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1.
Addict Behav ; 160: 108187, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39368272

RESUMO

INTRODUCTION: Irritable bowel syndrome (IBS) is a prevalent disorder of gut-brain function associated with psychological distress as well as work and quality of life impairment. Smoking has been linked to gastrointestinal dysfunction, however, research focused on the prevalence of IBS and smoking is limited. Previous research has shown that anxiety sensitivity is linked to increased risk of aversive bodily experiences and subsequent coping-oriented regulation efforts. Higher anxiety sensitivity has also been associated with processes linked to tobacco cigarette smoking lapse and relapse. There is a need to clarify the explanatory roles of anxiety sensitivity in the context of more severe IBS symptoms among persons with IBS who are current smokers. METHOD: The present investigation evaluated the main and interactive effects of IBS symptom severity and anxiety sensitivity in relation to processes related to the maintenance and relapse of tobacco smoking among adults with IBS. The sample consisted of 263 (52.1 % female; Mage = 44.13 years, SD = 12.71) adults who met criteria for IBS and smoke at least 5 cigarettes per day. RESULTS: Hierarchical regression results indicated that both anxiety sensitivity and IBS symptom severity independently predicted greater perceived barriers to smoking cessation, severity of problems experienced during quitting, and negative reinforcement smoking expectancies. A statistically significant interaction further indicated that IBS symptom severity was more strongly associated with negative reinforcement smoking expectancies among participants with higher, relative to lower, anxiety sensitivity. CONCLUSIONS: This study is the first to show that both IBS symptom severity and anxiety sensitivity are related to greater perceived barriers to smoking cessation, previous difficulty quitting, and negative reinforcement expectancies among adults with IBS. There is a continued need to further scientific understanding of interrelations between anxiety sensitivity, IBS symptom severity, and smoking cessation-related beliefs and processes to identify novel approaches that can best support quitting among this understudied population.

2.
Cardiol Young ; : 1-4, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39381969

RESUMO

BACKGROUND: An aberrant right subclavian artery represents the most common aortic arch vascular anomaly. Conventional wisdom states that these anomalies do not result in dysphagia, but rather serve as "red herrings". Clearly, in the vast majority of cases, this holds true. Nonetheless, one should never say never. METHODS: Herein, we present a cohort of four children with debilitating dysphagia resulting from an aberrant right subclavian artery. Subclavian reimplantation via a right posterolateral thoracotomy was performed successfully in all cases. RESULTS: Dysphagia resolved postoperatively, and all patients were able to advance to a normal diet. They were able to gain appropriate weight postoperatively and continue to do well at most recent clinical follow-up. CONCLUSIONS: This case series suggests that aberrant right subclavian artery anatomy should be considered a potential aetiology of dysphagia, albeit rarely. Surgical intervention for select patients can provide dramatic resolution of symptoms.

3.
iScience ; 27(10): 110908, 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39351197

RESUMO

Cellular quiescence is a reversible and tightly regulated stem cell function essential for healthy aging. However, the elements that control quiescence during aging remain poorly defined. Using melanocyte stem cells (McSCs), we find that stem cell quiescence is neither passive nor static. For example, gene expression profiling of the transition from proliferating melanoblasts to quiescent melanocyte stem cells reveals tissue-specific regulation of the immune checkpoint protein PD-L1. In vitro, quiescence assays demonstrate that PD-L1 expression is a physiological attribute of quiescence in this cell lineage and reinforces this cell state. In vivo, a subset of quiescent McSCs is marked by PD-L1. While the overall number of McSCs decreases with age, PD-L1+ McSCs appear resistant to depletion. This phenomenon coincides with an aged McSC pool that exhibits a deeper transcriptomic quiescence. We predict that quiescent PD-L1+ stem cells retained with age may serve as cellular targets for reactivation.

