. Pharmacies were geomapped to within 2 miles of areas identified as having a potentially high volume of illicit drug commerce. Daytime venue sampling was used whereby separate investigators with lived/living drug use experience attempted to purchase syringes without a prescription. Investigator response when prompted for purchase rationale was "to protect myself from HIV and hepatitis C." A 24-item instrument measured sales outcome, pharmacy staff interaction (hostile/neutral/friendly), and the buyer's subjective experience. RESULTS: Only 24.6% (n = 28) of 114 purchase attempts across the 38 pharmacies resulted in syringe sale. Less than one quarter (21.1%) of pharmacies always sold, while 44.7% never sold. Independent and food store pharmacies tended not to sell syringes. There emerged distinct pharmacy staff interactions characterized by body language, customer query, normalization or othering response, response to purchase request and closure. Pharmacy discretion and pharmacy policy not to sell syringes without a prescription limited sterile syringe access. Investigators reported frequent and adverse emotional impact due to pharmacy staff negative and stigmatizing interactions. CONCLUSIONS: Pharmacies miss opportunities to advance efforts to eliminate bloodborne infections by stringent no-sale policy and discretion about syringe sale. State regulatory policy facilitating pharmacy syringe sales, limiting pharmacist discretion for syringe sales, and targeting pharmacy-staff level education may help advance the achievement of public health goals to eliminate bloodborne infections in Arizona.
Subject(s)
HIV Infections , Pharmacies , Pharmacy , Substance Abuse, Intravenous , Humans , HIV Infections/prevention & control , Syringes , ArizonaABSTRACT
BACKGROUND: Paediatric obesity disproportionately impacts individuals from minoritized racial and ethnic backgrounds. Recent guidelines support use of anti-obesity pharmacotherapy for adolescents with obesity, but the potential impact on disparities in obesity prevalence has not been evaluated. OBJECTIVES: To model changes in obesity prevalence with increasing utilization of anti-obesity pharmacotherapy among adolescents. METHODS: Data representative of American adolescents ages 12-17 years were obtained from the National Health and Nutrition Examination Survey, cycles 2011 through pre-pandemic 2020. A body mass index (BMI) reduction of 16.7% was applied to each participant based on clinical trial results of weekly subcutaneous semaglutide 2.4 mg among adolescents. Utilization disparities were based on utilization of the same medication class among adults. Obesity prevalence was calculated assuming utilization of 10%-100%, stratified by race and ethnicity. RESULTS: Among 4442 adolescents representing 26 247 384 American adolescents, projected overall obesity prevalence decreased from 22.2% to 8.4% with 100% utilization. However, disparities increased relative to Non-Hispanic White youth, with prevalence among Non-Hispanic Black and Mexican American youth ranging from 40%-60% higher to 90%-120% higher, respectively. CONCLUSIONS: Increasing utilization of anti-obesity pharmacotherapy may widen relative disparities in obesity, particularly if utilization is unequal. Advocacy for equitable access is needed to minimize worsening of obesity-related disparities.
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Ethnicity , Health Status Disparities , Pediatric Obesity , Adolescent , Child , Humans , Body Mass Index , Nutrition Surveys , Pediatric Obesity/drug therapy , Pediatric Obesity/ethnology , United States/epidemiology , Weight Loss , Clinical Trials as TopicABSTRACT
Pharmacological inhibition of dihydrofolate reductase (DHFR) is an established approach for treating a variety of human diseases, including foreign infections and cancer. However, treatment with classic DHFR inhibitors, such as methotrexate (MTX), are associated with negative side-effects and resistance mechanisms that have prompted the search for alternatives. The DHFR inhibitor pyrimethamine (Pyr) has compelling anti-cancer activity in in vivo models, but lacks potency compared to MTX, thereby requiring higher concentrations to induce therapeutic responses. The purpose of this work was to investigate structural analogues of Pyr to improve its in vitro and cellular activity. A series of 36 Pyr analogues were synthesized and tested in a sequence of in vitro and cell-based assays to monitor their DHFR inhibitory activity, cellular target engagement, and impact on breast cancer cell viability. Ten top compounds were identified, two of which stood out as potential lead candidates, 32 and 34. These functionalized Pyr analogues potently engaged DHFR in cells, at concentrations as low as 1 nM and represent promising DHFR inhibitors that could be further explored as potential anti-cancer agents.
