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Abstract The study’s goals are to fabricate PLGA nanoparticles (PNPs) loaded with apigenin (AP) and adenosine (AD) using a microfluidic preparation method to a standard emulsification method and investigate the possible heart-protective effects of AP-AD PNPs made using the emulsification method. Compared to microfluidics, the emulsification method fabricated small-size nanoparticles, which are better at encapsulating drugs, retaining more drugs, and having a low viscosity for the myocardial infarction (MI) injection. TheMI model was developed using SD rats injected under the skin with 85 mg/kg doxorubicin (DOX) for 2 days. The metabolic results showed that our AP-AD PNPs accelerated the blood flow in rats with MI, which increased the amounts of AP and AD in the circulatory system. This led to significant improvements in the cardiac index and lower amounts of AST, LDH, and CK in the blood. A histopathological study using Hematoxylin&eosin, and TUNEL staining showed that cardiac function had improved and apoptosis had decreased. Moreover, tests that checked the amounts of IL-6, TNF-α, NO, GSH, MDA, and SOD showed that AP-AD PNPs may help treat MI by reducing oxidative stress and inflammation, making it a potentially useful therapeutic approach.

Objective The knee joint of hemophiliacs may face the result of local morphological changes due to long‐term irritation of synovitis. This study aims to elucidate the morphological characteristics of distal femur in hemophilic arthritis (HA) and compare the compatibility of three types of prostheses with the anteroposterior (AP) and mediolateral (ML) dimensions of the femoral osteotomy surface. Methods This study retrospectively and randomly selected 50 patients with HA registered for treatment at our hospital from June 2016 to August 2022 as the study subjects, with an equal number of male osteoarthritis (OA) patients and healthy male individuals set as the control group. This study used medical digitalization software to simulate osteotomies on the distal femur during total knee arthroplasties (TKA) for 50 patients with HA, OA patients, and the healthy population, respectively, and measure the morphological parameters to compare with three commonly used femoral components of TKA in clinical practice. The differences between the femur resection of anteroposterior and mediolateral (FRAP, FRML) osteotomy surface and the prosthesis's BOX‐AP/ML were compared in three prostheses. One‐way ANOVA and multiple Kruskal–Wallis H test were used for the normal or non‐normal distribution data, and pairwise comparisons between groups were conducted using the Bonferroni method, and the linear correlation analysis was utilized to assess the relationship between section femoral morphological data and prosthesis parameters. Result In HA patients, the morphological characteristics of the distal femur were shown as shorter than femur AP (FAP), medial and lateral condyle anterior–posterior dimension (FMCAP, FLCAP), notch width (NW), posterolateral condyle height (PLCH), posteromedial condyle width (PMCW), and posterior condylar axis length (PCAL) dimension. They had comparatively smaller femur section aspect ratios (p

Abstract Abnormal subchondral bone remodeling plays a pivotal role in the progression of osteoarthritis (OA). Here, we analyzed subchondral bone samples from OA patients and observed a significant upregulation of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) specifically in subchondral bone osteoclasts. Notably, we found a strong correlation between UCHL1 expression and osteoclast activity in the subchondral bone during OA progression in both human and murine models. Conditional UCHL1 deletion in osteoclast precursors exacerbated OA progression, while its overexpression, mediated by adeno-associated virus 9, alleviated this process in male mice. Mechanistically, RANKL stimulates UCHL1 expression in osteoclast precursors, subsequently stabilizing CD13, augmenting soluble CD13 (sCD13) release, and triggering an autocrine inhibitory effect on the MAPK pathway, thereby suppressing osteoclast formation. These findings unveil a previously unidentified negative feedback loop, RANKL-UCHL1-sCD13, that modulates osteoclast formation and presents a potential therapeutic target for OA.

N6 adenosine methylation (m6A), one of the most prevalent internal modifications on mammalian RNAs, regulates RNA transcription, stabilization, and splicing. Growing evidence has focused on the functional role of m6A regulators on acute myeloid leukemia (AML). However, the global m6A levels after azacytidine (AZA) plus venetoclax (VEN) treatment in AML patients remain unclear. In our present study, bone marrow (BM) sample pairs (including pre-treatment [AML] and post-treatment [complete remission (CR)] samples) were harvested from three AML patients who had achieved CR after AZA plus VEN treatment for Nanopore direct RNA sequencing. Notably, the amount of m6A sites and the m6A levels in CR BMs was significantly lower than those in the AML BMs. Such a significant reduction in the m6A levels was also detected in AZA-treated HL-60 cells. Thirteen genes with decreased m6A and expression levels were identified, among which three genes (HPRT1, SNRPC, and ANP32B) were closely related to the prognosis of AML. Finally, we speculated the mechanism via which m6A modifications affected the mRNA stability of these three genes. In conclusion, we illustrated for the first time the global landscape of m6A levels in AZA plus VEN treated AML (CR) patients and revealed that AZA had a significant demethylation effect at the RNA level in AML patients. In addition, we identified new biomarkers for AZA plus VEN-treated AML via Nanopore sequencing technology in RNA epigenetics.

Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine (TCM) for over 13 centuries. However, the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare. Here, we present a new approach for creating artificial bear bile (ABB) as a high-quality and sustainable alternative to natural bear bile. This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields, including resources, chemistry, biology, medicine, pharmacology, and TCM. A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established, allowing for the systematic screening of therapeutic constituents. Through the utilization of chemical synthesis and enzyme engineering technologies, our research has achieved the environmentally friendly, large-scale production of bear bile therapeutic compounds, as well as the optimization and recomposition of ABB formulations. The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality, availability of raw materials, and independence from threatened or wild resources. Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile (DBB). Furthermore, preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB. This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs, thereby strengthening the integrity and sustainability of TCM.

Background In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens.Methods In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes.Results Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of −5.2% and −3.3%; both were >−10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1–3 severity.Conclusions Zuberitamab (375 mg/m2) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL.Trial registration number Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered.

ABSTRACT Background Endometrial cancer (EC) stands as the predominant gynecological malignancy impacting the female reproductive system on a global scale. N6‐methyladenosine, cuproptosis‐ and ferroptosis‐related biomarker is beneficial to the prognostic of tumor patients. Nevertheless, the correlation between m6A‐modified lncRNAs and ferroptosis, copper‐induced apoptosis in the initiation and progression of EC remains unexplored in existing literature. Aims In this study, based on bioinformatics approach, we identified lncRNAs co‐expressing with cuproptosis‐, ferroptosis‐, m6A‐ related lncRNAs from expression data of EC. By constructing the prognosis model in EC, we screened hub lncRNA signatures affecting prognosis of EC patients. Furthermore, the guiding value of m6A‐modified ferroptosis‐related lncRNA (mfrlncRNA) features was assessed in terms of prognosis, immune microenvironment, and drug sensitivity. Method Our research harnessed gene expression data coupled with clinical insights derived from The Cancer Genome Atlas (TCGA) collection. To forge prognostic models, we adopted five machine learning approaches, assessing their efficacy through C‐index and time‐independent ROC analysis. We pinpointed prognostic indicators using the LASSO Cox regression approach. Moreover, we delved into the biological and immunological implications of the discovered lncRNA prognostic signatures. Results The survival rate for the low‐risk group was markedly higher than that for the high‐risk group, as evidenced by a significant log‐rank test (p

Background Chimeric antigen receptor (CAR)-T cell has revolutionary efficacy against relapsed/refractory multiple myeloma (R/R MM). However, current CAR-T cell therapy has several limitations including long vein-to-vein time and limited viability.Methods A 4-1BB-costimulated B-cell maturation antigen (BCMA) CAR-T integrating an independently-expressed OX40 (BCMA-BBZ-OX40) was designed and generated by a traditional manufacturing process (TraditionCART) or instant manufacturing platform (named InstanCART). The tumor-killing efficiency, differentiation, exhaustion, and expansion level were investigated in vitro and in tumor-bearing mice. An investigator-initiated clinical trial was performed in patients with R/R MM to evaluate the outcomes of both TraditionCART and InstanCART. The primary objective was safety within 1 month after CAR-T cell infusion. The secondary objective was the best overall response rate.Results Preclinical studies revealed that integrated OX40 conferred BCMA CAR-T cells with superior cytotoxicity and reduced exhaustion levels. InstanCART process further enhanced the proliferation and T-cell stemness of BCMA-BBZ-OX40 CAR-T cells. BCMA-BBZ-OX40 CAR-T cells were successfully administered in 22 patients with R/R MM, including 15 patients with TraditionCART and 7 patients with InstanCART. Up to 50% (11/22) patients had a high-risk cytogenetic profile and 36% (8/22) had extramedullary disease. CAR-T therapy caused grade 1–2 cytokine release syndrome in 19/22 (80%) patients, grade 1 neurotoxicity in 2/22 (9%) patients and led to ≥grade 3 adverse events including neutropenia (20/22, 91%), thrombocytopenia (15/22, 68%), anemia (12/22, 55%), creatinine increased (1/22, 5%), hepatic enzymes increased (5/22, 23%), and sepsis (1/22, 5%). The best overall response rate was 100%, and 64% (14/22) of the patients had a complete response or better. The median manufacturing time was shorter for InstanCART therapy (3 days) than for TraditionCART therapy (10 days). Expansion and duration were dramatically higher for InstanCART cells than for TraditionCART cells.Conclusions BCMA-BBZ-OX40 CAR-T cells were well tolerated and exhibited potent responses in patients with R/R MM. InstanCART shortened the manufacturing period compared to TraditionCART, and improved the cellular kinetics. Our results demonstrated the potency and feasibility of OX40-modified BCMA CAR-T cells using InstanCART technology for R/R MM therapy.Trial registration number This trial was registered at www.clinicaltrials.gov as #NCT04537442.

