Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation.

The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo signaling pathway activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivation. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.

Review and meta-analysis of the genetic Minimal Cut Set approach for gene essentiality prediction in cancer metabolism.

Cancer metabolism is a marvellously complex topic, in part, due to the reprogramming of its pathways to self-sustain the malignant phenotype in the disease, to the detriment of its healthy counterpart. Understanding these adjustments can provide novel targeted therapies that could disrupt and impair proliferation of cancerous cells. For this very purpose, genome-scale metabolic models (GEMs) have been developed, with Human1 being the most recent reconstruction of the human metabolism. Based on GEMs, we introduced the genetic Minimal Cut Set (gMCS) approach, an uncontextualized methodology that exploits the concepts of synthetic lethality to predict metabolic vulnerabilities in cancer. gMCSs define a set of genes whose knockout would render the cell unviable by disrupting an essential metabolic task in GEMs, thus, making cellular proliferation impossible. Here, we summarize the gMCS approach and review the current state of the methodology by performing a systematic meta-analysis based on two datasets of gene essentiality in cancer. First, we assess several thresholds and distinct methodologies for discerning highly and lowly expressed genes. Then, we address the premise that gMCSs of distinct length should have the same predictive power. Finally, we question the importance of a gene partaking in multiple gMCSs and analyze the importance of all the essential metabolic tasks defined in Human1. Our meta-analysis resulted in parameter evaluation to increase the predictive power for the gMCS approach, as well as a significant reduction of computation times by only selecting the crucial gMCS lengths, proposing the pertinency of particular parameters for the peak processing of gMCS.

Temporal Outcomes of Patients Diagnosed With Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is increasingly recognized. Clinical outcomes have evolved over time amid changes in the diagnostic pathway and advances in therapeutics. We sought to evaluate clinical outcomes over time of patients with ATTR-CA with access to disease-modifying therapy. METHODS AND RESULTS: This is a retrospective cohort study of 419 patients diagnosed with ATTR-CA during 2001-2021, comparing clinical characteristics across eras. The primary end point was composite all-cause mortality or orthotopic heart transplantation (OHT). Time-to-event analysis was performed using Cox proportional hazard modeling controlling for differences among cohorts. Patients diagnosed in the more recent years had higher median age (2017-2021, 78 years; 2014-2016, 75 years; 2001-2013, 74 years) and more often had wild-type ATTR (81.9% vs 82.5% vs 56.4%), but less severe phenotypes as evidenced by more individuals with Columbia stage I disease (47.6% vs 35.9% vs 22.4%), owing to lower biomarkers, more patients in New York Heart Association functional classes I and II (68.9% vs 47.6% vs 43.6%), and lower use of loop diuretics (67.0% vs 78.6% vs 89.1%). Over time, patients were treated more frequently with tafamidis (74% vs 37% vs 32%). On multivariable analysis, greater Columbia score (hazard ratio 1.42, 95% confidence interval 1.30-1.54, P < .001) was predictive of death or OHT, whereas tafamidis (hazard ratio 0.31, 95% confidence interval 0.22-0.44, P < .001) was associated with greater survival and freedom from OHT. CONCLUSIONS: Patients recently diagnosed with ATTR-CA have earlier stage disease and substantially lower mortality. Tafamidis is associated with significantly improved survival and freedom from OHT.

Oligomerization mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.

Deltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognize ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerization, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function. While DTX3L and PARP9 are known to heterodimerize, and assemble into a high molecular weight oligomeric complex, the nature of the oligomeric structure, including whether this contributes to the ADP-ribose reader function is unknown. Here, we report a crystal structure of the DTX3L N-terminal D2 domain and show that it forms a tetramer with, conveniently, D2 symmetry. We identified two interfaces in the structure: a major, conserved interface with a surface of 973 Å2 and a smaller one of 415 Å2. Using native mass spectrometry, we observed molecular species that correspond to monomers, dimers and tetramers of the D2 domain. Reconstitution of DTX3L knockout cells with a D1-D2 deletion mutant showed the domain is dispensable for DTX3L-PARP9 heterodimer formation, but necessary to assemble an oligomeric complex with efficient reader function for ADP-ribosylated androgen receptor. Our results suggest that homo-oligomerization of DTX3L is important for the DTX3L-PARP9 complex to read mono-ADP-ribosylation on a ligand-regulated transcription factor.

