Safety of TNF-α inhibitors: A real-world study based on the US FDA Adverse Event Reporting System Database.

As a common treatment for rheumatoid arthritis (RA), the adverse reactions of TNF-α inhibitors (TNFis) in practical application have garnered attention. This study aims to investigate the adverse drug events (ADEs) associated with TNFi in RA patients as reported in the FDA Adverse Event Reporting System, to offer insights for clinical use. Cases related to RA and primarily involving TNFi were extracted from the FDA Adverse Event Reporting System database and compared by gender stratification. Screening was conducted based on reporting odds ratio and information component to identify positive ADEs for different TNFis and evaluate common and unique ADEs among various TNFis. There are 4 common ADEs among TNFis, including pulmonary tuberculosis, infection, hypersensitivity, and herpes zoster, as described in the package inserts. However, each TNFi has unique positive ADEs. Adalimumab has 63 unique positive ADEs, including lower respiratory tract inflammation, systemic lupus erythematosus rash, vascular dementia, ovarian neoplasm, adhesion, sarcoma, coccidioidomycosis, etc. Golimumab has 6 unique positive ADEs, including pneumonia cryptococcal, device deployment issue, pneumonia bacterial, polyneuropathy, device malfunction, device issue, etc; certolizumab has 24 unique positive ADEs, including maternal exposure before pregnancy, premature rupture of membranes, exposure via breast milk, staphylococcal sepsis, erysipelas, low birth weight baby, herpes virus infection, premature delivery, etc; etanercept has 180 unique positive ADEs, including joint destruction, chondrolysis, finger deformity, ankle deformity, joint warmth, etc; infliximab has 60 unique positive ADEs, including Hodgkin's disease, metastatic neoplasm, non-Hodgkin's Lymphoma, etc. Although the aforementioned 5 TNFis share common ADEs such as herpes zoster, clinicians must exercise caution when selecting specific medications, especially for RA patients concurrently suffering from malignancies. The analysis indicates that infliximab is associated with 60 unique positive ADEs, including Hodgkin's disease, metastatic neoplasm, and non-Hodgkin's lymphoma; therefore, these patients should use infliximab with greater caution. Similarly, certolizumab should be used with increased caution in pregnant and postpartum women.

Efficacy and safety of acupuncture for painful diabetic neuropathy: a systematic review and meta-analysis.

Background: Painful diabetic neuropathy (PDN) is a common chronic neurological complication of diabetes mellitus. Medications are often used to relieve pain, but with significant side effects. Acupuncture is now a component of pragmatic and integrative treatment for PDN. An increasing number of relevant randomized controlled trials have been published in recent years, but a comprehensive meta-analysis has not yet been performed. The aim of this paper is to verify the effectiveness and safety of acupuncture for PDN by meta-analysis and trial sequential analysis (TSA). Methods: All participants in this study should have had a PDN diagnosis and the trial group was treated with acupuncture. Eight databases, including EMbase, PubMed, Web of science, Cochrane Library, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to 5 April 2023. Meta-analysis was conducted utilizing RevMan 5.3 and Stata 15.0. TSA was performed to assess the adequacy of sample size for the outcomes. Results: A total of 36 studies, comprising 2,739 PDN patients, were included. Among them, 1,393 patients were assigned to the trial group and 1,346 patients were treated in the control group. Outcomes covers the primary indicator Total effective rate (RR = 1.42, 95%CI [1.34, 1.52], p < 0.00001), with 21 studies reported, Pain intensity (SMD = -1.27, 95%CI [-1.58, -0.95], p < 0.00001), with 23 studies reported, and other outcomes, including motor nerve conduction velocity (MCV; MD = 3.58, 95%CI [2.77, 4.38], p < 0.00001), sensory nerve conduction velocity (SCV; MD = 3.62, 95%CI [2.75, 4.49], p < 0.00001), Depression score (SMD = -1.02, 95%CI [1.58, 0.46]), Toronto clinical scoring system (TCSS; MD = -2.41, 95%CI [-3.37, -1.45], p < 0.00001), Quality of life (SMD = 1.06, 95%CI [0.66, 1.46]), traditional Chinese medicine (TCM) syndrome score (MD = -4.99, 95%CI [-6.79, -3.18], p < 0.00001), suggesting that acupuncture have an ameliorating effect on PDN in various respect. Egger's test revealed publication bias for four outcomes. TSA showed that as for Total effective rate, Pain Intensity, MCV and SCV, the number of included studies was sufficient to support the conclusions. Conclusion: Acupuncture demonstrates significant effectiveness in improving PDN outcomes, including Total effective rate, Pain intensity, MCV, SCV, Depression score, TCSS, Quality of life, TCM syndrome score. But the Adverse events rate is no different in trail group and control group. The publication bias presented in Total effective rate, Pain intensity, MCV and SCV can be remedied by Trim and filling method. Systematic review registration: Prospero, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=477295.

