Combination Therapy Group Research Articles

Short-term efficacy and safety of endoscopic injection of low dose of sclerotherapy and cyanoacrylate injection for type GOV1 gastric varices combined with endoscopic variceal ligation for esophageal varices.

To explore the short-term efficacy and safety of endoscopic low dose injection of sclerotherapy and cyanoacrylate for gastric varices (GVs) combined with endoscopic variceal ligation (EVL) for esophageal varices (EVs) in cirrhosis with type GOV1 varices. A total of 521 patients with cirrhosis and GOV1 varices, who were divided into emergence endoscopy treatment layer and secondary prophylaxis for rebleeding layer, were selected. All patients underwent combined therapy or EVL alone (ligation therapy) for the treatment of type GOV1 varices. The baseline between the two groups with significant differences were used as covariates for 1:1 propensity score matching. The early rebleeding rate was compared and the risk factors for rebleeding were identified in each layer. After propensity score matching, a total of 122 patients were included in the emergence endoscopy treatment layer, and 234 patients were included in the secondary prophylaxis layer. The early rebleeding rates in the combined therapy group vs. ligation therapy group was 4.92% vs. 16.39% (P = 0.04) and 2.56% vs. 1.71% (P = 0.65) in the emergency endoscopy layer and in the secondary prophylaxis layer, respectively. The median length of hospital stay after endoscopy was 8days vs. 9days (P = 0.004) and 7days vs. 6days (P = 0.47), in each layer respectively. There was no significant difference in the adverse reactions of endoscopic treatment. EVL treatment (OR: 3.84; 95% CI: 1.05-13.96; P = 0.04) and discontinuation of NSBB (non-selective beta-blocker) use after discharge (OR: 3.58; 95% CI: 1.20-10.67; P = 0.02) were independent risk factors for early rebleeding after endoscopy in the emergency endoscopy layer. Combined therapy is comparable with ligation therapy in the short-term efficacy and safety of in cirrhosis patients with secondary prophylaxis for rebleeding while it is superior to EVL alone in cirrhosis in the emergency endoscopy treatment as it could reduce the early rebleeding rate and shorten the length of hospital stay.

EXTH-04. COMBINATION OF BEVACIZUMAB ENHANCES THE ANTI-TUMOR EFFICACY OF AD-SGE-REIC FOR GLIOMA

Abstract Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor gene and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we revealed the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC) and conducted the phase Ⅰ/Ⅱ a clinical trial for recurrent malignant glioma (jRCT2063190013). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic efficacy in patients with glioma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab in vitro and in vivo. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In glioma-bearing mouse models, survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab showed anti-glioma effects by suppressing the angiogenesis and invasion of tumor cells. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.

EXTH-01. EFFICACY OF PERAMPANEL AGAINST GLIOBLASTOMA CELLS

Abstract We investigated the antitumor effect of perampanel, which is the AMPA-type glutamate receptor antagonist widely used as an antiepileptic drug in Japan, on glioblastoma cells both in vitro and vivo. Commercially available glioblastoma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13) and newly established glioblastoma cell line 0125-DGC were used in the experiments. First, the antitumor effect of perampanel was evaluated by cell counting assay. The number of surviving cells after administrating drugs (perampanel, carbamazepine, sodium valproate, levetiracetam, and temozolomide) was counted. The cell proliferation inhibitory effect was observed in all cell lines after administration of perampanel and temozolomide. The antitumor effect was greater when perampanel and temozolomide were used together than when they were used alone. Next, we investigated the mechanism of the antitumor effect of perampanel on glioblastoma cells using FACS, western blotting, RT-PCR, and transwell assay. The expression levels of apoptosis-related proteins and mRNAs on glioblastoma cells were increased after administration of perampanel. Furthermore, perampanel demonstrated the inhibitory effect on the migration of glioblastoma cells. Finally, we evaluated the antitumor effect of perampanel in vivo. U-87MG cells were transplanted into the brains of immunodeficient mice, and these mice were treated by perampanel and/or temozolomide. The transplanted mice were divided into an untreated control group, a perampanel treatment group, a temozolomide treatment group, and a combination treatment group. As a result, survival times were significantly prolonged in all treatment groups compared to the untreated control group. Notably, survival times in the combination therapy group was significantly longer than in the monotherapy group. These results revealed that perampanel exhibits antitumor effects on glioblastoma cells by inducing apoptosis and suppressing cell migration ability. Furthermore, perampanel may enhance the antitumor effect of temozolomide for glioblastoma when it used as combination therapy.

