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Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.
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Neoplasias Colorrectales , Inestabilidad de Microsatélites , Microambiente Tumoral , Humanos , Inestabilidad Cromosómica/genética , Neoplasias Colorrectales/patología , Perfilación de la Expresión Génica , Quinasas p21 Activadas/genética , Filogenia , Mutación , Progresión de la Enfermedad , PronósticoRESUMEN
The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.
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Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Genómica , Humanos , Neoplasias/genética , Neoplasias/patología , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Proteínas Represoras/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Ciclo Celular , Movimiento Celular , Proliferación Celular , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pronóstico , Prolil Hidroxilasas/genética , Prolil Hidroxilasas/metabolismo , Proteínas Represoras/genética , Células Tumorales Cultivadas , Ubiquitinación , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Proteínas Quinasas/genética , Proteoma/análisis , Animales , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Bencimidazoles/uso terapéutico , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , SorafenibRESUMEN
Ceroid lipofuscinosis neuronal 5 (CLN5) and cathepsin D (CTSD) are soluble lysosomal enzymes that also localize extracellularly. In humans, homozygous mutations in CLN5 and CTSD cause CLN5 disease and CLN10 disease, respectively, which are two subtypes of neuronal ceroid lipofuscinosis (commonly known as Batten disease). The mechanisms regulating the intracellular trafficking of CLN5 and CTSD and their release from cells are not well understood. Here, we used the social amoeba Dictyostelium discoideum as a model system to examine the pathways and cellular components that regulate the intracellular trafficking and release of the D. discoideum homologs of human CLN5 (Cln5) and CTSD (CtsD). We show that both Cln5 and CtsD contain signal peptides for secretion that facilitate their release from cells. Like Cln5, extracellular CtsD is glycosylated. In addition, Cln5 release is regulated by the amount of extracellular CtsD. Autophagy induction promotes the release of Cln5, and to a lesser extent CtsD. Release of Cln5 requires the autophagy proteins Atg1, Atg5, and Atg9, as well as autophagosomal-lysosomal fusion. Atg1 and Atg5 are required for the release of CtsD. Together, these data support a model where Cln5 and CtsD are actively released from cells via their signal peptides for secretion and pathways linked to autophagy. The release of Cln5 and CtsD from cells also requires microfilaments and the D. discoideum homologs of human AP-3 complex mu subunit, the lysosomal-trafficking regulator LYST, mucopilin-1, and the Wiskott-Aldrich syndrome-associated protein WASH, which all regulate lysosomal exocytosis in this model organism. These findings suggest that lysosomal exocytosis also facilitates the release of Cln5 and CtsD from cells. In addition, we report the roles of ABC transporters, microtubules, osmotic stress, and the putative D. discoideum homologs of human sortilin and cation-independent mannose-6-phosphate receptor in regulating the intracellular/extracellular distribution of Cln5 and CtsD. In total, this study identifies the cellular mechanisms regulating the release of Cln5 and CtsD from D. discoideum cells and provides insight into how altered trafficking of CLN5 and CTSD causes disease in humans.
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Dictyostelium , Lipofuscinosis Ceroideas Neuronales , Humanos , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Catepsina D/metabolismo , Dictyostelium/metabolismo , Señales de Clasificación de Proteína , Proteínas de Membrana de los Lisosomas/genéticaRESUMEN
Highly pathogenic avian influenza viruses of the H5N1 clade 2.3.4.4b were detected in North America in the winter of 2021/2022. These viruses have spread across the Americas, causing morbidity and mortality in both wild and domestic birds as well as some mammalian species, including cattle. Many surveillance programs for wildlife as well as commercial poultry operations have detected these viruses. In this study, we conducted surveillance of avian species in the urban environment in New York City. We detected highly pathogenic H5N1 viruses in six samples from four different bird species and performed whole-genome sequencing. Sequencing analysis showed the presence of multiple different genotypes. Our work highlights that the interface between animals and humans that may give rise to zoonotic infections or even pandemics is not limited to rural environments and commercial poultry operations but extends into the heart of our urban centers.IMPORTANCEWhile surveillance programs for avian influenza viruses are often focused on migratory routes and their associated stop-over locations or commercial poultry operations, many bird species-including migratory birds-frequent or live in urban green spaces and wetlands. This brings them into contact with a highly dense population of humans and pets, providing an extensive urban animal-human interface in which the general public may have little awareness of circulating infectious diseases. This study focuses on virus surveillance of this interface, combined with culturally responsive science education and community outreach.
