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BACKGROUND: COVID-19 caused by SARS-CoV-2 has been inducing an ongoing global health and economic emergency. Although viral pneumonia is the most striking presentation for COVID-19 patients, it has been noticed that some patients may also be accompanied with an abnormal liver function. METHODS: CT was performed in both lungs, and routine bloodwork and the blood metabolic panel were measured. RESULTS: Here, we report on a young male patient without any history of live diseases who suffered simultaneously both SARS-CoV-2 caused pneumonia and hepatitis as evidenced by increased serum bilirubin together with increased serum transaminases. CONCLUSIONS: Studies on mechanisms whereby SARS-CoV-2 causing liver damages might provide more information about the pathogenesis of COVID-19 and help management of this global health emergency.
Assuntos
COVID-19 , Hepatopatias , Pneumonia Viral , Humanos , Masculino , Pneumonia Viral/diagnóstico , SARS-CoV-2RESUMO
BACKGROUND: Ciliated muconodular papillary tumor (CMPT) is an incredibly rare pulmonary tumor. Currently, little is known about CMPT, and it has not yet been classified by the World Health Organization. The clinical manifestation of CMPT is nonspecific and the diagnosis is only based on pathology. CMPT has been documented in limited reports as a benign tumor, thus the treatment is typically with surgical excision if a solid tumor is identifiable. The prognosis of CMPT is very positive, as no recurrence has been reported in the limited literature available. However, CMPT accompanied with adenocarcinoma in situ has not been reported previously in the literature. CASE PRESENTATION: In this report, we presented a case of a 53-year-old male smoker with CMPT associated with adenocarcinoma in situ. This diagnosis was confirmed by pathological examination, including immunohistostaining. No solid resectable lesion was identified on CT scan; therefore, no surgery was performed. The patient's adenocarcinoma in situ was disseminated in both lungs, thus chemotherapeutic treatment with cisplatin and pemetrexed was given. The patient will be continually followed up closely on a wait-and-watch basis. CONCLUSIONS: In summary, our report reveals a unique case of CMPT in conjunction with adenocarcinoma in situ, potentially revealing an association between CMPT and malignancy which has not been previously reported. More similar case studies will be beneficial to determine the authentic relationship between CMPT and adenocarcinoma in situ.
Assuntos
Adenocarcinoma in Situ/patologia , Carcinoma Papilar/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma in Situ/diagnóstico por imagem , Antineoplásicos/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Cisplatino/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Nocardia infection is a very rare bacterial infection caused by Gram-positive, aerobic nocardia species. However, in recent years, it has become a serious infection in immunocompromised patients. Earlier diagnosis plays a pivotal in the effective treatment of nocardia infection. METHODS: In this study, we reported a 65-year-old male patient with nephrotic syndrome who had disseminated abscesses in the lungs, right lower limb, and right cheek. RESULTS: Bacterial culture from these lesions confirmed the presence of nocardia. Timely administration of sensitive antibiotics resulted in a quick recovery for this patient. CONCLUSIONS: Nocardia infection should be considered in the differential diagnosis of infectious lesions, especially when a patient has multiple abscesses and an underlying disorder in which the immune function of the patient may be compromised.
