MolPad: An R-Shiny Package for Cluster Co-Expression Analysis in Longitudinal Microbiomics.

The R-Shiny package MolPad provides an interactive dashboard for understanding the dynamics of longitudinal molecular co-expression in microbiomics. The main idea for addressing the issue is first to use a network to overview major patterns among their predictive relationships and then zoom into specific clusters of interest. It is designed with a focus-plus-context analysis strategy and automatically generates links to online curated annotations. The dashboard consists of a cluster-level network, a bar plot of taxonomic composition, a line plot of data modalities, and a table for each pathway. Further, the package includes functions that handle the data processing for creating the dashboard. This makes it beginner-friendly for users with less R programming experience. We illustrate these methods with a case study on a longitudinal metagenomics analysis of the cheese microbiome.

Needle-free injection of basal insulin improves fasting glucose variability as assessed by continuous glucose monitoring in T2DM: a prospective randomized multicenter open-label crossover study.

BACKGROUND: Fasting glucose variability (FGV) extensively promotes the onset and development of diabetic complications. This study aimed to evaluate the FGV in type 2 diabetes mellitus (T2DM) patients administered basal insulin using a needle-free insulin injector (NFII). RESEARCH DESIGN AND METHODS: This was a prospective randomized multicenter open-label crossover study. We randomly assigned 48 T2DM patients to receive basal insulin by NFII or conventional insulin pen (CIP) for 7-14 days and were then crossed over after washout. We conducted continuous glucose monitoring to investigate the FGV, our primary outcome was a composite parameter of the FGV with a fasting blood glucose target between 4.4 and 6.1 mmol/L. RESULTS: The coefficient of variation for sensor glucose at 6 a.m. with CIP was 11.67 (8.70,14.81)% vs. 9.48 (6.48,12.24)% with NFII (p = 0.003), and the coefficient of variation for mean sensor glucose at 5-6 a.m. with CIP was 12.70 (9.17,16.56)% vs. 9.23 (7.01,11.98)% with NFII (p < 0.001). The overall basal insulin dosage with CIP injection was 18.00 (16.00, 20.00) IU vs. 16.00 (12.00, 19.00) IU during NFII (p < 0.003). CONCLUSION: Compared with CIP, the use of the NFII to inject basal insulin improved FGV in T2DM. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn Identifier is ChiCTR2000034674.

Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study.

BACKGROUND: Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. METHODS: This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. RESULTS: Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. CONCLUSIONS: Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.

Exploring the mechanism of cisplatin resistance by transcriptome sequencing and reversing the chemoresistance by autophagy inhibition in small cell lung cancer.

Cisplatin plays a key role in treating small cell lung cancer (SCLC); however, the rapid development of cisplatin resistance limits its treatment effect. The detailed mechanisms of cisplatin-resistance, particularly in SCLC, remain unclear. We analyzed the differentially expressed genes (DEGs) between cisplatin-resistant small cell lung cancer cell line H446/CDDP and its parental cell line H446, using the transcriptome sequencing technique. Gene ontology (GO) analysis and the subsequent tests demonstrated that the functions of protein ubiquitination and autophagy are more active in the H446/CDDP cells. Autophagy plays a protective role in the H446/CDDP cells by using the autophagy inhibitors, 3-methyladenine and bafilomycin A1. Moreover, antimalarial drugs that inhibit autophagy by increasing the pH of lysosomes can also enhance cisplatin-induced cell death.

Comparison of Blood Glucose Variability Between Exenatide and Biphasic Insulin Aspart 30 in Chinese Participants with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy: A Multicenter, Open-Label, Randomized Trial.

