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Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Leprosy patients have been found to have defects in T cells activation, which is critical to the clearance of the bacilli. Treg cell suppression is mediated by inhibitory cytokines such as IL10, IL-35 and TGF-ß and its frequency is higher in leprosy patients. Activation and overexpression of programmed death 1 (PD-1) receptor is considered to one of the pathways to inhibit T-cell response in human leprosy. In the current study we address the effect of PD-1 on Tregs function and its immuno-suppressive function in leprosy patients. Flow cytometry was used to evaluate the expression of PD-1 and its ligands on various immune cells T cells, B cells, Tregs and monocytes. We observed higher expression of PD-1 on Tregs is associated with lower production of IL-10 in leprosy patients. PD-1 ligands on T cells, B cells, Tregs and monocytes found to be higher in the leprosy patients as compared to healthy controls. Furthermore, in vitro blocking of PD-1 restores the Tregs mediated suppression of Teff and increase secretion of immunosuppressive cytokine IL-10. Moreover, overexpression of PD-1 positively correlates with disease severity as well as Bacteriological Index (BI) among leprosy patients. Collectively, our data suggested that PD-1 overexpression on various immune cells is associated with disease severity in human leprosy. Manipulation and inhibition of PD-1 signaling pathway on Tregs alter and restore the Treg cell suppression activity in leprosy patients.
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Interleucina-10 , Lepra , Humanos , Interleucina-10/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Mycobacterium leprae , Linfocitos T Reguladores , Citocinas/metabolismoRESUMEN
The development of low-Platinum content polymer electrolyte fuel cells (PEFCs) has been hindered by inexplicable reduction of oxygen reduction reaction (ORR) activity and unexpected O2 mass transport resistance when catalysts have been interfaced with ionomer in a cathode catalyst layer. In this study, we introduce a bottom-up designed spherical carbon support with intrinsic Nitrogen-doping that permits uniform dispersion of Pt catalyst, which reproducibly exhibits high ORR mass activity of 638 ± 68 mA mgPt-1 at 0.9 V and 100% relative humidity (RH) in a membrane electrode assembly. The uniformly distributed Nitrogen-functional surface groups on the carbon support surface promote high ionomer coverage directly evidenced by high-resolution electron microscopy and nearly humidity-independent double layer capacitance. The hydrophilic nature of the carbon surface appears to ensure high activity and performance for operation over a broad range of RH. The paradigm challenging large carbon support (~135 nm) combined with favourable ionomer film structure, hypothesized recently to arise from the interactions of an ionic moiety of the ionomer and Nitrogen-functional group of the catalyst support, results in an unprecedented low local oxygen transport resistance (5.0 s cm-1) for ultra-low Pt loading (34 ± 2 µgPt cm-2) catalyst layer.
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Obesity induces numerous physiological changes that can impact cancer risk and patient response to therapy. Obese patients with cervical cancer have been reported to have superior outcomes following chemoradiotherapy, suggesting that free fatty acids (FFA) might enhance response to radiotherapy. Here, using preclinical models, we show that monounsaturated and diunsaturated FFAs (uFFA) radiosensitize cervical cancer through a novel p53-dependent mechanism. UFFAs signaled through PPARγ and p53 to promote lipid uptake, storage, and metabolism after radiotherapy. Stable isotope labeling confirmed that cervical cancer cells increase both catabolic and anabolic oleate metabolism in response to radiotherapy, with associated increases in dependence on mitochondrial fatty acid oxidation for survival. In vivo, supplementation with exogenous oleate suppressed tumor growth in xenografts after radiotherapy, an effect that could be partially mimicked in tumors from high fat diet-induced obese mice. These results suggest that supplementation with uFFAs may improve tumor responses to radiotherapy, particularly in p53 wild-type tumors. SIGNIFICANCE: Metabolism of monounsaturated and diunsaturated fatty acids improves the efficacy of radiotherapy in cancer through modulation of p53 activity. See related commentary by Jungles and Green, p. 4513.
