Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Mol Cell ; 67(2): 266-281.e4, 2017 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-28648781

RESUMEN

Mec1ATR mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATR response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN de Hongos/metabolismo , Metabolismo Energético , Genoma Fúngico , Inestabilidad Genómica , Proteína Fosfatasa 2/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ceramidas/metabolismo , Ceramidas/farmacología , Citocromo-B(5) Reductasa/genética , Citocromo-B(5) Reductasa/metabolismo , Reparación del ADN/efectos de los fármacos , ADN de Hongos/genética , Activación Enzimática , Regulación Fúngica de la Expresión Génica , Genoma Fúngico/efectos de los fármacos , Inestabilidad Genómica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolómica , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Proteína Metiltransferasas/genética , Proteína Metiltransferasas/metabolismo , Proteína Fosfatasa 2/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Proteínas de Saccharomyces cerevisiae/genética , Sirolimus/farmacología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
2.
J Hand Ther ; 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38453574

RESUMEN

BACKGROUND: Cubital tunnel syndrome (CBTS) impairs hand function, with limited conservative options often leading to surgery. Chitosan neuroregenerative effects delivered via phonophoresis provide a rationale for testing this emerging treatment approach. PURPOSE: The primary goal of this research was to assess the impact of chitosan phonophoresis on the conductivity of the ulnar nerve, as well as its effects on pain levels and functional outcomes in individuals diagnosed with mild to moderate CBTS. STUDY DESIGN: Double-blind randomized controlled trial. METHODS: This was a prospective, double-blinded, randomized controlled study. The participants consisted of 54 individuals aged between 20-35 years who were randomly assigned using block randomization. The control group (n = 27) received standard hand therapy alone, while the experimental group (n = 27) received both standard hand therapy and chitosan phonophoresis. Both groups underwent three treatment sessions per week, each lasting for 60-72 minutes, over a period of five weeks. Pre- and post-intervention evaluations included assessments of ulnar nerve conduction velocity (NCV), pain assessment using the numerical pain rating scale (NPRS), as well as hand function evaluated using the Quick Disabilities of Arm Shoulder Hand (QuickDASH) questionnaire. RESULTS: After the intervention, the experimental group significantly improved in all outcome measures compared to the control group. Accordingly, ulnar NCV (MD = 2.233 m/sec; CI = 1.63:2.83; p < 0.001; η2p = 0.516), NPRS (MD = -1.11; CI = -1.71: -0.50; p < 0.001; η2p = 0.208) and QuickDASH (MD = -2.72; CI = -4.54:0.87; p < 0.007; η2p = 0.133). CONCLUSIONS: The study findings suggest that chitosan phonophoresis may have the potential as a supplementary treatment to hand therapy for individuals with mild to moderate CBTS. This approach demonstrated significant improvements in nerve conduction, pain reduction, and enhancement of hand function.

3.
BMC Public Health ; 21(1): 2070, 2021 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-34763694

RESUMEN

BACKGROUND: There is controversy regarding the role of in-person attendance in schools and transmission of the SARS-CoV-2 pandemic. Several studies have demonstrated no increase in transmission, while some have reported large outbreaks with in-person attendance. We determined the incidence and risk factors for SARS-CoV-2 infection among school staff after one school term. METHODS: Nasopharyngeal swabs (NPS) for SARS-CoV-2 RT-PCR and blood for SARS-CoV-2 antibody testing were obtained from staff at a large international school in Qatar at the beginning of the 2020-2021 school year and repeated at the end of the first term. RESULTS: A total of 376 staff provided samples for testing. At the beginning of the 2020-2021 school year, the PCR positivity for SARS-CoV-2 was 13%, while seropositivity was 30.1%. A majority of those who tested positive either by PCR or serologically, were non-teaching staff. At the end of the first school term four months later, only 3.5% of the initially antibody-negative staff had seroconverted. In multivariable logistic regression analysis, male gender (OR 11.48, 95%CI 4.77-27.64), non-teaching job category (OR 3.09, 95%CI 1.10-8.64), contact with a confirmed case (OR 20.81, 95%CI 2.90-149.18), and presence of symptoms in the preceding 2 weeks [1-2 symptoms OR 4.82, 95%CI 1.79-12.94); ≥3 symptoms OR 42.30, 95%CI 3.76-476.43) independently predicted SARS-CoV-2 infection in school staff before school starting. CONCLUSION: Male gender, non-teaching job, presence of symptoms, and exposure to a confirmed case were associated with higher risk of infection. These data can help policymakers in determining the optimal strategy for school reopening.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Masculino , Pandemias , Reacción en Cadena de la Polimerasa , Instituciones Académicas
4.
Int J Cancer ; 145(7): 1991-2001, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30848481