Abstract Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

ABSTRACTSolid cancer patients, compared to their healthy counterparts, are at a greater risk of contracting and suffering from severe complications and poorer prognosis after COVID-19 infections. They also have different immune responses after doses of COVID-19 vaccination, but limited evidence is available to reveal the effectiveness and help to guide immunization programs for this subpopulation; MEDLINE, Embase, Web of Science, Cochrane Library databases, and clinicaltrials.gov were used to search literature. The pooled seroconversion rate was calculated using a random-effects model and reported with a 95% confidence interval (CI); The review includes 66 studies containing serological responses after COVID-19 vaccination in 13,050 solid cancer patients and 8550 healthy controls. The pooled seropositive rates after the first dose in patients with solid cancer and healthy controls are 55.2% (95% CI 45.9%–64.5% N = 18) and 90.2% (95% CI 80.9%–96.6% N = 13), respectively. The seropositive rates after the second dose in patients with solid cancer and healthy controls are 87.6% (95% CI 84.1%–90.7% N = 50) and 98.9% (95% CI 97.6%-99.7% N = 35), respectively. The seropositive rates after the third dose in patients with solid cancer and healthy controls are 91.4% (95% CI 85.4%–95.9% N = 21) and 99.8% (95% CI 98.1%-100.0% N = 4), respectively. Subgroup analysis finds that study sample size, timing of antibody testing, and vaccine type have influence on the results; Seroconversion rates after COVID-19 vaccination are significantly lower in patients with solid malignancies, especially after the first dose, then shrinking gradually after the following two vaccinations, indicating that subsequent doses or a booster dose should be considered for the effectiveness of this subpopulation.

Despite recent progress in multiple myeloma (MM) treatments, most patients will relapse and require additional treatment. Intravenous daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown good efficacy in the treatment of MM. A subcutaneous version of daratumumab was formulated to reduce the burden of intravenous infusions. We aimed to investigate the efficacy and safety of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM based on the demonstrated noninferiority of subcutaneous daratumumab to intravenous daratumumab, with a shorter administration time and reduced infusion-related reaction rate in global studies. This phase 1, multicenter study (MMY1010; ClinicalTrials.gov Identifier: NCT04121260) evaluated subcutaneous daratumumab in Chinese patients with relapsed/refractory MM after 1 prior line (n = 1) or ≥2 prior lines (n = 20) of therapy, including a proteasome inhibitor and an immunomodulatory drug. Primary endpoints were pharmacokinetics and safety. Mean (standard deviation) maximum trough concentration of daratumumab was 826 (335) μg/mL, which was consistent with prior studies of subcutaneous daratumumab and intravenous daratumumab. Safety was consistent with safety profiles observed in other daratumumab studies, with no new safety concerns identified. Incidences of infusion-related reactions and injection-site reactions were low and consistent with other subcutaneous daratumumab studies. At a median follow-up of 7.5 months, the overall response rate was 57.1%, with a very good partial response or better rate of 38.1% and complete response or better rate of 19.0%. Our results demonstrate a favorable benefit/risk profile of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM, potentially impacting clinical administration of daratumumab in this population.

