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Genetically engineered mouse models (GEMMs) are vital for elucidating gene function and disease mechanisms. An overwhelming number of GEMM lines have been generated, but endeavors to collect and organize the information of these GEMMs are seriously lagging behind. Only a few databases are developed for the information of current GEMMs, and these databases lack biological descriptions of allele compositions, which poses a challenge for nonexperts in mouse genetics to interpret the genetic information of these mice. Moreover, these databases usually do not provide information on human diseases related to the GEMM, which hinders the dissemination of the insights the GEMM provides as a human disease model. To address these issues, we developed an algorithm to annotate all the allele compositions that have been reported with Python programming and have developed the genetically modified mice information database (GMMID; http://www.gmmid.cn), a user-friendly database that integrates information on GEMMs and related diseases from various databases, including National Center for Biotechnology Information, Mouse Genome Informatics, Online Mendelian Inheritance in Man, International Mouse Phenotyping Consortium, and Jax lab. GMMID provides comprehensive genetic information on >70 055 alleles, 65 520 allele compositions, and â¼4000 diseases, along with biologically meaningful descriptions of alleles and allele combinations. Furthermore, it provides spatiotemporal visualization of anatomical tissues mentioned in these descriptions, shown alongside the allele compositions. Compared to existing mouse databases, GMMID considers the needs of researchers across different disciplines and presents obscure genetic information in an intuitive and easy-to-understand format. It facilitates users in obtaining complete genetic information more efficiently, making it an essential resource for cross-disciplinary researchers. Database URL: http://www.gmmid.cn.
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Bases de Dados Genéticas , Animais , Camundongos , Alelos , Camundongos Transgênicos , HumanosRESUMO
Background: Psychological distress has been a growing challenge to healthy living worldwide. Special attention has been concentrated on examining the cost of psychological distress on the life satisfaction of college students who are vulnerable groups coping with the challenge. The purpose of this study is to explore the roles of physical literacy (PL) and mindfulness in mediating the impact of psychological distress on life satisfaction among college students in China. Methods: A sample of 653 students from six universities across three cities in China participated in an online survey, which included measures of PL, mindfulness, life satisfaction, as well as stress, anxiety, and depression levels. Structural equation modeling (SEM) was implemented to analyze the survey data. Results: The findings of the SEM analysis demonstrated an acceptable model fit (X2/df = 3.63, CFI = 0.951, TLI = 0.940, RMSEA = 0.068, 90% CI = [0.060, 0.075], SRMR = 0.051) with a large effect size (R 2 = 0.36) for life satisfaction, indicating that 36% of the variation in life satisfaction could be explained by the model. In addition, significant partial-mediation effects of PL and mindfulness were observed in the relationship between psychological distress and life satisfaction. These findings provide empirical support for the notion that interventions targeting PL and mindfulness practices may effectively enhance well-being and alleviate psychological distress among college students. Furthermore, this study suggests that integrating PL and mindfulness components into physical education and activity programs could be beneficial in meeting individuals' holistic health needs.
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Atenção Plena , Satisfação Pessoal , Estudantes , Humanos , Feminino , Masculino , Estudantes/psicologia , China , Universidades , Adulto Jovem , Angústia Psicológica , Inquéritos e Questionários , Adulto , Estresse Psicológico/psicologia , Ansiedade/psicologia , Depressão/psicologia , Adolescente , Adaptação PsicológicaRESUMO
Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A-Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics.