RESUMEN

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Resistencia a Antineoplásicos , Neoplasias Renales/genética , Mutación , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Exones , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/metabolismo , Ratones , Trasplante de Neoplasias , Análisis de Secuencia de ADN , Sunitinib
5.
Mol Cell ; 42(1): 23-35, 2011 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-21353614

RESUMEN

Deregulated oncogenes such as MYC and RAS are typically insufficient to transform cells on their own due to the activation of pathways that restrain proliferation. Previous studies have shown that oncogenic H-Ras can induce proliferative arrest or senescence, depending on the cellular context. Here, we show that deregulated H-Ras activity can also lead to caspase-independent cell death with features of autophagy. Ras-induced autophagy was associated with upregulation of the BH3-only protein Noxa as well as the autophagy regulator Beclin-1. Silencing of Noxa or Beclin-1 expression reduced Ras-induced autophagy and increased clonogenic survival. Ras-induced cell death was also inhibited by coexpression of Bcl-2 family members that inhibit Beclin-1 function. Ras-induced autophagy was associated with Noxa-mediated displacement of the Bcl-2 family member, Mcl-1, from Beclin-1. Thus, Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death, which represents a mechanism to limit the oncogenic potential of deregulated Ras signals.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Autofagia/genética , Genes ras , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Autofagia/fisiología , Proteína 5 Relacionada con la Autofagia , Proteína 7 Relacionada con la Autofagia , Secuencia de Bases , Beclina-1 , Caspasas/metabolismo , Línea Celular , Proliferación Celular , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Transformación Celular Neoplásica/genética , Ensayo de Unidades Formadoras de Colonias , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica , Técnicas de Silenciamiento del Gen , Genes bcl-2 , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Humanos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Enzimas Activadoras de Ubiquitina/genética
6.
Calcif Tissue Int ; 99(5): 481-488, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27376530

RESUMEN

Duffy antigen receptor for chemokines (DARC) binds to a number of pro-inflammatory chemokines, and since chemokines are known to regulate trafficking of osteoclast (OC) precursors, we predicted that DARC would regulate OC recruitment to sites of inflammation by modulating chemokine activity. To test this hypothesis, we evaluated the mRNA expression of Darc and the chemokines known to bind to DARC, in endothelial cells treated with bacterial lipopolysaccharide (LPS). The mRNA expression of Mcp-1, Rantes, Darc and Ccr5 was significantly increased in endothelial cells in response to LPS treatment. Blocking the function of DARC with neutralizing antibody partially abrogated the effect of LPS on the mRNA expression of Mcp-1 and Rantes. In vivo, mice with targeted disruption of Darc gene (Darc-KO) and control wild-type (WT) mice were used to assess the role of DARC in response to single LPS application on the top of parietal bones. Five hours post-LPS injection, local expression of Cd14 mRNA (a marker of inflammatory monocytes) was significantly increased in both lines of mice. However, the magnitude of increase was greater in WT mice compared with Darc-KO mice suggesting a role for DARC in mediating the recruitment of monocytes in response to LPS. Histological staining for tartrate-resistant acid phosphatase (TRAP) in calvaria sections taken from the injection sites revealed a significant reduction in TRAP-labeled surface per bone surface in response to LPS in Darc-KO mice compared with WT mice. Based on these findings, we concluded that DARC regulates recruitment of OC precursors at the inflammation site, probably through regulation of chemokines transcytosis across endothelial cell barrier.