Background: Our aim was to summarize our experience with the diagnosis and surgical treatment of solid pseudopapillary neoplasm (SPN) of the pancreas to provide a reference for the management of this rare condition. Methods: We collected and analyzed retrospective data on the clinical presentation, laboratory investigations, radiologic imaging, pathology and operative details of patients with SPN of the pancreas diagnosed between February 2001 and December 2009. Results: In all, 23 of 24 patients were women, and the mean age of all patients was 31 years. The most common clinical presentation was vague abdominal pain. Abdominal imaging showed solid or solid cystic masses in the pancreas, mostly in the tail or head of the gland. All patients were treated surgically. There were no postoperative deaths. After follow-up ranging from 4 to 109 months (median 68 mo), 20 of 22 patients who underwent curative resection were alive with no evidence of disease recurrence. Of the 2 patients with R1 resections, 1 died 42 months after surgery, whereas the other underwent a second operation and was alive after 36 months' follow-up. Conclusion: Solid pseudopapillary neoplasm of the pancreas is a relatively indolent tumour. The initial diagnosis of SPN of the pancreas is suggested by radiologic imaging findings but should be considered in the context of clinical and histopathologic characteristics. We advocate for complete surgical resection once SPN is diagnosed. Contexte : Nous voulions resumer notre experience du diagnostic et du traitement chirurgical du neoplasme pseudo-papillaire solide (NPS) du pancreas afin d'etablir un point de reference pour la prise en charge de ce probleme rare. Methodes : Nous avons reuni et analyse des donnees retrospectives sur la manifestation clinique, les examens de laboratoire, l'imagerie radiologique, la pathologie et les details operatoires de patients atteints de NPS du pancreas diagnostique entre fevrier 2001 et decembre 2009. Resultats : Au total, 23 des 24 patients etaient des femmes et l'age moyen de tous les patients s'etablissait a 31 ans. La manifestation clinique la plus courante etait une vague douleur abdominale. L'imagerie abdominale a revele la presence de masses solides ou kystiques solides au pancreas, surtout a la queue ou a la tete de la glande. Tous les patients ont ete traites par chirurgie. Il n'y a pas eu de deces apres l'intervention. Apres un suivi echelonne sur 4 a 109 mois (mediane de 68 mois), 20 des 22 patients qui ont subi une resection curative etaient vivants et ne presentaient aucun signe de reapparition de la maladie. Des 2 patients qui ont subi une resection R1, 1 est decede 42 mois apres l'intervention tandis que l'autre a subi une deuxieme intervention et etait vivant apres un suivi de 36 mois. Conclusion : Le neoplasme pseudo-papillaire solide du pancreas est une tumeur relativement indolente. Le diagnostic initial de NPS du pancreas est indique par les resultats d'imagerie radiologique, mais il faudrait l'envisager en presence de caracteristiques cliniques et histopathologiques. Nous preconisons la resection chirurgicale complete apres le diagnostic., A solid pseudopapillary neoplasm (SPN) of the pancreas is a rare pancreatic tumour. It was first described by Dr. Frantz in 1959,1 and was defined by the World Health Organization [...]

Education with advanced technologies improves the learning of students. Experiential learning prepares students to thrive in today’s digital world. Experiential learning and advanced technologies in education offer a lot of room to be explored. Thus, the objective of this study is to explore the student’s experience in using a business simulation and gamification platform on the student's knowledge of business competency and soft skills. This study also aimed to discover the experiential learning experience using the MonsoonSIM platform as a case study. This study used content analysis and narrative analysis to analyse the results. The focus group interview was carried out with the Universiti Malaysia Pahang Al-Sultan Abdullah (UMPSA) from Gambang and Pekan students who have played MonsoonSIM more than 10 times. The results indicated that business simulation and gamification can improve the students’ knowledge and soft skills by using MonsoonSIM. This study also provided significant implications for experiential learning, business simulation and gamification in the future for Malaysian education.

Harvest time is very important to rice due to its high correlation to rice yield, eating quality, etc.; however, the impact of harvest time on quality is still unclear. In this study, Nangeng 5718, a japonica rice planted in three regions in Jiangsu Province of China, was used to analyze and compare the milling quality, appearance quality, and physicochemical quality of japonica rice at different harvest times. The results showed that the 1000-grain weight of Nangeng 5718 exhibited no significant change at different harvest times (p > 0.05). The brown rice rate and rice yield at different harvest times were 82.3–85.4% and 66.3–76.1%, respectively. Harvest time had no significant effect on the brown of rice (p > 0.05). However, Nangeng 5718 planted in Nanjing had the highest rice yield at 50 days after heading, which was significantly different from that of rice harvested 65 days after heading (p < 0.05). Nangeng 5718 planted in Huai’an had the highest rice yield at 55 days after heading, which was significantly different from that of rice harvested 60 days after heading (p < 0.05). Harvest time had little effect on the length, width, and thickness of rice. The immature grain rate showed a decreasing trend with the increase in maturity. There were little differences in the protein content of Nangeng 5718 at different harvest times. Nangeng 5718 planted in Nanjing had the highest protein content at 50 days after heading. There was a significant difference between the rice harvested and the rice harvested 60 days after heading (p < 0.05). There were no significant differences between the other two regions (p > 0.05). The accumulated temperature in Nanjing was relatively high, and the RVA curve and RVA eigenvalues of rice varied greatly. The setback value of rice harvested at 50 days was significantly lower than that at 55 days and 60 days (p < 0.05). Rice has good gelatinizing properties. Therefore, timely harvesting and appropriate accumulated temperature could increase 1000-grain weight and rice yield, reduce the immature grain rate, and improve the gelatinization characteristics. Overall, the quality of Nangeng 5718 reached a good level when it was harvested 50 days after heading, with the accumulated temperature reaching 1051 °C. In fact, the harvest time should be chosen flexibly according to the weather conditions. Nangeng 5718 planted in Nanjing should be harvested earlier than 50 days, and rice from Huai’an and Lianyungang was of better quality when the harvest time was 50 days.