Assuntos
Síndrome Nefrótica/complicações , Nocardiose , Idoso , Humanos , Hospedeiro Imunocomprometido , Abscesso Pulmonar , Masculino , Nocardia , Dermatopatias BacterianasRESUMO
It is now widely accepted that mitochondrial biogenesis is inhibited in most cancer cells. Interestingly, one of the possible exceptions is colorectal cancer (CRC), in which the content of mitochondria has been found to be higher than in normal colon mucosa. However, to date, the causes and effects of this phenomenon are still unclear. In the present study, we systematically investigated the functional role of mitochondrial single-strand DNA binding protein (mtSSB), a key molecule in the regulation of mitochondrial DNA (mtDNA) replication, in the mitochondrial biogenesis and CRC cell growth. Our results demonstrated that mtSSB was frequently upregulated in CRC tissues and that upregulated mtSSB was associated with poor prognosis in CRC patients. Furthermore, overexpression of mtSSB promoted CRC cell growth in vitro by regulating cell proliferation. The in vivo assay confirmed these results, indicating that the forced expression of mtSSB significantly increases the growth capacity of xenograft tumors. Mechanistically, the survival advantage conferred by mtSSB was primarily caused by increased mitochondrial biogenesis and subsequent ROS production, which induced telomerase reverse transcriptase (TERT) expression and telomere elongation via Akt/mTOR pathway in CRC cells. In addition, FOXP1, a member of the forkhead box family, was identified as a new transcription factor for mtSSB. Moreover, our results also demonstrate that proinflammatory IL-6/STAT3 signaling facilitates mtSSB expression and CRC cell proliferation via inducing FOXP1 expression. Collectively, our findings demonstrate that mtSSB induced by inflammation plays a critical role in the regulation of mitochondrial biogenesis, telomerase activation, and subsequent CRC proliferation, providing a strong evidence for mtSSB as drug target in CRC treatment.
Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Interleucina-6/genética , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Telomerase/genética , Regulação para Cima/genética , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Humanos , Biogênese de Organelas , Fator de Transcrição STAT3 , Transdução de Sinais/genética , Ativação Transcricional/genéticaRESUMO
BACKGROUND: Primary hepatic tuberculosis is a very rare clinical form of tuberculosis, with atypical clinical presentations and nonspecific imaging features. This results in great difficulty to reach a correct and timely clinical diagnosis. Traditionally, liver biopsy is the gold standard for its diagnosis. Here we assessed the effectiveness of using a T-SPOT.TB test in the early diagnosis of primary hepatic tuberculosis. METHODS: We report a case of primary hepatic tuberculosis whose location of hepatic lesion renders it hard to perform a biopsy. Instead, a T-SPOT.TB test was utilized to help in the early diagnosis of this rare form of tuberculosis. A conventional fourdrug regimen for anti-tubercular therapy together with vitamin B6 was initiated and maintained for 6 months. RESULTS: The T-SPOT.TB test was highly positive for ESAT-6 (87 > 20) and CFP-10 (89 > 20). Dull pain in the upper right abdomen was gone 2 months post treatment. The abnormal lesions shown in an MRI reduced significantly 4 months post treatment. Spot count for ESAT-6 and CFP-10 decreased 6 months post treatment. CONCLUSIONS: The results of this study suggest the critical role of T-SPOT.TB test in the earlier diagnosis of prima¬ry hepatic tuberculosis for those patients who have difficulties having a hepatic biopsy.
Assuntos
Tuberculose Hepática/diagnóstico , Antígenos de Bactérias/análise , Proteínas de Bactérias/análise , Feminino , Humanos , Adulto JovemRESUMO
The anteroposterior patterning of the central nervous system follows an activation/transformation model, which proposes that a prospective telencephalic fate will be activated by default during the neural induction stage, while this anterior fate could be transformed posteriorly according to caudalization morphogens. Although both extrinsic signals and intrinsic transcription factors have been implicated in dorsoventral (DV) specification of vertebrate telencephalon, the DV patterning model remains elusive. This is especially true in human considering its evolutionary trait and uniqueness of gene regulatory networks during neural induction. Here, we point to a model that human forebrain DV patterning also follows an activation/transformation paradigm. Human neuroectoderm (NE) will activate a forebrain dorsal fate automatically and this default anterior dorsal fate does not depend on Wnts activation or Pax6 expression. Forced expression of Pax6 in human NE hinders its ventralization even under sonic hedgehog (Shh) treatment, suggesting that the ventral fate is repressed by dorsal genes. Genetic manipulation of Nkx2.1, a key gene for forebrain ventral progenitors, shows that Nkx2.1 is neither necessary nor sufficient for Shh-driven ventralization. We thus propose that Shh represses dorsal genes of human NE and subsequently transforms the primitively activated dorsal fate ventrally in a repression release manner.
