CHRONOS-4: Phase 3 study of copanlisib plus rituximab-based immunochemotherapy in relapsed indolent B-cell lymphoma.

Copanlisib, a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α and δ isoforms, previously demonstrated durable responses as monotherapy and improved progression-free survival (PFS) in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). CHRONOS-4 was a phase 3, randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of copanlisib in combination with standard immunochemotherapy in patients with relapsed iNHL. Patients (n=524) were randomized (1:1) to copanlisib (60 mg IV) plus immunochemotherapy (rituximab and bendamustine [R-B] or placebo plus R-B). Copanlisib/placebo were administered with R-B (days 1, 8, and 15 of each 28-day cycle) for ≤6 cycles and as monotherapy from cycle 7 up to 12 months. The primary study endpoint was PFS. Median exposure was 8.5 months (0.2-12.9) for copanlisib plus R-B and 11.4 months (0.1-12.6) for placebo plus R-B. Median PFS was 32.9 months (95% CI, 24.4-38.6) for copanlisib plus R-B and 33.3 months (95% CI, 27.8-42.8) for placebo plus R-B (HR, 1.13 [95% CI, 0.88-1.44]; P=0.83). No differences between treatment arms were observed in overall survival (data not yet mature), objective response rate, and duration of response for the overall population or individual histology types. Overall, copanlisib plus R-B was associated with higher rates of serious treatment-emergent adverse events (TEAEs), grade 4 and 5 TEAEs, and treatment discontinuation. A number of serious TEAEs were infections. Overall, copanlisib plus R-B did not provide clinical benefit versus placebo plus R-B and was associated with worse tolerability in patients with relapsed iNHL. ClinicalTrials.gov: NCT02626455.

Efficacy and Safety of a Self-Improved Continuous Bladder Irrigation Sensor Device in Patients after Transurethral Resection of the Prostate: A Prospective Study.

Purpose To explore the efficacy and safety of a self-improved continuous bladder irrigation (CBI) sensor device after transurethral resection of the prostate (TURP). Materials and Methods A total of 160 patients with benign prostatic hyperplasia who received TURP from June 2021 to May 2022 were selected. According to the envelope randomization method, patients were divided into a control group (80 cases) and study group (80 cases). In the control group, the speed of bladder flushing fluid was adjusted according to the clinical experience of nurses. On the basis of the control group, the self-improved CBI sensor device was used in the study group to observe the postoperative comfort and complication rate in the two groups. Results The comfort of patients in the study group was significantly higher than that of patients in the control group (97.50% vs. 88.75%, P = .023), and the number of postoperative complications in the control group was significantly higher than that in the study group (8.75% vs. 1.25%, P = .021). Meanwhile, the average amount of irrigation fluid in the study group was obviously lower than that in the control group (26.4 L vs. 27.8 L, P = .011). In addition, patients in the study group had a significantly shorter hospital stay than the controls (3.3 days vs. 3.6 days, P = .005). Conclusion Implementation of the new self-improved CBI sensor device for patients after TURP can improve their awareness regarding disease-related knowledge, alleviate their fear and anxiety, improve their compliance and comfort with treatment and nursing, and reduce the incidence of complications.

Preclinical evaluation and phase 1 study of the PI3Kα/δ inhibitor TQ-B3525 in Chinese patients with advanced cancers.

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ-B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs). METHODS: Oral TQ-B3525 was given at eight dose levels on a 28-day cycle. Primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety. RESULTS: TQ-B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose-escalation cohort; 17 in dose-expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT-evaluable patients; MTD was not identified. TQ-B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment-related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment-related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression-free survivals of 12.1 and 1.1 months; median overall survivals were not reached. CONCLUSION: TQ-B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ-B3525 (20 mg once daily) for R/R lymphoma.

Incremental regression of localization context for automatic segmentation of ossified ligamentum flavum from CT data.