Clinical Trial Diversity, Equity, and Inclusion: Roadmap of the Cardiothoracic Surgical Trials Network.

BACKGROUND: There is a recognized lack of diversity among patients enrolled in cardiovascular interventional and surgical trials. Diverse patient representation in clinical trials is necessary to enhance generalizability of findings, which may lead to better outcomes across broader populations. The Cardiothoracic Surgical Trials Network (CTSN) recently developed a plan of action to increase diversity among participating investigators and trial participants and is the focus of this review. METHODS: A review of literature and enrollment data from CTSN trials was conducted. RESULTS: CTSN completed more than a dozen major clinical trials (2008-2022), enrolling >4000 patients, of whom 30% were women, 11% were non-White, and 5.6% were Hispanic. CTSN also completed trials of hospitalized patients with coronavirus disease 2019, wherein enrollment was more diverse, with 42% women, and 58% were Asian, Black, Hispanic, or from another underrepresented racial group. The discrepancy in diversity of enrollment between cardiac surgery trials and coronavirus disease trials highlights the need for a more comprehensive understanding of (1) the prevalence of underlying disease requiring cardiac interventions across broad populations, (2) differences in access to care and referral for cardiac surgery, and (3) barriers to enrollment in cardiac surgery trials. CONCLUSIONS: Committed to diversity, CTSN's multifaceted action plan includes developing site-specific enrollment targets, collecting social determinants of health data, understanding reasons for nonparticipation, recruiting sites that serve diverse populations, emphasizing greater diversity among clinical trial teams, and implicit bias training. The CTSN will prospectively assess how these interventions influence enrollment as we work to ensure trial participants are more representative of the communities we serve.

Two Decades of Stroke in the United States: A Healthcare Economic Perspective.

INTRODUCTION: Stroke is a leading cause of morbidity and mortality in the USA and has implications on the financial health of patients, families, and healthcare systems. The objective of this study aimed to determine the economic perspective of stroke on the national healthcare system for the past 2 decades. METHODS: This retrospective study of inpatient subjects from 2000 to 2020 with stroke was collected from the Healthcare Cost and Utilization Project (HCUP). We queried patients admitted primarily for ischemic or hemorrhagic stroke. Patients were evaluated for demographics, length of stay (LOS), mortality, and hospital charges. Statistical Z-testing with a significance of p < 0.05 was conducted for the analysis. RESULTS: During the study period, 12,158,747 stroke subjects were studied, with 51.9% female and a mean age of 70.08 (±0.16) years old. The mean rate of stroke discharges per 100,000 persons was 187.71 (±3.44), decreasing from 200 to 193 during the study (p = 0.16). The mean percentage of deaths was 8.78% (±0.17), which decreased from 10.96% to 6.81% (p = 0.00). The mean LOS was 6.28 days (±0.08), which increased from 6.70 to 7.15 (p = 0.00). During the study period, the aggregated national bill was USD 725 billion. The mean hospital charges per patient were USD 57,178 (±1,504), increasing from USD 19,647 to USD 121,765 per person during the study period (p = 0.00), while mean hospital costs per stay were USD 15,781 (±330). These data closely conform to an exponential growth pattern, and forecasting per patient charges for the next 10 years demonstrates a cost of USD 287,836 by 2030. CONCLUSIONS: Our data show that the rate and mortality of stroke have decreased, but its charges and costs are increasing. The improvement in outcomes could be multifactorial such as establishment of comprehensive stroke centers and evolving treatment modalities. Ironically, the charges per patient increased more than sixfold with a national bill almost equal to the annual Medicare budget. Thus, the significance of preventive medicine, such as controlling hypertension, diabetes, and smoking cessation, cannot be understated. With such a dramatically increasing financial burden, improvements in mitigating risk factors, educational programs, and access to care may be a more cost-effective option.

The carboxy terminus causes interfacial assembly of oleate hydratase on a membrane bilayer.