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Gânglios Espinais , Neuralgia , Neuroglia , Receptores de N-Metil-D-Aspartato , Fator de Transcrição AP-2 , Animais , Neuralgia/metabolismo , Neuralgia/genética , Gânglios Espinais/metabolismo , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismo , Masculino , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Neuroglia/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , Ratos Sprague-Dawley , Hiperalgesia/metabolismo , Hiperalgesia/genéticaRESUMO
Despite frequent reports of mental health needs among older women with cancer, depressive symptoms often go unrecognized and untreated, particularly in socially vulnerable survivors. Here, we examined associations of sociodemographic factors and social limitations with depressive symptoms from pre-diagnosis to post-diagnosis in older women diagnosed with breast or gynecological cancer. Using the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) linked dataset, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between sociodemographic factors (race, ethnicity, marital status, rurality) and social limitations (i.e., health interfering with social activities) on depressive symptoms in women aged ≥65 years with breast or gynecologic cancer (n = 1,353). Most participants had breast cancer (82.0%), stage I-II cancer (85.8%), received surgery for their cancer (94.8%), and radiation treatment (50.6%). Prior to diagnosis, 11.8% reported depressive symptoms, which nearly doubled to 22.4% at follow-up. Participants were 2.7 times more likely of reporting depressive symptoms after cancer diagnosis compared with pre-cancer diagnosis (95%CI: 2.10-3.48). Race, ethnicity, rurality, marital status, and social interference were significantly associated with an increased risk of depressive symptoms after cancer diagnosis than before their cancer diagnosis (p < 0.05). In summary, depressive symptoms increased following a cancer diagnosis. Our results suggest potential avenues for intervention that could lead to reduced depressive symptoms among older female cancer survivors.
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Radiation-associated sarcomas (RASs) are rare tumors with limited contemporary data to inform prognostication and management. We sought to identify the clinical presentation, patterns of care, and prognostic factors of RASs. RAS patients treated at a single institution from 2015 to 2021 were retrospectively reviewed for clinicopathologic variables, treatment strategies, and outcomes. Thirty-eight patients were identified with a median follow-up of 30.5 months. The median age at RAS diagnosis was 68.4 years (27.9-85.4), with a median latency from index radiotherapy (RT) of 9.1 years (3.7-46.3). RAS histologies included angiosarcoma (26%), undifferentiated pleomorphic sarcoma (21%), and osteosarcoma (18%). Most were high-grade (76%). Genomic profiling revealed low tumor mutational burden, frequent inactivating TP53 mutations (44%), CDKN2A deletions (26%), and MYC amplifications (22%), particularly in breast angiosarcomas. Of 38 patients, 33 presented with localized disease, 26 of whom were treated with curative intent. Overall, the median progression-free survival (PFS) was 9.5 months (1.4-34.7), and the overall survival (OS) was 11.1 months (0.6-31.6). Patients with localized vs. metastatic RASs had a longer PFS (HR, 3.0 [1.1-8.5]; p = 0.03) and OS (HR, 3.0 [1.04-8.68]; p = 0.03). Among localized RAS patients, high grade was associated with shorter OS (HR, 4.6 [1.04-20.30]; p = 0.03) and resection with longer OS (mean 58.8 vs. 6.1 months, HR, 0.1 [0.03-0.28]; p < 0.001). Among patients undergoing resection, negative margins were associated with improved OS (mean 71.0 vs. 15.5 months, HR, 5.1 [1.4-18.2]; p = 0.006). Patients with localized disease, particularly those undergoing R0 resection, demonstrated significantly better outcomes. Novel strategies are urgently needed to improve treatment outcomes in this challenging group of diseases.
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Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.