Human adenovirus (HAdV) infection is a major cause of respiratory disease, yet no antiviral drugs have been approved for its treatment. Herein, we evaluated the antiviral and anti-inflammatory effects of cyclin-dependent protein kinase (CDK) inhibitor indirubin-3′-monoxime (IM) against HAdV infection in cells and a transgenic mouse model. After evaluating its cytotoxicity, cytopathic effect reduction, antiviral replication kinetics, and viral yield reduction assays were performed to assess the anti-HAdV activity of IM. Quantitative real-time polymerase chain reaction (qPCR), quantitative reverse transcription PCR (qRT-PCR), and western blotting were used to assess the effects of IM on HAdV DNA replication, transcription, and protein expression, respectively. IM significantly inhibited HAdV DNA replication as well as E1A and Hexon transcription, in addition to significantly suppressing the phosphorylation of the RNA polymerase II C-terminal domain (CTD). IM mitigated body weight loss, reduced viral burden, and lung injury, decreasing cytokine and chemokine secretion to a greater extent than cidofovir. Altogether, IM inhibits HAdV replication by downregulating CTD phosphorylation to suppress viral infection and corresponding innate immune reactions as a promising therapeutic agent.

Abstract Background We previously reported results of a pooled analysis of two zanubrutinib studies in relapsed or refractory (R/R) MCL showing better survival outcomes when zanubrutinib is used in second‐line versus later‐line. Here, we present an updated pooled analysis with a longer follow‐up of 35.2 months. Methods Data were pooled from two studies—BGB‐3111‐AU‐003 (NCT02343120) and BGB‐3111‐206 (NCT03206970) of zanubrutinib in R/R MCL. The patients were divided into two groups based on the treatment line of zanubrutinib: the second‐line and the later‐line group. The inverse propensity score weighting method was used to balance the baseline covariates between the groups. The primary outcome was overall survival (OS). Secondary outcomes included progression‐free survival (PFS), PFS, and OS rates, objective response rate (ORR), duration of response (DOR), and safety. Results Among 112 pooled patients, 41 (36.6%) patients received zanubrutinib as second‐line and 71 (63.4%) patients as later‐line therapy. After weighting, OS was significantly improved in the second‐line versus later‐line group (HR, 0.459 [95% CI: 0.215, 0.98]; p = 0.044) with median OS not estimable in both groups. The PFS was similar between the two groups (HR, 0.78 [95% CI: 0.443, 1.373]; p = 0.389) but with numerically longer median PFS in the second‐line versus later‐line group (27.8 vs. 22.1 months). ORR was numerically higher in the second‐line versus later‐line (88.6% vs. 85.7%), and DOR was similar between the two groups (25.2 vs. 25.1 months). Zanubrutinib showed a similar safety profile in both groups. Conclusion Zanubrutinib in second‐line treatment was associated with significantly improved OS compared with later‐line treatment of R/R MCL.

Abstract Geriatric assessment can aid in optimizing treatment strategies and supportive interventions for older patients with diffuse large B‐cell lymphoma (DLBCL). Fondazione Italiana Linformi has recently introduced novel geriatric assessment tools, simplified Geriatric Assessment (sGA) and Elderly Prognostic Index (EPI), aimed at tailoring the treatment and predicting the outcomes for older patients with DLBCL. The objectives of this study are the validation and possible modification of the sGA and EPI in China. In the study, both sGA and EPI demonstrated the predictive capabilities for overall survival (OS) and early mortality (both p

Objective This study was to explore the changes in bacterial bloodstream infection (BSI) in patients with haematological malignancies (HMs) before and during SARS-CoV-2 pandemic.Design Retrospective cohort study between 2018 and 2021.Setting The largest haematological centre in southern China.Results A total of 599 episodes of BSI occurring in 22 717 inpatients from January 2018 to December 2021 were analysed. The frequencies of the total, Gram-negative and Gram-positive BSI before and during the pandemic were 2.90% versus 2.35% (p=0.011), 2.49% versus 1.77% (p