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Ácidos Grasos , Neoplasias del Cuello Uterino , Ratones , Animales , Femenino , Humanos , Ácidos Grasos/metabolismo , Ácido Oléico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Proteína p53 Supresora de Tumor , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos no Esterificados/metabolismo , Obesidad/patología , Ácidos Grasos Monoinsaturados/metabolismoRESUMEN
An outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019 and spread so rapidly all around the globe. It's continued and spreading more dangerously in India and Brazil with higher mortality rate. Understanding of the pathophysiology of COVID-19 depends on unraveling of interactional mechanism of SARS-CoV-2 and human immune response. The immune response is a complex process, which can be better understood by understanding the immunological response and pathological mechanisms of COVID-19, which will provide new treatments, increase treatment efficacy, and decrease mortality associated with the disease. In this review we present a amalgamate viewpoint based on the current available knowledge on COVID-19 which includes entry of the virus and multiplication of virus, its pathological effects on the cellular level, immunological reaction, systemic and organ presentation. T cells play a crucial role in controlling and clearing viral infections. Several studies have now shown that the severity of the COVID-19 disease is inversely correlated with the magnitude of the T cell response. Understanding SARS-CoV-2 T cell responses is of high interest because T cells are attractive vaccine targets and could help reduce COVID-19 severity. Even though there is a significant amount of literature regarding SARS-CoV-2, there are still very few studies focused on understanding the T cell response to this novel virus. Nevertheless, a majority of these studies focused on peripheral blood CD4+ and CD8+ T cells that were specific for viruses. The focus of this review is on different subtypes of T cell responses in COVID-19 patients, Th17, follicular helper T (TFH), regulatory T (Treg) cells, and less classical, invariant T cell populations, such as δγ T cells and mucosal-associated invariant T (MAIT) cells etc that could influence disease outcome.
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COVID-19 , Brasil , Linfocitos T CD8-positivos , Humanos , SARS-CoV-2 , Subgrupos de Linfocitos TRESUMEN
Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural products have been used as healing agents. Likewise, most of the medicinal ingredients accessible today are originated from the natural resources. Regardless of achievements, developing bioactive compounds and drugs from natural products has remained challenging, in part because of the problem associated with large-scale sequestration and mechanistic understanding. With significant progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we may have come to a crossroads to review approaches to identify the potential natural products and investigate their therapeutic efficacy. In the present review, we summarize the recent developments in natural products-based cancer research and its application in generating novel systemic strategies with a focus on underlying molecular mechanisms in solid cancer.
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Productos Biológicos , Neoplasias , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Fitoquímicos/uso terapéuticoRESUMEN
Cervical cancer tumors with undetectable HPV (HPVU) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPVU tumors to date (HPVU = 35, HPV+ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV+ and HPVU tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPVU cancer cell lines. Patients with HPVU CC tumors had worse progression-free and overall survival outcomes compared to HPV+ patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPVU tumors, with converging functional roles in cell cycle progression. In vitro HPVU, but not HPV+, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPVU status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPVU CC patients.
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Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared with patients with HPV 16+ tumors, consistent with previously published studies. Using RNA sequencing analysis, we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas (n = 304). For the first time to our knowledge, transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional data set (n = 88) and within the HPV 16+ subset (n = 36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct mechanisms dependent upon p53-p21. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy, and these patients may benefit from alternative treatment strategies.
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Alphapapillomavirus/genética , Regulación Viral de la Expresión Génica , Infecciones por Papillomavirus/radioterapia , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/aislamiento & purificación , Biopsia , Cuello del Útero/patología , Cuello del Útero/virología , Quimioradioterapia , ADN Viral/genética , ADN Viral/aislamiento & purificación , Femenino , Estudios de Seguimiento , Técnicas de Genotipaje , Humanos , Persona de Mediana Edad , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/sangre , Infecciones por Papillomavirus/mortalidad , Infecciones por Papillomavirus/virología , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , RNA-Seq , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/virología , Transcripción ViralRESUMEN
PURPOSE: Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers. EXPERIMENTAL DESIGN: An SUVmax most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. RESULTS: SUVmax <11.4 was most prognostic for FFP (P = 0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect. CONCLUSIONS: SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism.See related commentary by Williamson et al., p. 4136.
