Bacteriocins in Cancer Treatment: Mechanisms and Clinical Potentials.

Cancer poses a severe threat to human health. Although conventional chemotherapy remains a cornerstone of cancer treatment, its significant side effects and the growing issue of drug resistance necessitate the urgent search for more efficient and less toxic anticancer drugs. In recent years, bacteriocins, antimicrobial peptides of microbial origin, have garnered significant attention due to their targeted antitumor activity. This unique activity is mainly attributed to their cationic and amphiphilic nature, which enables bacteriocins to specifically kill tumor cells without harming normal cells. When involving non-membrane-disrupting mechanisms, such as apoptosis induction, cell cycle blockade, and metastasis inhibition, the core mechanism of action is achieved by disrupting cell membranes, which endows bacteriocins with low drug resistance and high selectivity. However, the susceptibility of bacteriocins to hydrolysis and hemolysis in vivo limits their clinical application. To overcome these challenges, structural optimization of bacteriocins or their combination with nanotechnology is proposed for future development. This review aims to study the mechanism of action and current research status of bacteriocins as anticancer treatments, thus providing new insights for their clinical development and application.

Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review).

Several studies have indicated that the gut microbiome and tumor microbiota may affect tumors. Emerging metabolomics research illustrates the need to examine the variations in microbial metabolite composition between patients with cancer and healthy individuals. Microbial metabolites can impact the progression of tumors and the immune response by influencing a number of mechanisms, including modulation of the immune system, cancer or immune­related signaling pathways, epigenetic modification of proteins and DNA damage. Microbial metabolites can also alleviate side effects and drug resistance during chemotherapy and immunotherapy, while effectively activating the immune system to exert tumor immunotherapy. Nevertheless, the impact of microbial metabolites on tumor immunity can be both beneficial and harmful, potentially influenced by the concentration of the metabolites or the specific cancer type. The present review summarizes the roles of various microbial metabolites in different solid tumors, alongside their influence on tumor immunity and treatment. Additionally, clinical trials evaluating the therapeutic effects of microbial metabolites or related microbes on patients with cancer have been listed. In summary, studying microbial metabolites, which play a crucial role in the interaction between the microbiota and tumors, could lead to the identification of new supplementary treatments for cancer. This has the potential to improve the effectiveness of cancer treatment and enhance patient prognosis.

Highly specific vaginal microbiome signature for gynecological cancers.

To investigate the vaginal microbiota signature of patients with gynecologic cancer and evaluate its diagnostic biomarker potential. We incorporated vaginal 16S rRNA-seq data from 529 women and utilized VSEARCH to analyze the raw data. α-Diversity was evaluated utilizing the Chao1, Shannon, and Simpson indices, and ß-diversity was evaluated through principal component analysis using Bray-Curtis distances. Linear discriminant analysis effect size (LEfSe) was utilized to determine species differences between groups. A bacterial co-abundance network was constructed utilizing Spearman correlation analysis. A random forest model of gynecologic tumor risk based on genus was constructed and validated to test its diagnostic efficacy. In gynecologic cancer patients, vaginal α-diversity was significantly greater than in controls, and vaginal ß-diversity was significantly separated from that of controls; there was no correlation between these characteristics and menopause status among the subject women. Women diagnosed with gynecological cancer exhibited a reduction in the abundance of vaginal Firmicutes and Lactobacillus, while an increase was observed in the proportions of Bacteroidetes, Proteobacteria, Prevotella, Streptococcus, and Anaerococcus. A random forest model constructed based on 56 genus achieved high accuracy (area under the curve = 84.96%) in gynecological cancer risk prediction. Furthermore, there were discrepancies observed in the community complexity of co-abundance networks between gynecologic cancer patients and the control group. Our study provides evidence that women with gynecologic cancer have a unique vaginal flora structure and microorganisms may be involved in the gynecologic carcinogenesis process. A gynecological cancer risk prediction model based on characteristic genera has good diagnostic value.

Specific vaginal and gut microbiome and the anti-tumor effect of butyrate in cervical cancer women.