Assuntos
Padronização Corporal/fisiologia , Diferenciação Celular/fisiologia , Modelos Biológicos , Prosencéfalo/fisiologia , Transdução de Sinais/fisiologia , Linhagem Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prosencéfalo/citologia , Prosencéfalo/embriologia , RNA Mensageiro/metabolismo , Fatores de Tempo , TransfecçãoRESUMO
IFN-γ(-/-) NOD.H-2h4 mice develop autoimmune disease with extensive hyperplasia and proliferation of thyroid epithelial cells (TEC H/P) and fibrosis. Splenic T cells from donors with severe TEC H/P transfer TEC H/P to SCID recipients. The goal of this study was to determine what factors control TEC H/P development/progression by examining T cells, markers of apoptosis, senescence and proliferation in thyroids of SCID recipients over time. At 28days, T cell infiltration was maximal, thyrocytes were proliferating, and fibrosis was moderate. At days 60 and 90, thyroids were larger with more fibrosis. T cells, cytokines and thyrocyte proliferation decreased, and cell cycle inhibitor proteins, and anti-apoptotic molecules increased. T cells and thyrocytes had foci of phosphorylated histone protein H2A.X, indicative of cellular senescence, when TEC H/P progressed and thyrocyte proliferation declined. Some thyrocytes were regenerating at day 90, with irregularly shaped empty follicles and ciliated epithelium. Proliferating thyrocytes were thyroid transcription factor (TTF1)-positive, suggesting they derived from epithelial cells and not brachial cleft remnants.
Assuntos
Histonas/metabolismo , Linfócitos T/imunologia , Células Epiteliais da Tireoide/metabolismo , Glândula Tireoide/patologia , Tireoidite Autoimune/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Senescência Celular , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Fibrose , Humanos , Hiperplasia , Interferon gama/genética , Camundongos , Camundongos Knockout , Camundongos SCID , Células Epiteliais da Tireoide/patologia , Tireoidite Autoimune/patologia , Fatores de TranscriçãoRESUMO
BACKGROUND: Interleukin-32 (IL-32) is a recently recognized intracellular, proinflammatory cytokine which may play a role in cancer metastasis and patient survival. The role of IL-32 in cancer, especially its direct effect on cancer cells, is not well understood. MATERIAL AND METHODS: Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining, and caspase-3 activity assay were used to investigate the in vitro role for IL-32α in human melanoma growth. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. RESULTS: Exogenous administration of IL-32α inhibited proliferation of the HTB-72 human melanoma cell line, but had little effect on other melanoma cell lines. Inhibition of proliferation in HTB-72 correlated with increased expression of p21 and p53. IL-32α administration also increased apoptosis in HTB-72. This finding correlated with increased expression of TRAILR1. CONCLUSIONS: The data presented suggest a direct effect of IL-32α on the growth of human melanoma and give some insight into the mechanisms which may in part govern this effect. J. Surg. Oncol. 2016;113:364-369. © 2016 Wiley Periodicals, Inc.
Assuntos
Interleucinas/farmacologia , Melanoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Humanos , Imuno-Histoquímica , Melanoma/metabolismo , Melanoma/patologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/biossíntese , Proteína Supressora de Tumor p53/biossínteseRESUMO
BACKGROUND: IL-9 is a pleiotropic cytokine produced mainly by Th9 cells. IL-9 may have an anti-proliferative role in murine melanoma, however, its effect on human melanoma is unknown. METHODS: We examined the effects of IL-9 on proliferation and apoptosis in four human melanoma cell lines, HTB-65, HTB-72, CRL-11147, and SK-Mel-5. Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate. RESULTS: We found that IL-9 decreased the percentage of colonies of HTB-72 and SK-Mel-5 cells but not that of HTB-65 or CRL-11147 cells. PCNA mRNA, PCNA+ cells, PCNA staining intensity, and the OD value of HTB-72 melanoma cells were consistently decreased in the present of IL-9. IL-9 also increased TUNEL+ cells and the relative caspase-3 activity in HTB-72 melanoma cells. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. The anti-proliferative effect of IL-9 on HTB-72 cells correlated with higher expression of anti-proliferative molecule p21. Its pro-apoptotic effect on HTB-72 cells correlated with higher expression of the pro-apoptotic molecule TRAIL. CONCLUSIONS: IL-9 inhibits melanoma HTB-72 cell growth by upregulation of p21 and TRAIL. Understanding the interactions between IL-9 and melanoma may help direct strategies for cytokine-based immunotherapy development.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidores do Crescimento/metabolismo , Interleucina-9/metabolismo , Melanoma/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Interleucina-9/farmacologia , Regulação para CimaRESUMO