4.
bioRxiv ; 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39386503

RESUMO

Many fundamental insights into microbiology have come from imaging, which is typically synonymous with optical techniques. However, the sample preparation needed for many optical microscopy methods such as labeling, fixing, or genetic modification, limits the range of species and environments we can investigate. Here we demonstrate the use of electrical capacitance measurements as a non-optical method for imaging live microbial samples. In electrical capacitance imaging (ECI), samples are positioned in contact with a semiconductor sensor array, and localized capacitance measurements are made across the array. From these measurements, we generate textured images of a variety of microbial colonies. We determine that capacitance is correlated with local sample thickness by comparing ECI data to 3D confocal scans. We further illustrate with ECI that a difference in capacitance signal allows microbial species to be spatially distinguished in co-culture conditions. In order to highlight the versatility of our system, we capture the cross-sectional development of floating pellicle biofilms in a liquid culture at millimeter length scales during weeks-long time-lapse experiments. These novel results establish a new low-cost and portable platform which can be used for spatially and temporally resolved experiments in diverse environments with a wide variety of microbial species. IMPORTANCE: Microbes live in diverse environments, and occupy biological roles across many timescales. Investigating the full scope of microbial activity requires imaging systems appropriate to each context. Though optical microscopy is powerful, the use of light, lenses, and other hardware limits where it can be applied. At the same time, existing non-optical imaging methods are frequently destructive to samples and require extensive equipment. In this paper we present a non-optical imaging system that is small, cheap, requires no sample labeling, and is compatible with a variety of microbial species. Our system uses semiconductor chips to measure the inherent material properties of a sample with spatial sensitivity, producing images of microbes contrasted against their environment and each other. Our technique captures label-free, micrometer-resolution images with a pocket-sized device, enabling microbiological imaging experiments in new environments with new species.

5.
Cardiol Young ; : 1-7, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39376085

RESUMO

BACKGROUND: Society of Thoracic Surgeons Congenital Heart Surgery Database is the largest congenital heart surgery database worldwide but does not provide information beyond primary episode of care. Linkage to hospital electronic health records would capture complications and comorbidities along with long-term outcomes for patients with CHD surgeries. The current study explores linkage success between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health record data in North Carolina and Georgia. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database was linked to hospital electronic health records from four North Carolina congenital heart surgery using indirect identifiers like date of birth, sex, admission, and discharge dates, from 2008 to 2013. Indirect linkage was performed at the admissions level and compared to two other linkages using a "direct identifier," medical record number: (1) linkage between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health records from a subset of patients from one North Carolina institution and (2) linkage between Society of Thoracic Surgeons data from two Georgia facilities and Georgia's CHD repository, which also uses direct identifiers for linkage. RESULTS: Indirect identifiers successfully linked 79% (3692/4685) of Society of Thoracic Surgeons Congenital Heart Surgery Database admissions across four North Carolina hospitals. Direct linkage techniques successfully matched Society of Thoracic Surgeons Congenital Heart Surgery Database to 90.2% of electronic health records from the North Carolina subsample. Linkage between Society of Thoracic Surgeons and Georgia's CHD repository was 99.5% (7,544/7,585). CONCLUSIONS: Linkage methodology was successfully demonstrated between surgical data and hospital-based electronic health records in North Carolina and Georgia, uniting granular procedural details with clinical, developmental, and economic data. Indirect identifiers linked most patients, consistent with similar linkages in adult populations. Future directions include applying these linkage techniques with other data sources and exploring long-term outcomes in linked populations.

6.
J Interpers Violence ; : 8862605241285924, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39376104

RESUMO

Approximately 16% of Veterans experience military sexual trauma (MST), defined as sexual assault or harassment experienced during military service. Veterans across life stages may possess differing resources and face unique stressors that impact their ability to engage in mental health treatment or require additional liaison to services. The present study sought to characterize age-related differences in the socioecological contexts of Veterans seeking mental health treatment following MST in the domains of economic sufficiency, housing, spiritual coping, supportive relationships, and interpersonal violence. From 2009 to 2019, Veterans (N = 640) seeking mental health services following exposure to MST attended evaluation and treatment planning sessions at a Midwestern Veterans Health Administration posttraumatic stress disorder specialty clinic. Veterans completed semistructured interviews that included surveys and diagnostic screenings to assess psychosocial needs and resources. ANOVA and ordinal regressions were used to evaluate potential disparities in socioecological resources by age. No age-related differences in economic sufficiency and stable housing emerged, though most Veterans (57%) endorsed financial difficulties. Veterans who endorsed spiritual beliefs were significantly older than those who did not. Veterans who reported having a support system were significantly younger than Veterans who denied having a support system. Less than half (46%) of Veteran reported having peer relationships. Veterans who endorsed frequent interaction with their peers were significantly older than those who did not. Veterans who reported past-year exposure to interpersonal violence were significantly younger. Greater clarity about age-related differences in the socioecological contexts of Veterans can support clinicians in providing responsive mental health treatment and connecting Veterans to additional Veterans Health Administration resources following MST.