Asunto(s)
Quimiocinas , Quimiotaxis , Sistema del Grupo Sanguíneo Duffy , Osteoclastos , Receptores de Superficie Celular , Animales , Ratones , Proteínas Bacterianas/metabolismo , Quimiocinas/metabolismo , Quimiotaxis/fisiología , Sistema del Grupo Sanguíneo Duffy/metabolismo , Inflamación/metabolismo , Inflamación/patología , Lipopolisacáridos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoclastos/metabolismo , Receptores de Superficie Celular/metabolismo , Células Madre/metabolismo
7.
Org Biomol Chem ; 13(23): 6619-33, 2015 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-25988330

RESUMEN

3D-pharmacophore and 2D-QSAR modeling studies describe the anti-oncological properties of spiro-alkaloids. The dispiro[2H-indene-2,3'-pyrrolidine-2',3''-[3H]indole]-1,2''(1''H, 3H)-diones 20-38 were prepared via 1,3-dipolar cycloaddition reactions of azomethine ylides (generated in situ via decarboxylative condensation of isatins 7-9 with sarcosine 10) and 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones 11-19 in refluxing ethanol. Some of the spiro-alkaloids (21, 22, 29 and 37) revealed potent antitumor properties against melanoma carcinoma cell lines (GaLa, LuPiCi and LuCa) utilizing the in vitro SRB standard method exhibiting potency close to that of the standard reference doxorubicin.


Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Melanoma/tratamiento farmacológico , Relación Estructura-Actividad Cuantitativa , Alcaloides/síntesis química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Técnicas de Química Sintética , Reacción de Cicloadición , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología
8.
Arch Pharm (Weinheim) ; 347(6): 398-406, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24652680

RESUMEN

Herein, we report the synthesis of novel tetrahydro-ß-carbolines that induce cell death via the autophagic pathway. Five of the new compounds induced cell death in a panel of patient-derived human metastatic melanoma cells. The autophagic pathway was confirmed using LC3 autophagosome markers; the involvement of ATG7 and Beclin 1 autophagy regulating genes was confirmed using infection with short hairpin RNA (shRNA) to silence Beclin 1 and ATG7. Compound VIII (IC50 = 2.34-5.15 µM) displayed activities greater than cisplatin against a panel of patient-derived human metastatic melanoma cell lines. The structure-activity relationship (SAR) of this class and the role of the absolute stereochemistry and geometrical isomerism are evaluated.


Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Carbolinas/farmacología , Melanoma/secundario , Neoplasias Cutáneas/patología , Antineoplásicos/química , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 7 Relacionada con la Autofagia , Beclina-1 , Carbolinas/química , Línea Celular Tumoral , Cisplatino/farmacología , Descubrimiento de Drogas , Humanos , Isomerismo , Melanoma/genética , Melanoma/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Estructura Molecular , Interferencia de ARN , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Relación Estructura-Actividad , Transfección , Enzimas Activadoras de Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/metabolismo
9.
Physiother Res Int ; 29(1): e2042, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37493215

RESUMEN

BACKGROUND: Tendinopathy is caused by repetitive motion, excessive stress on the tendon, overstretch, and motion past the critical angle of rotation or translation. There are various treatment options available for tendinitis, including those affecting both the upper and lower limbs and those of calcific and non-calcific types. HYPOTHESIS/PURPOSE: Few reviews have analyzed the efficacy of Extracorporeal Shockwave Therapy (ESWT) in treating upper and lower limb tendinopathies while considering calcific and non-calcific-type tendinitis. This paper provides a review and meta-analysis on Randomized Controlled Trials (RCTs), which compared results from a group undergoing ESWT treatment to another group under different treatments. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic search was conducted on PubMed, Web of Science, Embase, the Cochrane Central Register of Control Trials (CENTRAL), and Physiotherapy Evidence Database (PEDro) databases for articles published up to January 2022. The reference lists of identified articles were further scanned. Twenty-two studies were included in the meta-analysis. RESULTS: Meta-analysis showed no difference in pain reduction in ESWT when compared with a comparison group at 4 (p = 0.26) and 12 weeks (p = 0.33). There were no differences in DASH scores at 12 months between the two groups (p = 0.32). CONCLUSION: Extracorporeal Shockwave Therapy (ESWT) is effective when used to treat lower limb and calcific tendinitis. It does not yield any better results than other treatment options in managing upper limb tendinopathies and non-calcific tendinopathies.


