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1.
Eur J Prev Cardiol ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38573232

RESUMO

AIM: In the current paper, we aim to explore the effect of both current and former long-term anabolic-androgenic steroid (AAS) use on regulation of systemic inflammatory markers and mediators of extracellular matrix (ECM) remodeling and their association with hormones and echocardiographic myocardial pathology in weightlifters. METHODS: In a cross-sectional study, 93 weightlifting AAS-users, of which 62 were current and 31 were past users, with at least one-year cumulative AAS-use (mean 11±7 accumulated years of AAS-use), were compared to 54 non-using weightlifting controls (WLC) using clinical interview, blood pressure measurements, and echocardiography. RESULTS: Serum levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF), interferon (IFN)γ, growth differentiation factor (GDF)-15 and matrix metalloproteinase (MMP-9), sex hormones and lipids were analyzed. Serum levels of IL-8, GDF-15 and MMP-9 were significantly increased in current AAS users compared to former users and WLC. MMP-9, but not IL-8, correlated consistently with sex-hormone levels, and sex-hormone levels correlated consistently with mean wall thickness, in current users. Moreover, HDL cholesterol was significantly lower in current versus former AAS users, in significantly inversely correlated with MMP-9 in current users. Further, in current users, MMP-9 and IL-8 correlated with markers of myocardial strain, and MMP9 also with indices of cardiac mass, which was not seen in former users. Mediation analyses suggested that MMP-9 could partly explain hormone-induced alterations in markers of myocardial damage in current users. CONCLUSION: In conclusion, long-term AAS is associated with increased levels of markers of inflammation and extracellular matrix remodeling, which seems to have a hormone-dependent (MMP-9) and hormone-independent (IL-8) association with markers of myocardial dysfunction.


Long-term use of anabolic-androgenic steroids (AAS) can increase inflammation and mediators of extracellular matrix (ECM) remodeling which potentially could be involved in myocardial pathology seen in these individuals. AAS use increased levels of inflammatory marker IL-8 and marker of ECM remodeling MMP-9.IL-8 and MMP-9 were both associated with myocardial pathology in current, but not former users, suggesting that these markers are association with risk of myocardial damage during AAS use.

2.
Clin Cancer Res ; 30(11): 2514-2530, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38252421

RESUMO

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.


Assuntos
Lectinas Tipo C , Receptores Imunológicos , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Camundongos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologia , Lectinas Tipo C/metabolismo , Lectinas Tipo C/imunologia , Lectinas Tipo C/antagonistas & inibidores , Linhagem Celular Tumoral , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Linfoma de Células T/terapia , Linfoma de Células T/tratamento farmacológico , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia
3.
JCO Oncol Pract ; 20(2): 220-227, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37683132

RESUMO

PURPOSE: This study investigated the effectiveness of algorithmic testing in hematopathology at the Brigham and Women's Hospital and Dana-Farber Cancer Institute (DFCI). The algorithm was predicated on test selection after an initial pathologic evaluation to maximize cost-effective testing, especially for expensive molecular and cytogenetic assays. MATERIALS AND METHODS: Standard ordering protocols (SOPs) for 17 disease categories were developed and encoded in a decision support application. Six months of retrospective data from application beta testing was obtained and compared with actual testing practices during that timeframe. In addition, 2 years of prospective data were also obtained from patients at one community satellite site. RESULTS: A total of 460 retrospective cases (before introduction of algorithmic testing) and 109 prospective cases (following introduction) were analyzed. In the retrospective data, 61.7% of tests (509 of 825) were concordant with the SOPs while 38.3% (316 of 825) were overordered and 30.8% (227 of 736) of SOP-recommended tests were omitted. In the prospective data, 98.8% of testing was concordant (244 of 247 total tests) with only 1.2% overordered tests (3 of 247) and 7.6% omitted tests (20 of 264 SOP-recommended tests; overall P < .001). The cost of overordered tests before implementing SOP indicates a potential annualized saving of $1,347,520 in US dollars (USD) in overordered testing at Brigham and Women's Hospital/DFCI. Only two of 316 overordered tests (0.6%) returned any additional information, both for extremely rare clinical circumstances. CONCLUSION: Implementation of SOPs dramatically improved test ordering practices, with a just right number of ancillary tests that minimizes cost and has no significant impact on acquiring key informative test results.


Assuntos
Medula Óssea , Hospitais , Humanos , Feminino , Medula Óssea/patologia , Estudos Retrospectivos , Biologia Molecular
4.
Antimicrob Agents Chemother ; 68(1): e0109923, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38059635

RESUMO

This was a phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of oral ceftibuten to describe the pharmacokinetics (PK) of cis-ceftibuten (administered form) and trans-ceftibuten (metabolite), and to describe safety and tolerability at higher than licensed doses. Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10. Non-compartmental methods were used to describe parent drug and metabolite PK in plasma and urine. Dose proportionality was examined using C max, AUC0-12, and AUC0-INF. Accumulation was calculated as the ratio of AUC0-12 on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean cis- and trans-ceftibuten C max were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 64.3%-86.9% of the administered dose over 48 h. Following multiple ascending doses, mean cis- and trans-ceftibuten C max were 21.7, 28.1, and 38.8 mg/L, and 1.4, 1.9, and 2.8 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 72.2%-96.4% of the administered dose at steady state. The exposure of cis- and trans-ceftibuten increased proportionally with increasing doses. Cis- and trans-ceftibuten accumulation factor was 1.14-1.19 and 1.28-1.32. The most common gastrointestinal treatment emergent AEs were mild and resolved without intervention. Ceftibuten was well tolerated. Dose proportionality and accumulation of cis- and trans-ceftibuten were observed. These results support the ongoing development of ceftibuten at doses up to 800 mg twice-daily. (The study was registered at ClinicalTrials.gov under the identifier NCT03939429.).


Assuntos
Ceftibuteno , Adulto , Humanos , Área Sob a Curva , Método Duplo-Cego , Voluntários Saudáveis , Administração Oral , Relação Dose-Resposta a Droga
5.
Mod Pathol ; 37(1): 100352, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37839675

RESUMO

In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Humanos , Medula Óssea/patologia , Células Dendríticas/metabolismo , Mutação , Leucemia Mieloide Aguda/patologia , Neoplasias Hematológicas/patologia , Neoplasias Cutâneas/patologia , Transtornos Mieloproliferativos/patologia , Proteínas Nucleares/genética
7.
Nature ; 618(7966): 834-841, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37286599

RESUMO

Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1-4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.


Assuntos
Transformação Celular Neoplásica , Células Dendríticas , Leucemia Mieloide Aguda , Neoplasias Cutâneas , Pele , Raios Ultravioleta , Humanos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Células da Medula Óssea/efeitos da radiação , Morte Celular/efeitos da radiação , Linhagem da Célula/genética , Linhagem da Célula/efeitos da radiação , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/efeitos da radiação , Células Clonais/metabolismo , Células Clonais/patologia , Células Clonais/efeitos da radiação , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Células Dendríticas/efeitos da radiação , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação/efeitos da radiação , Especificidade de Órgãos , Análise da Expressão Gênica de Célula Única , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversos , Pele/patologia , Pele/efeitos da radiação
8.
Leuk Lymphoma ; 64(5): 972-980, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36960680

RESUMO

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.


First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1Mut MS may be genetically distinct from NPM1Mut AML.NPM1Mut MS may have inferior overall survival compared to NPM1Mut AML.


Assuntos
Leucemia Mieloide Aguda , Sarcoma Mieloide , Humanos , Medula Óssea/patologia , Proteínas Nucleares/genética , Nucleofosmina , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/genética , Sarcoma Mieloide/patologia , Estudos Retrospectivos , Estudos de Coortes , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico
9.
Blood ; 141(15): 1817-1830, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36706355

RESUMO

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Ipilimumab/uso terapêutico , Decitabina/uso terapêutico , Síndromes Mielodisplásicas/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Recidiva
10.
Artigo em Inglês | MEDLINE | ID: mdl-33685898

RESUMO

The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.

11.
J Homosex ; 70(13): 3271-3295, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-35834605

RESUMO

Relatively little is known about how gender and sexual orientation intersect to predict young adults' responses to unwanted romantic and sexual overtures from men and women suitors. To better understand these potential differences, and explore possible mechanisms that explain them, this pre-registered study used an online questionnaire to assess reactions to both hypothetical and recalled suitors among a sample of 855 cisgender heterosexual and gay young adults (18-35) from the United States. Results revealed that gay women and heterosexual men reported the most negative hypothetical reactions to men (versus women) suitors, while gay women, heterosexual men, and heterosexual women all recalled more negative reactions to men than women suitors. Gay men recalled relatively benign reactions to suitors of both genders. A desire to be seen as one's true orientation was a mediating factor for both gay women's and heterosexual men's negative reactions to men suitors. These findings and their potential explanations highlight the complexity of how gender and sexual orientation intersect to shape responses to romantic and sexual overtures from men and women suitors.