7.
Commun Biol ; 7(1): 1268, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39369042

RESUMO

In the era of renewed space exploration, comprehending the effects of the space environment on human health, particularly for deep space missions, is crucial. While extensive research exists on the impacts of spaceflight, there is a gap regarding female reproductive risks. We hypothesize that space stressors could have enduring effects on female health, potentially increasing risks for future pregnancies upon return to Earth, particularly related to small-for-gestational-age (SGA) fetuses. To address this, we identify a shared microRNA (miRNA) signature between SGA and the space environment, conserved across humans and mice. These miRNAs target genes and pathways relevant to diseases and development. Employing a machine learning approach, we identify potential FDA-approved drugs to mitigate these risks, including estrogen and progesterone receptor antagonists, vitamin D receptor antagonists, and DNA polymerase inhibitors. This study underscores potential pregnancy-related health risks for female astronauts and proposes pharmaceutical interventions to counteract the impact of space travel on female health.


Assuntos
Recém-Nascido Pequeno para a Idade Gestacional , MicroRNAs , Voo Espacial , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Gravidez , Animais , Camundongos , Recém-Nascido , Ausência de Peso/efeitos adversos
8.
Int J Sports Physiol Perform ; : 1-11, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353577

RESUMO

PURPOSE: To examine the test-retest reliability of countermovement jump (CMJ) and isometric strength testing measures in elite-level under-18 and under-23 academy football players. METHODS: A total of 36 players performed 3 maximal CMJs and isometric abductor (IABS), adductor (IADS), and posterior chain (IPCS) strength tests on 2 separate test days using dual force plates (CMJ and IPCS) and a portable strength testing device (IABS and IADS). Relative (intraclass correlation coefficient) and absolute (coefficient of variation, standard error of the measurement, and minimal detectable change [MDC%]) reliabilities for 34 CMJ, 10 IABS, 10 IADS, and 11 IPCS measures were analyzed using between-sessions best, mean, and within-session methods. RESULTS: For all methods, relative reliability was good to excellent for all CMJ and all IADS measures and poor to good for all IABS and IPCS measures. Absolute reliability was good (ie, coefficient of variation < 10%) for 27 (best) and 28 (mean) CMJ variables and for 6 (IABS and IADS) and 2 (IPCS) isometric measures. Commonly used CMJ measures (jump height, eccentric duration, and flight-time:contraction-time ratio) had good to excellent relative reliability and an MDC% range of 14.6% to 23.7%. Likewise, commonly used isometric peak force measures for IABS, IADS, and IPCS had good to excellent relative reliability and an MDC% range of 22.2% to 26.4%. CONCLUSIONS: Commonly used CMJ and isometric strength measures had good test-retest reliability but might be limited by their MDC%. Rate-of-force-development measures (for all isometric tests) and impulse measures (IPCS) are limited by poor relative and absolute reliability and high MDC%. MDC% statistics should be considered in the context of typical responsiveness.