Abstract Objective To identify DNA methylation and clinical features, and to construct machine learning classifiers to assign the patients with major depressive disorder (MDD) into responders and non-responders after a 2-week treatment into responders and non-responders. Method Han Chinese patients (291 in total) with MDD comprised the study population. Datasets contained demographic information, environment stress factors, and the methylation levels of 38 methylated sites of tryptophan hydroxylase 2 (TPH2) genes in peripheral blood samples. Recursive Feature Elimination (RFE) was employed to select features. Five classification algorithms (logistic regression, classification and regression trees, support vector machine, logitboost and random forests) were used to establish the models. Performance metrics (AUC, F-Measure, G-Mean, accuracy, sensitivity, specificity, positive predictive value and negative predictive value) were computed with 5-fold-cross-validation. Variable importance was evaluated by random forest algorithm. Result RF with RFE outperformed the other models in our samples based on the demographic information and clinical features (AUC = 61.2%, 95%CI: 60.1-62.4%) / TPH2 CpGs features (AUC = 66.6%, 95%CI: 65.4-67.8%) / both clinical and TPH2 CpGs features (AUC = 72.9%, 95%CI: 71.8-74.0%). Conclusion The effects of TPH2 on the early-stage antidepressant response were explored by machine learning algorithms. On the basis of the baseline depression severity and TPH2 CpG sites, machine learning approaches can enhance our ability to predict the early-stage antidepressant response. Some potentially important predictors (e.g., TPH2-10-60 (rs2129575), TPH2-2-163 (rs11178998), age of first onset, age) in early-stage treatment response could be utilized in future fundamental research, drug development and clinical practice.

Objective The distal tibiofibular syndesmosis (DTS) is a fretting joint and it is still a hot issue how to satisfy strong internal fixation while allowing fretting. This study described and evaluated a new method for elastic fixation of DTS injury with Nice Knot. Methods The study was designed as a retrospective study. Between June 2020 and June 2021, 31 patients who were diagnosed with ankle fracture and DTS injury without additional orthopedic injuries were enrolled in this case series. The study included 22 males and nine females, with an average age of 34.71 ± 14.66 years. All patients were treated with Nice Knot binding for DTS. Surgical time, length of stay, time of DTS fixation, total weight‐bearing time, complications, imaging parameters, and functional scores at follow‐up were recorded. Paired sample t‐tests or single factor analyses of variance were used at intra‐group comparison. Results All patients completed surgery with normal syndesmotic parameters. The recovery of DTS injury was verified by Hook and lateral malleolus rotation tests. The average follow‐up time was 15.97 ± 3.30 months. Only one case showed superficial infection after surgery, and the wound healed after symptomatic treatment. In terms of imaging, there were no significant differences in tibiofibular clear space (TFCS), tibiofibular overlap distance (TFOS), medial clear space (MCS), and superior clear space (SCS) immediately and at different follow‐up points after surgery. All obtained excellent and good outcomes according to the AOFAS score at least follow‐up after surgery. Conclusions Nice Knot elastic fixation of DTS injury is firm and stable while maintaining the physiological micromotion of the ankle joint.

Background: The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate intensive chemotherapy. Objectives: We aimed to evaluate the efficacy of low-dose decitabine in previously untreated patients with AML aged ⩾65 years who were ineligible for intensive chemotherapy based on a comprehensive geriatric assessment. Design: We performed a prospective, multicenter, open-label, and non-randomized study. Methods: Patients were enrolled at four centers in Beijing between 1 January 2017 and 31 December 2020. They were treated with decitabine at a dose of 6 mg/m 2 for 10 days. The treatment was repeated every 28 days for one cycle for a total of six cycles. The primary endpoint of our study was overall survival (OS) at the end of the first year after enrolment. The secondary endpoints included overall response rate, leukemia-free survival, relapse rate, treatment-related mortality (TRM), quality of life, safety, and transfusion dependence. Patients were continuously monitored for toxicity. Results: Overall, 47 patients (30 males and 17 females) participated in this study. The median age of the enrolled patients was 78 (range, 65−90) years. The median follow-up time was 22.2 (range, 4.6−38.8) months. Fifteen (31.9%) patients achieved complete remission (CR), 11 (23.4%) patients achieved partial remission, 3 (6.4%) patients achieved hematological improvement only, and 18 (38.3%) patients did not achieve remission. The median time to obtain CR was 2 months. The median CR was 8.5 months. Of the patients, 36 (76.6%) patients completed six cycles of treatment with low-dose decitabine, and the 1-year OS was 36.1%. According to instrumental activities of daily living scales, age, comorbidities, and albumin (IACA) scores, the median survival was 11.2 months in the unfit group and 6 months in the frail group. The 1-year OS rates in the unfit and frail groups were 49.2% and 23.4%, respectively. Grade ⩾3 non-hematological toxicity was observed in 70.2% (33/47) of the patients. TRM occurred in three patients. No early deaths occurred after treatment. Conclusion: In newly diagnosed older patients with AML whose IACA assessment was unfit or frail for standard chemotherapy, treatment with low-dose decitabine demonstrated clinical activity and good security in our study.

