Comparative cardiovascular safety of LABA/LAMA FDC versus LABA/ICS FDC in patients with chronic obstructive pulmonary disease: a population-based cohort study with a target trial emulation framework.

BACKGROUND: Use of combinations of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant. AIM: The present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies. METHODS: We identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017-2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS). RESULTS: Among 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78-1.01) for the composite events, 0.80 (95% CI, 0.61-1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68-3.25) for unstable angina, 1.00 (95% CI, 0.80-1.24) for congestive heart failure, 0.62 (95% CI, 0.37-1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66-1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses. CONCLUSION: Our findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD.

Changes of ECG parameters after BNT162b2 vaccine in the senior high school students.

The purpose of this study is to determine the ECG parameter change and the efficacy of ECG screening for cardiac adverse effect after the second dose of BNT162b2 vaccine in young population. In December 2021, in cooperation with the school vaccination system of Taipei City government, we performed a ECG screening study during the second dose of BNT162b2 vaccines. Serial comparisons of ECGs and questionnaire survey were performed before and after vaccine in four male-predominant senior high schools. Among 7934 eligible students, 4928 (62.1%) were included in the study. The male/female ratio was 4576/352. In total, 763 students (17.1%) had at least one cardiac symptom after the second vaccine dose, mostly chest pain and palpitations. The depolarization and repolarization parameters (QRS duration and QT interval) decreased significantly after the vaccine with increasing heart rate. Abnormal ECGs were obtained in 51 (1.0%) of the students, of which 1 was diagnosed with mild myocarditis and another 4 were judged to have significant arrhythmia. None of the patients needed to be admitted to hospital and all of these symptoms improved spontaneously. Using these five students as a positive outcome, the sensitivity and specificity of this screening method were 100% and 99.1%, respectively.  Conclusion: Cardiac symptoms are common after the second dose of BNT162b2 vaccine, but the incidences of significant arrhythmias and myocarditis are only 0.1%. The serial ECG screening method has high sensitivity and specificity for significant cardiac adverse effect but cost effect needs further discussed. What is Known: • The incidence of cardiac adverse effects was reported to be as high as 1.5 per 10 000 persons after the second dose BNT162b2 COVID-19 vaccine in the young male population based on the reporting system. What is New: • Through this mass ECG screening study after the second dose of BNT162b2 vaccine we found: (1) The depolarization and repolarization parameters (QRS duration and QT interval) decreased significantly after the vaccine with increasing heart rate; (2) the incidence of post-vaccine myocarditis and significant arrhythmia are 0.02% and 0.08%; (3) The serial ECG screening method has high sensitivity and specificity for significant cardiac adverse effect.

Effectiveness and safety of direct oral anticoagulants versus warfarin in patients with atrial fibrillation and advanced kidney disease.

BACKGROUND: The effectiveness and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and advanced kidney disease (AKD) has not been fully established. OBJECTIVES: To determine the effectiveness and safety related to pooled or specific DOACs to that with warfarin in patients with AF and AKD. METHODS: Patients with AF and AKD (estimated glomerular filtration rate < 30 mL/min) who received DOAC or warfarin from July 2011 to December 2020 were retrospectively identified in a medical center in Taiwan. Primary outcomes were hospitalized for stroke/systemic embolism and major bleeding. Secondary outcomes included any ischemia and any bleeding. RESULTS: A total of 1,011 patients were recruited, of whom 809 (80.0%) were in the DOACs group (15.3% dabigatran, 25.4% rivaroxaban, 25.2% apixaban, and 14.1% edoxaban), and 202 (20.0%) in the warfarin group. DOACs had considerably lower risks of stroke/systemic embolism (adjusted hazard ratio [aHR] 0.29; 95% CI, 0.09-0.97) and any ischemia (aHR, 0.42; 95% CI, 0.22-0.79), but had comparable risks of major bleeding (aHR, 0.99; 95% CI, 0.34-2.92) and any bleeding (aHR, 0.74; 95% CI, 0.50-1.09) than warfarin. Apixaban was linked to considerably lower risks of any ischemia (aHR, 0.13; 95% CI, 0.04-0.48) and any bleeding (aHR, 0.53; 95% CI, 0.28-0.99) than warfarin. CONCLUSION: Among patients with AF and AKD, DOACs were linked to a lower risk of ischemic events, and apixaban was linked to a lower risk of any ischemia and any bleeding than warfarin.