The soluble flavoprotein oleate hydratase (OhyA) hydrates the 9-cis double bond of unsaturated fatty acids. OhyA substrates are embedded in membrane bilayers; OhyA must remove the fatty acid from the bilayer and enclose it in the active site. Here, we show that the positively charged helix-turn-helix motif in the carboxy terminus (CTD) is responsible for interacting with the negatively charged phosphatidylglycerol (PG) bilayer. Super-resolution microscopy of Staphylococcus aureus cells expressing green fluorescent protein fused to OhyA or the CTD sequence shows subcellular localization along the cellular boundary, indicating OhyA is membrane-associated and the CTD sequence is sufficient for membrane recruitment. Using cryo-electron microscopy, we solved the OhyA dimer structure and conducted 3D variability analysis of the reconstructions to assess CTD flexibility. Our surface plasmon resonance experiments corroborated that OhyA binds the PG bilayer with nanomolar affinity and we found the CTD sequence has intrinsic PG binding properties. We determined that the nuclear magnetic resonance structure of a peptide containing the CTD sequence resembles the OhyA crystal structure. We observed intermolecular NOE from PG liposome protons next to the phosphate group to the CTD peptide. The addition of paramagnetic MnCl2 indicated the CTD peptide binds the PG surface but does not insert into the bilayer. Molecular dynamics simulations, supported by site-directed mutagenesis experiments, identify key residues in the helix-turn-helix that drive membrane association. The data show that the OhyA CTD binds the phosphate layer of the PG surface to obtain bilayer-embedded unsaturated fatty acids.

Long-Term Mortality in Patients With Severe Hypercholesterolemia Phenotype From a Racial and Ethnically Diverse US Cohort.

BACKGROUND: Tools for mortality prediction in patients with the severe hypercholesterolemia phenotype (low-density lipoprotein cholesterol ≥190 mg/dL) are limited and restricted to specific racial and ethnic cohorts. We sought to evaluate the predictors of long-term mortality in a large racially and ethnically diverse US patient cohort with low-density lipoprotein cholesterol ≥190 mg/dL. METHODS: We conducted a retrospective analysis of all patients with a low-density lipoprotein cholesterol ≥190 mg/dL seeking care at Montefiore from 2010 through 2020. Patients <18 years of age or with previous malignancy were excluded. The primary end point was all-cause mortality. Analyses were stratified by age, sex, and race and ethnicity. Patients were stratified by primary and secondary prevention. Cox regression analyses were used to adjust for demographic, clinical, and treatment variables. RESULTS: A total of 18 740 patients were included (37% non-Hispanic Black, 30% Hispanic, 12% non-Hispanic White, and 2% non-Hispanic Asian patients). The mean age was 53.9 years, and median follow-up was 5.2 years. Both high-density lipoprotein cholesterol and body mass index extremes were associated with higher mortality in univariate analyses. In adjusted models, higher low-density lipoprotein cholesterol and triglyceride levels were associated with an increased 9-year mortality risk (adjusted hazard ratio [HR], 1.08 [95% CI, 1.05-1.11] and 1.04 [95% CI, 1.02-1.06] per 20-mg/dL increase, respectively). Clinical factors associated with higher mortality included male sex (adjusted HR, 1.31 [95% CI, 1.08-1.58]), older age (adjusted HR, 1.19 per 5-year increase [95% CI, 1.15-1.23]), hypertension (adjusted HR, 2.01 [95% CI, 1.57-2.57]), chronic kidney disease (adjusted HR, 1.68 [95% CI, 1.36-2.09]), diabetes (adjusted HR, 1.79 [95% CI, 1.50-2.15]), heart failure (adjusted HR, 1.51 [95% CI, 1.16-1.95]), myocardial infarction (adjusted HR, 1.41 [95% CI, 1.05-1.90]), and body mass index <20 kg/m2 (adjusted HR, 3.36 [95% CI, 2.29-4.93]). A significant survival benefit was conferred by lipid-lowering therapy (adjusted HR, 0.57 [95% CI, 0.42-0.77]). In the primary prevention group, high-density lipoprotein cholesterol <40 mg/dL was independently associated with higher mortality (adjusted HR, 1.49 [95% CI, 1.06-2.09]). Temporal trend analyses showed a reduction in statin use over time (P<0.001). In the most recent time period (2019-2020), 56% of patients on primary prevention and 85% of those on secondary prevention were on statin therapy. CONCLUSIONS: In a large, diverse cohort of US patients with the severe hypercholesterolemia phenotype, we identified several patient characteristics associated with increased 9-year all-cause mortality and observed a decrease in statin use over time, in particular for primary prevention. Our results support efforts geared toward early recognition and consistent treatment for patients with severe hypercholesterolemia.