PURPOSE: Segmentation of ossified ligamentum flavum (OLF) plays a crucial role in developing computer-assisted, image-guided systems for decompressive thoracic laminectomy. Manual segmentation is time-consuming, tedious, and label-intensive. It also suffers from inter- and intra-observer variability. Automatic segmentation is highly desired. METHODS: A two-stage, localization context-aware framework is developed for automatic segmentation of ossified ligamentum flavum. In the first stage, localization heatmaps of OLFs are obtained via incremental regression. In the second stage, the obtained heatmaps are then treated as the localization context for a segmentation U-Net. Our framework can directly map a whole volumetic data to its volume-wise labels. RESULTS: We designed and conducted comprehensive experiments on datasets of 100 patients to evaluate the performance of the proposed method. Our method achieved an average Dice similarity coefficient of 61.2 ± 7.6%, an average surface distance of 1.1 ± 0.5 mm, and an average positive predictive value of 62.0 ± 12.8%. CONCLUSION: To the best knowledge of the authors, this is the first study aiming for automatic segmentation of ossified ligamentum flavum. Results from the comprehensive experiments demonstrate the superior performance of the proposed method over the state-of-the-art methods.

Efficacy and safety of pelvic floor magnetic stimulation combined with mirabegron in female patients with refractory overactive bladder: a prospective study.

Objective: To observe the efficacy and safety of pelvic floor magnetic stimulation (PFMS) combined with mirabegron in female patients with refractory overactive bladder (OAB) symptoms. Patients and methods: A total of 160 female patients with refractory OAB symptoms were prospectively randomized into two groups. Eighty cases in the combination group accepted PFMS and mirabegron therapy and 80 cases as control only accepted mirabegron therapy (The clinical trial registry number: ChiCTR2200070171). The lower urinary tract symptoms, OAB questionnaire (OAB-q) health-related quality of life (HRQol), symptom bother score and OABSS between two groups were compared at the 1st, 2nd and 4th week ends. Results: All of 160 patients were randomly assigned to two groups, of which 80 patients were included in the combination group and 80 in the mirabegron group. The incidences of LUTS, including urgency, frequent urination, and incontinence episodes, in the 2nd week and the 4th week after combination treatment were significantly lower than those in the mirabegron group (p < 0.05). The incidence of drug-related adverse events between two groups was similar, and there was no statistically significant difference (p > 0.05). With respect to secondary variables, the OAB-q HRQol score in the combination group was statistically superior in comparison with that in the mirabegron group between the 2nd week and the 4th week (p < 0.05). This was consistent with the primary outcome. Meanwhile, from the second to fourth week, the OAB-q symptom bother score and OABSS in the combination group were both lower than in the mirabegron group (p < 0.05). Conclusion: Combination therapy of PFMS and mirabegron demonstrated significant improvements over mirabegron monotherapy in reducing refractory OAB symptoms for female patients, and providing a higher quality of life without increasing bothersome adverse effects. Clinical Trial Registration: https://www.chictr.org.cn/, ChiCTR-INR-22013524.

Direct Growth of Low Thermal Conductivity WTe2 Nanocrystalline Films on W Films.

WTe2 has attracted much attention because of its layered structure and special electronic energy band structure. However, due to the difficulty of evaporating the W element itself and the inactivity of the Te element, the obtained large-area WTe2 thin films are usually accompanied by many defects. In this paper, WTe2 nanocrystalline films were successfully prepared on quartz substrates using magnetron sputtering and chemical vapor deposition techniques. Various analytical techniques such as X-ray Diffraction, Raman spectra, X-ray Photoelectron Spectroscopy, Scanning Electron Microscope, and photoluminescence spectra are employed to analyze the crystal structure, composition, and morphology. The effects of different tellurization temperatures and tellurization times on the properties of WTe2 thin films were investigated. WTe2 nanocrystalline films with good crystallinity were obtained at 600 °C for 30 min. The thermal conductivity of the WTe2 films prepared under this condition was 1.173 Wm-1K-1 at 300 K, which is significantly higher than that of samples prepared using other methods.

RIRS with FV-UAS vs. MPCNL for 2-3-cm upper urinary tract stones: a prospective study.