Variable Resistance Training Combined With Static Traction Computer Vision Applied in Neck and Shoulder Rehabilitation Training for College Students

This study evaluates the effectiveness of static traction combined with variable resistance training in rehabilitating college students with neck and shoulder diseases. Ninety students were randomly assigned to receive either static traction alone or combined therapy. Visual analogue scale (VAS), neck disability index (NDI), cervical range of motion, electromyography (EMG), and soft tissue parameters were assessed pre- and post-treatment. Both groups showed improved VAS and NDI scores post-treatment, with greater enhancements in the combined therapy group. Cervical range of motion, EMG values, and soft tissue parameters also favored the combined therapy. Statistical analysis revealed significant differences (P<0.05) between groups. Static traction combined with variable resistance training effectively improves neck and shoulder function, reduces pain, and enhances rehabilitation outcomes compared to static traction alone. This approach shows promise for optimizing rehabilitation in college students with similar musculoskeletal conditions.

Evaluation of the Efficacy and Safety of On-Demand Tadalafil Alone or Combined With Lidocaine Spray for Treating Patients With Comorbid Erectile Dysfunction and Premature Ejaculation: A Randomized Controlled Trial

Background To evaluate the efficacy and safety of on-demand 20 mg tadalafil alone or combined with lidocaine spray for treating patients with comorbid erectile dysfunction (ED) and premature ejaculation (PE). Methods This randomized controlled trial included 98 patients with comorbid ED and PE, randomly assigned to the experimental group (n = 50, tadalafil alone) or the active control group (n = 48, tadalafil combined with lidocaine spray). Patients took tadalafil 30 min before sexual intercourse, while the combination therapy group also used lidocaine spray 5 min before intercourse. After 12 weeks of treatment, changes in the International Index of Erectile Function (IIEF-5), Chinese Index of Premature Ejaculation (CIPE-5), Intravaginal Ejaculatory Latency Time (IELT), and Sexual Satisfaction Score (SSS) were evaluated. Results Both groups showed significant improvement in IIEF-5 scores, but the difference between groups was not significant (F = 0.89, p = 0.45). The active control group showed significant improvement in CIPE-5 scores (p < 0.001), while the experimental group showed no significant change (p > 0.05). IELT in the active control group increased significantly from 25.7 s to 198.6 s (Z = 6.03, p < 0.001), while the experimental group showed no significant change (Z = 0.74, p = 0.46). SSS improved significantly in the active control group (p < 0.001) but not in the experimental group (p > 0.05). The incidence of adverse events was similar in both groups (14% vs 20.8%, p = 0.575). Conclusion Tadalafil combined with lidocaine spray is superior to tadalafil alone in improving symptoms, prolonging IELT, and enhancing sexual satisfaction in patients with comorbid ED and PE, with comparable safety. This combination therapy provides a new approach for improving treatment strategies for patients with comorbid ED and PE. Large-scale, multi-center randomized controlled trials are needed to further validate these findings.

Proton beam irradiation with anti-VEGF therapy for polypoidal choroidal vasculopathy: results of a 24-month, phase II randomized study.

To determine the efficacy and safety of proton beam irradiation (PBI) and anti-vascular endothelial growth factor (anti-VEGF) therapy for polypoidal choroidal vasculopathy (PCV)/ aneurysmal type 1 macular neovascularization (AT1). The randomized clinical trial consisted of newly diagnosed active PCV/AT1 patients who were randomized 1:1 to treatment with three initial monthly intravitreal anti-VEGF agent (conbercept) injections with or without single 14 GyE radiation. Subsequent anti-VEGF therapy was given pro re nata. The primary outcome measures were number of anti-VEGF injections, best-corrected visual acuity (BCVA), and central retinal thickness (CRT) at 24months. Secondary outcome measures included the polypoidal lesion regression rate, changes in the areas of polypoidal lesions and branching vascular network (BVN), and radiotherapy-related adverse events at 24months. A total of 45 eyes (86.5%) completed the 24-month follow-up. At 24months, the combination therapy group required fewer anti-VEGF injections compared with the monotherapy group (5.9 ± 4.1 vs. 8.8 ± 5.3; P = 0.04). The mean gains in BCVA and the mean decrease in CRT were not significantly different between the two groups (P = 0.85 and P = 0.17, respectively). Combination therapy was superior to monotherapy for complete polypoidal lesion regression (80.0% vs. 48%, P = 0.03) and change in BVN area (- 1.03 ± 1.24 mm2 vs. 0.36 ± 0.77 mm2, P < 0.01). The radiation-related microvascular abnormalities were observed in 55.0% of eyes following combination therapy at 15.7 ± 2.5months. PBI (14 GyE) combined with anti-VEGF therapy could decrease the need for additional anti-VEGF injections for PCV/AT1. Longer follow-up is needed to fully evaluate the long-term safety of PBI. What is known The current main methods for treating PCV/AT1 include anti-VEGF drugs as monotherapy or in combination with photodynamic therapy. However, some cases can be challenging with multiple repeated injections due to the relatively low regression rate of polyps and high recurrence rate. What is new Proton beam irradiation therapy with anti-VEGF drugs can synergistically promote the regression of polyps and the shrinkage of branching vascular network, and reduce the anti-VEGF treatment burden for patients with PCV/AT1. Radiation retinopathy was mild and did not appear to be visually significant at the 24-month follow-up. Proton beam irradiation can be a new strategy for the treatment of PCV/AT1.