OBJECTIVE: To investigate the vaginal and gut microbes changes during the carcinogenesis of cervical and the auxiliary diagnostic value. To investigate the effect of microbiome-specific metabolites butyric on cervical cancer cells. METHODS: We studied 416 vaginal 16S rRNA sequencing data and 116 gut sequencing data. Reads were processed using VSEARCH. We used Shannon index, Chao1 index, Simpson diversity index, ß diversity index, Linear discriminant analysis Effect Size (LEfSe), co-abundance network and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to explore microbiome differences between groups. We constructed random forest models based on genus and verified its discriminant effect. Finally, we used the cell counting kit-8 (CCK-8) method to detect cell proliferation capacity and flow cytometry to detect apoptosis and induction of cell cycle progression. RESULTS: Compared to the non-cancerous population, patients with cervical cancer had unique microbial community characteristics in both vaginal and gut ecological niches. Our predictive model based on genus in two ecological regions achieved high accuracy in the diagnosis of cervical cancer (vaginal model AUC=91.58 %; gut model AUC=99.95 %). Butyric inhibited cervical cancer cell proliferation in a concentration-dependent manner and promoted apoptosis of cancer cells. CONCLUSION: Significant differences were found in vaginal and gut microbes in patients with cervical cancer compared to the non-cancerous population. The prediction models constructed at the genus level in both ecological sites have good diagnostic value. Microorganisms may be involved in cervical cancer progression in a metabolite-dependent way, and targeting butyric may provide therapeutic options for cervical cancer.

The role of microbiota in the development and treatment of gastric cancer.

The stomach was once considered a sterile organ until the discovery of Helicobacter pylori (HP). With the application of high-throughput sequencing technology and macrogenomics, researchers have identified fungi and fivemajor bacterial phyla within the stomachs of healthy individuals. These microbial communities exert regulatory influence over various physiological functions, including energy metabolism and immune responses. HP is a well-recognized risk factor for gastric cancer, significantly altering the stomach's native microecology. Currently, numerous studies are centered on the mechanisms by which HP contributes to gastric cancer development, primarily involving the CagA oncoprotein. However, aside from exogenous infections such as HP and EBV, certain endogenous dysbiosis can also lead to gastric cancer through multiple mechanisms. Additionally, gut microbiota and its metabolites significantly impact the development of gastric cancer. The role of microbial therapies, including diet, phages, probiotics and fecal microbiota transplantation, in treating gastric cancer should not be underestimated. This review aims to study the mechanisms involved in the roles of exogenous pathogen infection and endogenous microbiota dysbiosis in the development of gastric cancer. Also, we describe the application of microbiota therapy in the treatment and prognosis of gastric cancer.

Identification of microbial markers associated with lung cancer based on multi-cohort 16 s rRNA analyses: A systematic review and meta-analysis.

BACKGROUND: The relationship between commensal microbiota and lung cancer (LC) has been studied extensively. However, developing replicable microbiological markers for early LC diagnosis across multiple populations has remained challenging. Current studies are limited to a single region, single LC subtype, and small sample size. Therefore, we aimed to perform the first large-scale meta-analysis for identifying micro biomarkers for LC screening by integrating gut and respiratory samples from multiple studies and building a machine-learning classifier. METHODS: In total, 712 gut and 393 respiratory samples were assessed via 16 s rRNA amplicon sequencing. After identifying the taxa of differential biomarkers, we established random forest models to distinguish between LC populations and normal controls. We validated the robustness and specificity of the model using external cohorts. Moreover, we also used the KEGG database for the predictive analysis of colony-related functions. RESULTS: The α and ß diversity indices indicated that LC patients' gut microbiota (GM) and lung microbiota (LM) differed significantly from those of the healthy population. Linear discriminant analysis (LDA) of effect size (LEfSe) helped us identify the top-ranked biomarkers, Enterococcus, Lactobacillus, and Escherichia, in two microbial niches. The area under the curve values of the diagnostic model for the two sites were 0.81 and 0.90, respectively. KEGG enrichment analysis also revealed significant differences in microbiota-associated functions between cancer-affected and healthy individuals that were primarily associated with metabolic disturbances. CONCLUSIONS: GM and LM profiles were significantly altered in LC patients, compared to healthy individuals. We identified the taxa of biomarkers at the two loci and constructed accurate diagnostic models. This study demonstrates the effectiveness of LC-specific microbiological markers in multiple populations and contributes to the early diagnosis and screening of LC.