To observe the efficacy and safety of retrograde intrarenal surgery (RIRS) combined with flexible vacuum-assisted ureteral access sheath (FV-UAS) and minimally invasive percutaneous nephrolithotomy (MPCNL) in patients with 2-3 cm upper urinary tract stones. A total of 160 patients with 2-3 cm upper urinary tract stones were prospectively randomized into 2 groups-80 in the FV-UAS group and 80 cases as control in the MPCNL group. The stone-free rates (SFRs) at different times (postoperative 1st day and 4th week) were considered as the primary outcome of the study. The secondary end points were operative time, hemoglobin decrease, postoperative hospital stay, and operation-related complications. There was no obvious difference between the two groups in patient's demographics and preoperative clinical characteristics (all P > 0.05). Postoperative data showed that mean decrease in hemoglobin level was less in FV-UAS group than that in MPCNL group (5.3 vs. 10.8 g/L, P < 0.001). Postoperative hospital stay in FV-UAS group was more shorten than that in MPCNL group (2.7 vs. 4.9 days, P < 0.001). There was no statistical significance between the two groups in SFRs during postoperative 1st day and 4th week (both P > 0.05). However, in terms of the rates of bleeding and pain, MPCNL group were both significantly higher than FV-UAS group (6.2 vs. 0.0%, P = 0.023; 16.2 vs. 2.5%, P = 0.003; respectively). Our study showed that RIRS with FV-UAS, a new partnership to treat 2-3 cm upper urinary tract stones, was satisfying as it achieved a high SFR rate and a low rate of complications. This method was safe and reproducible in clinical practice.

Neuroprotective effect of plasmalogens on AlCl3-induced Alzheimer's disease zebrafish via acting on the regulatory network of ferroptosis, apoptosis and synaptic neurotransmission release with oxidative stress as the center.

Plasmalogens (Pls) are considered to play a potential role in the treatment of neurodegenerative diseases. In the present study, an Alzheimer's disease (AD) model of zebrafish induced by AlCl3 was established to investigate whether the marine-derived Pls could alleviate cognitive impairments of AD zebrafish. Behavioral tests were carried out to assess the athletic ability. The transcriptional profiles of zebrafish in the control, AD model and AD_PLS group were compared and analyzed to determine the potential mechanisms of dietary Pls on AD. The study found that Pls could reverse athletic impairment in the AD zebrafish model, and the expression levels of genes related to ferroptosis, synaptic dysfunction and apoptosis were significantly altered between experimental groups. Further analysis showed that all of these genes were associated with oxidative stress (OS). These data suggest that healthy protective role of marine-derived Pls on AD zebrafish may result from inhibition of ferroptosis and neuronal apoptosis, restoring synaptic neurotransmission release, and reducing neuroinflammation. Among them, Oxidative stress is acted as the center to connect different regulation pathways. This study provides evidence to support the essential roles of OS in pathogenesis of AD, and the application of Pls in relieving AD.

Depression Following Acute Coronary Syndrome: A Review.

Depression is common among patients with acute coronary syndrome (ACS). Although multiple studies have confirmed that depression is an independent risk factor for poor outcomes in ACS, general awareness of this issue is still limited. Ongoing research has described detailed aspects of depression in ACS, with various mechanistic hypotheses put forward to explain the complexity of this comorbidity. Several investigations have explored management strategies in this subgroup of patients, including screening for depression, antidepressant treatment, and cardiac rehabilitation. However, evidence of long-term improvement in clinical outcomes is still scarce, and a more comprehensive understanding of the underlying mechanisms that link depression with ACS is required to further improve disease management.

The Prognostic Significance of Secondary Mitral Regurgitation in Heart Failure Patients with Varying Estimated Pulmonary Artery Systolic Pressure.

Background: Limited research has been conducted to investigate the impact of secondary mitral regurgitation (MR) in heart failure (HF) patients with different levels of estimated pulmonary artery systolic pressure (ePASP). Methods: A total of 468 patients suffering from HF and secondary MR were enrolled and categorized into non-severe and severe MR groups based on the degree of MR. The primary endpoint of the study was a composite of cardiovascular death and a first-heart-failure hospitalization. The secondary endpoints were the primary outcomes, individually. The outcomes of the two groups were compared. Patients were further classified based on whether their ePASP was ≥ 50 mmHg or < 50 mmHg. Subsequently, the outcomes of the non-severe and severe MR groups were compared within each ePASP category. Results: In a median (SD) follow-up of 694 (410) days, severe MR was associated with higher risk for primary endpoints in patients with heart failure, especially in those with ePASP ≥ 50 mmHg. In patients with ePASP < 50 mmHg, the prognostic value of severe MR was diminished. Conclusions: Assessment of the severity of MR can identify heart failure patients who are at greater risks for poor clinical outcomes. Additionally, the prognostic value of secondary MR was more pronounced in patients with elevated ePASP.