El bullying: una mirada desde los niños y las niñas / Bullying: A scope from boys and girls / Bullying: Um olhar de meninos e meninas

(analítico) Se presentan los resultados sobre cómo se comprende y se asume el bullying, en tanto problema escolar y social, desde la perspectiva infantil. Para ello, se realizó una investigación cualitativa, hermenéutico-comprensiva, con grupos focales mediados por títeres o videos, producción gráfica y narración de historias. Los participantes fueron 626 estudiantes de 5 a 7 años. La comprensión transitó por elementos congruentes con la teoría, como exclusión, acoso verbal, afectación de pertenencias y una nueva tipología: falta de solidaridad. En cuanto a las experiencias, precisan las burlas, el acoso físico y el hurto, asociadas al contexto familiar o a ninguna, estas últimas por la confluencia del espacio escolar y la familia en un mismo lugar en tiempos de educación remota. En cuanto a la solución, está apela a figuras de autoridad, familiares, asumir actitudes reconciliadoras o al juego.

(analytical) The paper presents the results on how bullying, as scholar and social problem, is understood and assumed from the child's perspective. Therefore, a qualitative, hermeneutic-comprehensive research was carried out and focus groups were done by means of moppets and videos, graphic production, and storytelling. The participants were 626 students from 5 to 7 years old. The understanding went through elements consistent with the theory, such as exclusion, verbal harassment, affectation of be-longings and a new typology, lack of solidarity. Regarding the experiences, they specify teasing, physical harassment, theft, associated with the family context or none, the latter due to the confluence of the school space and the family in the same place in times of remote education. As for the solution, it is appealing to authority figures, relatives, assuming reconciliatory attitudes and playing.

(analítico) O artigo apresenta os resultados sobre como o bullying, como um problema social e escolar, é compreendido e assumido na perspectiva da criança. Para isso, realizou-se uma investigação qualitativa, hermenêutica-compreensiva e grupos focais mediados por fantoches ou vídeos, produção gráfica e contação de histórias; os participantes foram 626 alunos de 5 a 7 anos. O entendimento passou por elementos condizentes com a teoria, como exclusão, assédio verbal, afetação de pertences e uma nova tipologia, falta de solidariedade. Quanto às vivências, especificam provocações, assédios físicos, furtos, associados ao contexto familiar ou nenhum, este último devido à confluência do espaço escolar e da família no mesmo local em tempos de educação a distância. Quanto à solução, é apelar a figuras de autoridade, familiares, assumindo atitudes de conciliação e brincadeiras.

Caracterización de aislamientos de Klebsiella pneumoniae doble productores de carbapenemasas en un hospital universitario / Phenotypic and genotypic characterization of double carbapenemase producing Klebsiella pneumoniaeisolates in a University Hospital

La emergencia de aislamientos de Klebsiella pneumoniaedoble productores de carbapenemasas (KPC y NDM) es una de las consecuencias de la pandemia causada por SARS-CoV-2 que ha causado un impacto significativo en las tasas de resistencia a los antimicrobianos en las infecciones intrahospitalarias por esta enterobacteria. Estos aislamientos representan un desafío para los servicios de salud, por su detección y caracterización y posterior tratamiento. En este trabajo se describen los aislamientos portadores de KPC y NDM recuperados durante 2022 aislados de distintas muestras clínicas de pacientes internados en un hospital universitario de la Ciudad de Buenos Aires, se los caracteriza fenotípicamente y genotípicamente como portadores de ambas carbapenemasas y se destaca la excelente actividad in vitro de la combinación ceftazidima-avibactam y aztreonam en el tratamiento de estas infecciones en donde las alternativas terapéuticas estarían limitadas a antibióticos no ß-lactámicos con porcentajes de resistencia que superan el 70%

The emergence of double-carbapenemase (KPC and NDM) producing Klebsiella pneumoniae isolates is one of the consequences derived from the SARS CoV-2 pandemic, which has caused significant impact on the antimicrobial resistance rates in hospital acquired infections. These isolates represent a real challenge for Health Services due to their difficult detection and characterization and subsequent treatment. In the present work we describe the double carbapenemase producing isolates recovered during the year 2022 from clinical samples belonging to hospitalized patients at a University Hospital in Buenos Aires city, we report their phenotypic and genotypic characterization and the excellent "in vitro" activity of the ceftazidime-avibactam-aztreonam combination in the treatment of infections in which the therapeutical options are restricted to non ß- lactamic antimicrobials which hold resistance rates higher than 70%

Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications.