Subject(s)
Antineoplastic Agents , Folic Acid Antagonists , Neoplasms , Humans , Pyrimethamine/pharmacology , Folic Acid Antagonists/pharmacology , Folic Acid Antagonists/chemistry , Methotrexate/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Biology , Tetrahydrofolate Dehydrogenase/chemistryABSTRACT
BACKGROUND AND PURPOSE: Radiostereometric analysis (RSA) is the gold standard for evaluation of migration of implants. CT-RSA has been shown to have precision at the level of RSA in hip, shoulder, and knee joint replacements. We aimed to assess the impact of dose reduction on precision of CT-RSA on tibial implants, comparing it with previously published data on precision of standard dose CT-RSA on tibial implants. MATERIAL AND METHODS: We performed a total knee arthroplasty on a porcine knee cadaver, and subsequent CT-RSA with low effective doses (0.02 mSv). We compared the results with previously published CT-RSA data with standard (0.08 mSv) dose. The primary outcome variable was the difference in precision of the maximum total translation (MTT). Secondary variables included ratios of variances and standard deviations, and precision of peripheral point translations, center-of-mass translations, and rotations. A difference of more than 0.1 mm in precision was defined as clinically relevant. Our hypothesis was that precisions of low and standard CT-RSA doses were equal. RESULTS: Low dose (mean 0.07, 95% confidence interval [CI] 0.06-0.08) and standard dose CT-RSA (0.08, CI 0.07-0.09) achieve similar precision, with difference in precision of MTT of 0.01, CI 0.00-0.02 mm. The F-statistic (0.99, CI 0.63-1.55) and sdtest (1.05, CI 0.43-2.58) also supported this. CONCLUSION: We conclude that the precision of low dose CT-RSA for tibial implants on a porcine cadaver is equal to standard dose CT-RSA. However, these findings should be confirmed in clinical trials.
Subject(s)
Arthroplasty, Replacement, Knee , Radiostereometric Analysis , Swine , Animals , Radiostereometric Analysis/methods , Drug Tapering , Tomography, X-Ray Computed/methods , CadaverABSTRACT
STATs are a family of transcription factors that regulate many critical cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of STATs is frequently observed in tumors and can directly drive cancer pathogenesis. STAT1 and STAT3 are generally viewed as mediating opposite roles in cancer development, with STAT1 suppressing tumorigenesis and STAT3 promoting oncogenesis. In this review, we investigate the specific roles of STAT1 and STAT3 in normal physiology and cancer biology, explore their interactions with each other, and offer insights into therapeutic strategies through modulating their transcriptional activity.
Subject(s)
Neoplasms , Signal Transduction , Humans , Signal Transduction/physiology , Neoplasms/etiology , Neoplasms/therapy , Neoplasms/pathology , Biology , STAT1 Transcription Factor/genetics , STAT3 Transcription FactorABSTRACT
Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.
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BACKGROUND: Opioid withdrawal is a regular occurrence among many people who use illicit opioids (PWUIO) that has also been shown to increase their willingness to engage in risk-involved behavior. The proliferation of fentanyl in the illicit opioid market may have amplified this relationship, potentially putting PWUIO at greater risk of negative health outcomes. Understanding the relationship between withdrawal and risk-involved behavior may also have important implications for the ways that problematic drug use is conceptualized, particularly in disease models of addiction, which position risk behavior as evidence of pathology that helps to justify ontological distinctions between addicts and non-addicts. Examining withdrawal, and its role in PWUIO's willingness to engage in risk, may aid in the development of alternative theories of risk involvement and create discursive spaces for de-medicalizing and de-othering people who use illegal drugs. METHODS: This article is based on 32 semi-structured interviews with PWUIO in the New York City area who also reported recent withdrawal experience. Interviews were conducted remotely between April and August 2022 and recorded for later transcription. Data were then coded and analyzed based on a combination of inductive and deductive coding strategies and informed by the literature. RESULTS: Participants described a strong relationship between withdrawal and their willingness to engage in risk-involved behavior that was exacerbated by the proliferation of fentanyl. Yet, their descriptions did not align with narratives of risk as a product of bad decisions made by individuals. Rather, data demonstrated the substantial role of social and structural context, particularly drug policies like prohibition and criminalization, in the kinds of risks that PWUIO faced and their ability to respond to them. CONCLUSIONS: Withdrawal should be taken more seriously both from an ethical perspective and as an important catalyst of risk behavior. However, theories that position activities taken to avoid withdrawal as irrational and as evidence of pathology are poorly aligned with the complexity of PWUIO's actual lives. We recommend the use of less deterministic and less medicalized theories of risk that better account for differences between how people view the world, and for the role of socio-structural forces in the production of risk.
Subject(s)
Drug Overdose , Substance Withdrawal Syndrome , Substance-Related Disorders , Humans , Analgesics, Opioid , Fentanyl , Risk-Taking , Drug Overdose/epidemiologyABSTRACT
Compound earthquakes involving simultaneous ruptures along multiple faults often define a region's upper threshold of maximum magnitude. Yet, the potential for linked faulting remains poorly understood given the infrequency of these events in the historic era. Geological records provide longer perspectives, although temporal uncertainties are too broad to clearly pinpoint single multifault events. Here, we use dendrochronological dating and a cosmogenic radiation pulse to constrain the death dates of earthquake-killed trees along two adjacent fault zones near Seattle, Washington to within a 6-month period between the 923 and 924 CE growing seasons. Our narrow constraints conclusively show linked rupturing that occurred either as a single composite earthquake of estimated magnitude 7.8 or as a closely spaced double earthquake sequence with estimated magnitudes of 7.5 and 7.3. These scenarios, which are not recognized in current hazard models, increase the maximum earthquake size needed for seismic preparedness and engineering design within the Puget Sound region of >4 million residents.