Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor

IntroductionImmune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. MethodsWe investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).ResultsThe genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs.DiscussionOur Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy

Eribulin Treatment Induces High Expression of miR-195 and Inactivates the Wnt/β - catenin Signaling Pathway in Triple-negative Breast Cancer

Triple-negative breast cancer （TNBC） accounts for 10-15％ of all breast cancer cases and shows a poor prognosis with 30％ distant metastasis. With few specific target molecules and ineffective hormonal and anti-HER2 treatment, an alternative therapeutic method for TNBC is urgently required. Recently, a non-taxane inhibitor of microtubule dynamics called eribulin was developed for breast cancer therapy. Eribulin induces irreversible mitotic mass formation in cancer cells during the G2-M phase, initiating apoptosis; however, the mechanism underlying this eribulin activity remains unclear. We reported previously that exposing non-basal-like （NBL） TNBC cells to eribulin increases miR-195 expression, which in turn decreases the expression of targeted Wnt3a. The present study sought to further clarify the mechanism of this antitumor effect by exploring how eribulin affects Wnt/β - catenin signaling based on miRNA expression changes in TNBC. In an NBL type of human breast cancer cell line （MDA-MB-231 cells）, we compared the expression levels of Wnt/β catenin signaling pathway proteins in cells exposed to an miR-195 mimic （cells transfected with miR-195 and in which Wnt3a expression was suppressed） and in cells exposed to eribulin. Expression levels of Wnt3a, β -catenin, and GSK-3β were measured by ELISA and observed by fluorescence immunostaining. Wnt3a and β -catenin expression was significantly lower and GSK-3β expression was significantly higher in the cells exposed to eribulin and transfected with miR-195 mimic than in the untreated controls, suggesting that eribulin inactivates the Wnt/β -catenin signaling pathway. Therefore, a novel antitumor mechanism of eribulin was determined, whereby eribulin induces high expression of miR-195 to inactivate the Wnt/β -catenin signaling pathway in NBL-type TNBC

Fragmented QRS complex in patients with systemic lupus erythematosus at the time of diagnosis and its relationship with disease activity.

OBJECTIVE:Cardiovascular disease is an important contributor to the mortality rate of patients with systemic lupus erythematosus (SLE), which is related to SLE disease activity. Fragmented QRS (fQRS) complexes, defined by additional spikes in the QRS complex, are useful for identifying myocardial scars on electrocardiography and can be an independent predictor of cardiac events. We aimed to assess the relationship between disease activity in patients with SLE and fQRS at the time of diagnosis. METHODS:Forty-four patients with SLE were included. Patients with cardiac diseases, other rheumatic diseases, and prior treatment at the time of electrocardiography measurement were excluded. The appearance of fQRS represented exposure. The primary outcome was SLE Disease Activity Index 2000 (SLEDAI-2K). Multiple regression analysis was conducted to assess the association between fQRS and SLEDAI-2K adjusted for age, sex, and time from the estimated onset date to the date of diagnosis. RESULTS:Among patients with SLE at diagnosis, 26 (59.1%) had fQRS. The median SLEDAI-2K was 18 (interquartile range [IQR], 12-22) and 9 (IQR, 8-15) in the fQRS(+) and fQRS(-) groups, respectively. SLEDAI-2K was significantly higher in the fQRS(+) group than in the fQRS(-) group (regression coefficient, 2.69; 95% confidence interval, 0.76-4.61; p = 0.008). CONCLUSION:Our results suggested that fQRS(+) patients with SLE had high disease activity. fQRS could likely detect subclinical myocardial involvement in patients with SLE and predict long-term occurrence of cardiac events

Cancer stem-like cells have cisplatin resistance and miR-93 regulate p21 expression in breast cancer

Aim: This study aims to examine the role of microRNAs (miRNAs) in regulating the expression of p21, a cyclin-dependent kinase inhibitor, and in inducing resistance to cisplatin, an anticancer drug. Methods: Human breast cancer cell line MDA-MB231 cells were separated into two subpopulations, cancer stem-like cells (CSCs) and cancer cells, based on the expression of cell surface antigens CD44 and CD24. Results: p21 protein expression was higher in CSCs than in cancer cells. Exposure of MDA-MB-231 cells to cisplatin increased p21 protein expression. However, p21 expression was significantly lower in cisplatin-treated CSCs than in cisplatin-treated cancer cells, suggesting that p21-dependent cell cycle suppression was lower in CSCs than in cancer cells. Moreover, caspase-3 activity was significantly lower in cisplatin-treated CSCs than in cisplatin-treated cancer cells, indicating that CSCs were more resistant to cisplatin-induced apoptosis than cancer cells. Treatment with miR-93 inhibitors increased p21 expression in CSCs, suggesting that miR-93 suppressed p21 expression. Conclusion: The results of the present study indicate that CSCs contribute to cisplatin resistance of MDA-MB231 cells and suggest that miR-93 inhibits the expression of p21, a factor involved in drug resistance