Asunto(s)
Calcinosis , Tendinopatía , Humanos , Calcinosis/complicaciones , Calcinosis/terapia , Tratamiento con Ondas de Choque Extracorpóreas/efectos adversos , Tratamiento con Ondas de Choque Extracorpóreas/métodos , Ondas de Choque de Alta Energía/uso terapéutico , Extremidad Inferior , Dolor de Hombro/terapia , Tendinopatía/terapia , Resultado del Tratamiento
10.
Physiother Res Int ; 29(3): e2093, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38780139

RESUMEN

OBJECTIVE: Forward head posture (FHP) is a common postural disorder that alters shoulder function. This study examined the efficacy of a corrective program involving postural correction exercises (PCEs), scapular stabilization exercises (SSEs), and kinesiotaping (KT) on improving craniovertebral angle (CVA), scapular position, and dominant hand grip strength (HGS) in individuals with FHP. METHODS: Sixty subjects (8 males and 52 females, 18-40 years old) were randomly allocated into four equal groups: Group A: received PCEs only, Group B: received PCEs and SSEs, Group C: received PCEs and KT, Group D: received PCEs, SSEs and KT. All subjects received treatment for 4 weeks (4 times/week) and postural advice. Outcome measures included cranio-vertebral angle (CVA), scapular position using Lateral Scapular Slide Test and dominant HGS using a CAMRY dynamometer that were assessed at baseline and 4 weeks post intervention. RESULTS: Comparing all groups post training revealed that there were statistically significant increases (p < 0.05) in all measured variables (CVA, scapular position and dominant HGS) in favor of group (D). CONCLUSION: Combination of PCEs, SSEs and KT interventions has achieved the best gains in terms of CVA, dominant HGS and regaining optimal scapular position in FHP subjects.


Asunto(s)
Fuerza de la Mano , Postura , Escápula , Humanos , Masculino , Femenino , Escápula/fisiología , Adulto , Postura/fisiología , Adulto Joven , Fuerza de la Mano/fisiología , Adolescente , Terapia por Ejercicio/métodos , Cabeza/fisiología , Resultado del Tratamiento
11.
Glob Epidemiol ; 8: 100149, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39021383

RESUMEN

Health care workers (HCWs) may be at a variable risk of SARS-CoV2 infection. Regardless of their involvement in providing direct clinical treatment, most of the prior research had included all HCWs. Understanding infection rates, risk factors and outcomes among different subgroups of HCWs is crucial. From February 28, 2020 to January 1, 2022, we conducted a retrospective analysis encompassing all full-time non-clinical staff (NCS) subcontracted with Hamad Medical Corporation (HMC) facilities. To determine current or previous SARS-CoV2 infection, all personnel underwent RT-PCR and/or serology testing. To identify the demographic factors linked to the risk of infection, we utilized Cox-Hazard regression analysis. Herein 3158/6231 (50.7%) subcontracted NCS tested positive for SARS-CoV-2 by RT-PCR or serology during the research period. The median age was 30 years (IQR 25,35), 69.8% of the population were males, 82.4% were from South Asia, 86.6% did not have any concomitant conditions. 6032 (96.8%) of the population lived in shared housing, while 4749 (76.2%) had low to median levels of education. While infection (PCR positive with or without seropositive results) was independently predicted by male gender, working in the catering, laundry, and security sectors and being intermediate (7-12 years of education), lower (0-6 years of education), higher (exposure to confirmed case), and having symptoms. Male gender, working in the security sectors and being intermediate (7-12 years of education) were independently associated with accidently detected cases (PCR negative and seropositive). 299 (4.8%) required hospitalization, of them 3 cases were severe pneumonia and one required ICU admission without mechanical ventilation, with no deaths reported. In conclusion Infection rates among NCS are high. The majority are asymptomatic and may contribute to ongoing illness spread in the public or in healthcare facilities. During a pandemic, routine screening of this population is crucial and may aid in containing the spread of infection.