Screening for important risk factors for cancer-specific mortality in patients with localized clear cell renal carcinoma.

Aim: To study the risk factors for cancer-specific mortality (CSM) among patients with localized clear cell renal carcinoma (LCCRC) in the Chinese population. Methods: The clinical data of 1,376 LCCRC patients were postoperatively collected to analyze the correlations between CSM and multiple factors using Cox regression analysis. Receiver operating characteristic curves were constructed as per the screened risk factors to identify factors with optimal criticality judgment values, which were then used as the scoring standard for the stratification evaluation of LCCRC prognosis. Results: The CSM rate was 5.6% (77/1,376 cases) and the median follow-up duration was 78.1 (60-105) months. Cox analysis revealed that age, tumor diameter, and nuclear grade were associated with CSM. The optimal criticality judgment values for age and tumor diameter using receiver operating characteristic curve analysis were 53 years and 5.8 cm, respectively. LCCRC prognosis divided into low-risk (≤ 2 points), intermediate-risk (3-4 points), and high-risk (5 points) showed CSM rates of 3.8%, 13.8%, and 58.3%, respectively, among patients with more than 5 years of follow-up. Conclusions: Age, tumor diameter, and nuclear grade were important risk factors for CSM in LCCRC patients. The scoring criteria including these three risk factors may be an important supplement to the prognostic model of LCCRC in the Chinese population.

Vaginal and tumor microbiomes in gynecological cancer (Review).

Cervical, ovarian and endometrial cancer are the three most common types of gynecologic cancer. As a hub, the vagina connects the site of gynecological cancer with the external environment. Lactobacilli participate in the formation of a healthy vaginal microenvironment as the first line of defense against pathogen invasion; a dysbiotic vaginal microenvironment loses its original protective function and is associated with the onset, metastasis, poor efficacy and poor prognosis of gynecological cancer. The early diagnosis of cancer is the key to improve the survival time of patients with cancer. The screening of Porphyromonas, Sneathia and Atopobium vaginae, and other microbial markers, can assist the diagnosis of gynecological cancer, and screen out the high-risk population as early as possible. With the in-depth study of the microbes in tumor tissues, reasearchers have analyzed the immunological associations of microorganisms in tumor tissues. Due to the structural-functional interconnection between the organ of gynecological tumorigenesis and the vagina, the present study aims to review the relationship between vaginal and tumor microorganisms and gynecological cancer in terms of occurrence, screening, treatment and prognosis.

Breast cancer brain metastasis: Current evidence and future directions.

Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths after lung cancer. Metastasis of the central nervous system is a terrible event for breast cancer patients, affecting their survival and quality of life. Compared with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients, brain metastases are more likely to affect patients with triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer. The treatment of breast cancer has improved greatly in the last two decades. However, brain metastases from breast cancer remain the leading cause of morbidity and mortality. Patients with breast cancer brain metastasis have been in an inferior position due to the lack of clinical research in this field, and they are often explicitly excluded from almost all clinical trials. The occurrence and progression of brain metastases will result in severe cognitive impairment and adverse physical consequences, so we must have a good understanding of the molecular mechanisms of breast cancer brain metastasis. In this article, we have retrieved the latest literature of molecules and pathways associated with breast cancer brain metastasis, summarized common therapy strategies, and discussed the prospects and clinical implications of targeting the molecules involved.

Skin cancer outcomes and risk factors in renal transplant recipients: Analysis of organ procurement and transplantation network data from 2000 to 2021.