A single-cell Raman-based platform to identify developmental stages of human pluripotent stem cell-derived neurons.

Stem cells with the capability to self-renew and differentiate into multiple cell derivatives provide platforms for drug screening and promising treatment options for a wide variety of neural diseases. Nevertheless, clinical applications of stem cells have been hindered partly owing to a lack of standardized techniques to characterize cell molecular profiles noninvasively and comprehensively. Here, we demonstrate that a label-free and noninvasive single-cell Raman microspectroscopy (SCRM) platform was able to identify neural cell lineages derived from clinically relevant human induced pluripotent stem cells (hiPSCs). By analyzing the intrinsic biochemical profiles of single cells at a large scale (8,774 Raman spectra in total), iPSCs and iPSC-derived neural cells can be distinguished by their intrinsic phenotypic Raman spectra. We identified a Raman biomarker from glycogen to distinguish iPSCs from their neural derivatives, and the result was verified by the conventional glycogen detection assays. Further analysis with a machine learning classification model, utilizing t-distributed stochastic neighbor embedding (t-SNE)-enhanced ensemble stacking, clearly categorized hiPSCs in different developmental stages with 97.5% accuracy. The present study demonstrates the capability of the SCRM-based platform to monitor cell development using high content screening with a noninvasive and label-free approach. This platform as well as our identified biomarker could be extensible to other cell types and can potentially have a high impact on neural stem cell therapy.

Potential short-term outcome advantage of low vs. high ligation of inferior mesenteric artery for sigmoid and rectal cancer: propensity score matching analysis.

BACKGROUND: Whether to ligate the inferior mesenteric artery at its root during anterior resection for sigmoid colon or rectal cancer is still under debate. This study compared the surgical outcomes, postoperative recovery, and anastomotic leakage between high and low ligation of the inferior mesenteric artery through a subgroup analysis. METHODS: This was a retrospective analysis of prospectively collected data. All patients who underwent colorectal resection for rectosigmoid cancer between December 2016 and December 2019 were enrolled. According to the surgical ligation level of the inferior mesenteric artery, the patients were categorized into either the high or low ligation group. The investigated population was matched using the propensity score method. RESULTS: Overall, 894 patients with sigmoid or rectal cancer underwent elective anterior resection with high (577 patients) or low (317 patients) ligation of the inferior mesenteric artery. After the propensity score matching, 245 patients in each group were compared. High ligation of the inferior mesenteric artery was associated with higher incidence of anastomotic leakage (14.9% vs. 5.6%, P = 0.041) for mid- to low-rectum tumors and a higher incidence of complications (8.6% vs. 3.3%, P = 0.013) of grades 1-2 according to the Clavien-Dindo classification system. CONCLUSION: Compared with high ligation, low ligation of the inferior mesenteric artery resulted in lower likelihood of morbidity and mortality in rectal and sigmoid cancers. Moreover, low ligation was less likely to result in anastomosis leakage in mid- to low-rectal cancers.

Mutation-Driven S100A8 Overexpression Confers Aberrant Phenotypes in Type 1 CALR-Mutated MPN.

Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.

Chrysophanol Suppresses Cell Growth via mTOR/PPAR-α Regulation and ROS Accumulation in Cultured Human Tongue Squamous Carcinoma SAS Cells.

Oral cancer, a type of head and neck cancer, can pose a significant risk of death unless diagnosed and treated early. Alternative treatments are urgently needed owing to the high mortality rate, limitations of conventional treatments, and many complications. The anthraquinone compound chrysophanol acts as a tumor suppressor on some types of cancer cells. To date, it has not been clarified how chrysophanol affects human tongue squamous carcinoma. This study was aimed to examine the effects of chrysophanol on oral cancer treatment. The results show that chrysophanol caused cell death, reduced the expression of the mammalian target of rapamycin (mTOR)/peroxisome proliferator-activated receptor-alpha (PPAR-α), and increased reactive oxygen species (ROS) production. We also used two ion chelators, deferoxamine (DFO) and liproxstatin-1 (Lipro), to further determine whether chrysophanol inhibits cell growth and regulates mTOR/PPAR-α expression and ROS production, both of which are involved in iron homeostasis. The results show that DFO and Lipro reversed the increase in cell death, downregulation of mTOR/PPAR-α, and decrease in ROS accumulation. In conclusion, chrysophanol inhibits the growth of oral squamous cell carcinoma cells by modulating mTOR/PPAR-α and by causing ROS accumulation.