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Tumores Neuroendócrinos , Octreotida , Receptores de Peptídeos , Humanos , Tumores Neuroendócrinos/radioterapia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Octreotida/efeitos adversos , Octreotida/administração & dosagem , Receptores de Peptídeos/metabolismo , Adulto , Resultado do Tratamento , Compostos Organometálicos/uso terapêutico , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/administração & dosagem , Idoso de 80 Anos ou mais , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/administração & dosagem , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patologia , Estudos RetrospectivosRESUMO
Genome-wide association studies have identified more than 290 single nucleotide variants (SNVs) associated with prostate cancer. These SNVs can be combined to generate a Polygenic Risk Score (PRS), which estimates an individual's risk to develop prostate cancer. Identifying individuals at higher risk for prostate cancer using PRS could allow for personalized screening recommendations, improve current screening tools, and potentially result in improved survival rates, but more research is needed before incorporating them into clinical use. Our study aimed to investigate associations between PRS and clinical factors in affected individuals, including age of diagnosis, metastases, histology, International Society of Urological Pathology (ISUP) Grade Group (GG) and family history of prostate cancer, while taking into account germline genetic testing in known prostate cancer related genes. To evaluate the relationship between these clinical factors and PRS, a quantitative retrospective chart review of 250 individuals of European ancestry diagnosed with prostate cancer who received genetic counseling services at The Ohio State University's Genitourinary Cancer Genetics Clinic and a 72-SNV PRS through Ambry Genetics, was performed. We found significant associations between higher PRS and younger age of diagnosis (p = 0.002), lower frequency of metastases (p = 0.006), and having a first-degree relative diagnosed with prostate cancer (p = 0.024). We did not observe significant associations between PRS and ISUP GG, histology or a having a second-degree relative with prostate cancer. These findings provide insights into features associated with higher PRS, but larger multi-ancestral studies using PRS that are informative across populations are needed to understand its clinical utility.
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Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract and a leading cause of cancer-related death worldwide. Since many CRC patients are diagnosed already in the advanced stage, and traditional chemoradiotherapy is prone to drug resistance, it is important to find new therapeutic targets. In this study, the expression levels of ALDOA and p-AKT were detected in cancer tissues and paired normal tissues, and it was found that they were significantly increased in CRC tissues, and their high expression indicated poor prognosis. Moreover, a positive correlation between the expression of ALDOA and p-AKT was found in CRC tissues and paired normal tissues. In addition, the Kaplan-Meier analysis revealed that the group with both negative of ALDOA/p-AKT expression had longer five-year survival rates compared with the other group. Besides, the group with both high expression of ALDOA/p-AKT had a worse prognosis compared with the other group. Based on the expression of ALDOA and p-AKT in tumor tissues, we can effectively distinguish tumor tissues from normal tissues through cluster analysis. Furthermore, we constructed nomograms to predict 3-year and 5-year overall survival, showing that the expression of ALDOA/p-AKT plays a crucial role in predicting the prognosis of CRC patients. Therefore, ALDOA/p-AKT may act as a crucial role in CRC, which may provide new horizons for targeted therapies for CRC.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas c-akt , Humanos , Prognóstico , Estimativa de Kaplan-Meier , Neoplasias Colorretais/metabolismo , Frutose-Bifosfato Aldolase/metabolismoRESUMO
OBJECTIVES: To examine associations of sociodemographic factors and social limitations with health-related quality of life (HRQOL) from pre- to postdiagnosis in older female cancer survivors. SAMPLE & SETTING: 9,807 women aged 65 years or older with breast or gynecologic cancer from the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey. METHODS & VARIABLES: Physical and mental HRQOL were assessed using the physical component summary (PCS) and mental component summary (MCS) of the Veterans RAND 12-Item Health Survey. Descriptive statistics and mixed-effects models for repeated measures were used. RESULTS: Social limitations were the only significant factor associated with changes in MCS scores. Race and ethnicity, rurality, and social interference were associated with significant decreases in PCS scores. IMPLICATIONS FOR NURSING: Nurses can assess mental and physical HRQOL after diagnosis and advocate for appropriate referrals. Oncology care should be tailored to cultural considerations, including race and ethnicity, rurality, and social support.
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Neoplasias dos Genitais Femininos , Fatores Sociais , Estados Unidos , Humanos , Idoso , Feminino , Medicare , Qualidade de Vida , EtnicidadeRESUMO
Objective: Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-ß agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor α-positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo. Results: Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.