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Animales Salvajes , Aves , Subtipo H5N1 del Virus de la Influenza A , Gripe Aviar , Animales , Humanos , Animales Salvajes/virología , Aves/virología , Genoma Viral/genética , Genotipo , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Subtipo H5N1 del Virus de la Influenza A/clasificación , Gripe Aviar/virología , Gripe Aviar/epidemiología , Gripe Humana/virología , Gripe Humana/epidemiología , Ciudad de Nueva York/epidemiología , Aves de Corral/virología , Secuenciación Completa del Genoma , Zoonosis Virales/virologíaRESUMEN
PURPOSE: Because multiple management options exist for clinical T1 renal masses, patients may experience a state of uncertainty about the course of action to pursue (ie, decisional conflict). To better support patients, we examined patient, clinical, and decision-making factors associated with decisional conflict among patients newly diagnosed with clinical T1 renal masses suspicious for kidney cancer. MATERIALS AND METHODS: From a prospective clinical trial, participants completed the Decisional Conflict Scale (DCS), scored 0 to 100 with < 25 associated with implementing decisions, at 2 time points during the initial decision-making period. The trial further characterized patient demographics, health status, tumor burden, and patient-centered communication, while a subcohort completed additional questionnaires on decision-making. Associations of patient, clinical, and decision-making factors with DCS scores were evaluated using generalized estimating equations to account for repeated measures per patient. RESULTS: Of 274 enrollees, 250 completed a DCS survey; 74% had masses ≤ 4 cm in size, while 11% had high-complexity tumors. Model-based estimated mean DCS score across both time points was 17.6 (95% CI 16.0-19.3), though 50% reported a DCS score ≥ 25 at least once. On multivariable analysis, DCS scores increased with age (+2.64, 95% CI 1.04-4.23), high- vs low-complexity tumors (+6.50, 95% CI 0.35-12.65), and cystic vs solid masses (+9.78, 95% CI 5.27-14.28). Among decision-making factors, DCS scores decreased with higher self-efficacy (-3.31, 95% CI -5.77 to -0.86]) and information-seeking behavior (-4.44, 95% CI -7.32 to -1.56). DCS scores decreased with higher patient-centered communication scores (-8.89, 95% CI -11.85 to -5.94). CONCLUSIONS: In addition to patient and clinical factors, decision-making factors and patient-centered communication relate with decisional conflict, highlighting potential avenues to better support patient decision-making for clinical T1 renal masses.
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Conflicto Psicológico , Toma de Decisiones , Neoplasias Renales , Humanos , Estudios Prospectivos , Neoplasias Renales/psicología , Neoplasias Renales/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estadificación de Neoplasias , Encuestas y Cuestionarios , Participación del Paciente , AdultoRESUMEN
BACKGROUND: Percutaneous mitral valvuloplasty (PMV) is a standard treatment for severe rheumatic mitral stenosis (RMS). However, the prognostic significance of the change in mitral valve area (∆MVA) during PMV is not fully understood.MethodsâandâResults: This study analyzed data from the Multicenter mitrAl STEnosis with Rheumatic etiology (MASTER) registry, which included 3,140 patients with severe RMS. We focused on patients with severe RMS undergoing their first PMV. Changes in echocardiographic parameters, including MVA quantified before and after PMV, and composite outcomes, including mitral valve reintervention, heart failure admission, stroke, and all-cause death, were evaluated. An optimal result was defined as a postprocedural MVA ≥1.5 cm2without mitral regurgitation greater than Grade II. Of the 308 patients included in the study, those with optimal results and ∆MVA >0.5 cm² had a better prognosis (log-rank P<0.001). Patients who achieved optimal results but with ∆MVA ≤0.5 cm² had a greater risk of composite outcomes than those with optimal outcomes and ∆MVA >0.5 cm² (nested Cox regression analysis, hazard ratio 2.27; 95% confidence interval 1.09-4.73; P=0.028). CONCLUSIONS: Achieving an increase in ∆MVA of >0.5 cm2was found to be correlated with improved outcomes. This suggests that, in addition to achieving traditional optimal results, targeting an increase in ∆MVA of >0.5 cm2could be a beneficial objective in PMV treatment for RMS.