12.
Nat Commun ; 15(1): 828, 2024 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-38280853

RESUMEN

Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR's impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.


Asunto(s)
Insulinas , Leucemia Mieloide Aguda , Humanos , Animales , Ratones , Restricción Calórica , Leucemia Mieloide Aguda/patología , Histona Demetilasas/genética , Células Madre Neoplásicas/patología , Línea Celular Tumoral
13.
EBioMedicine ; 102: 105048, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38484556

RESUMEN

BACKGROUND: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). METHODS: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases) or who did not develop lung cancer at an advanced age (extreme controls), selected from databases including over 6600 subjects. We selected individual coding genetic variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We validated the results from our discovery cohort, in which we analysed by WES extreme cases and controls presenting similar phenotypes. We developed ML models using both cohorts. FINDINGS: Mean age for extreme cases and controls was 50.7 and 79.1 years respectively, and mean tobacco consumption was 34.6 and 62.3 pack-years. We validated 16 individual variants and 33 variant-rich genes. The gene harbouring the most validated variants was HLA-A in extreme controls (4 variants in the discovery cohort, p = 3.46E-07; and 4 in the validation cohort, p = 1.67E-06). We trained ML models using as input the 16 individual variants in the discovery cohort and tested them on the validation cohort, obtaining an accuracy of 76.5% and an AUC-ROC of 83.6%. Functions of validated genes included candidate oncogenes, tumour-suppressors, DNA repair, HLA-mediated antigen presentation and regulation of proliferation, apoptosis, inflammation and immune response. INTERPRETATION: Individuals presenting extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma show different germline profiles. Our strategy may allow the identification of high-risk subjects and the development of new therapeutic approaches. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Persona de Mediana Edad , Anciano , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Fenotipo , Células Germinativas/patología
14.
Am J Phys Med Rehabil ; 102(6): 533-540, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36730000

RESUMEN

OBJECTIVE: The aim of this study was to examine the effects of combining extracorporeal shock wave therapy or local corticosteroid injections with a conventional physical therapy (CPT) program for patients with shoulder impingement syndrome. DESIGN: This was a prospective single-blinded, randomized controlled study. METHODS: Sixty patients with unilateral shoulder impingement syndrome >3 mos were allocated to group A (a 4-wk program of CPT plus a single local corticosteroid injection of 40 mg triamcinolone acetonide mixed with 1% xylocaine, n = 20), group B (CPT only, n = 20), and group C (CPT plus extracorporeal shock wave therapy, 2000 impulses, 0.2-0.3 mJ/mm 2 , one session per week for 3 wks, n = 20). Subacromial space, shoulder pain and disability index, and shoulder range of motion were assessed at baseline and 4 and 12 wks posttreatment. RESULTS: There were no between-group differences at 4 wks. At the 12-wk follow-up, no significant differences were found between groups A and B. There was a significant difference in favor of group C compared with group A with the expectation of shoulder internal rotation and subacromial space. Group C was also superior to group B in all outcomes except for subacromial space. CONCLUSION: The addition of extracorporeal shock wave therapy to CPT induced more noticeable intermediate-term effects than CPT plus local corticosteroid injection or CPT alone.


Asunto(s)
Tratamiento con Ondas de Choque Extracorpóreas , Síndrome de Abducción Dolorosa del Hombro , Humanos , Síndrome de Abducción Dolorosa del Hombro/tratamiento farmacológico , Estudios Prospectivos , Inyecciones Intraarticulares , Corticoesteroides/uso terapéutico , Dolor de Hombro/tratamiento farmacológico , Dolor de Hombro/etiología , Resultado del Tratamiento
15.
Cell Rep ; 42(6): 112616, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37289585

RESUMEN

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.