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OBJECTIVES: To identify trajectories of daily postconcussion symptoms (PCS) from the acute postinjury period to symptom resolution among concussed children and examine demographic factors and acute PCS associated with the identified symptom trajectories. SETTING AND PARTICIPANTS: Seventy-nine participants with a concussion were enrolled within 72 hours of injury and completed a daily survey that assessed PCS from enrollment until symptom resolution. DESIGN: This was a prospective cohort study among concussed children aged 11-17 years. MAIN MEASURES: Children rated their concussion symptoms daily using the Post-Concussion Symptom Scale. Symptom duration was assessed using participants' date of symptom resolution and coded as a dichotomous variable: (1) PCS duration 14 days or less or (2) PCS duration longer than 14 days. RESULTS: Of the 79 participants, most were male ( n = 53, 67%), injured during a sporting activity ( n = 67, 85%), or had PCS that persisted for more than 14 days post-injury ( n = 41, 52%). Group-based trajectory modeling yielded 4 trajectory groups: (1) low acute/resolved PCS ( n = 39, 49%), (2) moderate/persistent PCS ( n = 19, 24%), (3) high acute/persistent PCS ( n = 13, 16%), and (4) high acute/resolved PCS ( n = 8, 10%). No significant associations were found between demographic factors and the trajectory group. A higher symptom burden at injury was associated with an increased odds of being in the high acute/resolved or high acute/persistent recovery groups than being in the low acute/resolved group (odds ratio [OR] 1.39, 95% CI = 1.11-1.74; OR = 1.33, 95% CI = 1.11-1.60, respectively), as was a higher symptom severity at injury (OR = 1.09, 95% CI = 1.03-1.15; OR = 1.06, 95% CI = 1.02-1.11, respectively). CONCLUSION: Our findings may help clinicians identify concussed children on slower recovery trajectories, and implement early, individualized treatment plans that foster optimal recovery for concussed children.
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Traumatismos em Atletas , Concussão Encefálica , Síndrome Pós-Concussão , Esportes , Criança , Humanos , Masculino , Feminino , Traumatismos em Atletas/diagnóstico , Traumatismos em Atletas/epidemiologia , Traumatismos em Atletas/complicações , Estudos Prospectivos , Concussão Encefálica/diagnóstico , Concussão Encefálica/complicações , Síndrome Pós-Concussão/diagnóstico , Síndrome Pós-Concussão/epidemiologia , Síndrome Pós-Concussão/complicaçõesRESUMO
BACKGROUND: The glyoxalase system includes glyoxalase I (GLXI), glyoxalase II (GLXII) and glyoxalase III (GLXIII), which are responsible for methylglyoxal (MG) detoxification and involved in abiotic stress responses such as drought, salinity and heavy metal. RESULTS: In this study, a total of 620 GLX family genes were identified from 21 different plant species. The results of evolutionary analysis showed that GLX genes exist in all species from lower plants to higher plants, inferring that GLX genes might be important for plants, and GLXI and GLXII account for the majority. In addition, motif showed an expanding trend in the process of evolution. The analysis of cis-acting elements in 21 different plant species showed that the promoter region of the GLX genes were rich in phytohormones and biotic and abiotic stress-related elements, indicating that GLX genes can participate in a variety of life processes. In cotton, GLXs could be divided into two groups and most GLXIs distributed in group I, GLXIIs and GLXIIIs mainly belonged to group II, indicating that there are more similarities between GLXII and GLXIII in cotton evolution. The transcriptome data analysis and quantitative real-time PCR analysis (qRT-PCR) show that some members of GLX family would respond to high temperature treatment in G.hirsutum. The protein interaction network of GLXs in G.hirsutum implied that most members can participate in various life processes through protein interactions. CONCLUSIONS: The results elucidated the evolutionary history of GLX family genes in plants and lay the foundation for their functions analysis in cotton.