Combination Therapy Is Not Associated with Decreased Mortality in Infectious Endocarditis: A Systematic Review and Meta-Analysis

Untreated infective endocarditis (IE) is uniformly fatal. The practice of combination antibiotic therapy for IE is recommended by treatment guidelines but largely unsupported by high-quality evidence. This study aimed to assess the efficacy of combination antibiotic therapy compared to monotherapy in IE through a systematic review and meta-analysis. We systematically searched MEDLINE, Embase, Cochrane, Web of Science, and CINAHL from inception to 29 July 2024. Studies reporting mortality outcomes of combination therapy versus monotherapy in adult patients with IE were included. Non-English papers and studies with less than 10 patients in the combination therapy group were excluded. Two reviewers independently assessed the studies and extracted relevant data. Summaries of odds ratios (ORs) with 95% confidence intervals (CIs) were evaluated using random-effects models. Out of 4545 studies identified, 32 studies (involving 2761 patients) met the inclusion criteria for the meta-analysis. There was no significant difference in the risk of all-cause mortality between the monotherapy and combination therapy groups (OR = 0.90; 95% CI = 0.67–1.20). Similar results were observed in subgroup analyses based on mortality time points, bacterial species, publication date, and type of study. Studies conducted in Europe reported a statistically significant decrease in overall mortality risk with combination therapy (OR = 0.67; 95% CI = 0.51–0.89), though this result was driven entirely by a single outlier study. Combination antibiotic therapy in patients with IE was not associated with reduced mortality.

Accelerating Fracture Healing in Delayed Uniting Fractures: A Clinical Study

Background: Delayed union fractures pose a significant clinical challenge, often requiring enhanced treatment modalities to accelerate healing and improve patient outcomes. Various techniques, including autologous bone grafting and biologic agents like platelet-rich plasma (PRP) and bone morphogenetic proteins (BMPs), have been employed to stimulate bone regeneration. However, the optimal approach remains debated. Objective: This study aimed to compare the efficacy of autologous bone grafting, biologic agents, and combined therapies in promoting fracture healing, reducing pain, improving functional outcomes, and enhancing patient satisfaction in delayed union fractures. Methods: A prospective study was conducted on 80 patients with delayed union fractures. Patients were randomly assigned to one of four groups: standard care (control), autologous bone grafting, biologic agents (PRP and BMPs), or a combination of bone grafting and biologic agents. Radiographic healing was assessed at 6, 12, and 24 weeks. Pain intensity was measured using the Visual Analog Scale (VAS), functional outcomes were assessed using the AAOS lower limb function scale, and patient satisfaction was evaluated using a Likert scale. Results: The combined therapy group exhibited significantly faster radiographic healing, with 80% of patients showing callus formation at 6 weeks and 95% achieving complete union at 24 weeks, compared to 35% in the control group. The combined group also reported the greatest reduction in VAS pain scores, with a mean decrease from 7.8 to 1.5 at 24 weeks (p&lt;0.001). Functional outcomes were significantly improved in the combined group, with a mean AAOS score of 100 at 24 weeks, compared to 70 in the control group (p&lt;0.001). Additionally, 90% of patients in the combined group reported high satisfaction, compared to 40% in the control group. Conclusion: The combination of autologous bone grafting and biologic agents, such as PRP and BMPs, significantly accelerates ..........

Novel [18F]FPG-interleukin-2 conjugate for monitoring immune checkpoint therapy with positron emission tomography

18F-interleukin-2 based PET imaging of activated T cells serves as a potential tool for non-invasive response prediction, treatment evaluation, and patient stratification in cancer immune checkpoint therapy. Herein, we report the radiolabelling of interleukin-2 (IL-2) with a novel arginine selective bioconjugation reagent, 4-[18F]fluorophenylglyoxal ([18F]FPG). Good non-decay corrected bioconjugation efficiencies of 29 ± 4 % (n = 5) were obtained for the [18F]FPG-IL-2. [18F]FPG-IL-2 uptake by the phytohemagglutinin-activated Jurkat cells (50.5 ± 1.2 %, n = 3) was significantly higher compared to the non-activated Jurkat cells (12.9 ± 1.1 %, n = 3). The [18F]FPG-IL-2 uptake was blocked by the pre-treatment of activated Jurkat cells with excess native IL-2 (22.3 ± 2.2 %, n = 3). Dynamic PET imaging and ex vivo biodistribution study of [18F]FPG-IL-2 in healthy and CT26 tumour bearing mice demonstrated hepatobiliary and renal clearance with minimal uptake in other organs and CT26 tumours. [18F]FPG-IL-2 PET imaging was applied to non-invasively monitor immune checkpoint therapy in CT26 tumour bearing mice, treated with IgG (control), ⍺PD-1 (monotherapy), and ⍺PD-1+⍺CTLA-4 (combination therapy). Significant uptake was observed in the spleens and tumours of the mice in the combination therapy group, which was associated with increased cytotoxic CD8+ T-cell infiltration and reduced tumour volumes. [18F]FPG-IL-2 based PET imaging has the potential to monitor immune checkpoint therapy.