Subwavelength-resolution imaging of surface plasmon polaritons with up-conversion fluorescence microscopy.

Imaging and characterization of surface plasmon polaritons (SPPs) are crucial for the research and development of the plasmonic devices and circuits. Here, we report on direct imaging of SPPs propagation on SiO2/metal interface with subwavelength spatial resolution using up-conversion fluorescence microscopy, that exploits rare-earth ions, such as Er3+, Yb3+, and Nd3+, doped nanoparticles as the fluorophores. We demonstrated that by further taking the intensity ratio of the image obtained with fluorescent emission at different wavelengths, we are able to substantially enhance the features associated to the SPP wavefronts in the image for quantitative analysis, such as the wavevector and propagation direction of the SPPs. Our results agree with the theoretic prediction of the SPP wavelengths quantitatively. We further demonstrate the evolution of the SPP wavefronts due to refraction SPPs, and reproduced the experiment with finite difference time domain (FDTD) method simulations. The relative refractive index of SPP estimated from the experiment also agrees quantitatively with those extracted from the theory and the simulation.

Drug-Drug Interactions With Cyclosporine in the Anti-Hepatitis C Viral PrOD Combination Regimen of Paritaprevir/Ritonavir-Ombitasvir and Dasabuvir in Organ Transplant Recipients With Severe Hepatic Fibrosis or Cirrhosis.

BACKGROUND: The clinical guidelines suggest that the dosing of cyclosporine (CsA), during combination therapy with paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD), would be only one-fifth of the pre-PrOD total daily dose to be administered once daily. However, this dosing may not be applicable to all patients depending on their clinical condition. This study focuses on the pharmacokinetic dynamics of PrOD with CsA in Asian organ transplant recipients with severe liver fibrosis or cirrhosis who undergo concurrent treatment with PrOD treatment and CsA. The efficacy and safety of PrOD treatment was also evaluated. METHODS: Data from 7 patients obtained between January 2017 and September 2017 were retrospectively analyzed. Determinations of the blood concentrations of CsA were made, whether used as a single treatment or in combination therapy with PrOD. RESULTS: The combination regimen compared with CsA administered alone resulted in a 4.53-fold and 5.52-fold increase in the area under the concentration-time curve from time 0-12 hours (AUC0-12 h) of CsA on days 1 and 15, respectively. In addition, the maximal concentration, time to maximum concentration, and terminal phase elimination half-life (t1/2) of CsA were increased during the combined treatment of PrOD and CsA. The authors proposed reducing the CsA dosage during PrOD treatment to one-seventh of that of the pre-PrOD treatment of the total daily dose to maintain target CsA levels. All patients achieved sustained virologic responses at week 12. There were no episodes of serious adverse events or graft rejections observed. CONCLUSIONS: Although the combination with PrOD significantly affects the pharmacokinetics of CsA, it is effective and safe with regular monitoring of the CsA blood concentrations and appropriate CsA dose adjustment.

Prompt successful response to a COVID-19 outbreak: Performance of community-based rapid screening station.

An outbreak occurred in Wanhua District of Taipei City. It was traced to a cluster infection originating from a teahouse. To prevent further large-scaled community spread, the Taipei City Government established the first community rapid test screening station. This report describes the station's strategy and performance and key factors that contributed to its operation. The project involves collaboration among various departments of Taipei City Government, including the health, environmental, police, transportation, and fire departments. The station provides rapid screening, polymerase chain reaction (PCR) testing, and immediate isolation and follow-up medical services upon the detection of a positive case. These services are accessible to local residents and are intended to ease hospitals' burdens. In 36 days, a total of 8532 people were tested, and 419 confirmed cases were identified. Over the same period, the weekly number of positive cases in Wanhua District decreased from 356 to 40, and the PCR positive rate decreased from 21.7% to 1.2%. The policy of establishing rapid screening station, contact tracing and mask wearing policy are key strategies for interrupting chains of transmission of COVID-19. This intervention has become a model for preventing the spread of the epidemic and establishing community rapid screening stations in Taiwan.

TRIM37 Promotes Pancreatic Cancer Progression through Modulation of Cell Growth, Migration, Invasion, and Tumor Immune Microenvironment.