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Gossypium , Gossypium/enzimologia , Gossypium/genética , Evolução Molecular , Filogenia , Regiões Promotoras Genéticas , Mapas de Interação de ProteínasRESUMO
Gastric cancer (GC) is among of the leading causes of cancer mortality worldwide. This is because many patients are diagnosed with advanced GC and postoperative radiotherapy and chemotherapy have also exhibited limited effects on GC. TYRO3 has been considered carcinogenic and a potential therapeutic target for GC. However, TYRO3 function and mechanism in GC remains elusive. The study results indicated that TYRO3 was aberrantly elevated in GC tissues and predicted poor prognosis. TYRO3 is closely associated with clinicopathological indicators in GC tissues such as lymph node metastasis, venous invasion, neural invasion, and the tumor-node-metastasis stage. In addition, TYRO3 expression levels are closely related to the AKT-mTOR pathway in GC tissues. Moreover, the oncogenic role of TYRO3 was determined through in vitro and in vivo functional assays, and knockdown of the TYRO3 expression level in GC cell lines can effectively suppress the AKT-mTOR pathway and inhibit tumor cell proliferation and migration. In conclusion, this study provides a theoretical basis for establishing the potential association and regulatory mechanism between TYRO3 and AKT-mTOR and offers a new strategy for GC-targeted therapy.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Receptores Proteína Tirosina Quinases/genéticaRESUMO
The study aims to examine the mediation effects of physical literacy and physical activity behavior in a relationship between psychological distress and life satisfaction among Chinese college students during the real-life Coronavirus disease pandemic (COVID-19) circumstance. This study implemented a cross-sectional design, and 1,516 participants from 12 universities participated in this study. Structural equation modeling was used to examine a hypothesized model. The findings indicated an acceptable model fit (X 2[61] = 508.2, Comparative Fit Index [CFI] = 0.958, Tucker Lewis Index [TLI] = 0.946, Root Mean Square Error of Approximation [RMSEA] = 0.076, 90% CI [0.070, 0.082], Standardized Root Mean Square Residual [SRMR] = 0.047). The results indicated that college students with low participation in physical activity could experience less than healthy living conditions. The findings offered empirical support to the theory that physical literacy could advance individuals' healthy living by promoting physical activity participation. The study suggested that educational institutions and physical activity programs should cultivate individuals' physical literacy in order to promote lifelong healthy living.
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BACKGROUND: Despite immunotherapy's promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this study, we explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in advanced sarcoma outcomes. METHODS: Patients in The Ohio State University Sarcoma Clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single-agent ICI or ICI + combination) along with clinical covariates. ICI + combination was further categorized into ICI + medication, ICI + radiation, ICI + surgery, or ICI + multiple (more than 2 modalities). Statistical analysis included log-rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). RESULTS: Of the patients in the database, 135 met inclusion criteria. We demonstrated improved OS in patients treated with ICI + combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Patients with a documented immune-related adverse event (irAE) of dermatitis had improved OS, but only in the ICI + combination cohort (p = 0.021). Patients who received single-agent ICI and whose change in the neutrophil-to-lymphocyte ratio (NLR) was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI + combination therapy (p = 0.441). There were no differences in OS based on age, gender, histology, or subcategories of ICI + combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036) compared with their older counterparts in this dataset. Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048), or dermatitis (p = 0.003), had an improved PFS. There were no differences in PFS based on ICI regimen (or subcategories of ICI + combination), gender, histology, change in NLR, or grade of irAE. CONCLUSIONS: This retrospective study demonstrates that ICI + combination therapy can improve OS in some patients with advanced sarcoma. This is consistent with our prior results of ICI in sarcoma.