Synergistic effects of human umbilical cord mesenchymal stem cells/neural stem cells and epidural electrical stimulation on spinal cord injury rehabilitation

Spinal cord injury (SCI) is a severe neurological condition marked by a complex pathology leading to irreversible functional loss, which current treatments fail to improve. Epidural electrical stimulation (EES) shows promise in alleviating pathological pain, regulating hemodynamic disturbances, and enhancing motor function by modulating residual interneurons in the lower spinal cord. Cell transplantation (CT), especially using human umbilical cord mesenchymal stem cells (hUCMSCs) and neural stem cells (NSCs), has significantly improved sensory and motor recovery in SCI. However, the limitations of single treatments have driven the exploration of a multifaceted strategy, combining various modalities to optimize recovery at different stages. To comprehensively investigate the effectiveness of in situ transplantation of hUCMSCs/NSCs combined with subacute epidural electrical stimulation in a murine spinal cord crush injury model, providing valuable references for future animal studies and clinical research. In this study, we first examined neural stem cell changes via mRNA sequencing in an in vitro Transwell co-culture model. We then explored cell interaction mechanisms using proliferation assays, differentiation assays, and neuron complexity analysis. For animal experiments, 40 C57BL/6 mice were assigned to four groups (Injury/EES/CT/Combination). Histological evaluations employed HE and immunofluorescence staining, while electrophysiological and behavioral tests assessed motor recovery. Quantitative data were reported as mean ± standard error, with statistical analyses performed using GraphPad Prism and SPSS. Initially, we found that NSCs in the in vitro co-culture model showed a unique expression profile of differentially expressed genes (DEGs) compared to controls. GO/KEGG analysis indicated these DEGs were mainly linked to cell differentiation and growth factor secretion pathways. Neuronal and astrocytic markers further confirmed enhanced NSC differentiation and neuronal maturation in the co-culture model. In vivo, live imaging and human nuclei immunofluorescence staining revealed that transplanted cells persisted for some time post-transplantation. Histological analysis showed that during acute inflammation, both the stem cell and combined therapy groups significantly inhibited microglial polarization. In the chronic phase, these groups reduced fibrotic scar formation and encouraged astrocytic bridging. Behavioral tests, including swimming and gait analysis, demonstrated that combined CT and EES therapy was more effective than either treatment alone. In summary, the combined therapy offers a promising approach for spinal cord injury treatment, providing superior outcomes over individual treatments. Our findings underscore the potential of a combined treatment approach utilizing stem cells transplantation and EES as an effective strategy for the comprehensive management of spinal cord crush injury in mice. This integrated approach holds promise for enhancing functional recovery and improving the quality of life for individuals with spinal cord injury (SCI).

An Axially CBD‐Containing Novel Pt(IV) Prodrug Designed to Synergistically Enhance Antitumor Activity by Inducing Mitochondrial Dysfunction

ABSTRACTIn recent years, significant attention has been given to the strategy of linking novel active molecules with different biological targets and antitumor mechanisms to the axial positions of Pt(IV) complexes, aiming to synthesize new Pt(IV) antitumor complexes with excellent properties. In this study, Satraplatin analogs and the highly lipophilic bioactive molecule cannabidiol (CBD) were chosen as the main research subjects. By combining these two and introducing other bioactive small molecules, we aimed to enrich the functionalities of Pt(IV) antitumor complexes. Five new multifunctional Pt(IV) antitumor complexes, P1–P5, were prepared. All Pt(IV) prodrugs demonstrated antitumor effects in various tumor cell lines. Notably, compound P1 exhibited significant inhibitory effects, with half‐maximal inhibitory concentration (IC50) values that were 2.1, 1.5, and 1.3 times higher than those of satraplatin in HCT‐116, A549, and HeLa cell lines, respectively, and 2.4, 1.5, and 2.0 times higher than those of the combination of satraplatin and CBD. The cytotoxicity of P1 toward cancer cell lines is significantly higher than that of the combination therapy group, providing preliminary evidence that the strategy of combining CBD and platinum‐based antitumor drugs into a complex is highly effective in simultaneously enhancing the cytotoxicity of both, resulting in a good synergistic antitumor effect. Further research shows that after treating cells with P1, the induced ROS generation increases in a dose‐dependent manner, disrupting the cell's redox homeostasis, leading to oxidative stress, and ultimately causing cell apoptosis. This strategy of introducing the bioactive molecule CBD into platinum‐based drug formation complexes to improve efficacy has been shown to be feasible and deserves further study.

