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ESMO Open Jun 2024Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a...
BACKGROUND
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
PATIENTS AND METHODS
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Topics: Humans; Paclitaxel; Female; Middle Aged; Aged; Neoplasms; Male; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Taxoids; Maximum Tolerated Dose; Syk Kinase
PubMed: 38914452
DOI: 10.1016/j.esmoop.2024.103486 -
Molecular Metabolism Jun 2024Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing... (Review)
Review
Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We introduce genetic risk prediction models and discuss how they can be used to address disease heterogeneity. Finally, we present areas where investment will be critical for future use of genetics to address open questions and to develop new treatment and prevention strategies for T1D.
PubMed: 38914291
DOI: 10.1016/j.molmet.2024.101973 -
The Lancet. Global Health Jun 2024Pulse oximeters are essential for assessing blood oxygen levels in emergency departments, operating theatres, and hospital wards. However, although the role of pulse... (Review)
Review
Pulse oximeters are essential for assessing blood oxygen levels in emergency departments, operating theatres, and hospital wards. However, although the role of pulse oximeters in detecting hypoxaemia and guiding oxygen therapy is widely recognised, their role in primary care settings is less clear. In this Viewpoint, we argue that pulse oximeters have a crucial role in risk-stratification in both hospital and primary care or outpatient settings. Our reanalysis of hospital and primary care data from diverse low-income and middle-income settings shows elevated risk of death for children with moderate hypoxaemia (ie, peripheral oxygen saturations [SpO] 90-93%) and severe hypoxaemia (ie, SpO <90%). We suggest that moderate hypoxaemia in the primary care setting should prompt careful clinical re-assessment, consideration of referral, and close follow-up. We provide practical guidance to better support front-line health-care workers to use pulse oximetry, including rethinking traditional binary SpO thresholds and promoting a more nuanced approach to identification and emergency treatment of the severely ill child.
PubMed: 38914087
DOI: 10.1016/S2214-109X(24)00209-2 -
Aging Jun 2024Mitophagy serves as a critical mechanism for tumor cell death, significantly impacting the progression of tumors and their treatment approaches. There are significant...
Mitophagy serves as a critical mechanism for tumor cell death, significantly impacting the progression of tumors and their treatment approaches. There are significant challenges in treating patients with head and neck squamous cell carcinoma, underscoring the importance of identifying new targets for therapy. The function of mitophagy in head and neck squamous carcinoma remains uncertain, thus investigating its impact on patient outcomes and immunotherapeutic responses is especially crucial. We initially analyzed the differential expression, prognostic value, intergene correlations, copy number variations, and mutation frequencies of mitophagy-related genes at the pan-cancer level. Through unsupervised clustering, we divided head and neck squamous carcinoma into three subtypes with distinct prognoses, identified the signaling pathway features of each subtype using ssGSEA, and characterized subtype B as having features of an immune desert using various immune infiltration calculation methods. Using multi-omics data, we identified the genomic variation characteristics, mutated gene pathway features, and drug sensitivity features of the mitophagy subtypes. Utilizing a combination of 10 machine learning algorithms, we have developed a prognostic scoring model called Mitophagy Subgroup Risk Score (MSRS), which is used to predict patient survival and the response to immune checkpoint blockade therapy. Simultaneously, we applied MSRS to single-cell analysis to explore intercellular communication. Through laboratory experiments, we validated the biological function of SLC26A9, one of the genes in the risk model. In summary, we have explored the significant role of mitophagy in head and neck tumors through multi-omics data, providing new directions for clinical treatment.
PubMed: 38913914
DOI: 10.18632/aging.205964 -
Interdisciplinary Cardiovascular and... Jun 2024Diameter-based risk stratification for elective repair of ascending aortic aneurysm fails to prevent type A dissection in many patients. Aneurysm wall stresses may...
OBJECTIVES
Diameter-based risk stratification for elective repair of ascending aortic aneurysm fails to prevent type A dissection in many patients. Aneurysm wall stresses may contribute to risk prediction; however, rates of wall stress change over time are poorly understood. Our objective was to examine aneurysm wall stress changes over three to five years and subsequent all-cause mortality.
METHODS
Male veterans with <5.5-cm ascending aortic aneurysms and computed tomography at baseline and 3 to 5-years follow-up underwent three-dimensional aneurysm model construction. Peak circumferential and longitudinal wall stresses at systole were calculated using finite element analysis. Temporal trends were assessed by mixed-effects modelling. Changes in aortic wall stresses, diameter, and length over time were evaluated as predictors of subsequent 3-year all-cause mortality by Cox proportional hazards modelling.