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OBJECTIVE: To examine the acute and chronic effects of reducing prolonged sedentary time (ST) with physical activity (PA) on cognitive and brain health. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Scopus, CINAHL, PsycINFO, SPORTDiscus, Web of Science, and ProQuest Dissertation and Theses. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) published from inception to 17 June 2024, with healthy participants without cognitive impairment or neurological conditions that affect cognitive functioning, aged ≥4 years, testing acute and chronic effects of reducing ST and/or prolonged ST by reallocating ST to PA on cognitive function, brain function, and structure. RESULTS: We included 25 RCTs (n=1289) investigating acute (21 studies) and chronic (4 studies) effects on cognitive function (acute: n=20, chronic: n=4) and brain function (acute: n=7, chronic: n=1); there were no studies on brain structure. Acutely interrupting continuous ST with either multiple or a single PA bout improved cognitive function measured from 3 hours to three consecutive days based on 91 effect sizes (g=0.17, 95% CI: 0.05 to 0.29, p=0.005, I 2=45.5%). When comparing single versus multiple PA bouts, only multiple PA bouts yielded a positive effect on cognitive function based on 72 effect sizes (g=0.20, 95% CI: 0.06 to 0.35, p=0.006; I 2=48.8%). Chronic studies reported null findings on cognitive function (n=4), with some evidence of improved neural efficiency of the hippocampus (n=1). CONCLUSION: Interrupting ST with PA acutely improves cognitive function. The evidence from chronic studies remains inconclusive. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020200998.
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PURPOSE: To compare outcomes of patients who underwent rotator cuff repair (RCR) with concomitant biceps tenodesis with those who underwent an isolated RCR. METHODS: Exclusion criteria included previous ipsilateral shoulder surgery, irreparable rotator cuff tears, rotator cuff arthropathy, calcific tendinitis, adhesive capsulitis requiring a capsular release, or advanced osteoarthritis of the glenohumeral joint. Patients were indicated for biceps tenodesis if they had any degree of tendon tearing, moderate-to-severe tenosynovitis, instability, or a significant degenerative SLAP tear. Primary outcome measures included American Shoulder and Elbow Surgeons score, Simple Shoulder Test, EuroQoL 5-Dimension 5-Level visual analog scale, EuroQoL 5-Dimension 5-Level, and a site-specific questionnaire, which focused on surgical expectations, satisfaction, and complications. Multivariate analysis of variance to analyze descriptive statistics and determine significant differences between the patient groups for subjective and objective outcome measures were performed. RESULTS: There were no significant differences for pain/visual analog scale (0.34 ± 0.09 vs 0.47 ± 0.09, P = .31), American Shoulder and Elbow Surgeons score (96.69 ± 0.87 vs 94.44 ± 0.91, P = .07), and Simple Shoulder Test (11.42 ± 0.17 vs 10.95 ± 0.18, P = .06) between the RCR with concomitant biceps tenodesis and isolated RCR at a minimum of 2 years' postoperatively. This is despite the RCR with concomitant biceps tenodesis group having significantly larger rotator cuff tears (4.25 ± 0.30 cm2 vs 2.80 ± 0.32 cm2, P = .001) than the isolated RCR group. CONCLUSIONS: This study revealed that concomitant biceps tenodesis does not compromise outcomes when compared with an isolated RCR at 2-year follow-up, despite this group having larger rotator cuff tears. LEVEL OF EVIDENCE: Level III, retrospective case study.
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BACKGROUND: Most primary total hip arthroplasties (THAs) performed in the United States utilize cementless fixation with porous or hydroxyapatite (HA) coating. A previous meta-analysis comparing HA-coated versus non-HA-coated stems in primary THA published in 2013 found no significant difference between the 2. However, an updated analysis of the current literature is needed to assess the potential benefit of HA-coated stems in primary THA. METHODS: Various libraries were searched through May 2022 according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Studies included were randomized controlled trials comparing HA-coated femoral stems to non-HA-coated stems in primary THA. Outcomes included Harris Hip Score (HHS), endosteal bone formation, radiolucent lines, linear wear rate, revision for aseptic loosening, thigh pain, and heterotopic ossification. RESULTS: There were significantly fewer revisions for aseptic loosening (P = .004) and decreased postoperative thigh pain (P = .03) for patients who have with HA-coated stems. There was no significant difference in HHS (P = .20), endosteal bone formation (P = .96), radiolucent lines (P = .75), linear wear rate (P = .41), or heterotopic ossification (P = .71) between HA-coated and non-HA-coated stems. CONCLUSION: We found that HA-coated femoral stems in primary THA led to significantly fewer stem revisions for aseptic loosening and less postoperative thigh pain compared to non-HA-coated stems. These findings suggest HA-coated femoral stems should be preferred over non-HA-coated femoral stems in primary THA.