Combination of moderate-intensity statins and ezetimibe versus high-intensity statins alone for primary prevention of cardiovascular events

Abstract Background Combination of a moderate-intensity statin with ezetimibe can lead to similar reductions in cardiovascular events as monotherapy with a high-intensity statin in patients with established atherosclerotic cardiovascular disease (ASCVD). The comparative effectiveness of these two cholesterol-lowering strategies in the primary prevention setting is unknown. Purpose To compare incident ASCVD events associated with a combination of moderate-intensity statin and ezetimibe versus monotherapy with a high-intensity statin in adults without prior history of cardiovascular disease. Methods We conducted a new-user active comparator retrospective population-based cohort study in Canada. We included all adults aged ≥ 67 years (eligible for drug coverage) with a first prescription of either a combination of moderate-intensity statin with ezetimibe ("combination therapy") or high-intensity statin alone between January 2010 and December 2022. Patients were excluded if they had not received any prior lipid lowering therapies or had a history of myocardial infarction (MI), stroke, heart failure, peripheral vascular disease or prior coronary revascularisation at any time before or within 3 months of treatment initiation. The primary outcome was a composite of all-cause death, hospitalization for MI or stroke, or coronary revascularization. An inverse probability of treatment weighting propensity score was used to account for confounding (demographics, comorbidities, laboratory tests, other medications). Results Among 67,884 patients (mean age: 74.0±5.5y; 53% females), 8,798 (13%) initiated combination therapy and 59,086 (87%) initiated a high-intensity statin. At 1 year, after weighting, the mean achieved LDL-C was ~1.9 mmol/L in both groups. The median follow-up was 6.5 years. The cumulative incidence of the primary outcome at 10 years in the weighted cohort was 32.7% in the combination therapy group and 36.1% in the high-intensity statin group (HR: 0.87; 95% CI: 0.82 to 0.92; p&amp;lt;0.001; absolute risk reduction: 3.5%; 95% CI: 0.8 to 6.1; Figure 1). This result was primarily driven by a lower risk of all-cause death (HR: 0.85; 95% CI: 0.80 to 0.91; p&amp;lt;0.001; Figure 2) and stroke (cause-specific [cs] HR: 0.86; 95% CI 0.74 to 0.99; p=0.04), whereas no differences were observed in the risk of MI (csHR: 0.97; 95% CI: 0.82 to 1.15) or coronary revascularization (csHR: 0.97; 95% CI 0.85 to 1.11). Conclusion The combination of moderate-intensity statins with ezetimibe was associated with a lower risk of incident ASCVD compared with high-intensity statins alone among primary prevention patients in a real-world setting. These results were driven by a lower risk of all-cause death and stroke, but not coronary events. The influence of statin intolerance on the allocated strategy and adherence to therapy cannot be addressed in this analysis, which, along with verifying these estimates, may be best determined in a prospective randomized trial.

Bleeding and Thrombotic Events in Hemodialysis Patients with Atrial Fibrillation on Anticoagulation and Antiplatelet Therapy: A 24-Month Cohort Study

Background and Objectives: Patients undergoing chronic hemodialysis (HD) are predisposed to both thrombotic and bleeding complications due to the complex interplay of end-stage renal disease (ESRD), cardiovascular comorbidities, and the routine use of anticoagulant and antiplatelet therapies. This study aimed to investigate the incidence of bleeding and thrombotic events in chronic HD patients receiving anticoagulant and antiplatelet therapy, with a specific focus on those with atrial fibrillation (AF). Materials and Methods: A total of 224 patients, with 43 (19%) of them diagnosed with AF, were included in this single-center, observational cohort study conducted over 24 months. The cohort was divided into three groups: patients without anticoagulation, those on warfarin monotherapy, and those on combined warfarin and aspirin therapy. Bleeding events were classified as major, clinically relevant non-major bleeding (CRNMB), or minor bleeding, while thrombotic events included ischemic stroke, myocardial infarction, pulmonary embolism, and arteriovenous fistula thrombosis. Results: Overall, 35.7% of patients experienced a bleeding event, with major bleeding occurring in 9.4%. Patients with AF had significantly higher rates of major bleeding (18.6%) compared to those without AF (7.18%; p = 0.043), especially in the combined therapy group. Mortality due to bleeding was also higher in AF patients (14%). In contrast, thrombotic events occurred in 26.8% of patients, with AF patients experiencing significantly more events (48.8%) compared to non-AF patients (21.5%; p = 0.0006). The hazard ratio (HR) for major bleeding in patients on combined warfarin and aspirin therapy was 2.56 (p = 0.016), while the HR for thrombotic events was 2.34 (p = 0.0202). Conclusions: These findings highlight the increased risks of both bleeding and thrombosis in chronic HD patients with AF, particularly those on combined anticoagulation and antiplatelet therapy.