CD40 is expressed on cells of the immune system and in some tissues that are targets for autoimmune-mediated damage. It is not known if CD40 expression in target tissues plays a role in the pathology of autoimmune diseases. This study shows that agonistic anti-CD40 induces strong and sustained proliferation of thyroid epithelial cells (TECs), or thyrocytes, in IFN-γ(-/-) autoimmune-prone NOD and NOD.H-2h4 mice. TEC proliferation is accompanied by greatly increased expression of CD40 on TECs, development of fibrosis and hypothyroidism, and increased expression of proinflammatory molecules in thyroids. Bone marrow chimera experiments indicate that TEC expression of CD40 is required for anti-CD40-induced TEC proliferation, but lymphoid cells do not have to express CD40. TEC proliferation is reduced in wild-type mice given anti-CD40, presumably because they produce IFN-γ, which inhibits TEC proliferation. CD40 also increases on TECs during development of an autoimmune thyroid disease characterized by TEC hyperproliferation that develops spontaneously in IFN-γ(-/-) NOD.H-2h4 mice. TEC hyperproliferation development is accelerated in mice given agonistic anti-CD40. These studies provide new information regarding the role of target tissue expression of CD40 in development of autoimmunity and suggest that use of agonistic anti-CD40 for tumor therapy could result in autoimmune disease.
Assuntos
Anticorpos/fisiologia , Autoimunidade , Antígenos CD40/agonistas , Antígenos CD40/imunologia , Proliferação de Células , Células Epiteliais/imunologia , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Animais , Antígenos CD40/biossíntese , Células Epiteliais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Cultura Primária de Células , Glândula Tireoide/citologiaRESUMO
Interleukin-35 (IL-35), an IL-12 cytokine family member, mediates the immune inhibitory function of regulatory T cells (Treg). We assayed the presence of IL-35 in paraffin-embedded human pancreas cancer (PCAN) and unexpectedly found IL-35 was expressed mainly by epithelial derived PCAN cells, but not by Treg. We further examined the expression and effect of exogenous IL-35 in human PCAN cell lines and found IL-35 promoted growth and inhibited apoptosis in PCAN cell lines. IL-35 induced proliferation correlated with an increase in cyclin B, cyclin D, cdk2, and cdk4 and a decrease in p27 expression, while inhibition of apoptosis was associated with an increase in Bcl-2 and a decrease in TRAILR1. We conclude IL-35 is produced by PCAN in vivo and promotes PCAN cell line growth in vitro. These results might indicate an important new role for IL-35 as an autocrine growth factor in PCAN growth.
Assuntos
Apoptose , Comunicação Autócrina , Interleucinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Anticorpos Neutralizantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Comunicação Autócrina/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismoRESUMO
BACKGROUND: Metagenomic next-generation sequencing (mNGS) demonstrates great promise as a diagnostic tool for determining the cause of pathogenic infections. The standard diagnostic procedures (SDP) include smears and cultures and are typically viewed as less sensitive and more time-consuming when compared to mNGS. There are concerns about the logistics and ease of transition from SDP to mNGS. mNGS lacks standardization of collection processes, databases, and sequencing. Additionally, there is the burden of training clinicians on interpreting mNGS results. OBJECTIVE: Until now, few studies have explored factors that could be used as early adoption candidates to ease the transition between SDP and mNGS. This study evaluated 123 patients who had received both SDP and mNGS and compared several variables across a diagnostic test evaluation. METHODS: The diagnostic test evaluation observed metrics such as sensitivity, specificity, positive and negative likelihood ratios (PLR, NLR), positive and negative predictive values (PPV, NPV), and accuracy. Factors included various sample sources such as bronchoalveolar lavage fluid (BALF), lung tissue, and cerebral spinal fluid (CSF). An additional factor observed was the patient's immune status. RESULTS: Pathogen detection was found to be significantly greater for mNGS for total patients, BALF sample source, CSF sample source, and non-immunocompromised patients (p<0.05). Pathogen detection was found to be insignificant for lung tissue sample sources and immunocompromised patients. Sensitivity, PLR, NLR, PPV, NPV, and accuracy appeared to be higher with mNGS for the total patients, BALF sample source, and non-immunocompromised patients when compared with SDP (p<0.05). CONCLUSION: With higher metrics in sensitivity, specificity, PLR, NLR, PPV, NPV, and accuracy for overall patients, mNGS may prove a better diagnostic tool than SDP. When addressing sample sources, mNGS for BALF-collected samples appeared to have higher scores than SDP for the same metrics. When patients were in a non-immunocompromised state, mNGS also demonstrated greater diagnostic benefits to BALF and overall patients compared to SDP. This study demonstrates that using BALF as a sample source and selecting non-immunocompromised patients may prove beneficial as early adoption factors for mNGS standard protocol. Such a study may pave the road for mNGS as a routine clinical method for determining the exact pathogenic etiology of lung infections.