Asunto(s)
Autofagia Mediada por Chaperones , Complejo I de Transporte de Electrón , Neoplasias , Humanos , Autoantígenos/metabolismo , Línea Celular Tumoral , Metabolismo Energético , Neoplasias/patología , Fosforilación Oxidativa , Proteína Fosfatasa 2/antagonistas & inhibidores , Proteína Fosfatasa 2/metabolismo , Transducción de Señal , Complejo I de Transporte de Electrón/antagonistas & inhibidores
16.
PLoS One ; 18(10): e0291989, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37792687

RESUMEN

BACKGROUND: There is debate over whether physical attendance at school affects the spread of the SARS-CoV-2 pandemic. METHODS: A cohort of personnel from several schools in Qatar provided nasopharyngeal swabs (NPS) for SARS-CoV-2 RT-PCR and rapid antigen testing. Each of them was monitored for infection until February 2022. RESULTS: In total, 3,241 employees gave samples for analysis. Prior to the start of the 2020-2021 academic year (Group I), 3.49% of samples tested positive for SARS-CoV-2. Most of the positive PCR results were from male, senior, non-teaching staff members. Only 110 (3.39%) employees who had enrolled in face-to-face instruction before the B.1.1.7 variant's emergence (Group II), 238 (7.34%) after the B.1.1.7 variant's emergence (Group III), and 410 (12.65%) after the introduction of the Omicron variant (Group IV) had reported infection by PCR test. Most people who tested positive by PCR after enrolling in school were young, female teachers. In the Cox Proportional-Hazards Model, exposure to a confirmed case, the presence of symptoms in the two weeks prior to exposure in all groups-young age in Groups II and III, male gender in Groups I and IV, shared housing in Group III, and the presence of comorbidities in Groups II and III independently predicted SARS-CoV-2 infection in school staff. CONCLUSION: Critical information about the risk of SARS-CoV-2 infection in school workers during the whole pandemic is provided by our study. School operations in Qatar were made safer through initial and ongoing screenings, as well as widespread vaccination of school personnel.


Asunto(s)
COVID-19 , SARS-CoV-2 , Femenino , Masculino , Humanos , SARS-CoV-2/genética , COVID-19/epidemiología , Instituciones Académicas , Reacción en Cadena de la Polimerasa
17.
Front Vet Sci ; 10: 1229151, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37483300

RESUMEN

Introduction: Domestic dogs and cats can be a source of human infection by a wide diversity of zoonotic pathogens including parasites. Genotyping and subtyping tools are useful in assessing the true public health relevance of canine and feline infections by these pathogens. This study investigated the occurrence, genetic diversity, and zoonotic potential of common diarrhea-causing enteric protist parasites in household dogs and cats in Egypt, a country where this information is particularly scarce. Methods: In this prospective, cross-sectional study a total of 352 individual fecal samples were collected from dogs (n = 218) and cats (n = 134) in three Egyptian governorates (Dakahlia, Gharbeya, and Giza) during July-December 2021. Detection and identification of Cryptosporidium spp., Giardia duodenalis, Enterocytozoon bieneusi, and Blastocystis sp. were carried out by PCR and Sanger sequencing. Basic epidemiological variables (geographical origin, sex, age, and breed) were examined for association with occurrence of infection by enteric protists. Results and discussion: The overall prevalence rates of Cryptosporidium spp. and G. duodenalis were 1.8% (95% CI: 0.5-4.6) and 38.5% (95% CI: 32.0-45.3), respectively, in dogs, and 6.0% (95% CI: 2.6-11.4) and 32.1% (95% CI: 24.3-40.7), respectively, in cats. All canine and feline fecal samples analyzed tested negative for E. bieneusi and Blastocystis sp. Dogs from Giza governorate and cats from Dakahlia governorate were at higher risk of infection by Cryptosporidium spp. (p = 0.0006) and G. duodenalis (p = 0.00001), respectively. Sequence analyses identified host-adapted Cryptosporidium canis (n = 4, one of them belonging to novel subtype XXe2) and G. duodenalis assemblages C (n = 1) and D (n = 3) in dogs. In cats the zoonotic C. parvum (n = 5) was more prevalent than host-adapted C. felis (n = 1). Household dogs had a limited (but not negligible) role as source of human giardiasis and cryptosporidiosis, but the unexpected high frequency of zoonotic C. parvum in domestic cats might be a public health concern. This is the first molecular-based description of Cryptosporidium spp. infections in cats in the African continent to date. Molecular epidemiological data provided here can assist health authorities and policy makers in designing and implementing effective campaigns to minimize the transmission of enteric protists in Egypt.