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Fluorodesoxiglucosa F18/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Femenino , Humanos , Inflamación/diagnóstico por imagen , Inflamación/etiología , Inflamación/metabolismo , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Neoplasias del Cuello Uterino/complicaciones , Adulto JovenRESUMEN
PURPOSE: Cervical cancer represents the fourth most frequent malignancy in the world among women, and mortality has remained stable for the past 4 decades. Intravenous cisplatin with concurrent radiation therapy is the standard-of-care for patients with local and regional cervical cancer. However, cisplatin induces serious dose-limiting systemic toxicities and recurrence frequently occurs. In this study, we aimed to develop an intracervical drug delivery system that allows cisplatin release directly into the tumor and minimize systemic side effects. METHODS AND MATERIALS: Twenty patient biopsies and 5 cell lines treated with cisplatin were analyzed for platinum content using inductively coupled plasma mass spectrometry. Polymeric implants loaded with cisplatin were developed and evaluated for degradation and drug release. The effect of local or systemic cisplatin delivery on drug biodistribution as well as tumor burden were evaluated in vivo, in combination with radiation therapy. RESULTS: Platinum levels in patient biopsies were 6-fold lower than the levels needed for efficacy and radiosensitization in vitro. Cisplatin local delivery implant remarkably improved drug specificity to the tumor and significantly decreased accumulation in the blood, kidney, and other distant normal organs, compared with traditional systemic delivery. The localized treatment further resulted in complete inhibition of tumor growth. CONCLUSIONS: The current standard-of-care systemic administration of cisplatin provides a subtherapeutic dose. We developed a polymeric drug delivery system that delivered high doses of cisplatin directly into the cervical tumor, while lowering drug accumulation and consequent side effects in normal tissues. Moving forward, these data will be used as the basis of a future first-in-human clinical trial to test the efficacy of localized cisplatin as adjuvant or neoadjuvant chemotherapy in local and regional cervical cancer.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Inyecciones Intralesiones/métodos , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biopsia , Línea Celular Tumoral , Quimioradioterapia/métodos , Cisplatino/efectos adversos , Cisplatino/análisis , Cisplatino/farmacocinética , Implantes de Medicamentos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Polímeros/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Distribución Tisular , Carga Tumoral , Neoplasias del Cuello Uterino/química , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
Nuclear Factor-κappa B (NF-κB) is a family of critical transcription factors of the inflammatory pathway and plays an imperative role in the progression of various cancers such as breast, lung, liver, pancreatic, prostate and multiple types of lymphoma. NF- κB develops an inherent relationship between inflammation and cancer. It is a crucial factor that controls the ability of malignant and pre-neoplastic cells to prevent programmed cell death-based tumor-surveillance channels. Due to its high significance in the onset and progression of various cancers, it has become an excellent target for cancer therapy. The emerging targeted therapies provide a lot of hope, whereby a single protein or generally the target enzyme is completely blocked. Several natural compounds have shown anticancer and anti-inflammatory activities by inhibiting the NF-κB pathway in various cancer types. About 750 natural and synthetic inhibitors of the NF-κB have been reported. These inhibitors include microbial and viral proteins, small RNA/DNA, antioxidants, small molecules, peptides, and engineered constitutively active polypeptides, all of which may inhibit canonical and alternative NF-κB pathways. Thus, blocking or targeting the NF-κB-signaling pathways using natural and synthetic compounds could be a potential mechanism to cure the NF-κB induced tumors.
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FN-kappa B , Neoplasias , Factor B del Complemento , Humanos , Quinasa I-kappa B , FN-kappa B/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Factores de TranscripciónRESUMEN
The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN-/- cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT. In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells in vitro and in vivo These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
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Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glutaminasa/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Compuestos de Sulfhidrilo/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Modelos Animales de Enfermedad , Femenino , Glutamina/metabolismo , Glutatión/metabolismo , Glucólisis , Humanos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We introduce a novel self-standing, nanoporous carbon scaffold (NCS, 25 µm thick), with an ordered inverse opal pore structure (â¼85 nm pore) as a microporous layer (MPL) in a polymer electrolyte membrane fuel cell. Unlike previous studies, through chemical functionalization of the pore surfaces, the wettability of the MPL is controllably modified without altering the pore structure. Ex situ environmental scanning electron microscopy experiments revealed water sorption in the hydrophilic NCS under moderate relative humidity (RH) conditions but not in the hydrophobic NCS, wherein water condensation on the surface was noted only at high RH. The influence of structure and wettability of different MPLs on cell performance was gleaned from steady-state cell polarization behavior. For cells operated under dry conditions (≤80% RH), the limiting current for cells with a hydrophilic NCS MPL was the highest while that for cells with a hydrophobic NCS MPL was the lowest regardless of the level of water saturation (RH).
