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1.
Oncoimmunology ; 11(1): 2063225, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35481289

RESUMEN

While regulatory T cells (Tregs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of Tregs by promoting the conversion of conventional CD4+ T cells (Tconvs) into Tregs. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-ß directly promotes the conversion of CD4+ Tconvs into Tregsin vitro, we additionally show that TAMs enhance PD-1 expression on CD4+ T cells. This indirectly contributes to the intratumoral accumulation of Tregs, as loss of PD-1 on CD4+ Tconvs abrogates intratumoral conversion of adoptively transferred CD4+ Tconvs into Tregs. Combined, this study provides insights into the complex immune cell crosstalk between CD4+ T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of Tregs in breast tumors.


Asunto(s)
Neoplasias de la Mama , Linfocitos T Reguladores , Femenino , Humanos , Tolerancia Inmunológica , Receptor de Muerte Celular Programada 1 , Microambiente Tumoral , Macrófagos Asociados a Tumores
2.
Cell Rep ; 38(9): 110447, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35235800

RESUMEN

Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (Tregs) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive Tregs during primary tumor growth. Tumor-educated Tregs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as Treg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that Tregs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased Treg/NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent.


Asunto(s)
Neoplasias de la Mama , Animales , Neoplasias de la Mama/patología , Carcinogénesis/patología , Femenino , Humanos , Células Asesinas Naturales/patología , Ganglios Linfáticos , Metástasis Linfática/patología , Ratones
3.
Front Pharmacol ; 12: 596535, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33679394

RESUMEN

The antihelmintic drug ABZ and its metabolites belong to the chemical family of benzimidazoles (BZM) that act as potent tubulin polymerization inhibitors, suggesting a potential re-direction of BZMs for cancer therapy. Applying UV-Vis spectrometry we here demonstrate ABZ as a DNA intercalator. This insight led us to determine the primary mode of ABZ action in mammalian cells. As revealed by RNA sequencing, ABZ did neither grossly affect replication as analyzed by survival and replication stress signaling, nor the transcriptome. Actually, unbiased transcriptome analysis revealed a marked cell cycle signature in ABZ exposed cells. Indeed, short-term exposure to ABZ arrested mammalian cells in G2/M cell cycle stages associated with frequent gains and losses of chromatin. Cellular analyses revealed ABZ as a potent mammalian spindle poison for normal and malignant cells, explaining the serious chromosome segregation defects. Since chromosomal aberrations promote both cancer development and cell death, we determined if besides its general cytotoxicity, ABZ could predispose to tumor development. As measured by loss of heterozygosity (LOH) in vitro and in vivo ABZ was found as a potent inducer of LOH and accelerator of chromosomal missegregation.

4.
Nat Metab ; 2(10): 1046-1061, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32958937

RESUMEN

Following activation, conventional T (Tconv) cells undergo an mTOR-driven glycolytic switch. Regulatory T (Treg) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived Treg (tTreg) cells can become glycolytic in response to tumour necrosis factor receptor 2 (TNFR2) costimulation. This costimulus increases proliferation and induces a glycolytic switch in CD3-activated tTreg cells, but not in Tconv cells. Glycolysis in CD3-TNFR2-activated tTreg cells is driven by PI3-kinase-mTOR signalling and supports tTreg cell identity and suppressive function. In contrast to glycolytic Tconv cells, glycolytic tTreg cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2hiCD4+CD25hiCD127lo effector T cells, which were FOXP3+IKZF2+, revealed an increase in glucose consumption and intracellular lactate levels, thus identifying them as glycolytic tTreg cells. Our study links TNFR2 costimulation in human tTreg cells to metabolic remodelling, providing an additional avenue for drug targeting.


Asunto(s)
Glucólisis/efectos de los fármacos , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Linfocitos T Reguladores/metabolismo , Complejo CD3/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Glucosa/metabolismo , Glucosa/farmacología , Humanos , Ácido Láctico/sangre , Ácido Láctico/metabolismo , Metaboloma , Fosfatidilinositol 3-Quinasas/metabolismo , ARN/química , Receptores Tipo II del Factor de Necrosis Tumoral/efectos de los fármacos , Análisis de Secuencia de ARN , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo
5.
Cureus ; 11(7): e5124, 2019 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-31523555

RESUMEN

Introduction Pancytopenia is a common presentation in the pediatric population. It is a manifestation of various diseases, and its etiology can be explained on the basis of bone marrow examination. The study aims to determine the etiological factors leading to pancytopenia via bone marrow examination in pediatric patients presenting in our hospital. Materials and methods This retrospective cross-sectional study was conducted in the Department of Pathology at a public sector tertiary care hospital. Data were recorded by convenience sampling from the patients' database from January 2015 to April 2018. Patients aged 2 months to 15 years who had pancytopenia on peripheral blood smear and were admitted for bone marrow examination were included in the study. Patients who were beyond these age limits, diagnosed cases of aplastic anemia and leukemia, and those with a recent history of blood transfusion were excluded from the study. The analysis was done via the Statistical Package for Social Sciences (SPSS) v.23.0 (IBM SPSS Statistics, Armonk, NY, USA), and descriptive statistics were applied. Results Of 115 cases, 58 (50.4%) were males and 57 (49.6%) were females. Megaloblastic anemia was present in 32 (27.8%) patients, and it was the most common cause of pancytopenia. Non-malignant disorders were seen in 95 cases (82.6%) and malignant disorders were seen in 20 (17.4%) cases. Conclusion Megaloblastic anemia is the most common cause, and acute lymphoblastic leukemia is the most common malignant cause of pancytopenia in children. There was no significant gender predilection among causes of pancytopenia.