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Artroplastia de Reemplazo de Cadera , Prótesis de Cadera , Osificación Heterotópica , Humanos , Durapatita , Diseño de Prótesis , Reoperación , Dolor , Resultado del Tratamiento , Falla de PrótesisRESUMEN
Importance: Renal cell carcinoma (RCC) is a common malignancy, with an estimated 434â¯840 incident cases worldwide in 2022. In the US, it is the sixth most common cancer among males and ninth among females. Observations: Clear cell RCC is the most common histologic subtype (75%-80% of cases) and is characterized by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene. Many patients (37%-61%) are diagnosed with RCC incidentally on an abdominal imaging study such as ultrasound or computed tomographic scan, and 70% of patients have stage I RCC at diagnosis. Although its incidence has increased approximately 1% per year from 2015 through 2019, the mortality rate of RCC has declined about 2% per year in the US from 2016 through 2020. Patients with a solid renal mass or complex cystic renal mass should be referred to urology. Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy, ablative techniques (eg, cryoablation, radiofrequency ablation, radiation), or active surveillance for some patients (especially those with renal masses <2 cm). For patients with renal masses less than 4 cm in size (48% of patients), partial nephrectomy can result in a 5-year cancer-specific survival of more than 94%. For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%, with a median overall survival of 46 to 56 months. Conclusions and Relevance: RCC is a common malignancy that is often diagnosed incidentally on an abdominal imaging study. Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV. First-line treatments for early-stage RCC are partial or radical nephrectomy, which can result in 5-year cancer-specific survival of more than 94%, ablative techniques, or active surveillance. New treatment options for patients with metastatic RCC include immune checkpoint inhibitors and tyrosine kinase inhibitors.
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BACKGROUND: Neurological symptoms associated with coronavirus disease 2019 (COVID-19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post-COVID-19 timeframe. PURPOSE: To determine whether adults who experienced flu-like symptoms due to COVID-19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu-like symptoms but tested negative for COVID-19. STUDY TYPE: Prospective observational. POPULATION: A total of 39 adults who previously self-isolated at home due to COVID-19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu-like symptoms but had a negative COVID-19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis). FIELD STRENGTH AND SEQUENCES: A 3.0 T; T1-weighted magnetization-prepared rapid gradient and echo-planar turbo gradient-spin echo arterial spin labeling sequences. ASSESSMENT: Arterial spin labeling was used to estimate CBF. A self-reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID-19 and control groups and between those with (n = 11) and without self-reported ongoing fatigue (n = 28) within the COVID-19 group. STATISTICAL TESTS: Between-group and within-group comparisons of CBF were performed in a voxel-wise manner, controlling for age and sex, at a family-wise error rate of 0.05. RESULTS: Relative to controls, the COVID-19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t-statistic = 5.21). Within the COVID-19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self-reported on-going fatigue. DATA CONCLUSION: These cross-sectional data revealed regional CBF decreases in the COVID-19 group, suggesting the relevance of brain physiology in the post-COVID-19 timeframe. This research may help elucidate the heterogeneous symptoms of the post-COVID-19 condition. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.
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COVID-19 , Adulto , Femenino , Humanos , Masculino , Circulación Cerebrovascular/fisiología , COVID-19/diagnóstico por imagen , Prueba de COVID-19 , Estudios Transversales , Fatiga/diagnóstico por imagen , Imagen por Resonancia Magnética , Marcadores de Spin , Persona de Mediana EdadRESUMEN
BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.
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Trastorno Bipolar , Trastorno Depresivo Resistente al Tratamiento , Adulto , Humanos , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/tratamiento farmacológico , Óxido Nitroso/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Antidepresivos/uso terapéutico , Neuroimagen , Midazolam , Resultado del Tratamiento , Método Doble CiegoRESUMEN
The prevalence of depression and the use of antidepressant medications have risen steadily in the United States over the past three decades. Antidepressants are the most commonly prescribed medications for U.S. adults 20 to 59 years of age. Second-generation antidepressants (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators, atypical antidepressants) are first-line therapy for depression. Psychotherapy, including cognitive behavior therapy and other types of individual and group therapy, is also a first-line treatment. The combination of medication and psychotherapy is preferred for severe depression. Treatment history, comorbidities, costs, and risk of adverse effects should be considered when choosing an antidepressant medication. Although many patients use antidepressants indefinitely, few studies have examined safety and effectiveness beyond two years. There is an increased risk of relapse or recurrence of depressive symptoms when an antidepressant is discontinued, compared with continued use. Gradually tapering the dosage while concurrently providing cognitive behavior therapy can decrease this risk. High-quality evidence on antidepressant use in pregnancy is lacking. Depression and use of antidepressants are both associated with preterm birth.