Adverse tumor events induced by ranitidine: an analysis based on the FAERS database.

BACKGROUND: Ranitidine induced tumor adverse events remains a contradictory clinical question, due to the limited evidence of tumor risk associated with ranitidine in the real world. The purpose of this study was to evaluate the association of ranitidine with all types of tumors through the FAERS database and to provide a reference for clinical use. RESEARCH DESIGN AND METHODS: Cancer cases associated with ranitidine in the FAERS database from the first quarter of 2004 to the fourth quarter of 2023 were extracted to analyze demographic characteristics, and a disproportion analysis was performed. RESULT: A total of 662,998 ranitidine-related cancer cases were screened, and the 50-59 and 60-69 groups accounted for the largest proportion. In PT signal detection, ranitidine was associated with 98 PT, including penal cancer stage II, gastric cancer stage II, et al. In terms of outcome events, adverse events were higher in men (20.65%) than in women (18.47%). CONCLUSIONS: Ranitidine may induce various tumor-related adverse reactions, especially in long-term users and elderly patients. For these patients, tumor screening should be strengthened, and long-term use of ranitidine should be avoided. Since this study cannot prove causality, further evidence is needed for prospective studies with a larger sample size.

Exploring the evolutionary mechanism of hepatitis B and gastric cancer based on Mendelian randomization combined with bioinformatics analysis.

Chronic hepatitis B virus infection (HBV) infection appears to be associated with extrahepatic cancers. This study aims to evaluate the causality and evolutionary mechanism of chronic HBV infection and gastric cancer through Mendelian randomization (MR) analysis and bioinformatics analysis. We conducted 2-sample MR to investigate the causal relationship between chronic HBV infection and gastric cancer. We identified 5 independent genetic variants closely associated with exposure (chronic HBV infection) as instrumental variables in a sample of 1371 cases and 2938 controls of East Asian descent in Korea. The genome wide association study (GWAS) data for the outcome variable came from the Japanese Biobank. Bioinformatics analysis was used to explore the evolutionary mechanism of chronic HBV infection and gastric cancer. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify key targets that are commonly associated with both diseases, and their biological functions were investigated. Multiple machine-learning models were employed to select hub genes. The MR analysis showed a positive causal relationship between chronic HBV infection and gastric cancer (IVW: OR = 1.165, 95% CI = 1.085-1.250, P < .001), and the result was robust in sensitivity analysis. According to the bioinformatics analysis, the 5 key targets were mainly enriched in Toll-like receptor signaling and PI3K-Akt signaling. Two hub genes, CXCL9 and COL6A2, were identified, and a high-performing predictive model was constructed. Chronic HBV infection is positively associated with gastric cancer, and the evolutionary mechanism may be related to Toll-like receptor signaling. Prospective studies are still needed to confirm these findings.

Stable Flexible Electronic Devices under Harsh Conditions Enabled by Double-Network Hydrogels Containing Binary Cations.