TRIM37 dysregulation has been observed in several cancer types, implicating its possible role in tumorigenesis. However, the role of TRIM37 in pancreatic cancer progression remains unclear. In the present study, we observed that TRIM37 knockdown resulted in reduced proliferation, clonogenicity, migration, and invasion ability of pancreatic cancer cells. Furthermore, an in vivo study using an orthotopic syngeneic animal model further confirmed that reduced expression of TRIM37 in cancer cells suppressed tumor growth in vivo. Moreover, in mice bearing TRIM37 knockdown pancreatic cancer cells, the proportion of CD11b+F4/80+MHCIIlow immunosuppressive macrophages was significantly reduced in tumor milieu, which might be due to the regulatory role of TRIM37 in cytokine production by pancreatic cancer cells. Collectively, these findings suggest a key role of TRIM37 in promoting pancreatic cancer progression.

Surgical and Anatomic Consideration in Endoscopic Dacryocystorhinostomy of a Patient with Damaged Sinonasal Anatomy Post-Caldwell-Luc Surgery: A Case Report.

Background: The Caldwell-Luc (CL) procedure, an outdated operative procedure that is used to treat inflammatory sinus diseases, is rarely performed presently. However, physicians may encounter patients with a history of CL surgery who develop considerable postoperative changes that may lead to diagnostic confusion in imaging evaluation; increase the difficulty of future surgery, such as sinonasal surgery; and increase the incidence of future intraoperative complications. Case summary: A 67-year-old man with a surgical history of chronic sinusitis reported epiphora of the left eye for five years. Balloon dacryocystoplasty was attempted but failed. Endo-DCR (Endoscopic dacryocystorhinostomy) was indicated; however, preoperative CT (computed tomography) imaging and nasal endoscopic examination showed sinonasal anomalies and the loss of internal landmarks for localizing the lacrimal sac. Preoperative CT results indicated previous CL surgery. Endo-DCR was performed with the aid of nasal forceps and a 20-gauge vitreoretinal fiberoptic endoilluminator. A six-month follow-up revealed the complete resolution of symptoms and no signs of recurrence. Conclusions: Epiphora might be a delayed complication of the CL procedure. Before performing endo-DCR, ophthalmologists should be familiar with the sinonasal anatomy and carefully assess preoperative imaging to identify anatomical variations. Nasal forceps and transcanalicular illumination can assist in determining the precise location of the lacrimal sac during endo-DCR.

Comparison of antiplatelet antibody profiles between hepatitis C virus-associated immune thrombocytopenia and primary immune thrombocytopenia.

Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP) has been assumed to be one of secondary ITP and associated with antiplatelet antibodies. This study was to clarify the antibody profile in HCV-ITP compared with primary ITP. We enrolled 55 HCV-ITP, 30 primary ITP, 11 Helicobacter pylori-ITP, 21 HCV control, and 16 healthy volunteers. We reviewed their blood cell counts, autoimmune markers, and spleen size. We used enzyme-linked immunosorbent assay kit to detect the specific antibody to glycoproteins IIb/IIIa, Ia/IIa, Ib/IX, IV, and human leukocyte antigen (HLA) class I. Compared with primary ITP patients, HCV-ITP patients had an older age, lower white blood cell (WBC) count and fewer presented with severe thrombocytopenia. The rate of positive antibody detection was 63.6% for the HCV-ITP group higher than the rate of 40% for the primary ITP. In the HCV control, antiplatelet antibodies were detected in 38.1% patients and no one had more than two types of antibodies. The antiplatelet antibodies correlated to severer thrombocytopenia. An HLA class I antibody was associated with lower WBCs and larger spleen. In conclusion, HCV-ITP patients had a high rate of positive antiplatelet antibody. The antibodies were associated with not only lower platelets but also leukopenia and splenomegaly.

Real-world experience with Ropeginterferon-alpha 2b (Besremi) in Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND/PURPOSE: Ropeginterferon alpha-2b (Ropeg) is a novel pegylated interferon-alpha recently approved for the treatment of polycythemia vera (PV) in Europe. However, other than data from clinical trials, little is known about this agent in real world practice. METHODS: A compassionate use program employing Ropeg for treating patients with unmet medical need was initiated in Taiwan in 2017. Herein, we collected clinical data and assessed the safety as well as efficacy of Ropeg in nine patients treated in this program. RESULTS: Collectively, among evaluable patients, both the molecular response and complete blood count remission rates were 62.5%. Most therapy-related side effects were mild, and there was no treatment discontinuation attributable to intolerable adverse events. The agent also showed efficacy in symptom amelioration and spleen size reduction. Although no specific patterns of cytokine level alteration could be identified, significantly attenuated plasma levels of inflammation markers were observed in one particular patient who happened to have normalized spleen size and most remarkable reduction in JAK2 mutant allele burden, indicating all-around improvement in every aspect of this case. Furthermore, plasma hepcidin levels increased in two-thirds of PV patients, illustrating the potential of Ropeg to restore normal regulation of erythropoiesis. Using RNA sequencing on pre- and post-treatment samples from one patient, we demonstrated altered expression of genes participating in IFN response, inflammation, apoptosis, and cellular differentiation. CONCLUSION: Conclusively, observed signs of efficacy and safety in our real-world experience prove Ropeg as a promising option for the treatment of MPN.