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Antidepresivos de Segunda Generación , Trastorno Depresivo , Nacimiento Prematuro , Recién Nacido , Adulto , Femenino , Embarazo , Humanos , Estados Unidos , Depresión/tratamiento farmacológico , Antidepresivos/uso terapéutico , Antidepresivos/efectos adversos , Trastorno Depresivo/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Antidepresivos de Segunda Generación/uso terapéuticoRESUMEN
INTRODUCTION: Total elbow arthroplasty (TEA) is often used to manage advanced arthropathies of the elbow caused by inflammatory conditions such as rheumatoid arthritis (RA). Recent literature has shown that use of TEA is decreasing in patients with RA, part of which can be attributed to early medical management involving disease-modifying antirheumatic drugs (DMARDs). However, there is a significant economic barrier to accessing DMARD therapy. The purpose of this study was to compare the use of TEA between patients with and without DMARD therapy from 2010 to 2020. METHODS: A retrospective cohort analysis was performed using a national insurance claim database to investigate the trends of patients with RA undergoing TEA from 2010-2020. Patients who underwent TEA and had a diagnosis of RA were identified using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD)-9 and ICD-10 codes between 2010 and 2020. These patients were then stratified into 2 cohorts: those with DMARD prescription claims and those without. A linear regression, compound annual growth rate (CAGR) analysis, and χ2 analysis were conducted to compare trends and demographic variables, including insurance type, between cohorts. Additionally, a multivariable logistic regression was subsequently performed to observe odds ratios (ORs) and 95% confidence intervals. RESULTS: From 2010 to 2020, there has been no significant change in the incidence of TEA in RA patients without DMARD prescriptions, whereas there has been a statistically significantly decreasing rate of TEA observed in RA patients with DMARD prescription claims. The analysis showed that there was a CAGR of -4%. For patients with a diagnosis of RA and DMARD prescription claims, the highest incidence of undergoing TEA was seen in the age group of 60-69 years, whereas patients with a diagnosis of RA and no DMARD prescription claims had the highest incidence of undergoing TEA in the age group of 70-79 years. CONCLUSION: The incidence of patients undergoing TEA with a diagnosis of RA and DMARD prescription claims has shown a statistically significant decrease from 2010 to 2020, whereas no significant difference was observed for patients without DMARD prescription claims. There were no statistically significant differences in the insurance plans between cohorts.
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Antirreumáticos , Artritis Reumatoide , Artroplastia de Reemplazo de Codo , Humanos , Persona de Mediana Edad , Anciano , Antirreumáticos/uso terapéutico , Estudios Retrospectivos , Codo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/cirugíaRESUMEN
In clear cell renal cell carcinoma (ccRCC), the von Hippel-Lindau tumor suppressor gene/hypoxia inducible factor (VHL/HIF) axis lays the groundwork for tumorigenesis and is the target of many therapeutic agents. HIF activation alone, however, is largely insufficient for kidney tumor development, and secondary mutations in PBRM1, BAP1, SETD2, KDM5C, or other tumor suppressor genes are strong enablers of tumorigenesis. Interestingly, it has been discovered that VHL loss and subsequent HIF activation results in upregulation of a negative feedback loop mediated by ISGF3, a transcription factor activated by type I interferon (IFN). Secondary mutations in the aforementioned tumor suppressor genes all partially disable this negative feedback loop to facilitate tumor growth. The convergence of several cancer genes on this pathway suggests that it plays an important role in ccRCC development and maintenance. Tumors with secondary mutations that dampen the negative feedback loop may be exquisitely sensitive to its reactivation, and pharmacological activation of ISGF3 either alone or in combination with other therapies could be an effective method to treat patients with ccRCC. In this review, we examine the relevance of the type I IFN pathway to ccRCC, synthesize our current knowledge of the ccRCC tumor suppressors in its regulation, and explore how this may impact the future treatment of patients with ccRCC.
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Carcinoma de Células Renales , Interferón Tipo I , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Interferón Tipo I/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/tratamiento farmacológico , Transformación Celular Neoplásica/genéticaRESUMEN
White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.
Asunto(s)
Leucoaraiosis , Sustancia Blanca , Vasos Coronarios , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Leucoaraiosis/patología , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
PURPOSE: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. METHODS: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. RESULTS: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81-98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2-8%) and Hispanics (2-5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. CONCLUSION: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Negro o Afroamericano , Hispánicos o Latinos , Humanos , Grupos Raciales , Neoplasias de la Vejiga Urinaria/terapia , Población BlancaRESUMEN
BACKGROUND: FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance. METHODS: 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients. RESULTS: Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response. CONCLUSIONS: Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.