Abstract Objective To investigate the clinical efficacy of plasma exchange (PE) with or without prednisone and hydroxychloroquine (HCQ) for the treatment of systemic lupus erythematosus (SLE) during pregnancy. Methods The clinical characteristics of 14 pregnant women with SLE admitted to our hospital were retrospectively analyzed, including 7 only treated with prednisone and HCQ (non‐PE group) as well as 7 combined PE (PE group). The delivery situations of 14 patients were recorded. Data like erythrocyte sedimentation rate (ESR), urine protein, platelet count, and SLEDAI scores were compared between two groups before treatment and 3, 6, and 12 months after delivery. Results Three patients in the non‐PE group ended in miscarriage while all patients in the PE group were delivered successfully. Eleven successfully delivered fetuses in the two groups were healthy, and the Apgar scores were over 8. The ESR of the PE group was significantly lower than that of the non‐PE group at 6 and 12 months after delivery, while there was no statistical difference in ESR between the two groups before treatment and 3 months after delivery. The ESR and urine protein were significantly higher in the non‐PE group at months 3, 6, and 12 postpartum. There was a significant decrease in disease activity postpartum in the PE group compared to predelivery disease activity. The change in platelet counts between the two groups significantly increased over time in the PE group, while SLEDAI scores decreased. Conclusions The combination of PE and oral prednisone and HCQ is possibly a more effective treatment than oral prednisone and HCQ alone for patients with active SLE during pregnancy. This treatment option reduces pregnancy loss and promotes the patients' postpartum condition to a certain extent.

The discovery of hydrocarbon in the Pagoda Formation in South China has received attention from the petroleum industry. This research paper identifies the discontinuity surface underlying the Pagoda Formation. The Upper Ordovician strata were correlated in different regions using the conodont biostratigraphy, and δ13C and δ18O isotope stratigraphy. The biostratigraphic result illustrates that three conodont zones can be established in each study section, and one to three conodont zones are missing in the lower Pagoda Formation and the strata underlying the Pagoda Formation of the Upper Yangtze Platform. Moreover, the chemostratigraphic result highlighted that the development of the lower δ13C isotope positive excursion events in the Xiaogangwan and Liangcun areas was less complete than that in the Jiaodingshan area. Combined with the cyclostratigraphic results, the development of the δ13C isotope positive excursion is not complete. The development of the δ13C excursion event is more complete in the south and east than in the center and north. This demonstrates that the Pagoda Formation began its deposition at different times and the transgression process may have advanced from the southeast to the north and that the contact between the Pagoda Formation and the underlying formation is not conformable. It is proposed that the Late Ordovician in the South China Plate was affected by the tectonic movement and the cooling paleoclimate at that time, which resulted in the discontinuity between the Pagoda Formation and the underlying strata. The unconformity could be the channel for hydrocarbon migration or for the high-quality oil and gas reservoirs being developed and preserved under the unconformity surface.

Abstract Background The effect of neuroinflammatory cytokines on cognitive deficits in patients with major depressive disorder (MDD) can be altered by selective serotonin reuptake inhibitors (SSRIs). This study aimed to examine serum interleukin-8 (IL-8) levels, cognitive function, and their associations in MDD patients with SSRIs. Methods Thirty SSRI-treated MDD patients and 101 healthy controls were recruited for this study. We examined cognitive performance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-8 levels using the Human Inflammatory Cytokine Cytometric Bead Array in both cases and controls. Results The RBANS test scores were significantly lower in MDD patients with SSRIs than in healthy controls after controlling for covariates (all p

Abstract Background Ibrutinib has revolutionized the treatment of mantle cell lymphoma (MCL). Both ibrutinib monotherapy and ibrutinib‐based combination therapy are important salvage options for patients with relapsed/refractory (R/R) MCL. The real‐world efficacy and safety profile of the two strategies in Chinese patients with R/R MCL remain unclarified. Methods In the present study, data of 121 R/R MCL patients who received either ibrutinib monotherapy (N = 68) or ibrutinib combination therapy (N = 53) in 13 medical centers in China were retrospectively reviewed. Results With a median follow‐up of 20.5 months, the overall response rate was 60.3% versus 84.9% (p = 0.003), complete remission rate was 16.2% versus 43.4% (p