Purpose: Posttransplant skin cancer is the most common malignancy after patients have undergone renal transplantation. Through comprehensive observation with a large sample size nationwide, understanding the risk factors and outcome of posttransplant skin cancer will help to develop appropriate patient surveillance and disease prevention strategies. Materials and methods: This retrospective population-based cohort study was based on Organ Procurement and Transplantation Network data released in March 2021. Characteristics and outcomes, including patient survival and graft survival of recipients, were compared. Risk factors for posttransplant skin cancer, cancer onset momentum, and mortality were determined. Results: A total of 199,564 renal transplant recipients were included. After renal transplantation, 7,334 (3.68%), 6,093 (3.05%), and 936 (0.47%) were diagnosed with squamous cell carcinoma, basal cell carcinoma, and melanoma, respectively. Skin cancer was the major cause of death (squamous cell carcinoma: 23.8%, basal cell carcinoma: 18%, and melanoma: 41.6%). Five-year survival rates ranked from best to worst were as follows: basal cell carcinoma (96.7 [95% confidence interval: 96.3-97.2]%), squamous cell carcinoma (94.1 [93.5-94.6]%), melanoma (89.7 [87.7-91.6]%), and cancer-free (87.4 [87.2-87.5]%) (p < 0.001 for all except melanoma vs. cancer-free, p = 0.534). Regarding graft survival, death-censored graft survival, posttransplant skin cancer, and melanoma were significantly better than the cancer-free group (p < 0.001). Independent risk factors for developing posttransplant skin cancer included older age, male sex, Caucasian race, pretransplant malignancy, polycystic kidney disease-induced end-stage renal disease (ESRD), retransplantation, private health insurance, T-cell depletion induction, and tacrolimus/mycophenolic acid use. Caucasian race and pretransplant malignancy were independent risk factors for posttransplant skin cancer onset momentum. Male sex, Caucasian race, pretransplant malignancy, hypertension- or diabetes-induced ESRD, retransplantation, diabetes history, deceased donor, cyclosporin, and mTOR inhibitor use were independent risk factors for posttransplant skin cancer mortality. Conclusion: Although posttransplant skin cancer is a major cause of recipient death, information regarding its impact on patient and graft survival is limited. Given the differences regarding risk factors for posttransplant skin cancer incidence, onset momentum, and mortality, personalized approaches to screening may be appropriate to address the complex issues encountered by kidney transplant recipients.

Identifying distinctive tissue and fecal microbial signatures and the tumor-promoting effects of deoxycholic acid on breast cancer.

Introduction: A growing body of evidence indicates that the dysbiosis of both mammary and intestinal microbiota is associated with the initiation and progression of breast tumors. However, the microbial characteristics of patients with breast tumors vary widely across studies, and replicable biomarkers for early-stage breast tumor diagnosis remain elusive. Methods: We demonstrate a machine learning-based method for the analysis of breast tissue and gut microbial differences among patients with benign breast disease, patients with breast cancer (BC), and healthy individuals using 16S rRNA sequence data retrieved from eight studies. QIIME 2.0 and R software (version 3.6.1) were used for consistent processing. A naive Bayes classifier was trained on the RDP v16 reference database to assign taxonomy using the Vsearch software. Results: After re-analyzing with a total of 768 breast tissue samples and 1,311 fecal samples, we confirmed that Halomonas and Shewanella were the most representative genera of BC tissue. Bacteroides are frequently and significantly enriched in the intestines of patients with breast tumor. The areas under the curve (AUCs) of random forest models were 74.27% and 68.08% for breast carcinoma tissues and stool samples, respectively. The model was validated for effectiveness via cohort-to-cohort transfer (average AUC =0.65) and leave-one-cohort-out (average AUC = 0.66). The same BC-associated biomarker Clostridium_XlVa exists in the tissues and the gut. The results of the in-vitro experiments showed that the Clostridium-specific-related metabolite deoxycholic acid (DCA) promotes the proliferation of HER2-positive BC cells and stimulates G0/G1 phase cells to enter the S phase, which may be related to the activation of peptide-O-fucosyltransferase activity functions and the neuroactive ligand-receptor interaction pathway. Discussion: The results of this study will improve our understanding of the microbial profile of breast tumors. Changes in the microbial population may be present in both the tissues and the gut of patients with BC, and specific markers could aid in the early diagnosis of BC. The findings from in-vitro experiments confirmed that Clostridium-specific metabolite DCA promotes the proliferation of BC cells. We propose the use of stool-based biomarkers in clinical application as a non-invasive and convenient diagnostic method.

Transplant or dialysis: What's the better choice for RCC-induced ESRD patients? A 20-year analysis of OPTN/UNOS data.