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Catalyst layer (CL) ionomers control several transport and interfacial phenomena including long-range transport of protons, local transport of oxygen to Pt catalyst, effective utilization of Pt catalyst, electrochemical reaction kinetics and double-layer capacitance. In this work, the variation of these properties, as a function of humidity, for CLs made with two ionomers differing in side-chain length and equivalent weight, Nafion-1100 and Aquivion-825, was investigated. This is the first study to examine humidity-dependent oxygen reduction reaction (ORR) kinetics in-situ for CLs with different ionomers. A significant finding is the observation of higher ORR kinetic activity (A/cm2Pt) for the Aquivion-825 CL than for the Nafion-1100 CL. This is attributed to differences in the interfacial protonic concentrations at Pt/ionomer interface in the two CLs. The differences in Pt/ionomer interface is also noted in a higher local oxygen transport resistance for Aquivion-825 CLs compared to Nafion-1100 CLs, consistent with stronger interaction between ionomer and Pt for ionomer with more acid groups. Similar dependency on Pt utilization (ratio of electrochemically active area at any relative humidity (RH) to that at 100% RH) as a function of RH is observed for the two CLs. As expected, strong influence of humidity on proton conduction is observed. Amongst the two, the CL with high equivalent weight ionomer (Nafion-1100) exhibits higher conduction.
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Técnicas Electroquímicas , Polímeros de Fluorocarbono/química , Iones/química , Platino (Metal)/química , Catálisis , Suministros de Energía Eléctrica , Membranas Artificiales , Oxígeno/química , ProtonesRESUMEN
Shape and size controlled nanostructures are critical for nanotechnology and have versatile applications in understanding interfacial phenomena of various multi-phase systems. Facile synthesis of fluorescent nanostructures remains a challenge from conventional precursors. In this study, bio-inspired catecholamines, dopamine (DA), epinephrine (EP) and levodopa (LDA), were used as precursors and fluorescent nanostructures were synthesized via a simple one pot method in a water-alcohol mixture under alkaline conditions. DA and EP formed fluorescent spheres and petal shaped structures respectively over a broad spectrum excitation wavelength, whereas LDA did not form any particular structure. However, the polyepinephrine (PEP) micropetals were formed by weaker interactions as compared to covalently linked polydopamine (PDA) nanospheres, as revealed by NMR studies. Application of these fluorescent structures was illustrated by their adsorption behavior at the oil/water interface using laser scanning confocal microscopy. Interestingly, PDA nanospheres showed complete coverage of the oil/water interface despite its hydrophilic nature, as compared to hydrophobic PEP micropetals which showed a transient coverage of the oil/water interface but mainly self-aggregated in the water phase. The reported unique fluorescent organic structures will play a key role in understanding various multi-phase systems used in aerospace, biomedical, electronics and energy applications.
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Breast cancer is a major public health problem worldwide in women and current therapeutic strategies are not adequately effective for this deadly disease. We have previously shown the anti-proliferative activity of bitter melon extract (BME) in breast cancer cells. In this study, we observed that BME treatment induces autophagosome-bound Long chain 3 (LC3)-B and accumulates protein p62/SQSTM1 (p62) in breast cancer cells. Additionally, we observed that BME treatment in breast cancer cells increases phospho-AMPK expression and inhibits the mTOR/Akt signaling pathway. Subsequently, we demonstrated that BME feeding effectively inhibited breast cancer growth in syngeneic and xenograft mouse models. Further, we observed the increased p62 accumulation, induction of autophagy and apoptotic cell death in tumors from BME-fed animals. Taken together, our results demonstrate that BME treatment inhibits breast tumor growth, and this anti-tumor activity in breast cancer is, in part, mediated by induction of autophagy and modulation of the AMPK/mTOR pathway. The antitumor activity of BME by oral feeding in breast cancer models suggested the high potential for a clinical application.