RESULTS
Sixty-two male veterans were included in the study. Yearly changes in geometric and biomechanical measures were 0.12 mm/yr (95% CI, 0.04-0.20) for aortic diameter, 0.41 mm/yr (0.12-0.71) for aortic length, 1.19 kPa/yr (-5.94-8.33) for peak circumferential stress, and 0.48 kPa/yr (-3.89-4.84) for peak longitudinal stress. Yearly change in peak circumferential stress was significantly associated with hazard of death-hazard ratio for peak circumferential stress growth per 10 kPa/yr, 1.27 (95% CI, 1.02-1.60; p = 0.037); hazard ratio for peak circumferential stress growth ≥ 32 kPa/yr, 8.47 (95% CI, 2.42-30; p < 0.001).
CONCLUSIONS
In this population of nonsurgical aneurysm patients, large temporal changes in peak circumferential stress, but not aortic diameter or length, was associated with all-cause mortality. Biomechanical stress and stress changes over time may be beneficial as additional risk factors for elective surgery in small aneurysms.
PubMed: 38913870
DOI: 10.1093/icvts/ivae116 -
PloS One 2024The well-established inverse relationship between socioeconomic status (SES) and risk of developing coronary heart disease (CHD) cannot be explained solely by...
BACKGROUND
The well-established inverse relationship between socioeconomic status (SES) and risk of developing coronary heart disease (CHD) cannot be explained solely by differences in traditional risk factors.
OBJECTIVE
To model the role SES plays in the burden of premature CHD in Argentina.
MATERIALS AND METHODS
We used the Cardiovascular Disease Policy Model-Argentina to project incident CHD events and mortality in low and high-SES Argentinean adults 35 to 64 years of age from 2015 to 2024. Using data from the 2018 National Risk Factor Survey, we defined low SES as not finishing high-school and/or reporting a household income in quintiles 1 or 2. We designed simulations to apportion CHD outcomes in low SES adults to: (1) differences in the prevalence of traditional risk factors between low and high SES adults; (2) nontraditional risk associated with low SES status; (3) preventable events if risk factors were improved to ideal levels; and (4) underlying age- and sex-based risk.
RESULTS
56% of Argentina´s 35- to 64-year-old population has low SES. Both high and low SES groups have poor control of traditional risk factors. Compared with high SES population, low SES population had nearly 2-fold higher rates of incident CHD and CHD deaths per 10 000 person-years (incident CHD: men 80.8 [95%CI 76.6-84.9] vs 42.9 [95%CI 37.4-48.1], women 39.0 [95%CI 36.-41.2] vs 18.6 [95%CI 16.3-20.9]; CHD deaths: men 10.0 [95%CI 9.5-10.5] vs 6.0 [95%CI 5.6-6.4], women 3.2 [95%CI 3.0-3.4] vs 1.8 [95%CI 1.7-1.9]). Nontraditional low SES risk accounts for 73.5% and 70.4% of the event rate gap between SES levels for incident CHD and CHD mortality rates, respectively.
DISCUSSION
CHD prevention policies in Argentina should address contextual aspects linked to SES, such as access to education or healthcare, and should also aim to implement known clinical strategies to achieve better control of CHD risk factors in all socioeconomic levels.
Topics: Humans; Argentina; Adult; Middle Aged; Male; Female; Coronary Disease; Social Class; Risk Factors; Prevalence; Low Socioeconomic Status
PubMed: 38913678
DOI: 10.1371/journal.pone.0305948 -
PloS One 2024HIV/AIDS is a chronic disease that challenges public health worldwide and causes morbidity and mortality in humans. The main purpose of this study was to investigate the...
Determinants of longitudinal changes of CD4 cell count and survival time to death of HIV/AIDS patients treated at Yabelo General Hospital, the case of pastoralist area: Using joint modelling approach.
INTRODUCTION
HIV/AIDS is a chronic disease that challenges public health worldwide and causes morbidity and mortality in humans. The main purpose of this study was to investigate the determinants of longitudinal changes in CD4 cell count and survival time to death among HIV/AIDS patients as adults from January 2016 to December 2019 at Yabelo General Hospital. The intellectual gap in this study was focused on the study area, which means that the study related to joint modeling doesn't exist in the pastoralist community of Borena.
METHODS
This study involved 293 adult HIV-infected adults that could be collected from the recorded patient chart data, and the study design is a retrospective cohort design. The study used a Cox proportional hazard model, a linear mixed effect model, and a joint model, which is the combination of both model processes.
RESULTS
The joint model showed that longitudinal CD4 cell count is significantly associated with survival time (p-value = 0.0253). Covariates such as visiting time, age, weight, educational status, ART adherence, and functional status were statistically significant factors associated with mean changes in the CD4 cell count of HIV patients. WHO stage, educational status, place of residence, TB, family history, and opportunistic infection disease had a significant effect on the survival time of HIV patients.