Hydrogels are increasingly used in flexible electronic devices, but the mechanical and electrochemical stabilities of hydrogel devices are often limited under specific harsh conditions. Herein, chemically/physically cross-linked double-network (DN) hydrogels containing binary cations Zn2+ and Li+ are constructed in order to address the above challenges. Double networks of chemically cross-linked polyacrylamide (PAM) and physically cross-linked κ-Carrageenan (κ-CG) are designed to account for the mechanical robustness while binary cations endow the hydrogels with excellent ionic conductivity and outstanding environmental adaptability. Excellent mechanical robustness and ionic conductivity (25 °C, 2.26 S·m-1; -25 °C, 1.54 S·m-1) have been achieved. Utilizing the DN hydrogels containing binary cations as signal-converting materials, we fabricated flexible mechanosensors. High gauge factors (resistive strain sensors, 2.4; capacitive pressure sensors, 0.82 kPa-1) and highly stable sensing ability have been achieved. Interestingly, zinc-ion hybrid supercapacitors containing the DN hydrogels containing binary cations as electrolytes have achieved an initial capacity of 52.5 mAh·g-1 at a current density of 3 A·g-1 and a capacity retention rate of 82.9% after 19,000 cycles. Proper working of the zinc-ion hybrid supercapacitors at subzero conditions and stable charge-discharge for more than 19,000 cycles at -25 °C have been demonstrated. Overall, DN hydrogels containing binary cations have provided promising materials for high-performance flexible electronic devices under harsh conditions.

Mammalian target of rapamycin inhibitor rapamycin enhances anti-leukemia effect of imatinib on Ph+ acute lymphoblastic leukemia cells.

BCR-ABL fusion gene typically causes a type of acute lymphoblastic leukemia (ALL), known as Ph+ ALL. Although imatinib (IM) treatment induced high rates of complete response (CR), serious acute and late complications are frequent, whereas more vexatiously resistance to chemotherapy and clinical relapse develops. Therefore, the efficacy of treatment in Ph+ ALL is still to be determined. In this study, we focused our attention on the potential benefit of rapamycin (RAPA), an mammalian target of rapamycin (mTOR) inhibitor, in combination with IM on a Ph+ ALL cell line SUP-B15 and a primary Ph+ ALL sample in vitro. Analysis of cell proliferation showed that RAPA (50 nm) plus IM exerted good synergistic effect on Ph+ ALL cells. Notably, we found that IM treatment induced the abnormal activation of the components of mTOR signaling pathway and p-BCR-ABL, whereas RAPA potently eliminated this deleterious side effect induced by IM and might overcome the resistance to IM. The synergistic effect was also associated with the increase in autophagy, which seemed to have an opposite role with apoptosis in Ph+ ALL cells, and cell cycle arrest in G1 phase. Altogether, our results suggested that IM in combination with RAPA was more effective for Ph+ ALL cells than IM alone.

[Effects of bortezomib combined with daunorubicin on proliferation and apoptosis in primary adult acute leukemia].

OBJECTIVE: To assess effects of proteasome inhibitor Bortezomib (Bor) in combination with Daunorubicin (DNR) on proliferation, apoptosis and the expression of Bcl-2 mRNA in primary leukemia cells in vitro. METHODS: Primary leukemia cells were isolated from bone marrow of adult acute leukemia patients using Ficoll liquid, then the primary leukemia cells were treated with different concentration of these two drugs (Bor 5, 10, 20, 50 nmol/L, DNR 50, 100, 200, 500 nmol/L, and Bor 5, 10 nmol/L combined with DNR 50, 100, 200, 500 nmol/L respectively ). Cells proliferation, IC50 and CDI were analyzed by MTT assay, cellular apoptosis was observed by flow cytometry, Bcl-2 mRNA was analyzed by RT-PCR. RESULTS: Growth inhibition ratio of all the types of acute leukemia cells were increased with the treatment of DNR and Bor in dose-dependent manner. Combined with Bor (5, 10 nmol/L),the IC50 of DNR decreased from (102 +/- 27) nmol/L to (73 +/- 26), (55 +/- 22) nmol/L respectively. DNR 200 nmol/L combined with Bor 10 nmol/L showed a better synergism (CDI = 0. 17). Compared with control group and single drug (DNR or Bor) group, there were obvious increase of apoptosis ratio and obvious decrease of Bcl-2 in the group of DNR 100 nmol/L combined with Bor 20 nmol/L after 24 h or 48 h cultivation (P < 0.05). CONCLUSION: Bor combined with DNR shows synergetic effect in promoting the apoptosis of adult acute leukemia primary cells as well as inhibitory effect on the proliferation of leukemia cells.