RESUMO
Cervical cancer is one of the most common types of female cancers worldwide. IL-29 is an interesting cytokine in the IFNλ family. Its role in the pathogenesis of neoplasia is complicated and has been studied in other cancers, such as lung cancer, gastric cancer, and colorectal cancer. IL-29 has been previously reported to promote the growth of pancreatic cancer. However, the direct role of IL-29 in cervical cancer has not been studied yet. This study was performed to investigate the direct effect on cervical cancer cell growth. Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the effects of IL-29 on cell survival, proliferation, and apoptosis of a well-studied cervical cancer cell line, SiHa. We further investigated the potential molecular mechanisms by using RT-PCR and IHC. We found that the percentage of colonies of SiHa cells was decreased in the presence of IL-29. This was consistent with a decreased OD value of cancer cells. Furthermore, the relative caspase-3 activity in cancer cells increased in the presence of IL-29. The anti-proliferative effect of IL-29 on cancer cells correlated with increased expression of the anti-proliferative molecules p18 and p27. The pro-apoptotic effect of IL-29 on cancer cells correlated with increased expression of the pro-apoptotic molecule TRAILR1. IL-29 inhibits cervical cancer cell growth by inhibiting cell proliferation and promoting cell apoptosis. Thus, IL-29 might be a promising cytokine for immunotherapy of cervical cancer.
Assuntos
Citocinas , Interferon lambda , Interleucinas , Neoplasias do Colo do Útero , Feminino , Humanos , Apoptose , Caspase 3 , Linhagem Celular Tumoral , Proliferação de Células , Imunoterapia , Regulação para Cima , Neoplasias do Colo do Útero/terapiaRESUMO
Ovarian cancer is a prominent cancer worldwide with a relatively low survival rate for women diagnosed. Many individuals are diagnosed in the late stage of the disease and are prescribed a wide variety of treatment options. Current treatment options are primarily a combination of surgery and chemotherapy as well as a new but promising treatment involving immunotherapy. Nevertheless, contemporary therapeutic modalities exhibit a discernible lag in advancement when compared with the strides achieved in recent years in the context of other malignancies. Moreover, many surgery and chemotherapy options have a high risk for recurrence due to the late-stage diagnosis. Therefore, there is a necessity to further treatment options. There have been many new advancements in the field of immunotherapy. Immunotherapy has been approved for 16 various types of cancers and has shown significant treatment potential in many other cancers as well. Researchers have also found many promising outlooks for immunotherapy as a treatment for ovarian cancer. This review summarizes many of the new advancements in immunotherapy treatment options and could potentially offer valuable insights to gynecologists aimed at enhancing the efficacy of their treatment approaches for patients diagnosed with ovarian cancer.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , ImunoterapiaRESUMO
BACKGROUND/AIM: Recently developed vaccines for the SARS-CoV-2 virus utilize endogenous production of the virus' spike protein (SP), allowing the host to develop an immune response. As a result of the novelty of this virus and its vaccines, little is known overall about the potential effects of the SP on the pathogenesis of neoplasia, either from vaccination or from infection. This study was designed to investigate whether SARS-CoV-2 SP has any direct effect on SiHa cervical cancer cells. MATERIALS AND METHODS: The effects of SARS-CoV-2 SP on cervical cancer cell proliferation and apoptosis were investigated by using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits in a widely-used cervical cancer cell line, SiHa. RT-PCR and immunohistochemistry were also performed to determine the potential molecular mechanisms. RESULTS: The growth and proliferation of SiHa cancer cells were inhibited by SARS-CoV-2 SP. SARS-CoV-2 SP also induced apoptosis in SiHa cancer cells. The anti-proliferative effect of SARS-CoV-2 SP on SiHa cancer cells was associated with the up-regulation of the anti-proliferative molecule p53. The pro-apoptotic effect of SARS-CoV-2 SP on SiHa cells was associated with the up-regulation of the pro-apoptotic molecule TRAIL. CONCLUSION: SARS-CoV-2 SP inhibits the growth of cervical cancer via up-regulation of p53 and TRAIL. Further studies are needed to elaborate on the potential effects of the SARS-CoV-2 SP on other cancer cell lines and normal physiological cell lines for comparison.
