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1.
Int J Biol Macromol ; 280(Pt 4): 136244, 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39368578

RESUMEN

Sticholysin II (StII), a pore-forming toxin from the marine anemone Stichodactyla helianthus, enhances an antigen-specific cytotoxic T lymphocyte (CTL) response when co-encapsulated in liposomes with a model antigen. This capacity does not depend exclusively on its pore-forming activity and is partially supported by its ability to activate Toll-like receptor 4 (TLR4) in dendritic cells, presumably by interacting with this receptor or by triggering signaling cascades upon binding to lipid membrane. In order to investigate whether the lipid binding capacity of StII is required for immunomodulation, we designed a mutant in which the aromatic amino acids from the interfacial binding site Trp110, Tyr111 and Trp114 were substituted by Ala. In the present work, we demonstrated that StII3A keeps the secondary structure composition and global folding of StII, while it loses its lipid binding and permeabilization abilities. Despite this, StII3A upregulates dendritic cells maturation markers, enhances an antigen-specific effector CD8+ T cells response and confers antitumor protection in a preventive scenario in C57BL/6 mice. Our results indicate that a mechanism independent of its lipid binding ability is involved in the immunomodulatory capacity of StII, pointing to StII3A as a promising candidate to improve the reliability of the Sts-based vaccine platform.

2.
Int J Mol Sci ; 25(17)2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39273608

RESUMEN

The coronavirus disease 2019 (COVID-19) survivors are frequently observed to present persistent symptoms constituting what has been called "post-acute COVID-19 syndrome" (PACS) or "long COVID-19". Some clinical risk factors have been identified to be associated with PACS development; however, specific mechanisms responsible for PACS pathology remain unknown. This study investigates clinical, immunological, and metabolomic risk factors associated with post-acute COVID-19 syndrome (PACS) in 51 patients, assessed 7-19 months after acute infection. Among the participants, 62.7% were male and 37.2% were female, with an average age of 47.8 years. At the follow-up, 37.2% met the criteria for PACS, revealing significant differences in immunological and metabolomic profiles at the time of acute infection. Patients with PACS were characterized by elevated levels of mature low-density granulocytes (LDGs), interleukin-8 (IL-8), pyruvate, pseudouridine, and cystine. Baseline multivariate analysis showed increased pyruvate and decreased alpha tocopherol levels. At follow-up, there was a decrease in absolute B lymphocytes and an increase in non-classical monocytes and 3-hydroxyisovaleric acid levels. These findings suggest that specific immunological and metabolomic markers during acute infection can help identify patients at higher risk of developing persistent PACS.


Asunto(s)
COVID-19 , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , Femenino , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/complicaciones , Masculino , Persona de Mediana Edad , Adulto , Factores de Riesgo , Biomarcadores , Metabolómica/métodos , Anciano , Metaboloma , Interleucina-8/metabolismo
3.
Cureus ; 16(7): e64956, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39161472