Molecular heterogeneity unravelled by single-cell transcriptomics in patients with essential thrombocythaemia.

Significant phenotypic heterogeneity exists in patients with all subtypes of myeloproliferative neoplasms (MPN), including essential thrombocythaemia (ET). Single-cell RNA sequencing (scRNA-Seq) holds the promise of unravelling the biology of MPN at an unprecedented level of resolution. Herein we employed this approach to dissect the transcriptomes in the CD34+ cells from the peripheral blood of seven previously untreated ET patients and one healthy adult. The mutational profiles in these patients were as follows: JAK2 V617F in two, CALR in three (one type I and two type II) and triple-negative (TN) in two. Our results reveal substantial heterogeneity within this enrolled cohort of patients. Activation of JAK/STAT signalling was recognized in discrepant progenitor lineages among different samples. Significantly disparate molecular profiling was identified in the comparison between ET patients and the control, between patients with different driver mutations (JAK2 V617F and CALR exon 9 indel), and even between patients harbouring the same driver. Intra-individual clonal diversity was also found in the CD34+ progenitor population of a patient, possibly indicating the presence of multiple clones in this case. Estimation of subpopulation size based on cellular immunophenotyping suggested differentiation bias in all analysed samples. Furthermore, combining the transcriptomic information with data from targeted sequencing enabled us to unravel key somatic mutations that are molecularly relevant. To conclude, we demonstrated that scRNA-Seq extended our knowledge of clonal diversity and inter-individual heterogeneity in patients with ET. The obtained information could potentially leapfrog our efforts in the elucidation of the pathogenesis of the disease.

Correction to: Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy.

[This corrects the article DOI: 10.1186/s12935-020-01401-w.].

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy.

BACKGROUND: The mechanisms of neuronal protein γ-synuclein (SNCG) in the malignancy of oral squamous cell carcinoma (OSCC) are not clear. This study tested the hypothesis that SNCG is involved in nicotine-induced malignant behaviors of OSCC. The effect of nicotine on SNCG expression and epithelial-to-mesenchymal transition (EMT) markers were examined. METHODS: Short hairpin RNA (shRNA) and an antagonist specific for α7-nicotine acetylcholine receptors (α7-nAChRs) were used to examine the role of α7-nAChRs in mediating the effects of nicotine. Knockdown of SNCG in nicotine-treated cells was performed to investigate the role of SNCG in cancer malignancy. The in vivo effect of nicotine was examined using a nude mouse xenotransplantation model. RESULTS: Nicotine increased SNCG expression in a time- and dose-dependent manner. Nicotine treatment also increased E-cadherin and ZO-1 and decreased fibronectin and vimentin expression. After specific knockdown of α7-nAChRs and inhibition of the PI3/AKT signal, the effect of nicotine on SNCG expression was attenuated. Silencing of SNCG abolished nicotine-induced invasion and migration of OSCC cells. The xenotransplantation model revealed that nicotine augmented tumor growth and SNCG expression. CONCLUSION: Nicotine upregulated SNCG expression by activating the α7-nAChRs/PI3/AKT signaling that are participated in nicotine-induced oral cancer malignancy.

Systematic review and network meta-analysis: Comparative effectiveness of therapies for second-line Helicobacter pylori eradication.