Assuntos
Apoptose , Proliferação de Células , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Feminino , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Linhagem Celular Tumoral , SARS-CoV-2/fisiologia , COVID-19/virologia , COVID-19/metabolismo , COVID-19/patologia , Proteína Supressora de Tumor p53/metabolismo , Caspase 3/metabolismoRESUMO
BACKGROUND/AIM: Ovarian cancer (OVC) is a common, aggressive, and heterogeneous malignancy, with a widely variable prognosis. With the advances of modern immunology, mast cells (MCs) have been shown to play a significant role in the prognosis of some malignant tumors. However, the role of mast cells in the prognosis of OVC is unknown. MATERIALS AND METHODS: In this study, MC-associated prognostic genes (MRGs) were used to classify OVC from The Cancer Genome Atlas (TCGA)-OVC cohort. Genes were evaluated using univariate cox regression analysis. Twenty-nine prognostic gene signatures were identified using LASSO-COX analysis. COX regression models and principal component analysis (PCA) algorithms were used to construct MRG scores and individual MRGs patterns. External validation was performed in the TCGA-breast cancer (BRCA) and IMvigor210 cohorts. Immunity analysis based on MRGs was performed using CIBERSORT, and GSVA methods, and immunotherapy response was evaluated using the TIDE website. RESULTS: Using TCGA-OVC data, we established a model for constructing MRG scores based on the twenty-nine identified prognostic gene signatures using the PCA algorithm. MRG scores were found to be strongly correlated with immune cell infiltration and were excellent predictors of prognosis in patients with OVC. Low MRG scores were associated with better prognosis and better response to immunotherapy and chemotherapy. CONCLUSION: MC-related prognosis signature characterizes the immune landscape and predicts the prognosis of OVC. Understanding the correlation between MC-related gene signatures and immunotherapy and chemotherapy may improve the development of personalized clinical treatment strategies.
Assuntos
Mastócitos , Neoplasias Ovarianas , Humanos , Feminino , Mastócitos/imunologia , Mastócitos/patologia , Prognóstico , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Biomarcadores Tumorais/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Perfilação da Expressão Gênica , TranscriptomaRESUMO
As immunotherapy gains momentum as a promising approach for treating several types of cancer, IL-21 has emerged as the latest discovery within the γ chain cytokine family, known for its decisive effects on innate and adaptive immunity and immunopathology. Through the modulation of immune cells, IL-21 has demonstrated significant anti-tumor effects in preclinical studies. The potential of IL-21 in cancer treatment has been explored in phase I and II clinical trials, where it has been utilized both as monotherapy and in combination with other drug agents. Further investigation, alongside larger studies, is necessary before final evaluation and application of IL-21 as immunotherapy. This review aims to summarize these pre-clinical and clinical studies and to discuss the possible future directions of IL-21 immunotherapy development. Such a study may be helpful to accelerate the process of clinical application for IL21 immunotherapy.
