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Abstract Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post‐stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM‐MSC) downregulate bacterial load in the lungs of stroke mice models. RNA‐sequencing of the lung from BM‐MSC‐treated stroke models indicates that BM‐MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM‐MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration‐dependent extracellular vesicles. With liquid chromatography‐tandem mass spectrometry (LC‐MS/MS), the result shows that BM‐MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3‐associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM‐MSC is a promising therapeutic candidate against post‐stroke pneumonia, with dual functions of anti‐infection and immunol modulation, which is more than a match for antibiotics treatment.

m6A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m6A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network

Abstract Background Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. Methods In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis. Results We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. Conclusion In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.

Abstract Liver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.

Recurrent metastasis is a major fatal cause of breast cancer. Regretfully, the driving force and the molecular beneath have not been fully illustrated yet. In this study, a cohort of breast cancer patients with locoregional metastasis was recruited. For them, we collected the matched samples of the primary tumor and metastatic tumor, and then we determined the mutation profiles with whole-exome sequencing (WES). On basis of the profiles, we identified a list of deleterious variants in eight susceptible genes. Of them, filamin A (FLNA) was considered a potential driver gene of metastasis, and its low expression could enhance 5 years’ relapse survival rate by 15%. To prove the finding, we constructed a stable FLNA knockout tumor cell line, which manifested that the cell abilities of proliferation, migration, and invasion were significantly weakened in response to the gene knockout. Subsequently, xenograft mouse experiments further proved that FLNA knockout could inhibit local or distal metastasis. Putting all the results together, we consolidated that FLNA could be a potential driver gene to metastasis of breast cancer, in particular triple-negative breast cancer. Additional experiments also suggested that FLNA might intervene in metastasis via the regulation of MMP-1 expression. In summary, this study demonstrates that FLNA may play as a positive regulator in cancer proliferation and recurrence. It provides new insight into breast cancer metastasis and suggests a potential new therapeutic target for breast cancer therapy.

N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells’ proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development.

In work is described practical approach to the expert system building for the analysis skeleton planar scintigramms. The aim is to analyze the numerical characteristics of bone metastases by scintigraphy. Objective. Progress in the development of bioinformatics and mathematical methods in biomedicine, as well as the development of computer and telecommunications systems and networks determines the look of the present and future of oncology technology and of medicine in general. At last years of one of the directions of high-tech-medicine development is a processing the digital image: improvement of quality of image, recovering image, its recognition of separate elements. Recognition of pathological processes is one of the most important problems of processing the medical image. Methods and results. Method of computer-aided analysis of planar osteostsintigrammy studied the skeleton of patients with breast cancer are in complete remission and in the phase progression of the disease with metastases to the skeleton. As analyzed parameter was used brightness of images. The study of the physiological accumulation of radiopharmaceuticals in patients without metastasis to the skeleton indicates a wide variation in the brightness values of the scintigram in some areas of the skeleton. At the same anatomical areas of the skeleton there are significant differences in the values of the index of average brightness. In almost all areas of the skeleton averages of the brightness lesions hyperfixation RFP for scintigram significantly prevail over those of «physiological» lesions hyperfixation. Thus, there is a direct relationship between the levels of accumulation of the radiopharmaceutical in areas of the skeleton without metastatic lesion and bone metastases occurring in these zones. Consider methodological approaches to studies of quality of qualifier at the expert system building for the analysis skeleton planar scintigramms, as well as results of conducting calculations.

Death-associated protein kinase 1 (DAPK1) is a Ca2+/calmodulin regulated Ser/Thr kinase involved in various cellular processes including cell death, autophagy and inflammation. Its dysregulation has been linked to tumour metastasis, anti-viral responses, Alzheimer's disease and other neurological disorders. To further investigate the role of DAPK1 in these processes, we generated a DAPK1 knockout first (conditional ready) human embryonic stem (hES) cell line in which the endogenous DAPK1 can be easily restored with expression of FLPe. This cell line provides an ideal model to study the role of DAPK1 in human development and various pathologies related to DAPK1 dysregulation in vitro.