Purpose: The incidence of end-stage renal disease (ESRD) caused by renal cell carcinoma (RCC) is increasing with the high prevalence of RCC as well as those with treatment-related renal function impairment. Worries about tumor recurrence after transplant-related immunosuppression hinder the recommendation of kidney transplantation for RCC-induced ESRD patients. However, no direct analysis has been performed to identify whether kidney transplantation can offer better survival than maintaining dialysis. Materials and methods: This retrospective population-based cohort study was based on Organ Procurement and Transplantation Network data released in March 2021. Characteristics and outcomes were compared, including the patient and graft survival of candidates and recipients with RCC-induced ESRD etiology as well as other primary diseases. Results: Patients with RCC-induced ESRD were older; more likely to be male, White, and obese; and more likely to have a history of diabetes and dialysis. They also had higher creatinine levels, more delayed graft function, more primary non-function, and higher Kidney Donor Profile Index score donors, compared with the glomerulonephritis (GN) group. While waiting, RCC candidates suffered the worst outcomes of all groups, a 44% (adjusted hazard ratio [aHR], 1.44 [1.27-1.62]) higher risk of removal than GN patients. After transplantation, RCC recipients demonstrated comparable patient survival and better graft survival (p=0.21 and p=0.13, respectively). Compared with still-waiting RCC patients, the RCC recipients who received kidney transplants had significantly better outcomes (13.6 [9.3-17.8] vs. 61 [52-68.4] %), decreasing the death or deteriorating risk by 84% (aHR, 0.16 [0.13-0.20]). Conclusions: Patients with RCC-induced ESRD can dramatically benefit from kidney transplantation. Hence, these patients should not be limited to transplantation by strict strategies or a delayed waiting time out of their malignancy history.

Neutrophils in ANCA-associated vasculitis: Mechanisms and implications for management.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic autoimmune diseases, which is typified by inflammatory necrosis predominantly affecting the small vessels and often accompanied by positive ANCA. Clinically, AAV primarily includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). It has been found that in AAV pathogenesis, both innate and adaptive immunity are related to neutrophil function mutually. Many proteins, such as myeloperoxidase (MPO) and proteinase 3 (PR3), in neutrophil cytoplasm lead to the production of proteins such as MPO-ANCA and PR3-ANCA by activating adaptive immunity. In addition, through the process of neutrophil extracellular trap (NET) formation, activation of an alternative complement pathway and the respiratory burst can stimulate the neutrophils close to vascular endothelial cells and will participate the vessel inflammation. This review aims to reveal the potential mechanisms regulating the association between the neutrophils and various types of AAVs and to emphasize the results of recent findings on these interactions. Moreover, multiple underlying signaling pathways involved in the regulation of neutrophils during AAV processes have also been discussed. The ultimate goal of this review is to identify novel biomarkers and therapeutic targets for AAV management in the future.

Gut Microbes in Gynecologic Cancers: Causes or Biomarkers and Therapeutic Potential.

The human intestine is home to a variety of microorganisms. In healthy populations, the intestinal flora shares a degree of similarity and stability, and they have a role in the metabolism, immunological response, and physiological function of key organs. With the rapid advent of high-throughput sequencing in recent years, several researchers have found that dysbiosis of the human gut microflora potentially cause physical problems and gynecological malignancies among postmenopausal women. Besides, dysbiosis hinders tumor treatment. Nonetheless, the importance of maintaining homeostatic gut microbiota and the effective use of probiotics in the treatment of gynecological malignancies should not be disregarded. Moreover, intestinal flora regulation and the involvement of probiotics as well as associated biologically active substances in gynecological malignancies could be an adjuvant treatment modality related to surgery and chemoradiotherapy in the future. Herein, this article aims to review the potential relationship between gut microorganisms and postmenopausal status as well as gynecologic malignancies; then the relationship between gut microbes and early screening as well as therapeutic aspects. Also, we describe the role of probiotics in the prevention, treatment, and prognosis of gynecologic malignancies.

Primary Neuroendocrine Tumor of the Breast: Current Understanding and Future Perspectives.