Dutasteride, a 5 alpha reductase inhibitor, could be associated with the exacerbation of inflammation in patients with benign prostatic hyperplasia.

α-1 blockers and dutasteride are widely used as agents to treat benign prostatic hyperplasia (BPH); the impact of these drugs on prostatic inflammation is still unclear. Herein, we investigated the impact of α-1 blockers and dutasteride treatment of BPH in terms of the degree of prostatic inflammation. Tissue specimens were obtained from 143 BPH patients who were administered α-1 blockers up until their operation. Thirty-three of the patients had also been treated with dutasteride before the procedure. The degree of prostatic inflammation was quantified histologically by the ratio of high endothelial venule (HEV)-like vessels. We divided this retrospective cohort into α-1 blocker monotherapy and combination therapy (α-1 blockers + dutasteride) groups and evaluated clinical parameters of the two groups in relation to the degree of chronic prostatic inflammation. At the same time, we assessed factors exacerbating chronic prostatic inflammation. Comparison of the monotherapy and combination therapy groups showed no significant differences in the parameters of the urodynamic study or degree of chronic prostatic inflammation, whereas the IPSS total score, voiding subscore, nocturia, intermittency, weak stream, and straining were significantly lower in the combination than the monotherapy group. The duration of α-1 blockers administration was not correlated with the ratio of HEV-like vessels, while that of dutasteride was strongly correlated (correlation coefficient = 0.595; p < 0.001). Multiple regression analysis demonstrated that the duration of dutasteride administration was a key factor exacerbating the degree of chronic prostatic inflammation. The present study showed that despite their ameliorating effect on prostatic hyperplasia, dutasteride contributed significantly to chronic prostatic inflammation.

Synergistic effects of bloom helicase (BLM) inhibitor AO/854 with cisplatin in prostate cancer

To determine the synergistic effect and mechanism of AO/854, a new Bloom syndrome protein (BLM) helicase inhibitor, and cisplatin (CDDP), a DNA-crosslinking agent, cell viability assays, neutral comet assays, and Western blotting (WB) were performed on prostate cancer (PCa) cells. According to our findings, combining AO/854 and CDDP enhanced the antiproliferative capabilities of PC3 cell lines. As evidenced by the upregulation of γH2AX, cleaved caspase-3/caspase-3, and BAX/Bcl-2, AO/854 dramatically increased PC3 apoptosis and DNA damage induced by CDDP. Furthermore, combining AO/854 and CDDP synergistically inhibited PC3 cell migration and invasion. In addition, AO/854 inhibited CDDP-induced S-phase cell-cycle arrest in PC3 cells while enhancing G2/M-phase cell-cycle arrest. In vivo, the antitumor efficacy of the combination therapy group was greater than that of the groups treated with AO/854 or CDDP alone. Our findings indicate that synergistic chemotherapy with AO/854 and CDDP may be a novel anticancer strategy for PCa.

Switching from interleukin-6 receptor inhibitors to the direct interleukin-6 inhibitor olokizumab in patients with rheumatoid arthritis: efficacy and safety during one year of therapy