INTRODUCTION: To compare blood glucose variability (GV) in Chinese participants with type 2 diabetes mellitus (T2DM) whose blood glucose levels are inadequately controlled with metformin monotherapy after twice-daily exenatide or biphasic insulin aspart 30 (BIAsp30). METHODS: In this 16-week multicenter, randomized clinical trial, 104 participants were randomized 1:1 to receive exenatide (exenatide group) or BIAsp30 (BIAsp30 group) twice daily. All participants continued metformin treatment. The primary outcome was the change in GV as measured by a continuous glucose monitoring system (CGMS) from baseline to 16 weeks. RESULTS: At 16 weeks, both the Exenatide and BIAsp30 groups effectively decreased mean glucose (MG), but neither group changed the mean amplitude of glycemic excursion (MAGE), largest amplitude of glycemic excursion (LAGE), mean of daily difference (MODD), or standard deviation of blood glucose (SDBG). The decrease in 2-h post-breakfast glucose excursions was greater in the Exenatide group compared to the BIAsp30 group, with a least square (LS) mean difference [95% CI] of (1.58 [0.53, 2.63]). Exenatide also significantly reduced 2-h post-lunch glucose excursion compared to BIAsp30 (LS mean difference [95% CI], 1.19 [0.18, 2.20]). The Exenatide group had significantly reduced body weight and body mass index (BMI), while the BIAsp30 group had increased weight and had no change in BMI. Both treatments were well tolerated with no serious hypoglycemic events and with fewer identified hypoglycemic events in the Exenatide group than in the BIAsp30 group (5.77% vs. 17.31%, P < 0.01). CONCLUSION: Although there was no difference in change of GV between Exenatide and BIAsp30, exenatide provided more improvement in postprandial glucose excursion and weight control, without increasing the risk of hypoglycemia in Chinese patients with T2DM whose blood glucose was inadequately controlled with metformin. These findings may provide new options for patients who choose further hypoglycemic treatment, especially in patients with obesity who have large postprandial plasma glucose excursions. TRIAL REGISTRATION: ClinicalTrials.gov indentifier: NCT02449603.

Long-term Effects of Antihypertensive Drug Use and New-onset Osteoporotic Fracture in Elderly Patients: A Population-based Longitudinal Cohort Study.

BACKGROUND: Antihypertensive drugs have been linked to new-onset osteoporotic fracture (NOF), and different classes of antihypertensive drugs may alter the risk for the development of NOF; however, the classic effect of different antihypertensive drugs on the development of NOF in the elderly has not been well studied during long-term follow-up. METHODS: In this study, we investigated the association between different classic antihypertensives and the development of NOF in the elderly. This was a longitudinal cohort study performed using data from claim forms submitted to the Taiwan Bureau of National Health Insurance in Central Taiwan, China including case patients with NOF aged 65-80 years from January 2002 to December 2012 and non-NOF controls. Prescriptions for antihypertensives before the index date were retrieved from a prescription database. We estimated the hazard ratios (HR s) of NOF associated with antihypertensive use. Non-NOF controls served as the reference group. RESULTS: A total of 128 patients with NOF were identified from among 1144 patients with hypertension during the study period. The risk of NOF after adjusting age, sex, comorbidities, and concurrent medications was higher among the users of angiotensin-converting enzyme (ACE) inhibitors (HR, 1.64; 95% confidence interval [CI], 1.01-2.66) than among nonusers. Patients who took calcium channel blockers (CCBs) (HR, 0.70; 95% CI, 0.49-0.99) were at a lower risk of developing NOF than nonusers. Loop diuretics, thiazide diuretics, angiotensin receptor blocker, beta-blocker, and alpha-blocker were not associated with the risk of NOF. CONCLUSIONS: Elderly with hypertension who take CCBs are at a lower risk of NOF and that the use of ACE inhibitors was associated with a significantly increased risk of developing NOF during the 11-year follow-up.

Using protein microarray technology to screen anti-ERCC1 monoclonal antibodies for specificity and applications in pathology.

BACKGROUND: An antibody with cross-reactivity can create unexpected side effects or false diagnostic reports if used for clinical purposes. ERCC1 is being explored as a predictive diagnostic biomarker for cisplatin-based chemotherapy. High ERCC1 expression is linked to drug resistance on cisplatin-based chemotherapy. 8F1 is one of the most commonly used monoclonal antibodies for evaluating ERCC1 expression levels in lung cancer patient tissues, but it has been noted that this antibody cross-reacts with an unknown protein. RESULTS: By using a high density protein microarray chip technology, we discovered that 8F1 not only reacts with its authentic target, ERCC1, but also cross-reacts with an unrelated nuclear membrane protein, PCYT1A. The cross-reactivity is due to a common epitope presented on these two unrelated proteins. Similar to the subcellular localization of ERCC1, IHC tests demonstrated that PCYT1A is localized mainly on nuclear membrane. In this study, we also discovered that the PCYT1A gene expression level is significantly higher than the ERCC1 gene expression level in a certain population of lung cancer patient tissue samples. To develop the best monoclonal antibody for ERCC1 IHC analysis, 18 monoclonal antibodies were generated and 6 of them were screened against our protein microarray chip. Two clones showed high mono-specificity on the protein microarray chip test and both worked for the IHC application. CONCLUSION: In summary, the 8F1 clone is not suitable for ERCC1 IHC assay due to its cross-reactivity with PCYT1A protein. Two newly generated monoclonal antibodies, 4F9 and 2E12, demonstrated ultra-specificity against ERCC1 protein and superior performance for IHC analyses.