Paeonol suppresses fibroblast synovitis by increasing MANF expression / 中国药理学通报

Aim To investigate the possible mechanism of paeonol inhibiting the inflammatory response of fibroblast synovial cells (RA-FLSS) in rheumatoid arthritis. Methods CCK-8 assay was used to detect Paeonol's inhibitory level on the abnormal proliferation of arthritis human fibroblast synovial cells (RA-FLSs). The levels of endoplasmic reticulum stress-related proteins MANF and ATF6 were detected by Western blot. Cell localization of transcription factor p65 and Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF) was detected by immunofluorescence. RT-qPCR detected the changes of p65 target genes. Results Paeonol could significantly inhibit the abnormal proliferation of RA-FLSS cells. Paeonol activates ATF6 and increases the expression of MANF. Paeonol promoted the nuclear transfer of MANF protein and inhibited the transcriptional activity of p65. Conclusion Paeonol promotes the expression of MANF and nuclear transfer through the endoplasmic reticulum stress pathway and affects the progression of RA by inhibiting the transcriptional activity of p65.

Resveratrol mediates apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis by down-regulating mnsod / 中国药理学通报

Aim: To investigate the role of manganese superoxide dismutase (MS0D) protein expression in the proliferation and apoptosis of fibroblast-like synoviocyte (RA-FLS) in rheumatoid arthritis mediated by resveratrol(Res). Methods: After RA-FLSs was treated with Res, the expression of MnSOD protein was detected by CCK-8 method, and the expression of Mn- SOD protein was detected by, Western blot. After lentivirus infection with RA-FLSs, 8 mg · L-1 purine mycin was used to screen the infected cells, and three stable cell lines were established; MnSOD overexpression, MnSOD interference and MnSOD control. The mitochondria reactive oxygen species (mtROS) levels of each cell line treated with 5 μmol · L-1 hydrogen peroxide (H2O2) and 200 mol · L-1 Res were detected by laser confocal microscopy, and cell apoptosis was detected by flow cytometry. Results Res could inhibit the proliferation and the expression of MnSOD in RA- FLSs. The lentivirus-mediated MnSOD regulation could significantly increase or decrease the expression of Mn- SOD in RA-FLSs. MnSOD over expression could decrease the level of mtROS and apoptosis of the RA- FLSs treated with 5 μmol · L-1 H2O2 and 200 μmol · L-1 Res. While the MnSOD RNAi showed the opposite results. Conclusions: Res may up-regulate mtROS levels by inhibiting the expression of MnSOD, thus promoting the apoptosis of RA-FLSs.

Preliminary investigation of TIM-3 ligand galectin-9 inducing apoptosis of NK/T cell lymphoma cells / 中国肿瘤生物治疗杂志

@# Objective: To identify the expression pattern of TIM-3 in natural killer/T-cell lymphoma (NK/TCL) cell lines, and to investigate the effect and mechanism of its ligand galectin-9 (GAL-9) inducing apoptosis of NK/TCL cell lines. Methods: Expression of TIM-3 in NK cell of peripheral blood from healthy donors and NK/TCL cell lines (SNK-1、SNK-6、SNT-8) was detected by Western blotting. After being treated with rhGAL-9 at various concentrations for 24h, the cell proliferation ability was analyzed with CCK-8 assay. Apoptosis ratio of the cells was determined by flow cytometry. Expressions of caspase-3, PARP and their cleavages were detected by Western blotting; moreover, phosphorylation levels of proteins in MAPK signaling pathway were also detected by Western blotting. Results: The expression of TIM-3 in SNK-1, SNK-6 and SNT-8 cell lines was significantly higher than that of NK cells from healthy donors (P<0.05). CCK-8 result showed that rhGAL-9 obviously inhibited the proliferation of NK/TCL cell lines in a concentration dependent manner. Flow cytometry showed that rhGAL-9 induced the apoptosis of NK/TCLcells; and Western blotting proved that the expression of cleaved caspase-3, cleaved-PARP, and p-JNK in MAPK signaling pathway were significantly elevated. Conclusion: TIM-3 was over-expressed in NK/TCL cell lines, and its ligand galectin-9 induced cell apoptosis probably through the activation of JNK kinase pathways.

Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling

Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein malfunction and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracellular signaling pathways that can protect against or delay this pathogenic process. Here, we show that the DYNC1I1 deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF-MEK signaling protects against neuronal atrophy induced by DYNC1I1 deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demonstrate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.

Study on between magnetic resonance venography and digital subtraction angiography on the inferior vena cava obstructive interface morphology of Budd-Chiari syndrome / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To evaluate magnetic resonance venography (MRV) in diagnosing obstructive interface morphology of Budd-Chiari syndrome(BCS).</p><p><b>METHODS</b>MRV examination was performed on 44 cases of BCS, and the images of obstructive interface morphology of the inferior vena cava were reviewed by two radiologists.</p><p><b>RESULTS</b>In all 44 cases, there were 37 cases with complete obstruction and 7 with incomplete obstruction. MRV showed 4 cases with membrane with hole of incomplete obstruction. The morphologies MRV demonstrated that the proximal part of the 37 cases with complete obstruction were mainly divided into the cone type (36 cases) and the planum type (1 case). Besides, the type of distal end of obstruction were the cone type (30 cases), the planum type (4 cases) and the irregular type (3 cases). The overall sensitivity, specificity, positive and negative predictive values for the diagnosis of MRV were respectively 100%%, 57.1%, 92.5% and 100% as compared to the DSA.</p><p><b>CONCLUSION</b>The examination of MRV is capable of revealing the obstructive interface morphology of the inferior vena cava, especially for the distal end of obstruction. MRV can provide guidelines in interventional treatment of Budd-Chiari syndrome.</p>

Signal transducer and activator of transcription-3 activation after focal cerebral ischemia and reperfusion in rats / 中华神经医学杂志

Objective To investigate the activation of signal transducer and activator of transcription-3 (STAT3) in rats following focal cerebral ischemia/repeffusion (IR) and explore the correlation between STAT3 activation and the cerebral infract volume. Methods Ninety-nine SD rats were randomized into sham-operated group (n=9) and two IR groups with right middle cerebral artery occlusion with thread for 2 h (n=45) and 6 h (n=45) followed by reperfusion. At different time points after the end of the ischemia, the rats were sacrificed to obtain the brain tissue for triphenyltetrazolium chloride (TTC) staining to determine the infract volume. Immunohistochemistry and Western blot were used to detect the expressions of STAT3 and phosphorylated STAT3 (P-STAT3) in the brain tissue, and their correlations to the infarct volume were analyzed. Results Cerebral ischemia induced obvious infraction in the right hemisphere of the rats, where TTC staining was absent. Ischemia for 6 h resulted in more extensive areas without TTC staining than ischemia for 2 h (P<0.05). Reperfusion for 24 h after a 2-hour ischemia was associated with obviously reduced area free of TTC staining (P<0.05), whereas reperfusion for 24 h following a 6-hour ischemia only caused mild reduction of the TTC staining-free area. Immunohistochemistry of the brain tissue demonstrated the presence of STAT3 protein expression in the cytoplasm and P-STAT3 in the cell nuclei. IR was found to cause changes in the expression of P-STAT3 but not STAT3 protein, and the expression of P-STAT3 increased with the reperfusion time, reaching the peak level at 24 h of reperfusion. The activation level of STAT3 protein was inversely correlated to the dimension of the TTC staining-free area in the brain. Conclusion STAT3 is expressed in the cytoplasm and P-STAT3 in the cell nucleus of the brain tissue. Without causing obvious changes in STAT3 expression level, cerebral ischemia and reperfusion increases the phosphorylation level of STAT3 in inverse correlation to the size of the infarct area.