Objective: to investigate the efficacy and safety of olokizumab (OKZ) in patients with rheumatoid arthritis (RA) over a 12-month period after switching from interleukin (IL)-6 receptor inhibitors (iIL6R) for non-medical reasons.Material and methods. A retrospective cohort study conducted in 11 centers in the Russian Federation included 110 patients with confirmed diagnosis of RA according to 2010 ACR/EULAR criteria. In all patients in early 2022 (due to problems with drug supply during the coronavirus pandemic) iIL6R were switched for non-medical reasons to OKZ at a dose of 64 mg once every 2 weeks or once every 4 weeks in accordance with the instructions for the medical use of OKZ.Data on clinical efficacy, safety and changes in the dosing regimen of the drugs over an observation period of one year are presented. We assessed the dynamics of the clinical indicators: number of painful and swollen joints, pain on a visual analogue scale and DAS28-ESR/CRP indices. Routine laboratory tests included assessment of red and white blood cells count, ESR, hemoglobin, CRP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin and cholesterol. Adverse events (AEs) were recorded in accordance with standard practice.Results and discussion. After 6 months of therapy, the proportion of patients who achieved remission/low disease activity according to DAS28-ESR and DAS28-CRP decreased to 70.1% and 72.9%, respectively, and the proportion of patients with moderate and high activity according to DAS28-ESR increased to 26.1% and 3.7%, respectively, and according to DAS28-CRP to 21.5% and 5.6 %, respectively. After 12 months, remission/low disease activity according to DAS28-ESR and DAS28-CRP was achieved in 81.4% and 83.5% of patients, respectively, and 18.6% and 16.5% of patients had moderate activity.In the OKZ monotherapy group, after 6 months of treatment 22 (71.0%) patients were in remission/low disease activity according to DAS28-ESR and 23 (74.2%) patients according to DAS28-CRP. After one year of observation, remission/low disease activity according to DAS28-ESR and DAS28-CRP had 24 (88.9%) and 23 (85.2%) patients, respectively.In the combined therapy group of OKZ + disease-modifying antirheumatic drugs (DMARDs), remission/low disease activity according to DAS28-ESR was observed in 53 (70.7%) patients and according to DAS28-CRP – in 55 (73.3%) patients by the 6th month of therapy. After 12 months, in this group 55 (78.6%) patients showed remission/low disease activity according to DAS28-ESR and according to DAS28-CRP – 58 (82.9 %) patients.After 6 months, 107 (97.3 %) out of 110 patients included in the study continued treatment. In 1 (0.9%) case OKZ was discontinued due to insufficient effect, in 2 cases contact with the patients was lost. After 12 months, therapy was continued in 97 (88.2%) patients. In 5 (4.5%) cases treatment was discontinued due to insufficient efficacy, in 2 (1.8%) cases – due to increased AST/ALT levels, in another 2 (1.8 %) cases – for non-medical reasons, and in 1 case contact with the patient was lost.Conclusion. OKZ, a direct IL-6 inhibitor, provided effective control over RA symptoms after switching from iIL6R, which allowed to achieve the treatment goal of maintaining remission/low disease activity over 1 year in more than 80% of patients. OKZ has demonstrated a broad spectrum of capabilities in real-world clinical practice, even when used as monotherapy. In terms of safety profile, OKZ was comparable to other IL6 inhibitors.

Study on PINK1 Expression and Its Clinical Value in Diabetic Nephropathy.

To explore PTEN-induced putative kinase 1 (PINK1) expression and its clinical value in diabetic nephropathy. Ninety patients with diabetic nephropathy were recruited and divided into metformin hydrochloride monotherapy group, telmisartan monotherapy group and combination therapy (metformin and telmisartan) group. Renal function indices and PINK1 expression, inflammatory factors, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) levels were detected. The correlation between PINK1 and inflammatory factors, renal function indicators including estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR) and serum creatinine (SCr)] were analyzed by Pearson correlation. Following treatments, the combination therapy group exhibited increased PINK1 expression levels and decreased ROS levels compared to the groups receiving metformin hydrochloride or telmisartan monotherapy. The combination therapy group showed significant improvements in renal function indices and inflammatory markers. Additionally, the MMP ratio in the combination therapy group was higher compared to the two monotherapy groups. Furthermore, PINK1 was negatively correlated with UACR, SCr, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), while positively correlated with eGFR and interleukin-2 (IL-2). PINK1 exhibits low expression levels in patients with diabetic nephropathy and its expression is strongly associated with the inhibition of disease progression, thereby offering significant clinical diagnostic value. Additionally, it may serve as a potential biological marker for clinical diagnosis and treatment of diabetic nephropathy.

Impact of second-generation antipsychotics monotherapy or combined therapy in cytokine, lymphocyte subtype, and thyroid antibodies for schizophrenia: a retrospective study

BackgroundSchizophrenia (SCZ) shares high clinical relevance with the immune system, and the potential interactions of psychopharmacological drugs with the immune system are still an overlooked area. Here, we aimed to identify whether the second-generation antipsychotics (SGA) monotherapy or combined therapy of SGA with other psychiatric medications influence the routine blood immunity biomarkers of patients with SCZ.MethodsMedical records of inpatients with SCZ from January 2019 to June 2023 were retrospectively screened from June 2023 to August 2023. The demographic data and peripheral levels of cytokines (IL-2, IL-4, IL-6, TNF-α, INF-γ, and IL-17 A), lymphocyte subtype proportions (CD3+, CD4+, CD8 + T-cell, and natural killer (NK) cells), and thyroid autoimmune antibodies (thyroid peroxidase antibody (TPOAb), and antithyroglobulin antibody (TGAb)) were collected and analyzed.Results30 drug-naïve patients, 64 SGA monotherapy (20 for first-episode SCZ, 44 for recurrent SCZ) for at least one week, 39 combined therapies for recurrent SCZ (18 with antidepressant, 10 with benzodiazepine, and 11 with mood stabilizer) for at least two weeks, and 23 used to receive SGA monotherapy (had withdrawn for at least two weeks) were included despite specific medication. No difference in cytokines was found between the SGA monotherapy sub-groups (p > 0.05). Of note, SGA monotherapy appeared to induce a down-regulation of IFN-γ in both first (mean [95% confidence interval]: 1.08 [0.14–2.01] vs. 4.60 [2.11–7.08], p = 0.020) and recurrent (1.88 [0.71–3.05] vs. 4.60 [2.11–7.08], p = 0.027) episodes compared to drug-naïve patients. However, the lymphocyte proportions and thyroid autoimmune antibodies remained unchanged after at least two weeks of SGA monotherapy (p > 0.05). In combined therapy groups, results mainly resembled the SGA monotherapy for recurrent SCZ (p > 0.05).ConclusionThe study demonstrated that SGA monotherapy possibly achieved its comfort role via modulating IFN-γ, and SGA combined therapy showed an overall resemblance to monotherapy.