[The anti-leukemic effects of imatinib, daunorubicin and bortezomib on two leukemia cell lines with Ph(+)].

OBJECTIVE: To study the proliferative inhibition effects of imatinib, daunorubicin and bortezomib on two leukemia cell lines with Ph(+), chronic myelogenous leukemia cell line K562 expressing P210 protein and acute lymphoblastic leukemia cell line SUP-B15 expressing P190 protein. METHODS: (1) The cells of the two cell lines treated with imatinib, daunorubicin and bortezomib for 72 hours were analyzed by MTT assay for proliferation. The proliferative activity was displayed by growth curve and IC50 value. (2) The bcr-abl transcriptant in the cells treated with imatinib (final concentration at 0, 0.35, 1 micromol/L) for 48 hours was detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: (1) The IC50 values of K562 and SUP-B15 cell lines treated with imatinib, daunorubicin and bortezomib for 72 hours were respectively (0.286 +/- 0.060) micromol/L, (0.303 +/- 0.009) micromol/L, (22.127 +/- 3.592) nmol/L and (1.387 +/- 0.180) micromol/L, (0.117 +/- 0.017) micromol/L, (12.350 +/- 0.740) nmol/L. (2) There was no change of bcr-abl expression level in both cell lines after the treatment of imatinib. CONCLUSION: Imatinib, daunorubicin and bortezomib showed anti-cancer effects on Ph(+) leukemia cells in vitro. K562 cells were more sensitive to imatinib than the other two drugs, whereas SUP-B15 cells are more sensitive to daunorubicin and bortezomib. The short time intervention of imatinib has no effect on the expression of bcr-abl in Ph (+) leukemia cell lines.

Lentivirus-mediated RNA interference reversing the drug-resistance in MDR1 single-factor resistant cell line K562/MDR1.

Multidrug-resistance (MDR) is a major hindrance to successful chemotherapy. The emergence of MDR is multi-factorial. Among them, the MDR1 gene/P-glycoprotein (P-gp) is a popular and important reason. In our study, an MDR1 single-factorial drug-resistant leukemia cell line K562/MDR1 was constructed via transferring full-length human MDR1 cDNA into drug-sensitive K562 cells. The short-hairpin RNA (shRNA) targeting MDR1 gene was transfected into K562/MDR1 cell lines by the replication-defective lentiviral vector derived from HIV-1. The efficiency of RNA interference (RNAi) to silence the MDR1 gene and reverse multidrug-resistance in the MDR1 single-factor drug-resistance cell line K562/MDR1 was evaluated. The multi-factor resistant cell line K562/A02, induced by doxorubicin exposure, was used as a control. After RNA interference, the expression of the MDR1 gene and P-gp in K562/MDR1 was markedly down-regulated and the drug sensitivity was restored as IC(50) values became similar to the K562 sensitive cell line. The expression of the MDR1 gene and P-gp in K562/A02 was markedly down-regulated too, and drug-resistance to anticancer drug is reduced to some extent but the IC(50) was significantly higher than that of the sensitive cell line. These results demonstrated that lentivirus-mediated RNAi could efficiently down-regulate the expression of MDR1 and Pgp, and successfully reverse a cell's resistance to chemotherapeutic. Due to only MDR1 resistance, the K562/MDR1 cell showed much high specificity and thus is a better cell model for MDR1/P-gp research.