18.
Ortop Traumatol Rehabil ; 24(2): 87-94, 2022 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-35550356

RESUMEN

BACKGROUND: To investigate the effect of adding r-ESWT to a standard exercise program of chronic non-specific LBP on electrical muscle activity (EMG), pain and function. MATERIALS AND METHODS: Our single-blind randomized controlled trial enrolled 30 patients with chronic non-specific LBP randomly allocated to an r-ESWT (n=15) group and a control group (n=15). All patients received a standard exercise program, while r-ESWT was additionally administered in the r-ESWT group. EMG activity, pain and function were assessed before and after 6 weeks of treatment. RESULTS: After treatment, all outcome measures were significantly different (p < 0.05). The addition of r-ESWT produced a significant increase in EMG activity (of all muscles tested) and a reduction in pain intensity and functional disability scores (p < 0.05) compared to the control group. CONCLUSIONS: 1. A standard intervention offered either alone or with r-ESWT increased EMG activities, reduced pain, and enhanced function in patients with chronic non-specific LBP. 2. Adding r-ESWT to the standard intervention program might produce better results.


Asunto(s)
Ondas de Choque de Alta Energía , Dolor de la Región Lumbar , Humanos , Dolor de la Región Lumbar/terapia , Músculos , Proyectos Piloto , Método Simple Ciego , Resultado del Tratamiento
19.
BMJ Open Sport Exerc Med ; 8(4): e001459, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36530599

RESUMEN

Objective: This study aimed to investigate the efficacy of rectus femoris stretching on pain intensity, knee range of motion (ROM), spatiotemporal gait parameters and function in patients with knee osteoarthritis (KOA). Methods: This parallel group, single-blinded randomised controlled trial was conducted in two outpatient physical therapy clinics. Study participants (n=60, with age>45 years) with mild-to-moderate bilateral KOA were randomised into the study group (SG) and control group (CG). SG received rectus femoris stretching exercises together with stretching exercises of the calf, hamstring and iliotibial band, strength exercises for the quadriceps, gluteus medius, gluteus maximus and calf muscles, whereas, the CG received all exercises mentioned for SG except rectus femoris stretching. Pain intensity, ROM, spatiotemporal gait parameters and function were measured before and after 4 weeks of treatment. Results: The SG showed a significant improvement in the visual analogue scale, Western Ontario and McMaster Universities measure and ROM (p<0.001). The SG also had a significantly greater step length and speed than CG (p<0.001). Extension ROM did not significant difference between the groups (p>0.05). Conclusion: Simple rectus femoris stretching exercises are easy to perform even at home and are beneficial for pain, flexion ROM, function and spatiotemporal gait parameters, such as step length and speed, in KOA patients if the compliance with the exercise regimen is good. Trial registration number: Pan African Clinical Trials Registry PACTR202003828737019.

20.
Infect Drug Resist ; 15: 3871-3879, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35903580

RESUMEN

Objective: To determine the prevalence of SARS-CoV-2 virus infection among female workers who were restricted to working from home compared with those who continued to attend in-person work. Methods: As part of national surveillance program, serum samples for SARS-CoV-2 antibody testing and nasopharyngeal swabs for SARS-CoV-2 PCR were obtained on 1636 female school staff and salon/spa workers who were restricted to work remotely (restricted group) and 1190 female health-care workers who continued in-person work (unrestricted group). Results: Seropositivity rate was 5.1% among the restricted and 22.7% among the unrestricted group (P < 0.0001). Presence of symptoms at baseline (adjusted odds ratio [aOR], 2.88; 95% CI 2.09-3.97), contact with a confirmed case (aOR 2.34; 95% CI 1.37-3.98), and unrestricted work type (aOR 4.71; 95% CI 3.24-6.86) were associated with a higher risk of infection, while increasing age was associated with a lower risk of infection. Conclusion: Prevalence of SARS-CoV-2 infection as determined by seropositivity was higher among women who were not subject to workplace restrictions.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA