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Abstract Background Disease progression within 24 months (POD24) significantly impacts overall survival (OS) in patients with follicular lymphoma (FL). This study aimed to develop a robust predictive model, FLIPI-C, using a machine learning approach to identify FL patients at high risk of POD24. Methods A cohort of 1,938 FL patients (FL1-3a) from seventeen centers nationwide in China was randomly divided into training and internal validation sets (2:1 ratio). XGBoost was utilized to construct the POD24-predicting model, which was internally validated in the validation set and externally validated in the GALLIUM cohort. Key predictors of POD24 included lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) > ULN, low hemoglobin (Hb), elevated beta-2 microglobulin (β2-MG), maximum standardized uptake value (SUVmax), and lymph node involvement. The FLIPI-C model assigned 2 points to LMR and 1 point to each of the other variables. Results The FLIPI-C model demonstrated superior accuracy (AUC) for predicting POD24 and 3-year overall survival (OS) in both the internal (AUC POD24: 0.764, OS: 0.700) and external validation cohorts (AUC POD24: 0.703, OS: 0.653), compared to existing models (FLIPI, FLIPI-2, PRIMA-PI, FLEX). Decision curve analysis confirmed the superior net benefits of FLIPI-C. Conclusions Developed using a machine learning approach, the FLIPI-C model offers superior predictive accuracy and utilizes simple, widely available markers. It holds promise for informing treatment decisions and prognostic assessments in clinical practice for FL patients at high risk of POD24.

The pear (Pyrus spp.) is well known for diverse flavors, textures, and global horticultural importance. However, the genetic diversity responsible for its extensive phenotypic variations remains largely unexplored. Here, we de novo assembled and annotated the genomes of the maternal (PsbM) and paternal (PsbF) lines of the hybrid ‘Yuluxiang’ pear and constructed the pear pangenome of 1.15 Gb by combining these two genomes with five previously published pear genomes representing cultivated and wild germplasm. Using the constructed pangenome, we identified 21 224 gene PAVs (Presence-absence variation) and 1 158 812 SNPs (Single Nucleotide Polymorphism) in the non-reference genome that were absent in the PsbM reference genome. Compared with SNP markers, PAV-based analysis provides additional insights into the pear population structure. In addition, some genes associated with pear fruit quality traits have differential occurrence frequencies and differential gene expression between Asian and European populations. Moreover, our analysis of the pear pangenome revealed a mutated SNP and an insertion in the promoter region of the gene PsbMGH3.1 potentially enhance sepal shedding in ‘Xuehuali’ which is vital for pear quality. PsbMGH3.1 may play a role in the IAA pathway, contributing to a distinct low-auxin phenotype observed in plants by heterologously overexpressing this gene. This research helps capture the genetic diversity of pear populations and provides genomic resources for accelerating breeding.

Background: The western region of China has a dense population, relatively underdeveloped economy, and a significant number of left-behind children. Currently, the prevalence of adolescent psychological abuse, neglect, and the factors associated with these issues in the region remain unclear. This study aims to evaluate the current status of adolescent psychological abuse and neglect and its associated factors in this region.Methods: Data were collected from 50 schools in western China through cluster sampling to target adolescents aged 12 to 18. A comprehensive survey form was used to collect socio-demographic characteristics of adolescents. The Child Psychological Abuse and Neglect Scale was employed to assess the current psychological abuse and neglect of adolescents. Independent samples t-tests were used for inter-group comparisons. A Directed Acyclic Graph was constructed for controlling confounding variables. Subsequently, binary logistic regression analysis was performed, and a nomogram risk factors model was developed using R Studio.Results: This study included 12,743 teenagers, with an average age of 15.53(±1.39) years. Among them, 4,965 individuals, accounting for 39.0%, reported experiences of psychological abuse, while 4,167 individuals, accounting for 32.7%, reported experiences of neglect. The rates of psychological abuse and neglect in adolescents are influenced by gender, grade, left-behind experience, parental marital status, and living on campus (P

Abstract SKLB1028 is a novel multi‐target protein kinase inhibitor under investigation for the treatment of FLT3‐ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug–drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co‐administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co‐administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

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.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase 2 LOTIS-2 study. In the China bridging pivotal phase 2 OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥ 2 lines of systemic therapies were enrolled and treated with Lonca every 3 week with 150 μg/kg for 2 cycles; then 75 μg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data-cutoff, 64 patients received Lonca (median: 4.0 cycles [range: 1 to 17]). The median number of prior lines of therapies was 3.0 (range: 2 to 12). The ORR was 51.6% (95% CI: 38.7% to 64.2%), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) Grade ≥3 treatment-emergent adverse events (TEAEs), in which increased gamma glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAEs were reported in 35 of 64 patients with 4 fatal TEAEs. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

Abstract Klebsiella pneumoniae, a major clinical pathogen known for causing severe infections, is attracting heightened attention due to its escalating antibiotic resistance. Phages are emerging as a promising alternative to antibiotics; however, their specificity to particular hosts often restricts their use. In this study, a collection of 114 phages is obtained and subjected to analysis against 238 clinical K. pneumoniae strains, revealing a spectrum of lytic behaviors. A correlation between putative tail protein clusters and lysis patterns leads to the discovery of six receptor‐binding protein (RBP) clusters that determine host capsule tropism. Significantly, RBPs with cross‐capsular lysis capabilities are identified. The newly‐identified RBPs provide a toolbox for customizing phages to target diverse capsular types. Building on the toolbox, the engineered phages with altered RBPs successfully shifted and broadened their host capsule tropism, setting the stage for tunable phage that offer a precise and flexible solution to combat K. pneumoniae infections.

Abstract Background Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. Methods Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. Results Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. Conclusions Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. Trial registration ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Abstract Insertion sequences (ISs) promote the transmission of antimicrobial resistance genes (ARGs) across bacterial populations. However, their contributions and dynamics during the transmission of resistance remain unclear. In this study, we selected IS26 as a representative transposable element to decipher the relationship between ISs and ARGs and to investigate their transfer features and transmission trends. We retrieved 2656 translocatable IS26 ‐bounded units with ARGs (tIS26‐bUs‐ARGs) in complete bacterial genomes from the NCBI RefSeq database. In total, 124 ARGs spanning 12 classes of antibiotics were detected, and the average contribution rate of IS26 to these genes was 41.2%. We found that IS26 ‐bounded units (IS26‐bUs) mediated extensive ARG dissemination within the bacteria of the Gammaproteobacteria class, showing strong transfer potential between strains, species, and even phyla. The IS26‐bUs expanded in bacterial populations over time, and their temporal expansion trend was significantly correlated with antibiotic usage. This wide dissemination could be due to the nonspecific target site preference of IS26. Finally, we experimentally confirmed that the introduction of a single copy of IS26 could lead to the formation of a composite transposon mediating the transmission of “passenger” genes. These observations extend our knowledge of the IS26 and provide new insights into the mediating role of ISs in the dissemination of antibiotic resistance.

Abstract A drug–drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early‐phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three‐cycle, self‐controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1‐hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21‐fold based on maximum plasma concentration (Cmax), 8.37‐fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0–t), and 11.22‐fold based on area under the curve from zero to infinity (AUC0–∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27‐fold based on Cmax, ~0.18‐fold based on AUC0–t, and ~0.18‐fold based on AUC0–∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near‐maximal CYP3A levels.

Abstract Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors.

Abstract Anti-programmed cell death-1 (anti-PD-1) therapies have shown a favorable efficacy and good tolerance for relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). However, there are limited data on long-term outcomes among patients with r/r cHL who achieve an objective response to anti-PD-1 therapies. A total of 260 responders from four, phase 2 clinical trials were included in this study. The median age was 32 years with a male/female ratio of 1.3:1. After a median follow-up period of 31.1 months, 116 (44.6%) responders experienced disease progression and 18 (6.9%) died. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 55.1% and 89.7% overall. Patients with partial remission (PR) had inferior outcomes compared with those who achieved complete remission (3-year PFS, 29.5% vs. 72.3%, P

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 Background Streptococcus pneumoniae is a gram-positive opportunistic pathogen, and infection risks of S. pneumoniae can be profoundly augmented by its acquired multidrug-resistance (MDR). The rapid development of MDR in S. pneumoniae was attributed to the international dissemination of a small number of multidrug-resistant “clones.” Clonal complex (CC) 271 is a prevalent MDR CC in the world and the most prevalent CC in China. However, the evolutionary trajectories of multidrug-resistant S. pneumoniae CC271 in China still are largely unknown. Methods We investigated a collection of 1312 S. pneumoniae isolates collected from 28 tertiary hospitals in China from 2007 to 2020. Recombination prediction and recombination-masked phylogenetic analysis were combined to determine the population structure and mode of evolution of CC271. Data from the Global Pneumococcal Sequencing program (GPS) were combined to understand the global distribution of clones identified in this study. Bayesian analysis were recruited to analysis the evolutionary dynamics of dominant clones within CC271 in China. Results The phylogenomic analysis resulted in the discovery of two globally distributed clones, ST271-A and ST271-B. ST271-A was a derivative of ST236 and an ancestor of ST271-B and ST320, refining the internal phylogenetic relationship of CC271. ST271-B was the most dominant clone in China, with higher β-lactam resistance especially for cephalosporins comparing to other MDR clones. Bayesian skyline plot showed a rapid expansion of 19F ST271-B from 1995 to 2000, which correlates with the widespread use of cephalosporins in the 1990s in China. 19A ST320, a vaccine-escape clone, is the second largest population in China. The Bayesian skyline plot showed that the 19A ST320 began to expand rapidly around 2001, which appeared to coincide with the prevalence of 19A after application of PCV7 in 2000 in the USA. We also observed frequent transmission of 19A ST320 between countries. It suggests that mass vaccination in some countries could affect the prevalence of clones in unvaccinated countries in the context of high-frequency international transmission. Conclusions Our results refined the internal phylogenetic relationship of CC271, showing that the 19F ST271-B and 19A ST320 evolved independently from ST271-A, with different histories and driving forces for their evolution and dissemination in China.

The epidemic norovirus causes vomiting and diarrhea and is a highly contagious infection. The disease is affecting human lives in terms of deaths and medical expenses. This study examines the governing dynamics of norovirus by incorporating Lévy noise into a stochastic SIRWF (susceptible, infected, recovered, water contamination, and food contamination) model. The existence of a non-negative solution and its uniqueness are proved after model formulation. Subsequently, the threshold parameter is calculated, and this number is used to explore the conditions under which disease tends to exist in the population. Likewise, additional conditions are derived that ensure the elimination of the disease from the community. It is proved that the norovirus is extinct whenever the threshold parameter is less than one and it persists for Rs>1. The work assumes two working examples to numerically explain the theoretical findings. Simulations of the study are visually presented, and comparisons are made. The results of this study suggest a robust approach for handling complex biological and epidemic phenomena.

IntroductionSuicidal ideation is a critical early stage in the progression towards suicidal be havior. Prior research has established links between sleep quality, impulsivity, and suicidal tendencies, yet the interaction among these factors has been less explored. This study aims to explore the mediating role of impulsivity in the relationship between sleep quality and suicidal ideation in adolescents.MethodsEmploying a cross-sectional study design, 6,974 questionnaires were distributed,including the Socio-demographic Characteristics Questionnaire, Barratt Impulsiveness Scale, the Positive and Negative Suicide Ideation Inventory,and the Pittsburgh Sleep Quality Index Scale. The participants were high school and middle school students from 33 schools in northeastern Sichuan, China, selected through random cluster sampling.ResultsOf these 6,786 questionnaires were analyzed. The participant distribution included 47.2% male and 52.8% female students, with 68.3% from junior schools and 31.7% from senior schools. The prevalence of suicidal ideation was found to be 13.6%. The analysis, which involved correlation analysis and the construction of a structural equation model, revealed that sleep quality had a significant positive effect on impulsivity (β:0.289,p < 0.05), and impulsivity, in turn, had a positive impact on suicidal ideation (β:0.355,p < 0.05).Moreover, sleep quality was directly linked to suicidal ideation (β:0.208,p < 0.05). Thus, sleep quality affects suicidal ideation both directly and indirectly through impulsivity.DiscussionThe results of this study suggest that both sleep quality and impulsivity are significant direct influencers of suicidal ideation among adolescents in the region studied, with impulsivity also playing an indirect role in the relationship between sleep quality and suicidal ideation.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with antitumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/refractory mature Bcell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase 2 dose (RP2D). Overall, 134 Chinese patients were enrolled (dose escalation, n=27; dose expansion, n=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d. The primary efficacy end point of independent review committee–assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% CI, 37.5–64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the doseexpansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased doseproportionally with ascending dose levels from 200–800 mg, without observed saturation. Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Abstract Background Tetramates or tetramic acid-containing compounds (TACs) are a group of bioactive natural products featuring a pyrrolidine-2,4-dione ring acknowledged being closed via Dieckmann cyclization. The cariogenic Streptococcus mutans strains bearing a muc biosynthetic gene cluster (BGC) can synthesize mutanocyclin (MUC), a 3-acetylated TAC that can inhibit both leukocyte chemotaxis and filamentous development in Candida albicans. Some strains can also accumulate reutericyclins (RTCs), the intermediates of MUC biosynthesis with antibacterial activities. However, the formation mechanism of the pyrrolidine-2,4-dione ring of MUC and the distribution of muc-like BGCs along with their ecological functions has not been explored extensively. Results We demonstrated that a key intermediate of MUC biosynthesis, M-307, is installed by a hybrid nonribosomal peptide synthetase-polyketide synthase assembly line and its pyrrolidine-2,4-dione ring is closed via an unprecedented lactam bond formation style. Subsequent C-3 acetylation will convert M-307 to RTCs, which is then hydrolyzed by a deacylase, MucF, to remove the N-1 fatty acyl appendage to generate MUC. Distribution analysis showed that the muc-like BGCs distribute predominantly in human-associated bacteria. Interestingly, most of the muc-like BGCs possessing a mucF gene were isolated from human or livestock directly, indicating their involvement in alleviating the host’s immune attacks by synthesizing MUC; while those BGCs lacking mucF gene distribute mainly in bacteria from fermented products, suggesting that they tend to synthesize RTCs to compete with neighboring bacteria. It is noteworthy that many bacteria in the same habitats (e.g., the oral cavity) lack the muc-like BGC, but possess functional MucF homologues to “detoxify” RTCs to MUC, including several competitive bacteria of S. mutans. We also comparably studied the distribution of TAS1, a fungal enzyme responsible for the production of phytotoxic tenuazonic acids (TeAs), a class of 3-acetylated TACs with similar structure but distinct biosynthetic mechanism to MUC, and found that it mainly exists in plants or crops. Conclusions The in vivo and in vitro experiments revealed that the pyrrolidine-2,4-dione ring of MUC is closed via lactam bond formation, which may be adopted by many TACs without 3-acyl decorations. Besides, we found that muc-like BGCs are widespread in human-associated bacteria and their shapes and main products can be influenced by the habitat environment and vice versa. By comparing with TeAs, we provided thought-provoking insights into how ecological and evolutionary forces drive bacteria and fungi to construct a common 3-acetylated pyrrolidine-2,4-dione core through different routes, and how the biosynthetic processes are delicately controlled to generate diverse 3-acetylated TACs for environmental adaptation. Video Abstract

Acute diarrhea caused by consuming unclean water or food is known as the epidemic cholera. A model for the epidemic cholera is formulated by considering the instants at which a person contracts the disease and the instant at which the individual exhibits symptoms after consuming the poisoned food and water. Initially, the model is formulated from the deterministic point of view, and then it is converted to a system of stochastic differential equations. In addition to the biological interpretation of the stochastic model, we proved the existence of the possible equilibria of the associated deterministic model, and accordingly, stability theorems are presented. It is demonstrated that the proposed stochastic model has a unique global solution, and adequate criteria are constructed by using the Lyapunov function theory, which guarantees that the system has persistence in the mean whenever $ {\bf{R_s^0}} > 1 $. For the case of $ R_s < 1 $, we proved that the disease will tend to be eliminated from the community. Some graphical solutions were produced in order to better validate the analytical results that were acquired. This research can offer a solid theoretical foundation for comprehensive knowledge of other chronic communicable diseases. Additionally, our approach seeks to offer a technique for creating Lyapunov functions that may be utilized to investigate the stationary distributions of models with non-linear stochastic perturbations.

Abstract Background Autologous stem cell transplantation (ASCT) is the standard treatment strategy for refractory or relapsed classical Hodgkin lymphoma (R/R cHL). However, a single transplantation is insufficient to cure the disease because of unfavorable risk factors. Herein, we evaluated the outcomes of single or tandem ASCT in patients with R/R cHL, especially in high‐risk patients. Methods We retrospectively analyzed R/R cHL patients who underwent single or tandem ASCT between April 2000 and June 2021 at the Beijing Cancer Hospital and Peking University International Hospital. Results A total of 134 patients were enrolled. Patients were allocated to a favorable‐risk group (group A, n = 33), an unfavorable‐risk group (group B, n = 81) that underwent single ASCT, and an unfavorable‐risk group that underwent tandem ASCT (group C, n = 20). The median follow‐up time was 99 months (range, 91–107 months), and no treatment‐related deaths occurred after single or tandem ASCT. However, 27 patients (2 in group C) died during the follow‐up period. The groups A, B, and C had 5‐year progression‐free survival (PFS) rates of 77.05%, 45%, and 74.67%, respectively (p = 0.0014), and 5‐year overall survival (OS) rates of 89.85%, 76.06%, and 95%, respectively (p = 0.18). Neither the median PFS rates of groups A and C nor the OS rates of all groups were reached. Conclusions Our study discusses the advantages of tandem transplantation for high‐risk patients with R/R cHL.

Abstract Background To our knowledge, the different situations of identifying second primary malignant tumors (SPMTs) in lymphoma patients with synchronous solid tumors remain to be comprehensively investigated. Methods We retrospectively collected information pertaining to lymphoma patients with synchronous solid tumors (diagnosed within 6 months) at Peking University Cancer Hospital & Institute between 2009 and 2019. The non‐parametric Aalen–Johansen estimator was applied to calculate cumulative incidence function in the competing risk model. Furthermore, propensity score‐matched analysis was performed to compare survival differences in lymphoma patients with or without synchronous solid tumors. Results Thirty‐eight patients were enrolled. There were three situations of identifying SPMTs. First, in 15 patients (39.5%), SPMTs were identified before the initiation of any treatment. Among them, priority was given to anti‐lymphoma treatment in case of only three patients. Second, in 17 patients (44.7%), SPMTs were unexpectedly detected on surgical specimen assessment; of them, 13 received anti‐lymphoma treatment after surgery. Third, in six patients (15.8%), SPMTs were identified after the outset of treatment for the primary tumor; in this population, three of four patients with lymphoma switched toward the treatment plan for SPMTs. The 5‐year overall survival was 58.7%. The cumulative incidence function within 5 years was 26.6% for lymphoma and 14.7% for other solid tumors. The early identification of SPMTs was associated with better outcomes (p = 0.048). After balancing the baseline characteristics, no differences in survival were observed between lymphoma patients with and without synchronous solid tumors (p = 0.664). Conclusions This is the first study to present the different situations of identifying SPMTs in lymphoma patients with synchronous solid tumors. In only

Objectives: The emergence of carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) poses a great threat to public health. There is a paramount need to increase awareness of the epidemiology, evolution, and pathogenesis of CR-hvKP. Methods: We collected strains of K. pneumoniae for over two years in a hospital. CR-hvKP strains were screened by polymerase chain reaction (PCR) with primers targeting the virulence genes. Genome sequencing was used to determine phylogenetic relationships and genetic characterization of virulence elements. The population dynamics within these strains were analyzed through epidemiological data. The string test, siderophore secretion, and murine infection experiments were performed to investigate virulence potential of different clones. Results: A total of 1172 K. pneumoniae strains were isolated from 817 patients, and 125 isolates were identified as CR-hvKP. In all, 102 CR-hvKP strains belonged to sequence type (ST) 11. Genomic analysis demonstrated that three clones of ST11 successively replaced each other in the hospital. Among them, the strains of clade A and clade B acquired virulence plasmids and the strains of clade C acquired a new integrating conjugative element (ICE). Phenotypic experiments revealed enhanced virulence potential of the recent epidemic clone from clade B. Sequence type 11 strains were favorable hosts for the convergence of virulence and resistance, indicated by clonal replacement and acquisition patterns of virulence elements. Conclusion: The emergence of the enhanced virulence potential of ST11 CR-hvKP suggests that coevolution between hosts and exogenous factors can produce super-virulent CR-hvKP strains, highlighting the need to closely monitor changes in the virulence characteristics of CR-hvKP.

Abstract Background The difference between clinical characteristics and outcomes between follicular lymphoma grade 1–2 (FL1-2) and FL3a defined pathologically remains unclear, resulting in uncertainty how to treat FL3a. However, it may be crucial for clinicians to discriminate grade 3a and grade 1–2 for predicting prognosis and thus making treatment decisions. Methods We compared 1403 patients with FL1-2 and 765 patients with FL3a diagnosed between January 2000 and December 2020 from fifteen centers nationwide in China to describe differences in clinical characteristics and outcomes. Results Compared with FL1-2 patients, FL3a subgroup had a higher percentage of elderly patients (P = 0.003), and relatively more FL3a patients presented with increased levels of LDH (P

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Background: The actual relative dose intensity (RDI) of the attenuated R-CCOP regimen (rituximab, cytoxan, pegylated liposomal doxorubicin [PLD], vincristine, and prednisone) has not been fully investigated in Chinese geriatric patients with diffuse large B-cell lymphoma (DLBCL). In particular, the optimum dose for PLD remains unclear. Methods: We retrospectively collected clinical data from patients with untreated DLBCL aged 65–80 years subsequently treated with the R-CCOP. The restricted cubic spline model (RCS) was used to test the non-linear relationship between the predictors and outcomes. Results: Eighty-four patients were enrolled, with a median age of 73.5 years. More than half of the patients (54.8%) received at least 6 cycles. The median dose per cycle of cytoxan and PLD were 605.5 and 19.9 mg/m2. The 5-year progression-free survival (PFS), overall survival rate, and disease-specific survival rates were 38.7%, 44.8%, and 57.2%, respectively. The RDI of PLD (PLD-RDI,

ABSTRACTPurpose : A primary breast lymphomais a rare form of extranodal lymphoma type. We aimed to analyze prognosticriskfactors and explore relapse factors in primary breast diffuse large B cell lymphoma (PB-DLBCL).Methods : From November 2003 to September 2020, sixty-three patients from two medical centers newly diagnosed with PB-DLBCL patients were analyzed retrospectively.Results : The median age was 52, and >50% of patients were post-menopausal. The international prognostics index (IPI) (0–1) was mainlyin the low-risk group (84%), and there were four patients with stage IV (6%) who had bilateral breast involvement. With a median follow-up time of 4.92 years (3.17–8.00), five-year overall survival (OS) and progression-free survival (PFS) were 78.9% and 67.1%, respectively. Univariate and multivariate analyses showed that elevated erythrocyte sedimentation rate (ESR) and B symptoms were independent adverse prognostic risk factors for OS, whereas bilateral breast involvement was unfavorable for PFS. Disease recurrence and relapse occurred in 40% (25/63) patients, mainly in the breast, followed by the central nervous system (CNS) and skin/soft tissue.Conclusion : This is the first study to explore the prognostic risk factors and relapse factorsof PB-DLBCL in a relatively large Chinese PBL cohort. Local breast and CNS recurrence after standard R-CHOP treatment were the main issues we are facing now.

BackgroundFollicular lymphoma (FL) is characterized by an incurable course that frequently necessitates multiple lines of treatment. While a range of new approaches have broadened therapeutic options for patients in later lines, data regarding treatment patterns and outcomes of Chinese patients with relapsed/refractory(R/R) FL was scarcely reported.MethodsThis retrospective single-center study included patients diagnosed with FL grades 1–3a at our institution between January 2002 and December 2019. Endpoints of interest were analyzed according to lines and types of interventions. The endpoints mainly included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsThe study enrolled 566 biopsy-proven patients. Among them, 544 patients initiated the first line of treatment, followed by 240 initiating the second line, 146 initiating the third line, 88 initiating the fourth line, 47 initiating the fifth line, and 28 initiating the sixth line. In terms of treatment patterns, anti-CD20 chemotherapy was a major modality in the first and second lines. However, for patients in the third line and subsequent lines, treatment approaches were diverse, and participation in clinical trials for new medications was common, which correlated with a survival benefit. The study also revealed that clinical indicators (such as ORR, PFS, and OS) gradually decreased with each subsequent line of treatment. The ORR at the first line was 86.6%, but decreased to 48.6% at the third line and 40.4% at the sixth line, respectively. Similarly, median OS and PFS decreased to 88.8 and 7.1 months at the third line and further reduced to 21.7 and 2.8 months at the sixth line, respectively. A total of 133 patients developed progression within 24 months from the initiation of first line anti-CD20 chemotherapy (POD24), and these patients exhibited poorer response rates and outcomes in subsequent lines of therapycompared to the non-POD24 group.ConclusionThis study revealed the clinical routine practices and prognosis of R/R FL patients within the Chinese population. It underscored the unmet need for optimal strategies to improve survival and also served as a benchmark for future trials.

Reactive oxygen species (ROS) and salicylic acid (SA) are essential signaling molecules in plant cells that participate in responses to biotic and abiotic stresses. Changes in ROS and SA signals during interactions between pear and the pear scab pathogen Venturia nashicola remain unclear. Herein, we analyzed the roles of ROS in the signal transduction pathway of pear scab resistance using the highly resistant Huangguan and susceptible Xuehua cultivars of pear (Pyrus bretschneideri Rehd). Protoplasts, calluses, and leaves were obtained from 14-year-old pear trees and treated with V. nashicola for different periods. The results showed that ROS rapidly accumulated in protoplasts of both cultivars within a 120-min treatment period, but the fluorescence intensity of ROS differed between cultivars. The H2O2 content in fruit-derived calluses of Huangguan peaked at 48 h post-infection at levels 1.85 times higher than those in Xuehua. Induction of H2O2 by V. nashicola in Huangguan was more intense than in Xuehua over a 96-h treatment period. At 96 h post-infection, the malondialdehyde content in leaves of Huangguan was significantly lower than in Xuehua, while the activities of superoxide dismutase, peroxidase, and catalase, and the relative expression levels of PbMnSOD, PbPOD, and PbCAT genes were higher in Huangguan than Xuehua. V. nashicola infection also caused a continuous increase in the leaf SA content of Huangguan, which was 6.76 times higher than in Xuehua at 96 h post-infection, and V. nashicola exposure upregulated the expression of PbPAL, PbICS, PbPR1, and PbPR5. In summary, both ROS and SA participated in the responses of pear trees to V. nashicola infection and played vital roles in the signal transduction pathway of pear scab resistance.

The growth and development of apricot flower organs are severely impacted by spring frosts. To better understand this process, apricot flowers were exposed to temperatures ranging from 0 °C to −8 °C, including a control at 18 °C, in artificial incubators to mimic diverse low-temperature environments. We aimed to examine their physiological reactions to cold stress, with an emphasis on changes in phenotype, membrane stability, osmotic substance levels, and antioxidant enzyme performance. Results reveal that cold stress induces significant browning and cellular damage, with a sharp increase in browning rate and membrane permeability below −5 °C. Soluble sugars and proteins initially rise as osmoprotectants, but their content decreases at lower temperatures. Proline content consistently increases, suggesting a protective role. Antioxidant enzyme activities, including catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), exhibit a complex pattern, with initial increases followed by declines at more severe cold conditions. Correlation and principal component analyses highlight the interplay between these responses, indicating a multifaceted adaptation strategy. The findings contribute to the understanding of apricot cold tolerance and inform breeding efforts for improved crop resilience.

Abstract Background Circulating tumor DNA (ctDNA) has been proven to be a promising tumor-specific biomarker in solid tumors, but its clinical utility in risk stratification and early prediction of relapse for diffuse large B cell lymphoma (DLBCL) has not been well explored. Methods Here, using a lymphoma-specific sequencing panel, we assessed the prognostic and predictive utilities of ctDNA measurements before, during, and after first-line therapy in 73 Chinese DLBCL patients. Results The pretreatment ctDNA level serving as an independent prognostic factor for both progression-free survival (PFS, adjusted HR 2.47; p = 0.004) and overall survival (OS, adjusted HR 2.49; p = 0.011) was confirmed in our cohort. Furthermore, the patients classified as molecular responders who presented a larger decrease in ctDNA levels after the initial two treatment cycles had more favorable PFS (unreached vs. 6.25 months; HR 5.348; p = 0.0015) and OS (unreached vs. 25.87; HR 4.0; p = 0.028) than non-responders. In addition, interim ctDNA clearance may be an alternative noninvasive method of positron emission tomography and computed tomography (PET-CT) for predicting better PFS (HR 3.65; p = 0.0033) and OS (HR 3.536; p = 0.016). We also demonstrated that posttreatment ctDNA was a sensitive indicator for detecting minimal residual disease (MRD) in patients with a high risk of recurrence (HR 6.471; p = 0.014), who were otherwise claimed to achieve radiographic CR (complete remission). Conclusions CtDNA is a promising noninvasive tool for prognosis prediction, response assessment, and early relapse prediction of first-line treatment in DLBCL patients.

Abstract Primary central nervous system lymphoma (PCNSL) is a type of central nervous system restricted non-Hodgkin lymphoma, whose histopathological diagnosis is majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective and safe treatment for patients with PCNSL, a panel of experts from the Chinese Neurosurgical Society of the Chinese Medical Association and the Society of Hematological Malignancies of the Chinese Anti-Cancer Association jointly developed an evidence-based consensus. After comprehensively searching literature and conducting systematic reviews, two rounds of Delphi were conducted to reach consensus on the recommendations as follows: The histopathological specimens of PCNSL patients should be obtained as safely and comprehensively as possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids should be withdrawn from, or not be administered to, patients with suspected PCNSL before biopsy if the patient’s status permits. MRI (enhanced and DWI) should be performed for diagnosing and evaluating PCNSL patients where whole-body PET-CT be used at necessary time points. Mini-mental status examination can be used to assess cognitive function in the clinical management. Newly diagnosed PCNSL patients should be treated with combined high-dose methotrexate-based regimen and can be treated with a rituximab-inclusive regimen at induction therapy. Autologous stem cell transplantation can be used as a consolidation therapy. Refractory or relapsed PCNSL patients can be treated with ibrutinib with or without high-dose chemotherapy as re-induction therapy. Stereotactic radiosurgery can be used for PCNSL patients with a limited recurrent lesion who were refractory to chemotherapy and have previously received whole-brain radiotherapy. Patients with suspected primary vitreoretinal lymphoma (PVRL) should be diagnosed by vitreous biopsy. PVRL or PCNSL patients with concurrent VRL can be treated with combined systemic and local therapy.

IntroductionThe treatment for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL) is suboptimal. This open-label, multicenter, single-arm study aimed to investigate the antitumor activity and safety of camrelizumab (a PD-1 blockade) plus apatinib (an antiangiogenic agent) for patients with r/r PTCL.MethodsEligible patients with r/r PTCL were enrolled and received camrelizumab 200 mg intravenously every 2 weeks and apatinib 500 or 250 mg orally once daily, 4 weeks as a cycle. The primary endpoint was overall response rate (ORR).ResultsA total of 20 patients were enrolled and received study medications in the study, with a median number of prior treatment line of 3 (range 1-6). At the cutoff date of March 4, 2022, the median follow-up was 27.2 months (range: 0.5-39.9), and three patients remained on treatment. Six patients had early discontinuation without tumor response evaluation. For all patients, the ORR was 30% (6/20) (95% confidence interval [CI], 11.9% to 54.3%), with two patients (10%) achieving complete response. The median progression-free survival (PFS) and median overall survival for all patients were 5.6 months (95% CI, 1.8 to not reached) and 16.7 months (95% CI, 2.8 to not reached), respectively. Patients with PD-L1 expression ≥50% (3 patients) had a numerically higher ORR and longer median PFS than those with PD-L1 expression < 50% (5 patients). The most commonly reported grade 3 or higher adverse events were hyperlipidemia (15%), hypokalemia (15%) and anemia (15%). No treatment-related deaths occurred.DiscussionIn this study, PD-1 inhibitors plus low-dose antiangiogenic drugs presented preliminary antitumor activity and manageable toxicity in patients with r/r PTCL.

Abstract. Backgrounds:. GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China. Methods:. Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety. Results:. Overall, 58 patients with FL were randomized to the G-chemo (n = 25) and R-chemo arms (n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09–1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%). Conclusions:. The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit–risk profile in patients from China with FL. Trial registration:. ClinicalTrials.gov, No. NCT01332968.

According to China’s national standard, the design of flood retention areas should cover four hydrological situations associated with 10–100-year return period events, and their capacities should be kept operational for at least 30 years after completion. The Huai River basin is one of the large river basins in China, with an area of 270,000 km2 and 31 flood retention areas. To achieve integrated flood management by combining various uses in the flood retention areas, three scenarios were developed for three reference retention areas. The relative efficiency of each flood retention area is assessed using a data envelopment analysis model according to various standards over a period of 35 years after completion. The results show that by considering 10 indexes that refer to flood control capacity and social and economic influences, the partial wetland restoration solution would be the optimal flood management option for the Huai River basin, with highest efficiency. Moreover, by considering the 50-year return period flood standard as the threshold value, maintaining the status quo would be the more efficient approach. This strategy for the sustainable management of flood retention areas in the Huai River basin is promising and can be generalised for other large catchments in China.

Hypervirulent Klebsiella pneumoniae (hvKp) can cause serious infections and has been increasingly reported clinically. However, we still lack the knowledge to what degree hvKp colonize the community. In this study, we investigated colonization of hvKp in healthy human gut and the relationship between gut hvKp and clinically important invasive strains. We compile global genomes of gut K. pneumoniae for in-depth genetic analysis and found most hvKp genomes originated from Chinese datasets; therefore, we collected gut K. pneumoniae isolates from healthy people around China. The results revealed a moderate carriage rate of hvKp in the healthy population (4%–5.19%). Phylogenetic analysis indicated a close relationship between gut hvKp and fatal clinical strains. These results demonstrate that the human gut may serve as a reservoir of hvKp and that gut hvKp can play a role in infection of other body parts.

Abstract Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a high initial response rate followed almost invariably by relapse. Here we report the pooled data from 2 studies, BGB-3111-AU-003 and BGB-3111-206, to explore the efficacy of zanubrutinib monotherapy in relapsed/refractory (R/R) MCL. A total of 112 patients were included. Median follow-up durations were 24.7 and 24.9 months for BGB-3111-AU-003 and BGB-3111-206, respectively. Overall response rate (ORR) and complete response (CR) rate were 84.8% and 62.5%, and median duration of response, progression-free survival (PFS) and overall survival (OS) were 24.9, 25.8 and 38.2 months, respectively. After weighting, the PFS (median: NE vs. 21.1 months, P = 0.235) and OS (median: NE vs. 38.2 months, P = 0.057) were similar but numerically better in the second-line than later-line group. Zanubrutinib was well-tolerated with treatment discontinuation and dose reduction for adverse events in 12.5% and 2.7% of patients, respectively. Hypertension, major hemorrhage and atrial fibrillation/flutter rates were 11.6%, 5.4% and 1.8%, respectively. Zanubrutinib is efficacious in R/R MCL, with a favorable safety profile.

BackgroundThe role of consolidation therapy with autologous stem cell transplantation (ASCT) in patients with peripheral T-cell lymphoma (PTCL) in first complete remission (CR1) or partial remission (PR1) remains controversial. The existing data from China are limited. Therefore, we aimed to investigate the effect of ASCT on the survival of Chinese patients with PTCL showing response to induction chemotherapy at our hospital.MethodsWe retrospectively reviewed the data of patients with PTCL (excluding Natural killer/T cell lymphoma) in CR1 or PR1 treated at Peking University Hospital &Institute from 1996 to 2020. Propensity score matching (PSM) was used to balance clinical characteristics between the ASCT and non-ASCT groups. The primary endpoints were event-free survival (EFS) and overall survival (OS).ResultsOf the 414 selected patients, 73 received ASCT consolidation and 341 did not. Over a median follow-up of 5.7 years, survival was significantly better in the ASCT group than in the non-ASCT group (median EFS, 8.1 years vs. 2.8 years, P = 0.002; median OS, 14.9 years vs. 10.2 years, P = 0.007). The 5-year EFS and OS rates were 68.4% and 77.0% in ASCT group, and 43.2% and 57.6% in non-ASCT group, respectively. The survival benefit was confirmed in the propensity score matched cohort (46 patients who received ASCT and 84 patients who did not receive ASCT): P = 0.007 for median EFS and P = 0.022 for the median OS. Cox regression analysis showed that ASCT was independently associated with better survival: hazard ratio (HR) for EFS, 0.46 (95% CI: 0.28-0.76); HR for OS, 0.50 (95% CI: 0.31-0.84). Subgroup analysis showed that ASCT was more likely to benefit higher-risk patients and those with advanced disease. Among the subtypes of PTCL, the benefit was significant in angioimmunoblastic T-cell lymphoma (HR = 0.26 [95% CI: 0.10-0.66] for EFS and 0.29 [95% CI: 0.12-0.74] for OS), but not in the other subtypes.ConclusionASCT may improve the long-term survival of patients with PTCL in first CR or PR, especially for patients with angioimmunoblastic T-cell lymphoma. The specific groups most likely to benefit from upfront ASCT need to be clearly identified.

Introduction Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell-derived malignant disease. MCL is treated using general chemotherapy; however, disease progression and relapse are common; thus, the development of novel therapeutic targets for treatment of MCL is urgently required. Serum- and glucocorticoid-inducible kinase 1 (SGK1) is involved in various cellular activities, and its dysregulation contributes to the pathogenesis of multiple types of cancer. However, little is known regarding its functional roles and associated molecular mechanisms in MCL. Methods SGK1 inhibition mediated by either shRNA or treatment with SGK1 inhibitor (GSK650394) was conducted in MCL cell lines. Western blotting analysis was performed to figure out the expression of related proteins. MCL-cell-derived xenograft models were constructed to evaluate the anti-tumor effects of SGK1 inhibition or/and Bruton’s tyrosine kinase (BTK) inhibition in vivo. Results In this study, it was shown that inhibition of SGK1 significantly reduced cell proliferation, invasion and migration, increased apoptosis and blocked cell cycle progression in MCL cells. Furthermore, SGK1 inhibition significantly reduced the activation of ERK, AKT/mTOR, JAK2/STAT3 and the NF-κB signaling pathways. Using MCL-cell-derived xenograft mice models, SGK1 inhibition decreased tumor cell proliferation and tumor growth. Importantly, SGK1 overexpression significantly promoted xenograft tumor growth. Moreover, simultaneous inhibition of SGK1 and Bruton tyrosine kinase (BTK) resulted in synergistic anti-tumor effects on MCL both in vitro and in vivo. Conclusion SGK1 may be a novel candidate therapeutic target and simultaneous inhibition of SGK1 and BTK may be a promising therapeutic strategy for MCL patients. Further pre-clinical and even clinical studies of SGK1 inhibitor or combination with BTK inhibitor are essential.

Abstract YY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20–200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted. Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1 .