Assuntos
Minorias Sexuais e de Gênero , Adulto Jovem , Feminino , Humanos , Masculino , Estados Unidos , Comportamento Sexual , Identidade de Gênero , Heterossexualidade , Inquéritos e Questionários
13.
Nutr Diet ; 79(5): 572-581, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36127861

RESUMO

AIMS: This retrospective audit was conducted to investigate the association between outcome and protein-energy malnutrition diagnosed using Subjective Global Assessment (SGA), to evaluate the predictive validity of Subjective Global Assessment in adults admitted to intensive care. METHODS: The audit analysed the medical records of 1034 consecutive adult patients who had nutrition assessment on admission to the intensive care unit between January 2017 and July 2018. Extracted data included patient demographics, nutritional status, outcomes, and Acute Physiology and Chronic Health Evaluation II score. Regression was used to explore the association between Subjective Global Assessment and outcomes. RESULTS: The prevalence of protein-energy malnutrition was 39.5% (342 patients SGA-B, and 75 patients SGA-C), and there was a significant independent association between Subjective Global Assessment and outcomes both in surgical and non-surgical patients. Compared with well-nourished patients, mortality was significantly higher in the malnourished, during the intensive care admission (p = 0.007), in hospital (p < 0.0001), at 90 days (p = 0.001) and at 180 days (p = 0.002). Pressure injuries were more common (p = 0.01). Length of stay was longer in intensive care (p = 0.001) and in hospital (p < 0.001), with increased readmission rate (p < 0.001). CONCLUSION: Protein-energy malnutrition diagnosed by Subjective Global Assessment had a significant independent association with adverse clinical outcomes in critically ill patients. Subjective Global Assessment appears to have predictive validity in this patient population.


Assuntos
Desnutrição Proteico-Calórica , Adulto , Humanos , Estudos Retrospectivos , Tempo de Internação , Resultado do Tratamento , Unidades de Terapia Intensiva
14.
Am J Perinatol ; 2022 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-35815573

RESUMO

OBJECTIVE: The aim of the study is to describe a model of care and outcomes for placenta accreta spectrum (PAS) implemented in the context of a community based non-academic health system. STUDY DESIGN: The program for management of PAS includes a multidisciplinary team approach with protocols for ultrasound assessment, diagnosis, and surgery. The program was implemented in the two largest private hospitals in the Twin Cities, Minnesota, United States. Maternal and fetal outcomes as well as cost were compared for histopathologic confirmed PAS cases before (2007-2014, n = 41) and after (2015-2017, n = 26) implementation of the PAS program. RESULTS: Implementation of the PAS program was associated with ICU admission reductions from 53.7 to 19.2%, p = 0.005; a decrease of 1,682 mL in mean estimated blood loss (EBL) (p = 0.061); a decrease in transfusion from 85.4 to 53.9% (p = 0.005). The PAS program also resulted in a (non-significant) decrease in both surgical complications from 48.8 to 38.5% (p = 0.408) and postoperative complications from 61.0 to 42.3% (p = 0.135). The total cost of care for PAS cases in the 3 years after implementation of the program decreased by 33%. CONCLUSION: The implementation of a model of care for PAS led by a perinatology practice at a large regional non-academic referral center resulted in reductions of ICU admissions, operating time, transfusion, selected surgical complications, overall postoperative complications, and cost. KEY POINTS: · Implementation of a PAS care model resulted in reduced ICU admissions from 53.7% to 19.2%.. · Patient safety increased by reducing blood loss, transfusions and postoperative complications.. · This model decreased operating time, as well as total cost of care by 33%..

15.
Front Public Health ; 10: 881613, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35570919

RESUMO

The risk of potential SARS-CoV-2 transmission by infected mothers during labor and delivery has not been investigated in-depth. This work collected air samples close to (respiratory droplets) and more distant from (aerosol generation) unvaccinated patients who had previously tested positive for SARS-CoV-2 during labor within 5 days of a positive test. All but one of the patients wore masks during the delivery, and delivery was carried out in either birthing or negative pressure isolation rooms. Our work failed to detect SARS-CoV-2 RNA in any air samples for all of the six patients who gave birth vaginally, despite validation of the limit of detection of the samplers. In sum, this brief report provides initial evidence that the risk of airborne transmission of SARS-CoV-2 during labor may be mitigated by the use of masks and high ventilation rates common in many modern U.S. medical facilities; however more work is needed to fully evaluate the risk of SARS-CoV-2 transmission during labor and maternal pushing.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/epidemiologia , Feminino , Humanos , Máscaras , Mães , Gravidez , RNA Viral , SARS-CoV-2/genética
17.
Vet Comp Oncol ; 20(3): 613-622, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35338560