Primary neuroendocrine carcinoma of the breast (NECB) is characterized with heterogeneity, rarity, and poor differentiation, which is probably an underestimated subtype of breast cancer, including small cell NECs and large cell NECs. The diagnostic criteria for NECB have been constantly updated as the disease changes and the understanding increases. According to the latest WHO Classification, primary neuroendocrine neoplasm (NEN) of the breast consists of well-differentiated neuroendocrine tumors (NET), extremely aggressive neuroendocrine carcinomas (NEC) as well as invasive breast cancers of no special type (IBCs-NST) with neuroendocrine differentiation. The accurate diagnosis of NECB remains a challenge for its low incidence, which needs multi-disciplinary methods. For the rarity of the disease, there is a lack of large samples and prospective clinical research. For these invasive tumors, there are no standardized therapeutic guidelines or norms, and the treatment often refers to nonspecific breast cancer. In addition, the prognosis of such patients remains unknown. In 2003, the World Health Organization (WHO) listed NECB as an independent entity for the first time, while few features of NECB were clarified. In this review, it presents the WHO Classification, clinicopathologic characteristics, diagnosis, treatment, and prognosis of these patients. In addition, it summarizes the latest studies on molecular features of NECB, aiming to provide new therapeutic perspectives for the disease.

Predictive and Prognostic Role of Peripheral Blood T-Cell Subsets in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), as a highly aggressive and metastatic tumor, can still not contain the medical needs. It has become an urgent problem to develop prognostic markers further and realize precision medicine. The predictive and prognostic significance of peripheral blood lymphocytes, as well as the clinicopathological factors affecting them, were explored in the present study. METHODS: The clinicopathological data of 278 patients with TNBC were collected and analyzed retrospectively. Peripheral blood lymphocytes (pBL) and blood routine indexes before treatment were quantified by flow cytometry analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier curve and Cox hazard proportion regression model. The associations between hematologic parameters and treatment response and clinicopathological characteristics were estimated by the Mann-Whitney test and Spearman test. RESULTS: Compared with all blood routine indexes, only a significant correlation between better treatment efficacy and higher peripheral CD4 +/CD8 + ratio of TNBC patients was observed (P=0.059), particularly those treated with chemotherapy combined with immune checkpoint inhibitors (P=0.048). Among the pBL subsets, CD4 + T lymphocyte was the only independent factor that could predict the prognosis of metastatic TNBC. Patients presenting higher values of peripheral CD4 + T lymphocytes showed longer PFS (median PFS 9 months vs. 5 months; HR =0.65, 95%CI: 0.440-0.973, P = 0.032) and OS (median OS 31 months vs. 16 months; HR=0 .63, 95%CI: 0.417-0.940, P< 0.01). Especially CD4+ was found predictive for prognosis in TNBC patients who received chemotherapy (P<0.05). Finally, the older age, higher clinical stage, and more advanced treatment lines were related to the lower level of CD4 +. The older age and having received neoadjuvant therapy were related to the lower CD4 +/CD8 + ratio (P<0.05). CONCLUSION: The baseline CD4+/CD8+ cell ratio in peripheral blood is associated with therapeutic response, especially for chemotherapy combined with immunotherapy. Peripheral CD4+ cells can steadily predict all clinical outcomes for patients with mTNBC, and this clinical prognosis prediction is significantly related to chemotherapy. Peripheral CD4+ and CD4+/CD8+ are both closely associated with clinicopathological parameters.

Major depressive symptoms in breast cancer patients with ovarian function suppression: a cross-sectional study comparing ovarian ablation and gonadotropin-releasing hormone agonists.

BACKGROUND: Ovarian function suppression (OFS) is indicated in premenopausal women with early or metastasis breast cancer, which may be achieved with similar effect by gonadotropin-releasing hormone agonists (GnRHa) or ovarian ablation (OA). We examined whether there were differences in major depressive symptoms outcomes and its associated factors between gonadotropin-releasing hormone agonists (GnRHa) and ovarian ablation (OA) in premenopausal breast cancer patients. METHODS: Premenopausal breast cancer patients from seven hospitals who received OFS participated in the study between June 2019 and June 2020. The correlated variable was the type of ovarian suppression, categorized as either OA (n = 174) or GnRHa (n = 389). Major depressive symptoms was evaluated using the Patient Health Questionnaire (PHQ-9), and the Female Sexual Function Index questionnaire was used to assess sexual function. RESULTS: A total of 563 patients completed the surveys. The mean PHQ-9 sum score was slightly lower in the GnRHa cohort than in the OA cohort (11.4 ± 5.7 vs. 12.8 ± 5.8, P = 0.079). There were significantly fewer patients with major depressive symptoms (PHQ-9 ≥ 15) in the GnRHa cohort (31.1% vs. 40.2%, Exp (B)=1.805, P=0.004). Further, breast-conserving surgery and sexual dysfunction were negatively correlated with major depressive symptoms [mastectomy vs. breast-conserving: Exp (B) = 0.461, P <0.001;[sexual dysfunction vs. normal: Exp (B) = 0.512, P = 0.001]. CONCLUSIONS: This is the first study to demonstrate that GnRHa results in more favorable depressive symptoms outcomes than OA. Moreover, most patients preferred alternatives to their OFS treatment. These findings can contribute to improving and alleviating the adverse effects of OFS.

