Mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade and the emerging role of gut microbiome.

As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome.

Analysis of the Incidence and Clinical Significance of Long and Short Corrected QT Interval in Electrocardiogram in Healthy Population of Changsha in China

ABSTRACT Objective: To analyse the incidence of long and short corrected QT (QTc) in a healthy sample of the population of Changsha in China. Methods: Standard 12-lead electrocardiograms (ECGs) were performed on 4025 subjects in Changsha of China, whose age ranged from 6 minutes after birth to 83 years, between January 1993 and December 2012. Heart rate and QT interval were measured and recorded. Corrected QT was calculated with Bazett´s formula (QTc = QT/RR0.5). All recruited individuals had taken healthy examination, ruling out general health issue, in The Second Xiangya Hospital of Central South University. Statistical analyses were performed using the SPSS 16.0 software (IBM Corp, Armonk, NY, USA). Results: The incidence of short QTc was 7.13% (287/4025 cases). The peak values of the incidence were in the 30-40 years group (15.71%). The low values were in the 1-3 months group and 3-6 months group (0%, 0.76%), respectively. The incidence of long QTc was 3.16% (127/4025 cases). The values diminished significantly after adulthood. The low values were in the age groups of 18-30 years (0.86%) and 30-40 years (0.71%), respectively. After the age of 50 years, the incidence of long QTc increased with age 50-60 years and 60-70 years and 70-83 years (7.89%, 9.06%, 14.06%), respectively. There was no statistically significant difference between the genders (p > 0.05). Conclusion: The peak incidences of long and short QTc existed in two separate age groups in the healthy sample. The peak incidence of short QTc was in the age group of 18-40 years, and the peak incidence of long QTc was in the age group beyond the 50 years. For these two age groups, it was recommended to pay close attention to the changes in their QTc in order to prevent cardiovascular events.

Upregulation of miR-3658 in bladder cancer and tumor progression.

Despite increasing advances in surgical techniques and adjuvant chemotherapies, bladder cancer remains the ninth leading cause of male malignancy-associated deaths worldwide. Several microRNAs (miRNAs) have been identified to be closely associated with the progression and prognosis of, and response to treatments in various human cancers. However, few studies have investigated the role of miR-3658 in bladder cancer. In this study, we examined the expression of miR-3658 in 96 pairs of bladder cancer tissues and adjacent non-tumor tissues via quantitative reverse-transcription polymerase chain reaction. Results showed that expression of miR-3658 was up-regulated in the bladder cancer tissues as compared with that in the corresponding control tissues (4.15 ± 2.78 vs 2.17 ± 1.14; P < 0.0001). Furthermore, higher miR-3658 expression was significantly associated with lymph node invasion, distant metastasis, histological grade, TNM stage, and tumor recurrence in bladder cancer (all P < 0.0001). miR-3658 expression was not associated with other clinicopathological variables such as age, gender, tumor size, and number (all P > 0.05). Our study revealed that miR-3658 overexpression is involved in tumor progression of bladder cancer, indicating that the miRNA possesses prognostic values.