CONCLUSIONS
The estimated association parameter is a negative value, which indicates both outcomes are negatively associated, and higher values of the CD4 cell count are associated with better survival.
Topics: Humans; Male; CD4 Lymphocyte Count; Female; Adult; HIV Infections; Retrospective Studies; Middle Aged; Hospitals, General; Acquired Immunodeficiency Syndrome; Longitudinal Studies; Proportional Hazards Models
PubMed: 38913649
DOI: 10.1371/journal.pone.0305519 -
PloS One 2024Chemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global...
INTRODUCTION
Chemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed.
STRUCTURED EXPERT JUDGMENT (SEJ) PROCESS
A Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness.
MAIN FINDINGS
The foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants.
RANGE OF HEALTH IMPACTS
Based on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals.
FUTURE DIRECTIONS
These results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available.
Topics: Humans; Environmental Pollutants; Environmental Exposure; Expert Testimony; Endocrine Disruptors; Pesticides; Polychlorinated Biphenyls; Arsenic; Polycyclic Aromatic Hydrocarbons; Environmental Pollution; Asbestos; Dioxins
PubMed: 38913645
DOI: 10.1371/journal.pone.0298504 -
PloS One 2024In the first year of roll-out, vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevented almost 20 million deaths from coronavirus disease...
BACKGROUND
In the first year of roll-out, vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevented almost 20 million deaths from coronavirus disease 2019 (COVID-19). Yet, little is known about the factors influencing access to vaccination at the individual level within rural poor settings of low-income countries. The aim of this study was to examine determinants of vaccine receipt in rural India.
METHODS
A census of a rural village in Tamil Nadu was undertaken from June 2021 to September 2022. We surveyed 775 participants from 262 households. Household-level data on socioeconomic status (SES), water, sanitation, and hygiene practices, and individual-level demographic information, travel history, and biomedical data, including anthropometry, vital signs, and comorbidities, were collected. Logistic regression models with 5-fold cross-validation were used to identify the biomedical, demographic, and socioeconomic determinants of vaccine receipt and the timing of receipt within the first 30 days of eligibility. Vaccine ineligible participants were excluded leaving 659 eligible participants. There were 650 eligible participants with complete biomedical, demographic, and socioeconomic data.
RESULTS
There were 68.0% and 34.0% of individuals (N = 650) who had received one and two vaccine doses, respectively. Participants with household ownership of a permanent account number (PAN) or ration card were 2.15 (95% CI:1.32-3.52) or 3.02 (95% CI:1.72-5.29) times more likely to receive at least one vaccine dose compared to households with no ownership of such cards. Participants employed as housewives or self-employed non-agricultural workers were 65% (95% CI:0.19-0.67) or 59% (95% CI:0.22-0.76) less likely to receive at least one vaccine dose compared to salaried workers. Household PAN card ownership, occupation and age were linked to the timing of vaccine receipt. Participants aged ≤18 and 45-60 years were 17.74 (95% CI:5.07-62.03) and 5.51 (95% CI:2.74-11.10) times more likely to receive a vaccine within 30 days of eligibility compared to 19-44-year-olds. Biomedical factors including BMI, vital signs, comorbidities, and COVID-19 specific symptoms were not consistently associated with vaccine receipt or timing of receipt. No support was found that travel history, contact with COVID-19 cases, and hospital admissions influenced vaccine receipt or timing of receipt.
CONCLUSION
Factors linked to SES were linked to vaccine receipt, more so than biomedical factors which were targeted by vaccine policies. Future research should explore if government interventions including vaccine mandates, barriers to vaccine access, or peer influence linked to workplace or targeted vaccine promotion campaigns underpin these findings.
Topics: Humans; India; COVID-19 Vaccines; Female; Male; COVID-19; Rural Population; Adult; Middle Aged; Socioeconomic Factors; Adolescent; Vaccination; SARS-CoV-2; Young Adult
PubMed: 38913614
DOI: 10.1371/journal.pone.0305819 -
ELife Jun 2024Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with...
BACKGROUND
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.
METHODS
Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations.
RESULTS
Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB.
CONCLUSIONS
The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes.
FUNDING
This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.
Topics: Humans; Female; Longitudinal Studies; Pregnancy; Vagina; Premature Birth; Adult; Retrospective Studies; Proteome; Cytokines; Fetal Membranes, Premature Rupture; Young Adult; Immunoproteins
PubMed: 38913421
DOI: 10.7554/eLife.90943