Case Report: Effective Treatment With Pyrotinib and Capecitabine in a Heavily Pretreated Locally Advanced Breast Cancer Harboring Both HER2 Overexpression and Mutant.

The prognosis for female patients with locally advanced breast cancer (LABC) has improved with the emergence of novel drugs, especially for those who have HER2 overexpression or ERBB-2 amplification. Trastuzumab-based regimen has been the paradigm in guidelines as first-line therapy, whereas many patients got progressive disease after several cycles of treatment or rapidly progress because of primary resistance. Point mutations of ERBB2 gene occur in both HER2-amplication and non-amplification patients, with a 2% ratio in HER2 non-amplification cohort and 1.48% in HER2 amplication population. The acquired mutation ratio of ERBB2 substantially raised to 16.7%-17.7% in patients prior to trastuzumab treatment. ERBB2 mutation may be a critical reason of resistance and disease progression among the patients treated with anti-HER2 monoclonal trastuzumab or dual anti-HER2 antibodies with trastuzumab and pertuzumab, or tyrosine-kinase inhibitor. ERBB-2 mutation with L755S and V842I indicates resistance to trastuzumab, while that with L755S and K753I indicates resistance to lapatinib; these mutations maybe sensitive to pan-HER tyrosine-kinase inhibitors. A 48-year woman diagnosed with HER2-positive LABC developed trastuzumab resistance after three lines of trastuzumab cross-line treatment with partial response (PR) as the best response. The tissue was performed by next-generation sequencing (NGS), and the results discovered L755S in ERBB2 gene. Then, she received effective treatment with pyrotinib plus capecitabine and underwent mastectomy after six cycles of combined treatment with PR. Subsequently, breast mastectomy was performed, and she took pyrotinib plus capecitabine for 1 year and pyrotinib monotherapy for another 1 year as adjuvant therapy and achieved a long-term clinical benefit. In conclusion, pyrotinib is a potential neoadjuvant agent for patients who are heavily pretreated and harbor both ERBB2 amplification and ERBB2 mutant in locally advanced breast cancer.

Cellular signaling pathways of T cells in giant cell arteritis.

Giant cell arteritis (GCA) is a commonly occurring large vacuities characterized by angiopathy of medium and large-sized vessels. GCA granulomatous formation plays an important role in the pathogenesis of GCA. Analysis of T cell lineages and signaling pathways in GCA have revealed the essential role of T cells in the pathology of GCA. T cells are the dominant population present in GCA lesions. CD4+ T cell subtypes that are present include Th1, Th2, Th9, Th17, follicular helper T (Tfh) cells, and regulatory T (Treg) cells. CD8 T cells can primarily differentiate into cytotoxic CD8+ T lymphocytes and Treg cells. The instrumental part of GCA is the interplay between dendritic cells, macrophages and endothelial cells, which can result in the vascular injury and the characteristics granulomatous infiltrates formation. During the inflammatory loop of GCA, several signaling pathways have been reported to play an essential role in recruiting, activating and differentiating T cells, including T-cell receptor (TCR) signaling, vascular endothelial growth factor (VEGF)-Jagged-Notch signaling and the Janus kinase and signal transducer and activator of transcription (STAT) pathway (JAK-STAT) pathway. In this review, we have focused on the role of T cells and their potential signaling mechanism (s) that are involved in the pathogenesis of GCA. A better understanding of the role of T cells mediated complicated orchestration during the homeostasis and the changes could possibly favor developments of novel treatment strategies against immunological disorders associated with GCA.