RESUMEN

INTRODUCTION: Gallstone disease is extremely prevalent in Western society, and the prevalence of common bile duct (CBD) stones with concomitant cholelithiasis increases significantly in the elderly. Different variants influence the treatment of this pathological entity, such as the origin of the stones, their location and quantity, comorbidities of the patient, impaction, and size of the lithos, the latter being an independent predictive factor. In most situations, choledocholithiasis can be resolved with endoscopic retrograde cholangiopancreatography (ERCP); however, in complex cases, such as giant choledocholithiasis (GC), advanced surgical, endoscopic, and percutaneous techniques are required to remove gallstones. The main objective was to determine if there is a correlation between GC and primary choledocholithiasis (PC). The secondary objective consisted of describing the endoscopic characterization of GC. METHODS:  The present study is a cross-sectional and single-center study. The study population consisted of patients of the Institute for Social Security and Services for State Workers (ISSSTE by its acronym in Spanish) Regional Hospital, León, Guanajuato, belonging directly to this center or referred, who required medical attention by the General Surgery/Endoscopy Service with the diagnosis of choledocholithiasis, during the period between January 2017 and December 2022. The Kolmogorov-Smirnov test was used as the normality test. Quantitative variables were reported as mean and standard deviation if the data distribution was normal, in contrast with the expression of data in the median and interquartile range if an abnormal distribution was found. Moreover, the qualitative variables are reported in frequencies or percentages. The Chi-square test was performed as the independence test. The significance level was a 95% confidence interval (p-value 0.05). The effect size was calculated with the odds ratio (OR). RESULTS:  Out of a total of 177 patients, 33 corresponded to PC (18.6%), and 144 belonged to the secondary choledocholithiasis (SC) group (81.4%). Likewise, regarding the dimensions of the lithos, 59 patients (33.3%) presented GC and 118 (66.7%) presented non-GC. Among the 59 patients with GC, 36 were female (61%) and 23 were male (39%). Regarding age, the distribution was as follows: mean 62 ± 12 years, with a minimum value of 29 and a maximum of 88 years. The non-parametric test used to determine the existence or not of a correlation between the variables was Pearson's Chi-square, whose value was 60.509, with a p < 0.001, demonstrating the presence of a correlation between PC and GC. The effect size was corroborated and defined with the OR, whose value was 39.6 (confidence interval (CI) 11.308-139.069). CONCLUSIONS:  There is a significant correlation between GC and PC, and it was found that mechanical lithotripsy was the most performed initial extraction method for GC; furthermore, a higher rate of complete endoscopic resolution was found, as well as no complications related to the procedure, which contrasts with the literature. It would be interesting to use the information revealed in the present study as a landmark in future research in this regard.

4.
JACC Adv ; 3(1): 100744, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38939802

RESUMEN

Background: Post-traumatic stress disorder (PTSD) is associated with increased rates of incident ischemic heart disease (IHD) in women. Objectives: The purpose of this study was to determine mechanisms of the PTSD-IHD association in women. Methods: In this retrospective longitudinal cohort study, data were obtained from electronic health records of all U.S. women veterans who were enrolled in Veterans Health Administration care from January 1, 2000 to December 31, 2017. Propensity score matching was used to match women with PTSD to women without PTSD on age, number of prior Veterans Health Administration visits, and presence of various traditional and nontraditional cardiovascular risk factors at index visit. Cox regression was used to model time until incident IHD diagnosis (ie, coronary artery disease, angina, or myocardial infarction) as a function of PTSD and potential mediating risk factors. Diagnoses of IHD, PTSD, and risk factors were defined by International Classification of Diseases-9th or -10th Revision, and/or Current Procedural Terminology codes. Results: PTSD was associated with elevated rates of developing each risk factor. Traditional risk factors (hypertension, hyperlipidemia, smoking, diabetes) accounted for 24.2% of the PTSD-IHD association, psychiatric risk factors (eg, depression, anxiety, substance use disorders) accounted for 33.8% of the association, and all 13 risk factors accounted for 48.5% of the association. Conclusions: Traditional IHD risk factors explained a quarter of the PTSD-IHD association in women veterans, and over half of the risk of IHD associated with PTSD remained unexplained even when adjusting for a wide range of risk factors. To be actionable, factors underlying the remaining PTSD-IHD association warrant timely investigation.