Background Enterobacterial translocation is a leading contributor to fatal infection among patients with acute ischaemic stroke (AIS). Accumulative evidence suggests that mesenchymal stem cell (MSC) effectively ameliorates stroke outcomes. Whether MSC could inhibit post-stroke enterobacterial translocation remains elusive.Methods Patients with AIS and healthy individuals were enrolled in the study. Mice subjected to transient middle cerebral artery occlusion were treated with bone marrow-derived MSC (BM-MSC) right after reperfusion. Enterobacterial translocation was evaluated with Stroke Dysbiosis Index and circulating endotoxin. Thickness of mucus was assessed with Alcian blue staining. Hepatic glucocorticoid (GC) metabolism was analysed with expression of HSD11B2, HSD11B1 and SRD5A1.Results We report that the gut mucus layer was attenuated after the stroke leading to pronounced enterobacterial translocation. The attenuation of the gut mucus was attributed to diminished mucin production by goblet cells in response to the elevated systemic GC after cerebral ischaemia. Transferred-BM-MSC restored the mucus thickness, thus preserving gut microbiota homeostasis and preventing enterobacterial invasion. Mechanistically, the transferred-BM-MSC stationed in the liver and enhanced peroxisome proliferator-activated receptor γ signalling in hepatocytes. Consequently, expression of HSD11B2 and SRD5A1 was increased while HSD11B1 expression was downregulated which promoted GC catabolism and subsequently restored mucin production.Conclusions Our findings reveal that MSC transfer improves post-stroke gut barrier integrity and inhibits enterobacterial translocation by enhancing the hepatic GC metabolism thus representing a protective modulator of the liver-gut-brain axis in AIS.

Cancer stem cells are enriched in triple-negative breast cancer (TNBC) tumor tissues, which present strong capacities of proliferation and tumorigenicity. The present study detected the distribution of cancer stem cell markers cluster of differentiation (CD)44/CD24 and analyzed the clinical outcomes of different CD44/CD24 phenotypes in patients with TNBC. Multivariate Cox regression analyses were performed with regard to the prognostic value of cancer stem cell markers CD44/CD24, aldehyde dehydrogenase 1 and other baseline clinical characteristics, including tumor size, lymph node involved, adjuvant chemotherapy, Ki-67, breast cancer susceptibility gene 1, cellular tumor antigen p53, vimentin and basal-like status. The multivariate analyses showed that three of these factors, CD44/CD24 phenotype, basal-like status and number of lymph nodes involved, had an impact on overall survival. Furthermore, patients with CD44+/CD24- phenotype, basal-like tumors and ≥4 lymph nodes involved had a signifi- cantly worse prognosis. The expression of CD44 and CD24 was detected by double-staining immunohistochemistry, which can locate cancer stem cells individually. Overall, the present results indicated that CD44/CD24 status evaluated by double-staining immunohistochemistry constitutes an independent prognostic factor for TNBC. [ABSTRACT FROM AUTHOR]