Comparison of Atorvastatin Alone and its Combination with Ezetimibe among Mixed Hyperlipidemic Patients

Background: Lowering the lipid levels remains the basis of recent medical therapy for preventing cardiovascular events. Statin treatment to attain target low-density lipoprotein cholesterol (LDL-C) levels is still associated with residual risk. Objective: To compare the efficacy of Atorvastatin and Atorvastatin combined with Ezetimibe among mixed hyperlipidemic patients. Methodology: This was a prospective interventional study among the 58 diagnosed mixed hyperlipidemic patients in the outpatient department (OPD) of the Department of Cardiology at the Sylhet MAG Osmani Medical College Hospital during February to November, 2023. Patients were divided into two groups. Group I had a combination of Atorvastatin 10mg and Ezetimibe 10mg, whereas Group II took Tab. Atorvastatin 20mg once daily at night for 12 weeks. Results: After 12 weeks of treatment, a comparison of lipid profile changes between the combination therapy group and the Atorvastatin group revealed a significant reduction (p&lt;0.05) in total cholesterol (35.7% vs. 30.1%), triglycerides (30.6% vs. 16%), and LDL-C (47.5% vs. 40.1%). In the combination therapy group, ALT levels increased by 4.6%, compared to a 3.8% increase with Atorvastatin treatment alone. Combination therapy led to a 2.07% elevation in CK levels, while the Atorvastatin treatment group showed a 1.9% increase in CK values. The differences in HDL-C, ALT, and CK levels between the two groups were not statistically significant (p&gt;0.05). Conclusion: The study revealed that combination therapy of Atorvastatin with Ezetimibe is more effective in reducing LDL-C, TG, and total cholesterol in patients with mixed hyperlipidemia compared to Atorvastatin alone. Journal of Monno Medical College June, 2024; 10 (1):23-29

Analysis of risk factors and different treatments for infections caused by carbapenem-resistant Acinetobacter baumannii in Shaanxi, China

BackgroundThe global threat of Carbapenem-resistant Acinetobacter baumannii (CRAB) has intensified as resistance to carbapenems continues to rise in recent decades. We aimed to explore risk factors, molecular epidemiology, and antimicrobial therapy of CRAB infection.MethodsThe clinical data of 110 patients infected with A. baumannii from December 2021 to December 2022 were retrospectively analyzed. Patients were divided into a carbapenem-resistance group (55 patients) and carbapenem-sensitive group (CSAB; 55 patients) based on resistance to carbapenem, and the risk factors of patients infected with CRAB were analyzed. Fifty-five patients with CRAB infection who received antimicrobial therapy were divided into a combination therapy group (45 patients) and a monotherapy group (10 patients), and differences between the two groups were compared. Whole-genome sequencing analysis was performed to assess resistance genes. Phylogenetic analysis was performed to explore the characteristics of CRAB isolates.ResultsAmong the total 110 patients, the rate of poor prognosis in the CRAB group was 43.6% (24/55). Mechanical ventilation (odds ratio [OR] = 5.364, 95% confidence interval [CI] 1.462–19.679, P = 0.011) and puncture (OR = 19.935, 95% CI 1.261–315.031, P = 0.012) were independent risk factors for CRAB infection. Of 55 patients in the antimicrobial regimen study, 45 received combination therapy (including dual, triple, or quadruple antibiotic therapy) and 10 received monotherapy. Univariate analysis revealed significant differences between the combination group and monotherapy group for admission to the intensive care unit and wound infection (P < 0.05). The CRAB strains of 26 patients taking carbapenem-based combination therapy were mainly ST208, ST1968, and ST195, among which patients with ST1968 strains had higher 28-day mortality. Furthermore, the blaOXA−23 gene was harbored in ST1968, ST195, and ST208.ConclusionsMortality was significantly higher in patients infected with CRAB than with CSAB. Mechanical ventilation and puncture were independent risk factors in predicting CRAB infections. The distribution of CRAB was dominated by ST208, ST1968, and ST195, among which patients with ST1968 had higher 28-day mortality. The blaOXA−23 gene appears to be widely disseminated.