5.
Clin Rheumatol ; 43(7): 2253-2260, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38842744

RESUMEN

Up to 30% of patients with celiac disease (CD) suffer from concurrent autoimmune disease, compared to 3% of the general population. The association between CD and the current clinical phenotypes of inflammatory myopathies (IIM) patients has not been thoroughly addressed. Assess the CD features among patients with IIM and their relationship with the clinical phenotype and the myositis specific (MSA) and associated antibodies (MAA). For this cross-sectional study, we recruited 99 adult patients classified as IIM from a tertiary center in Mexico. We assessed serum MSA, MAA, and CD-associated autoantibodies (IgA anti-tissue transglutaminase (tTG) and both IgA and IgG anti-deaminated gliadin peptide (DGP)). Patients with highly suggestive serology for CD were then tested for IgG anti-endomysium antibodies, and a duodenal biopsy was performed. 70.7% of patients were positive for at least one antibody. Nine duodenal biopsies were taken, revealing findings compatible with celiac disease in two cases. Subjects with anti-MDA5 antibodies were more likely to have positive anti-tTG IgA antibodies (OR 6.76, 95% CI 1.85-24.62, P = 0.013) and suggestive CD serology (OR 6.41, 95% CI 1.62-25.29, P = 0.009). Patients with anti-Mi2 antibodies were more likely to have positive anti-DGP IgG antibodies (OR 3.35, 95% CI 1.12-9.96, P = 0.039), while positivity for these autoantibodies was less frequent in patients with anti-NXP2 antibodies (OR 0.22, 95% CI 0.06-0.80, P = 0.035). There is a higher prevalence of serologic and definite CD in patients with IIM compared to the general population. Identifying this subgroup of patients may have prognostic and therapeutic implications. Key points • The study estimated a serological celiac disease (CD) prevalence of 70.7% in patients with idiopathic inflammatory myopathies (IIM) and a biopsy-confirmed prevalence of 2%, suggesting that IIM patients should be considered a high-risk population for CD. • We identified a significant association between serological CD and the presence of anti-MDA5 and anti-Mi2 antibodies, suggesting a potential justification for celiac disease screening in this specific subgroup of patients. • The impact of gluten-free diets on IIM patients with serological markers of CD remains untested and warrants further investigation through prospective, randomized studies.


Asunto(s)
Autoanticuerpos , Enfermedad Celíaca , Miositis , Humanos , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/sangre , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/complicaciones , Estudios Transversales , Femenino , Masculino , Persona de Mediana Edad , Adulto , Prevalencia , Autoanticuerpos/sangre , Miositis/inmunología , Miositis/epidemiología , Miositis/sangre , México/epidemiología , Transglutaminasas/inmunología , Anciano , Inmunoglobulina A/sangre , Gliadina/inmunología , Inmunoglobulina G/sangre , Proteína Glutamina Gamma Glutamiltransferasa 2
6.
Int J Mol Sci ; 25(5)2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38473963

RESUMEN

The protein p32 (C1QBP) is a multifunctional and multicompartmental homotrimer that is overexpressed in many cancer types, including colon cancer. High expression levels of C1QBP are negatively correlated with the survival of patients. Previously, we demonstrated that C1QBP is an essential promoter of migration, chemoresistance, clonogenic, and tumorigenic capacity in colon cancer cells. However, the mechanisms underlying these functions and the effects of specific C1QBP protein inhibitors remain unexplored. Here, we show that the specific pharmacological inhibition of C1QBP with the small molecule M36 significantly decreased the viability rate, clonogenic capacity, and proliferation rate of different colon cancer cell lines in a dose-dependent manner. The effects of the inhibitor of C1QBP were cytostatic and non-cytotoxic, inducing a decreased activation rate of critical pro-malignant and mitogenic cellular pathways such as Akt-mTOR and MAPK in RKO colon cancer cells. Additionally, treatment with M36 significantly affected the mitochondrial integrity and dynamics of malignant cells, indicating that p32/C1QBP plays an essential role in maintaining mitochondrial homeostasis. Altogether, our results reinforce that C1QBP is an important oncogene target and that M36 may be a promising therapeutic drug for the treatment of colon cancer.


Asunto(s)
Neoplasias del Colon , Citostáticos , Humanos , Citostáticos/farmacología , Mitógenos/farmacología , Transducción de Señal , Proteínas Mitocondriales/metabolismo , Proliferación Celular , Proteínas Portadoras/metabolismo
7.
Anticancer Drugs ; 35(7): 638-640, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38513159

RESUMEN

Mutations in tyrosine kinase domain of epidermal growth factor receptor (EGFR) are observed in approximately 15% of non-small cell lung cancer adenocarcinoma. Exon 19 deletions or exon 21 L858R mutations are predominant in frequency and show high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Exon 18 mutations are extremely rare and the delE709_T710insD mutation accounts for only 0.16% of mutations when occurring as a sole mutation. This specific mutation in exon 18 seems to respond to certain EGFR TKIs such as afatinib. However, given the rarity of this mutation, determining the most effective TKI for its treatment remains unclear. We report a 70-year-old woman diagnosed with stage IV-A lung adenocarcinoma harboring EGFR delE709_T710insD mutation treated in first-line with Osimertinib using standard schedule and doses experiencing renal toxicity and disease progression after 9 weeks of treatment.