9.
Lancet Infect Dis ; 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39389071

RESUMO

BACKGROUND: There is a need for additional therapeutic options for serious infections caused by Gram-negative pathogens. In the phase 3, descriptive REVISIT study, we investigated the safety and efficacy of aztreonam-avibactam in the treatment of complicated intra-abdominal infections or hospital-acquired pneumonia or ventilator-associated pneumonia (HAP-VAP) caused, or suspected to be caused, by Gram-negative bacteria. METHODS: This prospective, multinational, open-label, central assessor-masked study enrolled adults who were hospitalised with a complicated intra-abdominal infection or HAP-VAP. Patients were randomly allocated via block randomisation using interactive response technology stratified by infection type in a 2:1 ratio to aztreonam-avibactam (with metronidazole for complicated intra-abdominal infection) or meropenem with or without colistin for 5-14 days for complicated intra-abdominal infection or 7-14 days for HAP-VAP. The primary endpoint was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population. Secondary endpoints included 28-day mortality in the ITT population and safety in patients in the ITT population who received study drug (safety analysis set). No formal hypothesis testing was planned. The study was registered with ClinicalTrials.gov (NCT03329092) and EudraCT (2017-002742-68) and is complete. FINDINGS: Between April 5, 2018, and Feb 23, 2023, we screened 461 patients. 422 patients were enrolled and randomly allocated (282 in the aztreonam-avibactam group and 140 in the meropenem group, forming the ITT analysis set), of whom ten patients (seven in the aztreonam-avibactam group and three in the meropenem group) were randomly allocated but did not receive study treatment. 271 (64%) of 422 patients had at least one Gram-negative pathogen from an adequate specimen identified at baseline. The most frequent baseline pathogens were Enterobacterales (252 [93%] of 271). Overall, 19 (24%) of 80 isolates tested for carbapenemases were carbapenemase-positive (serine, metallo-ß-lactamase, or both). 193 (68·4%) of 282 patients in the aztreonam-avibactam group and 92 (65·7%) of 140 in the meropenem group had clinical cure at the test-of-cure visit (treatment difference 2·7% [95% CI -6·6 to 12·4]). For patients with complicated intra-abdominal infection, the adjudicated clinical cure rate was 76·4% (159 of 208) for the aztreonam-avibactam group and 74·0% (77 of 104) for the meropenem group. Cure rates in patients with HAP-VAP were 45·9% (34 of 74) for aztreonam-avibactam and 41·7% (15 of 36) for meropenem. 28-day all-cause mortality rates were 4% (12 of 282) for aztreonam-avibactam and 7% (ten of 140) for meropenem; in patients with complicated intra-abdominal infection, mortality was 2% (four of 208) and 3% (three of 104) for aztreonam-avibactam and meropenem, respectively, and in patients with HAP-VAP, mortality was 11% (eight of 74) and 19% (seven of 36), respectively. Aztreonam-avibactam was generally well tolerated, and safety findings were consistent with the known safety profile of aztreonam monotherapy. There were no treatment-related serious adverse events in the aztreonam-avibactam group. INTERPRETATION: These phase 3 efficacy and safety data provide support for aztreonam-avibactam as a potential therapeutic option for complicated intra-abdominal infection or HAP-VAP caused by Gram-negative bacteria. FUNDING: Pfizer.

10.
Chem Sci ; 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39309095

RESUMO

Although there are few reduced dinitrogen complexes of scandium, this metal has revealed a new structural type in reductive dinitrogen chemistry by reduction of bis(pentamethylcyclopentadienyl) scandium halides under N2. Reduction of (Cp* = C5Me5) with potassium graphite (KC8) under dinitrogen generates the dark blue paramagnetic complex , 1. This end-on bridging (N[double bond, length as m-dash]N)2- complex is a diradical with a magnetic moment of 2.8µ B. Upon further reduction of 1 with KC8, the orange diamagnetic trimetallic complex , 2, is obtained. This complex has an unprecedented structure in which two side-on bridging (N[double bond, length as m-dash]N)2- ligands are bound to the central (Cp*Sc)2+ moiety. Complex 2 can also be obtained directly from reduction of or a mixture of and with KC8. The reaction of with KC8 in the presence of 18-crown-6 or 2.2.2-cryptand affords 2 along with small amounts of , 3, which is green at room temperature and purple at low temperature and displays a mixture of side-on and end-on bridging isomers in the crystal structure collected at -180 °C. Density functional theory (DFT) calculations are consistent with a triplet ground state for the end-on complex 1 and singlet ground states for the side-on complexes 2 and 3.