At present, most of the gait-based smartphone authentication researches focus on a single controlled scenario without considering the impact of multi-scenario changes on the authentication accuracy.The movement direction of the smartphone and the user changes in different scenarios, and the user’s gait data collected by the orientation-sensitive sensor will be biased accordingly.Therefore, it has become an urgent problem to provide a multi-scenario high-accuracy gait authentication method for smartphones.In addition, the selection of the model training algorithm determines the accuracy and efficiency of gait authentication.The current popular authentication model based on long short-term memory (LSTM) network can achieve high authentication accuracy, but it has many training parameters, large memory footprint, and the training efficiency needs to be improved.In order to solve the above problems a multi-scenario gait authentication scheme for smartphones based on Gate Recurrent Unit (GRU) was proposed.The gait signals were preliminarily denoised by wavelet transform, and the looped gait signals were segmented by an adaptive gait cycle segmentation algorithm.In order to meet the authentication requirements of multi-scenario, the coordinate system transformation method was used to perform direction-independent processing on the gait signals, so as to eliminate the influence of the orientation of the smartphone and the movement of the user on the authentication result.Besides, in order to achieve high-accuracy authentication and efficient model training, GRUs with different architectures and various optimization methods were used to train the gait model.The proposed scheme was experimentally analyzed on publicly available datasets PSR and ZJU-GaitAcc.Compared with the related schemes, the proposed scheme improves the authentication accuracy.Compared with the LSTM-based gait authentication model, the training efficiency of the proposed model is improved by about 20%.

Abstract Background Several methods can assist in detecting early esophageal cancer (EEC) and staging esophageal cancer (EC) invasion depth. Objective To evaluate the accuracy of magnifying endoscopy with narrow-band imaging (ME-NBI) plus endoscopic ultrasonography (EUS) for diagnosing EC. Methods We searched the PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases for relevant studies. The Quality Assessment of Diagnostic Accuracy Studies 2 (QADAS2) was used to assess the studies’ methodological quality. The sensitivity, specificity, positive likelihood (LR+), negative likelihood (LR−), and diagnostic odds ratio (DOR) were calculated, and the summary receiver operating characteristic (SROC) curves were drawn to evaluate the diagnostic performance. Results Seven studies were included. The meta-analysis suggested that the pooled sensitivity, specificity, LR+, LR−, and DOR of ME-NBI plus EUS for diagnosing EC were 0.947 (95% confidence interval [CI], 0.901–0.975), 0.894 (95% CI, 0.847–0.931), 7.989 (95% CI, 4.264–14.970), 0.066 (95% CI, 0.035–0.124), and 137.96 (95% CI, 60.369–315.27), respectively. Those values for staging the invasive depth were 0.791 (95% CI, 0.674–0.881), 0.943 (95% CI, 0.906–0.968), 13.087 (95% CI, 7.559–22.657), 0.226 (95% CI, 0.142–0.360), and 61.332 (95% CI, 27.343–137.57). The areas under the curves (AUCs) for diagnosis and staging were 0.97 and 0.95, respectively. Conclusions ME-NBI plus EUS might be an adequate diagnostic and staging modality for EC. Due to the study limitations, more large-scale, high-quality studies are needed to confirm the diagnostic accuracy of ME-NBI plus EUS.

Summary: Sequence variation resulting from the evolution of IGH clones and immunophenotypic drift makes it difficult to track abnormal B cells in children with precursor B cell acute lymphoblastic leukemia (pre-B-ALL) by flow cytometry, qPCR, or next-generation sequencing (NGS). The V-(D)-J regions of immunoglobulin and T cell receptor of 47 pre-B-ALL samples were sequenced using the Illumina NovaSeq platform. The IGH rod-like tracer consensus sequence was extracted based on its rod-like alpha-helices structural similarity predicted by AlphaFold2. Additional data from published 203 pre-B-ALL samples were applied for validation. NGS-IGH (+) patients with pre-B-ALL had a poor prognosis. Consistent CDR3-coded protein structures in NGS-IGH (+) samples could be extracted as a potential follow-up marker for pre-B-ALL children during treatment. IGH rod-like tracer from quantitative immune repertoire sequencing may serve as a class of biomarker with significant predictive values for the dynamic monitoring of MRD in pre-B-ALL children.

An asymmetric aza-BODIPY analogue bearing quinoxaline moiety was synthesized via a titanium tetrachloride-mediated Schiff-base-forming reaction of 6,7-dimethyl-1,4-dihydroquinoxaline-2,3-dione and benzo[d]thiazol-2-amine. This novel aza-BODIPY analogue forms a complementary hydrogen-bonded dimer due to the quinoxaline moiety in the crystal structure. It also shows intense absorption and fluorescence, with fluorescence quantum yields close to unity. The electrochemical measurements and the DFT calculations revealed the presence of the low-lying HOMO, which benefits their potential applications as an electron-transporting material.