Asunto(s)
Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Exones , Neoplasias Pulmonares , Humanos , Compuestos de Anilina/uso terapéutico , Acrilamidas/uso terapéutico , Femenino , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéutico , Estadificación de Neoplasias , Indoles , Pirimidinas
8.
Pol J Microbiol ; 73(1): 11-20, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38437469

RESUMEN

Serratia marcescens is a global opportunistic pathogen. In vitro cytotoxicity of this bacterium is mainly related to metalloprotease serralysin (PrtS) activity. Proteolytic capability varies among the different isolates. Here, we characterized protease production and transcriptional regulators at 37°C of two S. marcescens isolates from bronchial expectorations, HU1848 and SmUNAM836. As a reference strain the insect pathogen S. marcescens Db10 was included. Zymography of supernatant cultures revealed a single (SmUNAM836) or double proteolytic zones (HU1848 and Db10). Mass spectrometry confirmed the identity of PrtS and the serralysin-like protease SlpB from supernatant samples. Elevated proteolytic activity and prtS expression were evidenced in the HU1848 strain through azocasein degradation and qRT-PCR, respectively. Evaluation of transcriptional regulators revealed higher eepR expression in HU1848, whereas cpxR and hexS transcriptional levels were similar between studied strains. Higher eepR expression in HU1848 was further confirmed through an in vivo transcriptional assay. Moreover, two putative CpxR binding motifs were identified within the eepR regulatory region. EMSA validated the interaction of CpxR with both motifs. The evaluation of eepR transcription in a cpxR deletion strain indicated that CpxR negatively regulates eepR. Sequence conservation suggests that regulation of eepR by CpxR is common along S. marcescens species. Overall, our data incorporates CpxR to the complex regulatory mechanisms governing eepR expression and associates the increased proteolytic activity of the HU1848 strain with higher eepR transcription. Based on the global impact of EepR in secondary metabolites production, our work contributes to understanding virulence factors variances across S. marcescens isolates.


Asunto(s)
Ataxia , Condrodisplasia Punctata , Enfermedades Genéticas Ligadas al Cromosoma X , Discapacidad Intelectual Ligada al Cromosoma X , Convulsiones , Serratia marcescens , Humanos , Serratia marcescens/genética , Péptido Hidrolasas/genética
9.
Int J Cardiol ; 401: 131825, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38309590

RESUMEN

INTRODUCTION: Baseline cardiovascular (CV) risk stratification is recommended in all cancer patients. Integrating all clinical information (personal/family history, ECG and echocardiogram) can properly identify high-risk patients. We aimed to evaluate the concealed inherited CV conditions detected in mandatory CV screening performed at a Cardio-Oncology Unit. METHODS: retrospective study of all consecutive cancer patients referred to the Cardio-Oncology Unit for CV evaluation (2020-2023). Inherited CV conditions diagnosis and genetic testing was performed according to guidelines. RESULTS: 1984 cancer patients underwent CV screening. Sanger sequencing was indicated in 1 patient, excluding the genetic family disease. NGS sequencing was performed in 11 cancer patients with normal left ventricular ejection fraction (LVEF): 2 due to aortic syndrome evaluation (identifying 1 vascular Ehrler-Danlos syndrome due to COL3A1 p.Arg242Ter), 4 channelopathies (2 Long QT syndrome and 2 Brugada's), 4 hypertrophic cardiomyopathies and 1 non-dilated left ventricular cardiomyopathy (NDLVC). Among the 12 patients with reduced LVEF, one was diagnosed with NDLVC, and chemotherapy-induced dilated cardiomyopathy was only ascribable in 3 of them. CONCLUSION: Integrating clinical information at mandatory baseline CV toxicity risk cardio-oncology evaluation, can identify high-risk cancer patients with concealed inherited conditions. Keeping an "inherited cardiovascular disease-oriented mindset" to implement opportunist screenings is encouraged.