In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate a FLU-resistant cell line (LN-FLU). These LN-FLU cells displayed characteristics of cancer stem cells, exhibited drug resistance, and showed a significantly reduced expression of Cyclin D1, along with the overexpression of p16, pointing to a proliferation arrest. In comparing the cancer stem-like LN-FLU cells to the LNCaP cells, we observed a decrease in the expression of CTP-choline cytidylyl transferase α (CCTα), as well as a decline in choline kinase, suggesting altogether a downregulation of the phosphatidylcholine biosynthetic pathway. In addition, we found decreased levels of the protein methyl transferase PRMT2 and the upregulation of the histone deacetylase Sirtuin1 (Sirt1). Analysis of the human prostate cancer samples revealed similar results in a population with high expressions of the stem cell markers Oct4 and ABCB1A1. Our findings suggest that the adaptation of prostate cancer cells to antiandrogens could induce reprogramming into stem cells that survive in a low phosphocholine metabolism and cell cycle arrest and display drug resistance.

Synthetic Dual Cysteine-ADP Ribosylated Peptides from the Androgen Receptor are Recognized by the DTX3L/PARP9 Complex.

Androgen signaling in prostate cancer cells involves multisite cysteine ADP-ribosylation of the androgen receptor (AR) by PARP7. The AR modification is read by ADP-ribosyl binding macrodomains in PARP9, but the reason that multiple cysteines are modified is unknown. Here, we use synthetic peptides to show that dual ADP-ribosylation of closely spaced cysteines mediates recognition by the DTX3L/PARP9 complex. Mono and dual ADP-ribosylated cysteine peptides were prepared using a novel solid-phase synthetic strategy utilizing a key, Boc-protected, ribofuranosylcysteine building block. This synthetic strategy allowed us to synthesize fluorescently labeled peptides containing a dual ADP-ribosylation motif. It was found that the DTX3L/PARP9 complex recognizes the dual ADP-ribosylated AR peptide (Kd = 80.5 nM) with significantly higher affinity than peptides with a single ADP-ribose. Moreover, oligomerization of the DTX3L/PARP9 complex proved crucial for ADP-ribosyl-peptide interaction since a deletion mutant of the complex that prevents its oligomer formation dramatically reduced peptide binding. Our data show that features of the substrate modification and the reader contribute to the efficiency of the interaction and imply that multivalent interactions are important for AR-DTX3L/PARP9 assembly.

Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections in Tlaxcala, Mexico.

Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are widely recognised as two prevalent sexually transmitted infections that can have detrimental effects on women's reproductive health. Previous research has concentrated on studying high-risk populations, resulting in limited epidemiological data regarding the general population. Therefore, the objective of this study was to estimate the prevalence of CT and NG among women attending public primary health care in Tlaxcala, Mexico. The study sample included 2,396 women already participating in the cervical cancer screening programme, from July to November 2014. After obtaining informed consent, the CT and NG tests were conducted on cervical samples, using a nucleic acid amplification test. We estimate the prevalence with 95% confidence intervals (CIs). Women who tested positive were promptly notified and provided with appropriate treatment. In our study population, CT and NG prevalences were 3.2 (95% CI: 2.6-4.0) and 0.01 (95% CI: 0.01-0.03), respectively. CT prevalence was higher in younger women (age < 40), although the results indicate a low prevalence; due to the potentially significant impact of CT and NG on women's health, we require adequate surveillance, and guaranteeing rapid referral to the correct treatment is a priority for the control of these diseases.

E-Cigarette Use Among US Adults in the 2021 Behavioral Risk Factor Surveillance System Survey.