Assuntos
Imunoterapia , Interleucinas , Neoplasias , Humanos , Interleucinas/uso terapêutico , Interleucinas/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , AnimaisRESUMO
Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.
Assuntos
Citosol , Secreção de Insulina , Células Secretoras de Insulina , Insulina , Camundongos Endogâmicos C57BL , Animais , Células Secretoras de Insulina/metabolismo , Concentração de Íons de Hidrogênio , Citosol/metabolismo , Camundongos , Insulina/metabolismo , Masculino , Dieta Hiperlipídica , Intolerância à Glucose/metabolismo , Glucose/metabolismo , HumanosRESUMO
IFN-γ(-/-) NOD.H-2h4 mice develop an autoimmune disease characterized by hyperplasia and proliferation of thyroid epithelial cells (TEC H/P). Proliferating TECs produce TGF-ß, and IFN-γ inhibits TEC H/P. In the present study, cultured TECs were used to directly determine the mechanisms by which these cytokines act on TECs to result in proliferation or inhibition of proliferation. With TECs from IFN-γ(-/-) NOD.H-2h4 mice or mice expressing the dominant negative TGF-ß type II receptor on TECs, TGF-ß was shown to promote TEC proliferation and IFN-γ was shown to inhibit TEC proliferation in vitro. TGF-ß may promote TEC proliferation by down-regulating antiproliferative molecules p21 and p27, whereas IFN-γ may inhibit proliferation by up-regulating antiproliferative molecules p18 and p21 and down-regulating the pro-proliferative molecule cyclin D. Inhibition of AKT abolished the effect of TGF-ß on p21 and p27, resulting in similar proliferation of TGF-ß-treated and control TECs. Increased expression of proliferating cell nuclear antigen (PCNA), TGF-ß, and p-AKT and decreased expression of p21 and p27 by proliferating TECs correlated with the proliferative state of TEC H/P. Taken together, the results suggest that TGF-ß promotes TEC proliferation by down-regulating p21 and p27 via the AKT pathway in IFN-γ(-/-) NOD.H-2h4 mice, which may have significant implications for development of effective therapeutic strategies targeting the TGF-ß and AKT pathways for treatment of hyperplasia and/or neoplasia.
Assuntos
Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Interferon gama/deficiência , Proteínas Proto-Oncogênicas c-akt/fisiologia , Glândula Tireoide/citologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Apoptose , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo , Células Epiteliais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta , Transdução de Sinais/fisiologia , Glândula Tireoide/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Radiotherapy (XRT) is used to improve local control of melanoma and for palliation of metastatic disease. Clinical use of XRT for melanoma is often limited by extent of disease and the relative radioresistance of melanoma may limit the effectiveness of XRT. Our group and others have previously shown that resveratrol (RSV) enhances radiation sensitivity in radioresistant prostate cancer cell lines. MATERIAL AND METHODS: In this study, the effects of XRT in combination with RSV on radioresistant melanoma lines, SK-Mel-5 and HTB-65, were evaluated by assessment of proliferation and apoptosis. Clonogenic assay, comparison of proliferating cell nuclear antigen staining, Quick Cell Proliferation assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate. RESULTS: We found that the percentage of colonies, proliferating cell nuclear antigen + cells and the optical density value of melanoma cells were decreased after addition of RSV to XRT (XRT/RSV). TUNEL + cells and the relative caspase-3 activity in melanoma cells were increased after addition of RSV to XRT (XRT/RSV). We investigated the possible molecular mechanisms of decreased proliferation and increased apoptosis by using reverse transcriptase-polymerase chain reaction and immunohistochemical staining. The anti-proliferative effect of XRT/RSV correlated with decreased expression of pro-proliferative molecule cyclin B, cyclin D, cdk2 and cdk4. The pro-apoptotic effect of XRT/RSV correlated with decreased expression of the anti-apoptotic molecule FLIP, Bcl-2, and survivin. CONCLUSION: These data suggest that RSV enhances radiation sensitivity of melanoma cells by inhibiting proliferation and promoting apoptosis. Resveratrol may have a potential role as a radiation sensitizer for melanoma treatment.