Asunto(s)
Cardiomiopatías , Cardiomiopatía Dilatada , Enfermedades Cardiovasculares , Neoplasias , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/genética , Volumen Sistólico , Cardiooncología , Estudios Retrospectivos , Función Ventricular Izquierda , Neoplasias/diagnóstico , Neoplasias/genética
10.
Clin Transl Oncol ; 26(6): 1532-1538, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38102374

RESUMEN

PURPOSE: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC). METHODS: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay). RESULTS: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff. CONCLUSIONS: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Antígeno B7-H1/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Supervivencia sin Progresión , Femenino , Masculino , Antineoplásicos Inmunológicos/uso terapéutico , Anciano , Persona de Mediana Edad , Quimioterapia de Mantención , Tasa de Supervivencia
11.
Animals (Basel) ; 13(11)2023 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-37889770

RESUMEN

Although there is evidence that psychological stress may be associated with increased cancer risk, the effect of stress on cancer risk is difficult to study, both in humans, due to socioeconomic factors, and in animal models, due to questionable biological relevance. Here, we test whether heritable canine temperament that increases psychological stress is associated with cancer risk. The study data are breed-specific averages of incidences of multiple cancer types and of temperament classes. The latter are derived from a latent class analysis of behavioral questionnaires completed by owners (C-BARQ). We thus classified the dogs according to whether they are calm vs. reactive within and across breeds. Using meta-analysis approaches, we modeled the risk of multiple cancer types in calm vs. reactive dogs. We adjusted for breed averages of body mass and lifespan, which are common confounders that impact cancer. Our study confirms that body size has a significant effect of on risk of multiple types of cancers in dogs and shows for the first time that temperament also has a moderate effect. These findings suggest dog models of heritable psychological stress are suitable for molecular epidemiological and translational studies on its effects on cancer risk.

12.
Artículo en Inglés | MEDLINE | ID: mdl-37171451

RESUMEN

Six Gram-negative, rod-shaped bacterial strains isolated from Heterorhabditis amazonensis entomopathogenic nematodes were characterized to determine their taxonomic position. 16S rRNA and gyrB gene sequences indicate that they belong to the class Gammaproteobacteria, family Morganellaceae and genus Photorhabdus, and that some of them are conspecifics. Two of them, APURET and JART, were selected for further molecular characterization using whole genome- and whole-proteome-based phylogenetic reconstructions and sequence comparisons. Phylogenetic reconstructions using whole genome and whole proteome sequences show that strains APURET and JART are closely related to Photorhabdus luminescens subsp. luminescens ATCC 29999T and to P. luminescens subsp. mexicana MEX47-22T. Moreover, digital DNA-DNA hybridization (dDDH) values between APURET and P. luminescens subsp. luminescens ATCC 29999T, APURET and P. luminescens subsp. mexicana MEX47-22T, and APURET and JART are 61.6, 61.2 and 64.1 %, respectively. These values are below the 70 % divergence threshold that delimits prokaryotic species. dDDH scores between JART and P. luminescens subsp. luminescens ATCC 29999T and between JART and P. luminescens subsp. mexicana MEX47-22T are 71.9 and 74.8 %, respectively. These values are within the 70 and 79 % divergence thresholds that delimit prokaryotic subspecies. Based on these genomic divergence values, APURET and JART represent two different taxa, for which we propose the names: Photorhabdus aballayi sp. nov. with APURET (=CCM 9236T =CCOS 2019T) as type strain and Photorhabdus luminescens subsp. venezuelensis subsp. nov. with JART (=CCM 9235T =CCOS 2021T) as type strain. Our study contributes to a better understanding of the biodiversity of an important bacterial group with enormous biotechnological and agricultural potential.