6.
Future Microbiol ; 14: 599-608, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30864465

RESUMEN

Aim: This study aimed at detecting and quantifying Merkel cell polyomavirus (MCPyV) viral loads in the peripheral blood of healthy Pakistani individuals. Patients & methods: A total of 221 whole blood samples obtained from healthy individuals were examined by qPCR. Results & conclusion: MCPyV was detected in the peripheral blood of 31.2% healthy individuals. The rate of MCPyV positivity decreased from young (36%), to middle (33.7%) and elder (25.3%) age groups. Our data revealed higher prevalence of MCPyV in women (43.93%) than men (25.80%). The MCPyV viral load was calculated in the range of 0.06 -11 copies/ng of isolated DNA. The MCPyV viral load increased from young (median = 3.35) to elder (median = 5.66) age groups. The MCPyV circulate at a higher frequency by residing dormant in certain blood cells, which might act as potential vehicles for the spread of MCPyV infection among general population.


Asunto(s)
ADN Viral/análisis , Poliomavirus de Células de Merkel/genética , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/epidemiología , Carga Viral , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Niño , Femenino , Humanos , Inmunocompetencia , Masculino , Poliomavirus de Células de Merkel/aislamiento & purificación , Persona de Mediana Edad , Pakistán/epidemiología , Prevalencia , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Factores Sexuales , Adulto Joven
7.
Saudi Med J ; 37(11): 1268-1271, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27761569

RESUMEN

OBJECTIVES: To test various items in hospital environment as reservoirs of bacteria. Methods: This simple descriptive study was conducted between June and December 2014. Pediatric wards of 4 different hospitals of Faisalabad, Pakistan were selected and 8 different items per hospital were sampled (n=160). Poisson regression analysis was carried out with R software and using lme4 package. Results: There were no differences between the  hospitals regarding total number of bacterial isolates or bacterial isolates per sample source or prevalent bacterial species. Utensile tables were significantly the least contaminated source when comparing all sample sources from all hospitals (p=0.05). When testing if the bacterial species differed significantly between sample sources, Escherichia coli (p=0.05) and Bacillus (p=0.04) were found significantly high on utensils, while Pseudomonas was found significantly less on curtains (p=0.03) and doors (p=0.02). Conclusion: Due to unhygienic practices in hospitals children are exposed to pathogens steers to life threatening infection. A good control strategy should be implemented to avoid health care-associated infection.


Asunto(s)
Infección Hospitalaria/microbiología , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacillaceae , Bacillus cereus/aislamiento & purificación , Niño , Infección Hospitalaria/epidemiología , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/microbiología , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Grampositivas/epidemiología , Hospitales Pediátricos , Humanos , Pruebas de Sensibilidad Microbiana , Pakistán/epidemiología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/aislamiento & purificación , Estudios Retrospectivos
8.
Eur J Gastroenterol Hepatol ; 25(2): 166-79, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23044807

RESUMEN

OBJECTIVE: The south-east Asian and sub-Saharan African populations are the most susceptible to hepatocellular carcinoma (HCC). We aimed to establish whether XRCC1, XRCC3, and XPD are associated with liver cancer in Pakistan and to examine the interaction of hepatitis B virus (HBV) or hepatitis C virus (HCV) with repaired genes in the occurrence of liver cancer. MATERIALS AND METHODS: We enrolled 74 healthy individuals, 75 had either HBV or HCV, and 50 were HCC patients. The characteristic information of all the study participants were collected through a standard interviewer-administered questionnaire. The PCR-RFLP was used to identify the genotype of the patients. RESULTS: The results of our study indicated that the patients infected with HBV or HCV had a four or three-fold greater risk of developing liver cancer. Patients older than 55 years of age had a significantly higher risk of developing cancer compared with younger patients. The homozygous wild types Arg/Arg for 280 and Thr/Thr for 241 were more frequent in the controls than in the cases. The allelic frequency of mutant 280His and 399Gln was more pronounced among HCC cases than the controls or the HBV-infected patients. CONCLUSION: The frequency of the XPD gene in the controls was in Hardy-Weinberg equilibrium, indicating that the gene played a protective role in the Pakistani population. XRCC1 or XRCC3 was associated with liver cancer in the Pakistani population; however, the XPD gene played a vital role in the repair of DNA damage.


Asunto(s)
Carcinoma Hepatocelular/genética , Reparación del ADN/genética , Hepatitis B Crónica/complicaciones , Hepatitis C Crónica/complicaciones , Neoplasias Hepáticas/genética , Adolescente , Adulto , Antropometría/métodos , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Niño , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversos , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto Joven
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