Importance: After the initial disruption from the COVID-19 pandemic, it is unclear how patterns of e-cigarette use in the US have changed. Objective: To examine recent patterns in current and daily e-cigarette use among US adults in 2021. Design, Setting, and Participants: This cross-sectional study used data from the 2021 Behavioral Risk Factor Surveillance System (BRFSS) database. The BRFSS is the largest national telephone-based survey of randomly sampled adults in the US. Adults aged 18 years or older, residing in 49 US states (all except Florida), the District of Columbia, and 3 US territories (Guam, Puerto Rico, and the US Virgin Islands), were included in the data set. Data analysis was performed in January 2023. Main Outcomes and Measures: The main outcome was age-adjusted prevalence of current and daily e-cigarette use overall and by participant characteristics, state, and territory. Descriptive statistical analysis was conducted, applying weights to account for population representation. Results: This study included 414 755 BRFSS participants with information on e-cigarette use. More than half of participants were women (51.3%). In terms of race and ethnicity, 0.9% of participants were American Indian or Alaska Native, 5.8% were Asian, 11.5% were Black, 17.3% were Hispanic, 0.2% were Native Hawaiian or Other Pacific Islander, 62.2% were White, 1.4% were of multiple races or ethnicities, and 0.6% were of other race or ethnicity. Individuals aged 18 to 24 years comprised 12.4% of the study population. The age-standardized prevalence of current e-cigarette use was 6.9% (95% CI, 6.7%-7.1%), with almost half of participants using e-cigarettes daily (3.2% [95% CI, 3.1%-3.4%]). Among individuals aged 18 to 24 years, there was a consistently higher prevalence of e-cigarette use, with more than 18.6% reporting current use and more than 9.0% reporting daily use. Overall, among individuals reporting current e-cigarette use, 42.2% (95% CI, 40.7%-43.7%) indicated former combustible cigarette use, 37.1% (95% CI, 35.6%-38.6%) indicated current combustible cigarette use, and 20.7% (95% CI, 19.7%-21.8%) indicated never using combustible cigarettes. Although relatively older adults (aged ≥25 years) who reported current e-cigarette use were more likely to report former or current combustible cigarette use, younger adults (aged 18-24 years) were more likely to report never using combustible cigarettes. Notably, the proportion of individuals who reported current e-cigarette use and never using combustible cigarettes was higher in the group aged 18 to 20 years (71.5% [95% CI, 66.8%-75.7%]) compared with those aged 21 to 24 years (53.0% [95% CI, 49.8%-56.1%]). Conclusion and Relevance: These findings suggest that e-cigarette use remained common during the COVID-19 pandemic, particularly among young adults aged 18 to 24 years (18.3% prevalence). Notably, 71.5% of individuals aged 18 to 20 years who reported current e-cigarette use had never used combustible cigarettes. These results underscore the rationale for the implementation and enforcement of public health policies tailored to young adults.

Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation.

The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo kinase cascade activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivation. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.

Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.

First nosocomial outbreak of SME-4-producing Serratia marcescens in South America / Primer brote nosocomial por Serratia marcescens productora de SME-4en Sudamérica

Abstract Carbapenemase-producing-Serratia marcescens isolates, although infrequent, are considered important nosocomial pathogens due to their intrinsic resistance to polymyxins, which limits therapeutic options. We describe a nosocomial outbreak of SME-4-producing S. marcescens in Buenos Aires city which, in our knowledge, represents the first one in South America.

Resumen Los aislamientos de origen nosocomial de Serratia marcescens productores de car-bapenemasa, si bien son infrecuentes, son considerados importantes patógenos debido a su resistencia intrínseca a las polimixinas, lo cual limita aún más las opciones terapéuticas. En este trabajo se describe un brote nosocomial causado por S. marcescens portadora de car-bapenemasa de tipo SME-4 en la Ciudad de Buenos Aires, el cual representaría el primero en Sudamérica.

Cedrela domatifolia (Meliaceae), un nuevo registro de cedro para el Perú

Cedrela domatifolia W. Palacios es registrada por primera vez para Perú en el valle de Chanchamayo, departamento de Junín. Con esta adición se elevan a 11 especies del género Cedrela (Meliaceae) en el Perú. La característica vegetativa más resaltante de C. domatifolia son los domacios prominentes, situados en las axilas de los nervios secundarios de las láminas por el envés. En caracteres florales, los pétalos son de color rojo a fucsia, una característica no común en el género.

A new record of Cedrela domatifolia W. Palacios is presented in Chanchamayo Valley, department of Junin, which adds to 11 the number of Cedrela (Meliaceae) species recorded in Peru. The most notorious vegetative character of the species are the prominent domatia in the axils of the secondary nerves of blades. At floral characters, the petals are red to fuchsia, an uncommon feature in the genus.