Background: The intake of soy isoflavones among women with breast cancer has become a public health concern, because these compounds have weak estrogenic effects. There is little clinical evidence about their safety for patients with breast cancer who are receiving adjuvant endocrine therapy. Methods: For patients who underwent surgery for breast cancer between August 2002 and July 2003 and who were receiving adjuvant endocrine therapy, we examined associations between dietary intake of soy isoflavones and recurrence of breast cancer and death. We measured dietary intake of soy isoflavones at baseline using a validated food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by means of multivariable Cox proportional hazards regression models. We further stratified the analyses by hormonal receptor status and endocrine therapy. Results: The median follow-up period for the 524 patients in this study was 5.1 years. Among premenopausal patients, the overall death rate (30.6%) was not related to intake of soy isoflavones (HR = 1.05, 95% CI 0.78-1.71 for the highest quartile [> 42.3 mg/day] v. the lowest quartile [< 15.2 mg/day], p for trend = 0.87). Relative to postmenopausal patients in the lowest quartile of soy isoflavone intake, the risk of recurrence for postmenopausal patients in the highest quartile was significantly lower (HR = 0.67, 95% CI 0.54-0.85, p for trend = 0.02). Inverse associations were observed in patients with estrogen and progesterone receptor positive disease and those receiving anastrozole therapy. Interpretation: High dietary intake of soy isoflavones was associated with lower risk of recurrence among postmenopausal patients with breast cancer positive for estrogen and progesterone receptor and those who were receiving anastrozole as endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: The intake of soy isoflavones among women with breast cancer has become a public health concern, because these compounds have weak estrogenic effects. There is little clinical evidence about their safety for patients with breast cancer who are receiving adjuvant endocrine therapy. Methods: For patients who underwent surgery for breast cancer between August 2002 and July 2003 and who were receiving adjuvant endocrine therapy, we examined associations between dietary intake of soy isoflavones and recurrence of breast cancer and death. We measured dietary intake of soy isoflavones at baseline using a validated food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by means of multivariable Cox proportional hazards regression models. We further stratified the analyses by hormonal receptor status and endocrine therapy. Results: The median follow-up period for the 524 patients in this study was 5.1 years. Among premenopausal patients, the overall death rate (30.6%) was not related to intake of soy isoflavones (HR = 1.05, 95% CI 0.78-1.71 for the highest quartile [> 42.3 mg/day] v. the lowest quartile [< 15.2 mg/day], p for trend = 0.87). Relative to postmenopausal patients in the lowest quartile of soy isoflavone intake, the risk of recurrence for postmenopausal patients in the highest quartile was significantly lower (HR = 0.67, 95% CI 0.54-0.85, p for trend = 0.02). Inverse associations were observed in patients with estrogen and progesterone receptor positive disease and those receiving anastrozole therapy. Interpretation: High dietary intake of soy isoflavones was associated with lower risk of recurrence among postmenopausal patients with breast cancer positive for estrogen and progesterone receptor and those who were receiving anastrozole as endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: Fatigue is prevalent in breast cancer survivors and has profound effects on daily life. The interference of fatigue with endocrine therapy may be difficult to separate. This study investigates the prevalence and severity of fatigue and identifies the demographic, clinical, and lifestyle factors associated with cancer-related fatigue (CRF) in breast cancer patients undergoing endocrine therapy in an urban area. Methods: Women with stage I-IIIA breast cancer were recruited and asked to participate (n = 371) in the study. The 315 women who responded to the questionnaire (84.9%), 54 (17.1%) had completed endocrine therapy and 261 (82.9%) were still undergoing endocrine therapy. The patients had been diagnosed at an average of 31 months prior to recruitment (range, 7 to 60 months); the average age was 48 (range, 33 to 72) years. The 11-point scale and Visual Analog Scale (VAS) were employed to quantify the level of fatigue experienced by the patients. Logistic regression analyses and a trend test method were performed to evaluate factors associated with CRF. Results: Among the 315 patients, 189 (60%) had experienced or were experiencing CRF during endocrine therapy. Logistic regression analysis was performed to identify factors associated with CRF, including BMI (body mass index), clinical stage, menopausal status, duration of endocrine therapy, physical activity, and diet. Factors unrelated to CRF were age, marital status, treatment, endocrine therapy drugs, alcohol intake, and smoking. The trend test method revealed an association between physical activity and dietary level and the intensity of CRF. Conclusions: The present findings suggest that fatigue is an important problem in the majority of breast cancer patients during endocrine therapy. We found that BMI, clinical stage, menopausal status, duration of endocrine therapy, physical activity, and diet are associated with fatigue. Future research should focus on the impact factors of CRF and lifestyle in the management of breast cancer patients. [ABSTRACT FROM AUTHOR]

Capecitabine is a novel fluoropyrimidine carbamate, which has a broader spectrum of antitumor activity than other fluoropyrimidines, such as 5-FU, DFUR, or UFT; it has proved effective over a wide dose range. Recent research has suggested that frequent administration of lower doses of certain chemotherapeutic drugs might enhance their antiangiogenic effect. The present study investigated the antiangiogenic effect of capecitabine on breast cancer. In order to augment its efficacy, we combined capecitabine chemotherapy with ginsenoside Rg3. Our results indicate that a metronomic regimen of capecitabine inhibited angiogenesis in breast cancer, and its antiangiogenic effects may be further enhanced by the concurrent administration of ginsenoside Rg3. As an antiangiogenic method, this regimen presented better antitumor effects, less toxicity, and reduced susceptibility to drug resistance. [ABSTRACT FROM AUTHOR]

The fatigue prevalence in breast cancer survivors is high during the endocrine treatment. However, there are few evidence-based interventions to manage this symptom. The aim of this study was to investigate the effectiveness of spore powder of Ganoderma lucidum for cancer-related fatigue in breast cancer patients undergoing endocrine therapy. Spore powder of Ganoderma lucidum is a kind of Basidiomycete which is a widely used traditional medicine in China. 48 breast cancer patients with cancer-related fatigue undergoing endocrine therapy were randomized into the experimental or control group. FACT-F, HADS, and EORTC QLQ-C30 questionnaires data were collected at baseline and 4 weeks after treatment. The concentrations of TNF-a, IL-6, and liver-kidney functions were measured before and after intervention. The experimental group showed statistically significant improvements in the domains of physical well-being and fatigue subscale after intervention. These patients also reported less anxiety and depression and better quality of life. Immune markers of CRF were significantly lower and no serious adverse effects occurred during the study. This pilot study suggests that spore powder of Ganoderma lucidum may have beneficial effects on cancer-related fatigue and quality of life in breast cancer patients undergoing endocrine therapy without any significant adverse effect. [ABSTRACT FROM AUTHOR]