Asunto(s)
Nematodos , Photorhabdus , Animales , Filogenia , ARN Ribosómico 16S/genética , Proteoma/genética , Técnicas de Tipificación Bacteriana , Análisis de Secuencia de ADN , ADN Bacteriano/genética , Composición de Base , Ácidos Grasos/química , Nematodos/microbiología
14.
Arch Orthop Trauma Surg ; 143(8): 5001-5006, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36905426

RESUMEN

BACKGROUND: Two of the most commonly used classifications for the posterior malleolus fracture are Haraguchi and Bartonícek. Both classifications are based on the morphology of the fracture. This study makes an inter- and intra-observer agreement analysis of the mentioned classifications. METHODS: 39 patients with ankle fractures who met inclusion criteria were selected. All the fractures were analyzed and classified twice by each of the 20 observers using Bartonícek and Haraguchi's classifications, with a window period of at least 30 days between the two rounds. RESULTS: Analysis was made by Kappa coefficient (ƙ). The global intraobserver value was ƙ = 0.627 in the Bartonícek classification and ƙ = 0.644 in the Haraguchi one. The first round global interobserver ƙ = 0.589 (0.574-0.604) on the Bartonícek classification and ƙ = 0.534 (0.517-0.551) on the Haraguchi one. Second round coefficients were ƙ = 0.601 (0.585-0.616) and ƙ = 0.536 (0.519-0.554), respectively. The best agreement was when there was involvement of the posteromedial malleolar zone with ƙ = 0.686 and ƙ = 0.687 in Haraguchi II and ƙ = 0.641 and ƙ = 0.719 in Bartonícek III. No differences were observed in Kappa values when an experience-based analysis was made. CONCLUSION: Bartonícek and Haraguchi classifications of the posterior malleolus fracture have both substantial intraobserver agreement but moderate to substantial agreement in interobserver analysis. LEVEL OF EVIDENCE: IV.


Asunto(s)
Fracturas de Tobillo , Humanos , Reproducibilidad de los Resultados , Variaciones Dependientes del Observador
15.
Clin Lung Cancer ; 24(1): 11-17, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36253271

RESUMEN

INTRODUCTION: Antibiotic exposure is associated with worse clinical outcomes in patients receiving immune checkpoint inhibitors (ICI). We analyzed antibiotic prescription patterns in lung cancer and melanoma, two malignancies in which ICI are used broadly across stages. METHODS: We performed a retrospective cohort study of adults in the U.S. Veterans Affairs (VA) medical system diagnosed with lung cancer or melanoma from 2003 to 2016. We defined antibiotic exposure as receipt of a prescription for a systemic antibacterial agent between 6 months before and 6 months after cancer diagnosis. Demographics, clinical variables, prescriptions, and diagnostic codes were abstracted from the VA Corporate Data Warehouse. Antibiotic exposure was compared using t tests, Chi-square, and multivariate analyses. RESULTS: A total of 310,321 patients (280,068 lung cancer, 30,253 melanoma) were included in the analysis. Antibiotic exposure was more common among patients with lung cancer (42% vs. 24% for melanoma; P < .001). Among antibiotic-exposed patients, those with lung cancer were more likely to receive prescriptions for multiple antibiotics (47% vs. 30% for melanoma; P < .001). In multivariate analyses, antibiotic exposure was associated with lung cancer diagnosis (HR 1.50; 95% CI, 1.46-1.55), comorbidity score (HR 1.08; 95% CI, 1.08-1.09), non-white race (HR 1.11; 95% CI, 1.06-1.17), and female gender (HR 1.31; 95% CI, 1.24-1.37). CONCLUSION: Among cancer patients, antibiotics are prescribed frequently. Antibiotic exposure is more common in certain cancer types and patient populations. Given the negative effect antibiotic exposure has on immunotherapy outcomes, these observations may have clinical and healthy policy implications.


Asunto(s)
Neoplasias Pulmonares , Melanoma , Adulto , Humanos , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Estudios Retrospectivos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Melanoma/tratamiento farmacológico , Prescripciones , Inmunoterapia/efectos adversos
17.
Rheumatology (Oxford) ; 62(2): 775-784, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35766810