11.
Acta Pharm Sin B ; 14(9): 3931-3948, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39309509

RESUMO

Cholangiocarcinoma (CCA) is a bile duct malignancy with a dismal prognosis. This study systematically investigated the role of the ribosomal protein S6 (RPS6) gene, which is dependent in CCA. We found that RPS6 upregulation in CCA tissues was correlated with a poor prognosis. Functional investigations have shown that alterations in RPS6 expression, both gain- and loss-of function could affect the proliferation of CCA cells. In xenograft tumor models, RPS6 overexpression enhances tumorigenicity, whereas RPS6 silencing reduces it. Integration analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle, especially DNA replication. Immunoprecipitation followed by mass spectrometry has identified numerous spliceosome complex proteins associated with RPS6. Transcriptomic profiling revealed that RPS6 affects numerous alternative splicing (AS) events, and combined with RNA immunoprecipitation sequencing, revealed that minichromosome maintenance complex component 7 (MCM7) binds to RPS6, which regulates its AS and increases oncogenic activity in CCA. Targeting RPS6 with vivo phosphorodiamidate morpholino oligomer (V-PMO) significantly inhibited the growth of CCA cells, patient-derived organoids, and subcutaneous xenograft tumor. Taken together, the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.

12.
Sensors (Basel) ; 24(17)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39275486

RESUMO

Antimicrobial resistance (AMR) poses a significant threat to global health, powered by pathogens that become increasingly proficient at withstanding antibiotic treatments. This review introduces the factors contributing to antimicrobial resistance (AMR), highlighting the presence of antibiotics in different environmental and biological matrices as a significant contributor to the resistance. It emphasizes the urgent need for robust and effective detection methods to identify these substances and mitigate their impact on AMR. Traditional techniques, such as liquid chromatography-mass spectrometry (LC-MS) and immunoassays, are discussed alongside their limitations. The review underscores the emerging role of biosensors as promising alternatives for antibiotic detection, with a particular focus on electrochemical biosensors. Therefore, the manuscript extensively explores the principles and various types of electrochemical biosensors, elucidating their advantages, including high sensitivity, rapid response, and potential for point-of-care applications. Moreover, the manuscript investigates recent advances in materials used to fabricate electrochemical platforms for antibiotic detection, such as aptamers and molecularly imprinted polymers, highlighting their role in enhancing sensor performance and selectivity. This review culminates with an evaluation and summary of commercially available and spin-off sensors for antibiotic detection, emphasizing their versatility and portability. By explaining the landscape, role, and future outlook of electrochemical biosensors in antibiotic detection, this review provides insights into the ongoing efforts to combat the escalating threat of AMR effectively.


Assuntos
Antibacterianos , Técnicas Biossensoriais , Técnicas Eletroquímicas , Técnicas Biossensoriais/métodos , Antibacterianos/análise , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Humanos
13.
bioRxiv ; 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39282299

RESUMO

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.

14.
Elife ; 122024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39287504

RESUMO

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.


Assuntos
Fator de Iniciação 2B em Eucariotos , Animais , Camundongos , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Estresse Fisiológico/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Humanos , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Feminino , Acetamidas , Cicloexilaminas
15.
Hepatol Commun ; 8(10)2024 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-39330965

RESUMO

BACKGROUND: HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. METHODS: We utilized computational deconvolution and cell-cell interaction analyses to cell type-specific (tumor-enriched and vessel-enriched) spatial transcriptomic data collected from 41 resected HCC tissue specimens. RESULTS: We report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. CONCLUSIONS: Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous signaling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer-endothelial cell interactions and related drug targets.


Assuntos
Carcinoma Hepatocelular , Células Endoteliais , Perfilação da Expressão Gênica , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/genética , Células Endoteliais/metabolismo , Comunicação Celular/genética , Transcriptoma , Masculino , Transdução de Sinais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Prognóstico
18.
J Am Chem Soc ; 146(40): 27451-27459, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39321462

RESUMO

Histone serotonylation has emerged as a key post-translational modification. WDR5 preferentially binds to serotonylated histone 3 (H3), and this binding event has been associated with tumorigenesis. Herein, we utilize genetic code expansion, structure-activity relationship studies, and computation to study an edge-face aromatic interaction between WDR5 Phe149 and serotonin on H3 that is key to this protein-protein interaction. We find experimentally that this edge-face aromatic interaction is unaffected by modulating the electrostatics of the face component but is weakened by electron-withdrawing substituents on the edge component. Overall, these results elucidate that this interaction is governed by van der Waals forces as well as electrostatics of the edge ring, a result that clarifies discrepancies among previous theoretical models and model system studies of this interaction type. This is the first evaluation of the driving force of an edge-face aromatic interaction at a protein-protein interface and provides a key benchmark for the nature of these understudied interactions that are abundant in the proteome.