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Antineoplásicos Imunológicos , Dermatite , Humanos , Estudos Retrospectivos , Antineoplásicos Imunológicos/farmacologia , Biomarcadores , Imunoterapia/métodos , Dermatite/tratamento farmacológico , Dermatite/etiologiaRESUMO
Gastric cancer (GC) is the most common gastrointestinal cancer and the leading cause of worldwide cancer-associated mortality. Several GC patients are diagnosed at the advanced stage with an unsatisfactory 5-year survival rate. Rab1A was significantly associated with IL4Rα expression in non-small cell lung cancer. However, their potential correlation in expression and prognosis remains largely unknown in GC. In this study, Rab1A/IL-4Rα was significantly increased in GC than in para-cancerous tissues, and Rab1A/IL-4Rα overexpression caused poor prognosis among GC patients. Rab1A expression was significantly correlated with IL-4Rα expression in GC tissues, as determined by IHC analysis. In addition, the mRNA expression of Rab1A was closely linked with the IL-4Rα mRNA expression in GC tissue expressed by qPCR. Furthermore, the Kaplan-Meier analysis demonstrated that the group with negative Rab1A and IL-4Rα expression had longer 5-year survival rates than the other group. Besides, the group with positive Rab1A and IL-4Rα expression had a worse prognosis than the other group. Finally, nomograms revealed the overall 3 and 5-year survival determined crucial roles of Rab1A/IL-4Rα expression in predicting the prognosis of GC patients. Therefore, Rab1A/IL-4Rα is vital in GC, providing a novel perspective on targeted GC therapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Gástricas , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
BACKGROUND: Chemokine-mediated neuroinflammation plays an important role in the pathogenesis of neuropathic pain. The chemokine CC motif ligand 7 (CCL7) and its receptor CCR2 have been reported to contribute to neuropathic pain via astrocyte-microglial interaction in the spinal cord. Whether CCL7 in the trigeminal ganglion (TG) involves in trigeminal neuropathic pain and the involved mechanism remain largely unknown. METHODS: The partial infraorbital nerve transection (pIONT) was used to induce trigeminal neuropathic pain in mice. The expression of Ccl7, Ccr1, Ccr2, and Ccr3 was examined by real-time quantitative polymerase chain reaction. The distribution of CCL7, CCR2, and CCR3 was detected by immunofluorescence double-staining. The activation of extracellular signal-regulated kinase (ERK) was examined by Western blot and immunofluorescence. The effect of CCL7 on neuronal excitability was tested by whole-cell patch clamp recording. The effect of selective antagonists for CCR1, CCR2, and CCR3 on pain hypersensitivity was checked by behavioral testing. RESULTS: Ccl7 was persistently increased in neurons of TG after pIONT, and specific inhibition of CCL7 in the TG effectively relieved pIONT-induced orofacial mechanical allodynia. Intra-TG injection of recombinant CCL7 induced mechanical allodynia and increased the phosphorylation of ERK in the TG. Incubation of CCL7 with TG neurons also dose-dependently enhanced the neuronal excitability. Furthermore, pIONT increased the expression of CCL7 receptors Ccr1, Ccr2, and Ccr3. The intra-TG injection of the specific antagonist of CCR2 or CCR3 but not of CCR1 alleviated pIONT-induced orofacial mechanical allodynia and reduced ERK activation. Immunostaining showed that CCR2 and CCR3 are expressed in TG neurons, and CCL7-induced hyperexcitability of TG neurons was decreased by antagonists of CCR2 or CCR3. CONCLUSION: CCL7 activates ERK in TG neurons via CCR2 and CCR3 to enhance neuronal excitability, which contributes to the maintenance of trigeminal neuropathic pain. CCL7-CCR2/CCR3-ERK pathway may be potential targets for treating trigeminal neuropathic pain.