BACKGROUND AND AIM: The eradication rate of Helicobacter pylori (H. pylori) has been declining over the past decades. A rescue plan is needed for increasing populations with treatment failure. However, the optimum second-line eradication regimen remains inconclusive. We conducted a network meta-analysis to assess the comparative effectiveness of second-line H. pylori eradication therapies and determine the optimum regimen. METHODS: We searched electronic databases from January 2005 to February 2018 for randomized controlled trials assessing the effectiveness of second-line regimens in patients with persistent H. pylori infection after first-line treatment. Bayesian network meta-analysis was performed to combine the direct and indirect evidence and to investigate the rank order of second-line therapies. We also appraised the quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation guidance. RESULTS: Twenty-six trials with 3628 participants who received second-line eradication therapy were identified. All regimens showed pooled eradication rates < 90%. Compared with 7-day triple therapy, quinolone-based (odds ratio [OR] 4.29, 95% credible interval [CrI] 1.67-12.12, surface under the cumulative ranking [SUCRA] 0.95), non-quinolone-based bismuth-containing quadruple therapies for 10 days or more (OR 2.25, 95% CrI 1.10-4.62, SUCRA 0.78), and sequential therapy (OR 2.91, 95% CrI 1.16-7.65, SUCRA 0.66) showed significantly higher effectiveness. Overall, regimens with longer duration demonstrated higher eradication rates but higher rates of adverse events. More adverse events were reported in those patients treated with concomitant therapy. CONCLUSIONS: Quinolone-based bismuth-containing quadruple therapies for 10 days or more are the optimum second-line regimens for H. pylori eradication.

Cyclosporine for the treatment of lupus nephritis in patients with systemic lupus erythematosus.

AIMS: This study aimed to assess retrospectively the efficacy and safety of cyclosporin A (CsA) therapy in patients with lupus nephritis (LN). MATERIALS AND METHODS: From September 2005 to August 2015, eligible patients with LN undergoing CsA treatment were enrolled in the study. Medical charts as well as clinical and laboratory data were retrospectively reviewed. The data were evaluated at 0, 1, 6, 12 month(s) after the start of CsA. Serum creatinine (SCr), estimated glomerular filtration rate (eGFR), urine protein/creatinine ratio (uPCR), complement components C3, C4, and anti-double stranded DNA antibody (anti-dsDNA) titers were recorded. Renal response to CsA (complete response (CR) and partial response (PR)) and relapse after stopping CsA were set as primary endpoint, and adverse events, progression to end-stage renal disease (ESRD), and all-cause mortality as secondary endpoint. RESULTS: Among 60 patients enrolled, 11.7%, 20%, 25% achieved CR and 65.0%, 51.7%, 40% achieved PR at 1, 6, and 12 months, respectively. The SCr and eGFR remained stable during follow-up. After 1 year, CsA led to a decrease in median uPCR (3.79 to 0.51, p < 0.001) and anti-dsDNA (10.1 to 5.7 IU/mL, p = 0.011), an increase in mean C3 (75.9 to 88.5 mg/dL, p < 0.001) and C4 (15.9 to 19.5 mg/dL, p < 0.001) as well as a decrease in glucocorticoid dose. There were no deaths or progression to ESRD originating from adverse events in our study. CONCLUSION: CsA is an effective and safe treatment for patients with LN. Further randomized controlled trials are needed.
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HIC1 and RassF1A Methylation Attenuates Tubulin Expression and Cell Stiffness in Cancer.

Cell stiffness is a potential biomarker for monitoring cellular transformation, metastasis, and drug resistance development. Environmental factors relayed into the cell may result in formation of inheritable markers (e.g., DNA methylation), which provide selectable advantages (e.g., tumor development-favoring changes in cell stiffness). We previously demonstrated that targeted methylation of two tumor suppressor genes, hypermethylated in cancer 1 (HIC1) and Ras-association domain family member 1A (RassF1A), transformed mesenchymal stem cells (MSCs). Here, transformation-associated cytoskeleton and cell stiffness changes were evaluated. Atomic force microscopy (AFM) was used to detect cell stiffness, and immunostaining was used to measure cytoskeleton expression and distribution in cultured cells as well as in vivo. HIC1 and RassF1A methylation (me_HR)-transformed MSCs developed into tumors that clonally expanded in vivo. In me_HR-transformed MSCs, cell stiffness was lost, tubulin expression decreased, and F-actin was disorganized; DNA methylation inhibitor treatment suppressed their tumor progression, but did not fully restore their F-actin organization and stiffness. Thus, me_HR-induced cell transformation was accompanied by the loss of cellular stiffness, suggesting that somatic epigenetic changes provide inheritable selection markers during tumor propagation, but inhibition of oncogenic aberrant DNA methylation cannot restore cellular stiffness fully. Therefore, cell stiffness is a candidate biomarker for cells' physiological status.