Assuntos
Histonas , Eletricidade Estática , Histonas/química , Histonas/metabolismo , Humanos , Ligação Proteica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Processamento de Proteína Pós-Traducional , Modelos Moleculares , Relação Estrutura-Atividade
19.
Cancer ; 130 Suppl 20: 3602-3611, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39254372

RESUMO

BACKGROUND: Poor comprehension of prostate cancer (PCa) medical terms can create barriers to PCa treatment discussions. The authors measured comprehension of PCa terms and its relationship to health literacy in a group of Black men who were newly diagnosed with PCa. They examined whether tailoring communication with alternative colloquial words would be helpful and acceptable. METHODS: Patients were recruited from urology clinics (N = 152). After they met with their providers to discuss PCa treatment options, they participated in an educational supplement delivered as a structured interview. The supplement tailored PCa treatment information by allowing men to choose between colloquial and medical terms for genitourinary (GU) function. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine, and comprehension of common PCa terms was assessed using published methods. Pearson correlation was used to estimate the association between health literacy and comprehension of PCa terms. Spearman rank correlation (r) was used to assess the relation between the total number of medical terms preferred (range, 0-10) and Rapid Estimate of Adult Literacy in Medicine scores (range, 0-66). RESULTS: Most patients (62%) had low health literacy, which was strongly correlated with their understanding of PCa terms (r = 0.526; p < .001). Poor comprehension of many PCa terms established the need to use alternative language for GU function (only 20% knew the word incontinence). There was a statistically significant positive association between the number of medical terms preferred and health literacy (r = 0.358; p < .001). A majority of patients (91%) preferred a mixture of medical and colloquial terms. CONCLUSIONS: Tailoring communications with colloquial terms for GU function was preferred by most patients regardless of health literacy.


Assuntos
Compreensão , Letramento em Saúde , Idioma , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/terapia , Idoso , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Comunicação , Relações Médico-Paciente , Idoso de 80 Anos ou mais
20.
Artigo em Inglês | MEDLINE | ID: mdl-39311804

RESUMO

Introduction: The use of medical cannabis (MC) to treat a host of conditions has expanded considerably in the United States; however, precise quantitative assessments of purchasing characteristics are unknown. This study sought to characterize the trends in MC purchases, US dollars spent, and type and amount purchased by demographic and clinical characteristics. Materials and Methods: This descriptive exploratory association study examined statewide MC registry data in Arkansas linked at the person level with statewide transaction data documenting each MC purchase. MC transaction data (May 11, 2019-August 31, 2022) were assessed to identify persons who could be linked to the registry data and made at least one purchase. Individual demographic characteristics and MC qualifying conditions (QCs) were ascertained. Product types were classified into plant cannabis, cannabis extract for inhalation (vape), edibles, and others. The average daily total delta-9-tetrahydrocannabinol (THC) purchased was calculated based on the concentration and quantity purchased. Purchasing characteristics are described and demographic and clinical factors associated with THC purchased per day and dollars spent per year were estimated by ordinary least square regression and general linear models with a gamma distribution. Results: On average, 89,057 MC purchasers spent $3343 (interquartile range [IQR], $907-$4802), had 33.34 (IQR, 8.32-46.03) transaction days per year, and purchased 162.32 mg (IQR, 30.51-237.69) of THC per day. Most persons predominantly purchased plant cannabis (68.27%), followed by edibles (14.92%) and vape (11.96%). Individuals younger than 18 years of age (ß=-78.23; 95% confidence interval [CI], -116.599 to -39.863), persons 70 and older (ß = -122.30; 95% CI, -128.18 to -116.422), and women (ß=-33.70; 95% CI, -35.95 to -31.446) purchased less THC per day than their counterparts after multivariate adjustment. The most common QCs were pain and post-traumatic stress disorder (PTSD), and compared to those with cancer, persons with pain (ß = 26.30; 95% CI, 18.636-33.96) and PTSD (ß = 38.34; 95% CI, 30.467-46.222) purchased more THC per day. Conclusion: The average THC purchased per person per day exceeds typically recommended daily doses for therapeutic uses, and further research is warranted to assess the safety and benefits of MC across these conditions.

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