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Quimiocina CCL7 , MAP Quinases Reguladas por Sinal Extracelular , Neuralgia , Neuralgia do Trigêmeo , Animais , Camundongos , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Quimiocina CCL7/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hiperalgesia/metabolismo , Ligantes , Sistema de Sinalização das MAP Quinases , Neuralgia/metabolismo , Gânglio Trigeminal/metabolismo , Neuralgia do Trigêmeo/metabolismo , Receptores CCR2/metabolismo , Receptores CCR3/metabolismoRESUMO
Motivational interviewing (MI) is a promising behavioral intervention for improving parent and adult caregiver (PAC) health behavior for obesity and cancer prevention. This study explored the preliminary effects of MI from a registered dietitian (RDMI) within an obesity prevention intervention to promote PAC behavior change and positive proxy effects on children and the home environment. N = 36 PAC/child dyads from low-resource communities were enrolled in a randomized trial testing a 10-week obesity prevention intervention. Intervention dyads were offered RDMI sessions. Data were collected at baseline and post-intervention (PAC diet quality (Healthy Eating Index (HEI)), child skin carotenoids, home environment, and PAC ambivalence regarding improving diet). Results show that for every RDMI dose, PAC HEI scores increased (0.571 points, p = 0.530), child skin carotenoid scores improved (1.315%, p = 0.592), and the home food environment improved (3.559%, p = 0.026). There was a significant positive relationship between RDMI dose and change in ambivalence (ρ = 0.533, p = 0.007). Higher baseline ambivalence was associated with greater dose (ρ = -0.287, p = 0.173). Thus, RDMI for PACs may improve diets among PACs who are otherwise ambivalent, with potential effects on the diets of their children and the home food environment. Such intervention strategies have the potential for greater effect, strengthening behavioral interventions targeting obesity and cancer.
Assuntos
Entrevista Motivacional , Neoplasias , Obesidade Infantil , Adulto , Criança , Humanos , Terapia Comportamental , Cuidadores , Dieta , Entrevista Motivacional/métodos , Obesidade Infantil/prevenção & controleRESUMO
Itch is an uncomfortable and complex sensation that elicits the desire to scratch. The nucleus accumbens (NAc) activity is important in driving sensation, motivation, and emotion. Excitatory afferents from the medial prefrontal cortex (mPFC), amygdala, and hippocampus are crucial in tuning the activity of dopamine receptor D1-expressing and D2-expressing medium spiny neurons (Drd1-MSN and Drd2-MSN) in the NAc. However, a cell-type and neural circuity-based mechanism of the NAc underlying acute itch remains unclear. We found that acute itch induced by compound 48/80 (C48/80) decreased the intrinsic membrane excitability in Drd1-MSNs, but not in Drd2-MSNs, in the NAc core of male mice. Chemogenetic activation of Drd1-MSNs alleviated C48/80-induced scratching behaviors but not itch-related anxiety-like behaviors. In addition, C48/80 enhanced the frequency of spontaneous EPSCs (sEPSCs) and reduced the paired-pulse ratio (PPR) of electrical stimulation-evoked EPSCs in Drd1-MSNs. Furthermore, C48/80 increased excitatory synaptic afferents to Drd1-MSNs from the mPFC, not from the basolateral amygdala (BLA) or ventral hippocampus (vHipp). Consistently, the intrinsic excitability of mPFC-NAc projecting pyramidal neurons was increased after C48/80 treatment. Chemogenetic inhibition of mPFC-NAc excitatory synaptic afferents relieved the scratching behaviors. Moreover, pharmacological activation of κ opioid receptor (KOR) in the NAc core suppressed C48/80-induced scratching behaviors, and the modulation of KOR activity in the NAc resulted in the changes of presynaptic excitatory inputs to Drd1-MSNs in C48/80-treated mice. Together, these results reveal the neural plasticity in synapses of NAc Drd1-MSNs from the mPFC underlying acute itch and indicate the modulatory role of the KOR in itch-related scratching behaviors.SIGNIFICANCE STATEMENT Itch stimuli cause strongly scratching desire and anxiety in patients. However, the related neural mechanisms remain largely unclear. In the present study, we demonstrated that the pruritogen compound 48/80 (C48/80) shapes the excitability of dopamine receptor D1-expressing medium spiny neurons (Drd1-MSNs) in the nucleus accumbens (NAc) core and the glutamatergic synaptic afferents from medial prefrontal cortex (mPFC) to these neurons. Chemogenetic activation of Drd1-MSNs or inhibition of mPFC-NAc excitatory synaptic afferents relieves the scratching behaviors. In addition, pharmacological activation of κ opioid receptor (KOR) in the NAc core alleviates C48/80-induced itch. Thus, targeting mPFC-NAc Drd1-MSNs or KOR may provide effective treatments for itch.