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Natural killer (NK) cells are one of the major components of innate immunity, with the ability to mediate antitumor activity. Understanding the role of NK-cell-mediated tumor killing in controlling of solid tumor growth is still in the developmental stage. We have shown recently that bitter melon extract (BME) modulates the regulatory T cell (Treg) population in head and neck squamous cell carcinoma (HNSCC). However, the role of BME in NK-cell modulation against HNSCC remains unknown. In this study, we investigated whether BME can enhance the NK-cell killing activity against HNSCC cells. Our results indicated that treatment of human NK-cell line (NK3.3) with BME enhances ability to kill HNSCC cells. BME increases granzyme B accumulation and translocation/accumulation of CD107a/LAMP1 in NK3.3 cells exposed to BME. Furthermore, an increase in cell surface expression of CD16 and NKp30 in BME-treated NK3.3 cells was observed when cocultured with HNSCC cells. Collectively, our results demonstrated for the first time that BME augments NK-cell-mediated HNSCC killing activity, implicating an immunomodulatory role of BME. Cancer Prev Res; 10(6); 337-44. ©2017 AACR.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Citotoxicidad Inmunológica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inmunomodulación/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Momordica charantia/química , Extractos Vegetales/farmacología , Carcinoma de Células Escamosas/inmunología , Línea Celular Tumoral , Proteínas Ligadas a GPI/metabolismo , Granzimas/metabolismo , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas de Membrana de los Lisosomas/metabolismo , Medicina Tradicional/métodos , Receptor 3 Gatillante de la Citotoxidad Natural/metabolismo , Extractos Vegetales/uso terapéutico , Receptores de IgG/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunologíaRESUMEN
Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSC) play a significant role in recurrence and chemoresistance. We previously observed that c-Fos was highly upregulated in the HNSCC sphere-forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.Experimental Design and Results: We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in nontumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Furthermore, subcutaneous transplantation of c-Fos-overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared with parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial-mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2, and Notch1). Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells.Conclusions: Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment. Clin Cancer Res; 23(12); 3120-8. ©2016 AACR.
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Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Recurrencia Local de Neoplasia/genética , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Reprogramación Celular/genética , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Ratones , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer is a major public health problem worldwide in women and existing treatments are not adequately effective for this deadly disease. microRNAs (miRNAs) regulate the expression of many target genes and play pivotal roles in the development, as well as in the suppression of many cancers including breast cancer. We previously observed that miR-203 was highly upregulated in breast cancer tissues and in ER-positive breast cancer cell lines. In our present study, we observed that anti-miR-203 suppresses breast cancer cell proliferation in vitro. Orthotopic implantation of miR-203 depleted MCF-7 cells into nude mice displays smaller tumor growth as compared to control MCF-7 cells. Furthermore, miR-203 expression is significantly higher in ER-positive breast cancer patients as compared to ER-negative patients. We identified suppressor of cytokine signaling 3 (SOCS3) as a direct target of miR-203. Here we observed that miR-203 expression is inversely correlated with SOCS3 expression in ER-positive breast cancer samples. Additionally, we found that anti-miR-203 suppressed the expression of pStat3, pERK and c-Myc in MCF-7 and ZR-75-1 cells. We also demonstrated that anti-miR-203 decreased mammospheres formation and expression of stem cell markers in MCF-7 and ZR-75-1 cells. Taken together, our data suggest that anti-miR-203 has potential as a novel therapeutic strategy in ER-positive breast cancer treatment.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Proteína Quinasa 6 Activada por Mitógenos/metabolismo , Trasplante de Neoplasias , Células Madre Neoplásicas/citología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and leading cause of cancer related mortality worldwide. Despite the advancement in treatment procedures the overall survival rate of patients has not considerably enhanced in the past few decades. Therefore, new strategies to achieve a favorable response for the improvement in the prognosis of HNSCC are urgently needed. In this study, we examined the role of bitter melon extract (BME) in HNSCC tumor microenvironment. Mouse head and neck cancer (SCCVII) cells were subcutaneously injected into the flanks of syngeneic mice. We observed that oral gavage of BME significantly inhibits the tumor growth in mice as compared to control group. Further study suggested that BME inhibits cell proliferation as evident from low expression of proliferating cell nuclear antigen (PCNA) and c-Myc in the tumors of BME fed mice as compared to that of control group. We next investigated the role of BME as an immunomodulator in HNSCC model. Forkhead box protein P3+ (FoxP3+) T cells suppress tumor immunity. Our data suggested that BME treatment decreases the infiltrating regulatory T (Treg) cells by inhibiting FoxP3+ populations in the tumors and in spleens. Additionally, BME treatment reduces Th17 cell population in the tumor. However, BME treatment did not alter Th1 and Th2 cell populations. Together, our findings offer a new insight into how bitter melon extract inhibits head and neck tumor growth by modulating cell proliferation and Treg populations, with implications for how to control tumor-infiltrating lymphocytes and tumor progression.