RESUMO

Orally administered daily chemotherapy offers a novel treatment approach for canine lymphoma in a population of dogs that have failed or not tolerated maximum tolerable dose chemotherapy. A multidrug oral chemotherapy protocol was designed and implemented for the treatment of 50 dogs with multicentric lymphoma with minimal side effects. The protocol consisted of oral procarbazine, prednisolone and cyclophosphamide (PPC) administered daily. Efficacy and toxicity were evaluated by clinical and laboratory evaluation. An overall response rate of 70% was achieved, with 24% and 46% of dogs having a partial and complete response, respectively, to treatment with the PPC protocol. Response to the PPC protocol (complete or partial) and age were the only factors identified as prognostic for time from initiation of the PPC chemotherapy until death. Overall, the protocol was very well tolerated with only one dog requiring protocol discontinuation due to grade 4 thrombocytopenia. Eight dogs recorded gastrointestinal toxicities, seven grade I and one grade II toxicity. These findings demonstrate that the administration of a continuous oral combination chemotherapy can provide comparable survival times in the rescue setting in dogs with multicentric lymphoma with minimal side effects.


Assuntos
Doenças do Cão , Linfoma , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doenças do Cão/tratamento farmacológico , Cães , Doxorrubicina/uso terapêutico , Linfoma/tratamento farmacológico , Linfoma/veterinária , Prednisolona/uso terapêutico , Procarbazina/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
18.
Cancer Discov ; 12(2): 522-541, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34615655

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDC). BPDCN occurs at least three times more frequently in men than in women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN, and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. SIGNIFICANCE: Sex bias in cancer is well recognized, but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.This article is highlighted in the In This Issue feature, p. 275.


Assuntos
Células Dendríticas/metabolismo , Transtornos Mieloproliferativos/genética , Ribonucleoproteínas/genética , Apoptose , Feminino , Identidade de Gênero , Humanos , Masculino , Mutação
19.
Int J Cancer ; 150(5): 753-760, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34626122

RESUMO

Few data exist on Epstein-Barr virus (EBV) prevalence across the full spectrum of lymphoma subtypes, particularly in sub-Saharan Africa. The objective of our study was to test the presence of EBV in a nationally representative sample of malignant lymphomas diagnosed in the Butaro Cancer Center of Excellence (BCCOE) in Rwanda. Of 102 Hodgkin (HL) and 378 non-Hodgkin lymphomas (NHL) diagnosed in BCCOE between 2012 and 2018, 52 HL and 207 NHL were successfully tested by EBV-encoding RNA in situ hybridization. EBV prevalence was 54% in HL, being detected in all classical HL subtypes: mixed-cellularity (n = 3/8), nodular-sclerosis (n = 7/17) and lymphocyte-rich (n = 2/3). EBV prevalence was 9% in NHL, being 10% among 158 B-cell NHL, 3% among 35 T-cell NHL and the single NK-cell NHL was EBV-positive. Among B-cell NHL, EBV was present in the majority of Burkitt (n = 8/13), and was also rarely detected in follicular (n = 1/4) and acute B-cell lymphoblastic (n = 1/45) lymphomas. Five of the 45 (11%) diffuse large B-cell lymphomas (DLBCLs) were EBV-positive, including three out of five plasmablastic lymphoma (PBL). Of 39 HL and 163 NHL of known human immunodeficiency virus (HIV) status, 2 (5%) and 14 (9%) were HIV-positive, respectively, of which only four were also EBV-positive (2 PBL, 2 HL). In summary, we report rare regional-level data on the association of EBV with classical HL, Burkitt and DLBCLs, and report sporadic detection in other subtypes possibly related to EBV. Such data inform the burden of disease caused by EBV and can help guide application of future advances in EBV-specific prevention and therapeutics.


Assuntos
Herpesvirus Humano 4/isolamento & purificação , Linfoma/virologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Linfoma/classificação , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Ruanda , Fatores de Tempo , Adulto Jovem
20.
Ecol Food Nutr ; 61(3): 353-366, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34968147

RESUMO

The study examines the extent to which Hispanic/Latino Americans and non-Hispanic White Americans report that meat is an important aspect of their cultural beliefs and practices. An online national survey was completed using quota sampling to recruit approximately equal groups of U.S. Hispanic/Latino and non-Hispanic White Americans (n = 512). A path model predicting willingness to reduce meat consumption was estimated. Hispanic/Latino Americans viewed meat as a more integral aspect of their cultural food practices, and reported that meat dishes comprise a higher percentage of their culture's traditional foods. Cultural beliefs were associated with meat consumption and willingness to reduce meat consumption.


Assuntos
Hispânico ou Latino , População Branca , Adulto , Humanos , Carne , Estados Unidos
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