RESUMEN

OBJECTIVE: To assess the proportion of myeloid-derived suppressor cells (MDSCs), their expression of arginase-1 and programmed cell death ligand 1 (PD-L1) and their relationship with the clinical phenotype of patients with idiopathic inflammatory myopathies (IIMs). METHODS: We recruited 37 IIM adult patients and 10 healthy donors in Mexico City. We evaluated their clinical features, the proportion of MDSCs and their expression of PD-L1 and arginase-1 by flow cytometry. Polymorphonuclear (PMN)-MDSCs were defined as CD33dim, CD11b+ and CD66b+ while monocytic (M)-MDSCs were CD33+, CD11b+, HLA-DR- and CD14+. Serum cytokines were analysed with a multiplex assay. We compared the quantitative variables with the Kruskal-Wallis and Mann-Whitney U tests and assessed correlations with Spearman's ρ. RESULTS: Most patients had dermatomyositis [n = 30 (81.0%)]. IIM patients had a peripheral expansion of PMN-MDSCs and M-MDSCs with an enhanced expression of arginase-1 and PD-L1. Patients with active disease had a decreased percentage {median 1.75% [interquartile range (IQR) 0.31-5.50 vs 10.71 [3.16-15.58], P = 0.011} of M-MDSCs and a higher absolute number of PD-L1+ M-MDSCs [median 23.21 cells/mm3 (IQR 11.16-148.9) vs 5.95 (4.66-102.7), P = 0.046] with increased expression of PD-L1 [median 3136 arbitrary units (IQR 2258-4992) vs 1961 (1885-2335), P = 0.038]. PD-L1 expression in PMN-MDSCs correlated with the visual analogue scale of pulmonary disease activity (r = 0.34, P = 0.040) and damage (r = 0.36, P = 0.031), serum IL-5 (r = 0.55, P = 0.003), IL-6 (r = 0.46, P = 0.003), IL-8 (r = 0.53, P = 0.018), IL-10 (r = 0.48, P = 0.005) and GM-CSF (r = 0.48, P = 0.012). M-MDSCs negatively correlated with the skeletal Myositis Intention to Treat Index (r = -0.34, P = 0.038) and positively with IL-6 (r = 0.40, P = 0.045). CONCLUSION: MDSCs expressing arginase-1 and PD-L1 are expanded in IIM and correlate with disease activity, damage accrual and serum cytokines.


Asunto(s)
Células Supresoras de Origen Mieloide , Arginasa/genética , Arginasa/metabolismo , Interleucina-6/metabolismo , Antígeno B7-H1/metabolismo , Citocinas/metabolismo
18.
Toxicon ; 222: 106994, 2023 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-36529153

RESUMEN

Sticholysin I (StI) is a water-soluble protein with the ability to bind membranes where it oligomerizes and forms pores leading to cell death. Understanding the assembly property of this protein may be valuable for designing potential biotechnological tools, such as stable or structurally defined nanopores. In order to get insights into the stabilization of StI oligomers by disulfide bonds, we designed and characterized single and double cysteine mutants at the oligomerization interface. The oligomer formation was induced in the presence of lipid membranes and visualized by SDS-PAGE. The contribution of the oligomeric structures to the membrane binding and pore-forming capacities of StI was assessed. Single and double cysteine introduction at the protein-protein oligomerization interface does not considerably affect the conformation and function of the monomeric protein. In the presence of membranes, a cysteine double mutation at positions 15 and 59 favored formation of different size oligomers stabilized by disulfide bonds. The results of this work highlight the relevance of these positions (15 and 59) to be considered for developing biosensors based on nanopores from StI.


Asunto(s)
Cisteína , Toxinas Biológicas , Cisteína/química , Disulfuros
19.
Arch Med Res ; 53(8): 840-858, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36470770

RESUMEN

BACKGROUND: The oncogenic process is orchestrated by a complex network of chromatin remodeling elements that shape the cancer epigenome. Histone variant H2A.Z regulates DNA control elements such as promoters and enhancers in different types of cancer; however, the interplay between H2A.Z and the pancreatic cancer epigenome is unknown. OBJECTIVE: This study analyzed the role of H2A.Z in different DNA regulatory elements. METHODS: We performed Chromatin Immunoprecipitation Sequencing assays (ChiP-seq) with total H2A.Z and acetylated H2A.Z (acH2A.Z) antibodies and analyzed published data from ChIP-seq, RNA-seq, bromouridine labeling-UV and sequencing (BruUV-seq), Hi-C and ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) in the pancreatic cancer cell line PANC-1. RESULTS: The results indicate that total H2A.Z facilitates the recruitment of RNA polymerase II and transcription factors at promoters and enhancers allowing the expression of pro-oncogenic genes. Interestingly, we demonstrated that H2A.Z is enriched in super-enhancers (SEs) contributing to the transcriptional activation of key genes implicated in tumor development. Importantly, we established that H2A.Z contributes to the three-dimensional (3D) genome organization of pancreatic cancer and that it is a component of the Topological Associated Domains (TADs) boundaries in PANC-1 and that total H2A.Z and acH2A.Z are associated with A and B compartments, respectively. CONCLUSIONS: H2A.Z participates in the biology and development of pancreatic cancer by generating a pro-oncogenic transcriptome through its posttranslational modifications, interactions with different partners, and regulatory elements, contributing to the oncogenic 3D genome organization. These data allow us to understand the molecular mechanisms that promote an oncogenic transcriptome in pancreatic cancer mediated by H2A.Z.


Asunto(s)
Histonas , Neoplasias Pancreáticas , Humanos , Histonas/genética , Histonas/metabolismo , Nucleosomas , Cromatina/genética , ADN , Neoplasias Pancreáticas/genética
20.
Rev. cuba. angiol. cir. vasc ; 23(3)sept.-dic. 2022.
Artículo en Español | LILACS, CUMED | ID: biblio-1441489

RESUMEN

Introducción: La endotelitis es causada por mecanismos complejos asociados a comorbilidades inmunitario-metabólicas como expresión del daño producido por diversos agentes, como el caso de las acciones proinflamatorias debidas a la interacción del virus SARS-CoV-2 con los ácidos biliares, que pueden estar implicadas en la mortalidad por la COVID-19. Objetivo: Describir las evidencias biomoleculares de la citotoxicidad de los ácidos biliares sobre el endotelio y la posible relación con la endotelitis de los cortes histológicos de tejidos de fallecidos por la COVID-19, asociada o no a las comorbilidades conocidas. Métodos: Se realizó una revisión sistemática y crítica de los artículos reportados sobre ácidos biliares y endotelitis desde 1963 hasta 2021 en los sitios web (PubMed, SciELO, Lilacs y Elservier). Se citó la histología del tejido pulmonar con daño endotelial en 34 fallecidos por COVID-19 en el Hospital Militar Central "Luis Díaz Soto", cuyos cortes histológicos fueron examinados en el Hospital Clínico Quirúrgico "Hermanos Ameijeiras". Asimismo, se describieron las acciones y las propiedades físico-químicas de los ácidos biliares que pudieran relacionarse con la endotelitis observada en dichos cortes histológicos. Conclusiones: Los ácidos biliares hidrofóbicos conjugados con glicinas, por sus propiedades e incrementos séricos hallados en las comorbilidades inmunitario-metabólicas y en las enfermedades hepato-intestinales, pudieran tener un papel en la endotelitis presente en pacientes de la COVID-19, con estadíos graves y críticos(AU)


Introduction: Endotheliitis is caused by complex mechanisms associated with immune-metabolic comorbidities as an expression of the damage produced by various agents, such as the case of proinflammatory actions due to the interaction of the SARS-CoV-2 virus with bile acids, which may be involved in mortality from COVID-19. Objective: To describe the biomolecular evidence of bile acid cytotoxicity on the endothelium and the possible relationship with endothelitis of histological sections of tissues from COVID-19 deaths, associated or not with known comorbidities. Methods: A systematic and critical review of the articles reported on bile acids and endothelitis from 1963 to 2021 was conducted on the websites (PubMed, SciELO, Lilacs and Elservier). It was cited the histology of lung tissue with endothelial damage in 34 deceased by COVID-19 at "Luis Díaz Soto" Central Military Hospital, whose histological sections were examined at "Hermanos Ameijeiras" Clinical Surgical Hospital. Likewise, the actions and physicochemical properties of bile acids that could be related to observed endothelitis in these histological sections were described. Conclusions: Hydrophobic bile acids conjugated with glycine, due to their properties and serum increases found in immune-metabolic comorbidities and hepato-intestinal diseases, could have a role in endothelitis present in COVID-19 patients, with severe and critical stages(AU)


Asunto(s)
Humanos , Literatura de Revisión como Asunto , Bases de Datos Bibliográficas
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