Search

Modification of g-C 3 N 4 with metal-free biomaterials through an environmentally friendly, low-energy, facile, and rapid single-step method is desired for the preparation of photocatalysts with efficient activity and high selectivity of CO 2 reduction but remains a great challenge. Herein, we develop a phase-transitioned protein modification strategy for photocatalysts through superfast amyloid-like protein assembly on surfaces using a one-step sequential coating method. Metal-free carbon nitride/protein heterojunction composite photocatalysts (the phase-transitioned lysozyme (PTL), phase-transitioned bovine serum albumin (PTB), and phase-transitioned ovalbumin (PTO)-coated carbon nitride@SiO 2 (CN@SiO 2 ) and bioinspired carbon nitride hollow nanospheres (CN-HS) obtained by etching of CN@SiO 2 ) are prepared using lysozyme, bovine serum albumin, and ovalbumin. The insulator-semiconductor heterojunctions formed at the protein-carbon nitride interface promote the migration and separation of photogenerated charges. The exposed hydrophobic alkyl and aryl groups of the surface-modified protein enable the formation of a CO 2 -aqueous solution-photocatalyst three-phase interface on the catalyst surface and the exposed -NH 2 groups provide sites for CO 2 adsorption, which effectively increases CO 2 mass transfer and its adsorption as well as hydrophobicity, promoting CO 2 reduction and inhibiting hydrogen production. Therefore, protein modification effectively improves the CO 2 reduction activity and CO selectivity. For instance, compared to CN-HS, the CO yield of the PTL-modified CN-HS (1346.5 μmol g -1 ) increased by 24.5 times and the CO selectivity reached 90.5%. These findings represent a critical advancement in the surface modification of carbon nitride for CO 2 reduction and the design of bioinspired materials for various applications.

Background: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APL). However, the management of high-risk APL has not been conclusively established. The optimal dosage of anthracycline in the induction has long been debated when ATO is added., Objectives: To explore the management of high-risk APL regarding the optimal dosage of anthracycline in the induction and the predicators of prognosis., Design: This was a retrospective study in the real-world setting., Methods: High-risk APL patients defined as white blood cell (WBC) greater than 10 × 10 9 /L who received ATO-based induction regimens were included. Data on clinical characteristics, treatment regimens, and prognosis including early death (ED) and overall survival (OS) were collected from medical records. Risk factors of ED and OS were analyzed., Results: This research included a total of 130 participants. Fifty (38.5%) patients received ATO+ATRA dual induction plus standard-dose anthracycline (ATO + ATRA + stDNR). Fifty-nine (45.4%) patients received ATO + ATRA with consecutive low-dose anthracycline (ATO + ATRA + ldDNR). Twenty-one (16.2%) patients were treated with ATO and various chemotherapies (ATO + others). Compared with the other two groups, the ATO + ATRA + stDNR group had the lowest ED rate of 4.0% (10.2% and 52.4%, respectively; p  < 0.001). Multivariate analysis revealed that age ⩾60 years (odds ratio (OR) = 8.888, 95% confidence interval (CI): 1.126-70.129), prothrombin time (PT) ⩾18 s (OR = 4.749, 95% CI: 1.252-18.007) and WBC ⩾100 × 10 9 /L (OR = 10.591, 95% CI: 1.995-56.232) were independent risk factors for ED. The 5-year OS rates of the three induction groups were 96%, 80%, and 31%, respectively. None of the 48 patients who underwent ATO + ATRA + stDNR induction relapsed, whereas 9.4% (5/53) patients in ATO + ATRA + ldDNR group relapsed, and the relapse rate was 30.0% (3/10) in ATO + others group ( p  = 0.003). The survival advantage of ATO + ATRA + stDNR was demonstrated by a Cox regression (hazard ratio (HR) = 5.079, 95% CI: 1.071-24.079). WBC ⩾100 × 10 9 /L was correlated with an inferior OS (HR = 3.402, 95% CI: 1.359-8.518)., Conclusion: Compared with low-dose anthracycline, standard-dose anthracycline combined with ATO and ATRA dual induction resulted in excellent outcome for high-risk APL patients., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: Dihydrolipoamide S-acetyltransferase ( DLAT ) is a subunit of the pyruvate dehydrogenase complex (PDC), a rate-limiting enzyme complex, that can participate in either glycolysis or the tricarboxylic acid cycle (TCA). However, the pathogenesis is not fully understood. We aimed to perform a more systematic and comprehensive analysis of DLAT in the occurrence and progression of tumors, and to investigate its function in patients' prognosis and immunotherapy., Methods: The differential expression, diagnosis, prognosis, genetic and epigenetic alterations, tumor microenvironment, stemness, immune infiltration cells, function enrichment, single-cell analysis, and drug response across cancers were conducted based on multiple computational tools. Additionally, we validated its carcinogenic effect and possible mechanism in glioma cells., Results: We exhibited that DLAT expression was increased in most tumors, especially in glioma, and affected the survival of tumor patients. DLAT was related to RNA modification genes, DNA methylation, immune infiltration, and immune infiltration cells, including CD4+ T cells, CD8+ T cells, Tregs, and cancer-associated fibroblasts. Single-cell analysis displayed that DLAT might regulate cancer by mediating angiogenesis, inflammation, and stemness. Enrichment analysis revealed that DLAT might take part in the cell cycle pathway. Increased expression of DLAT leads tumor cells to be more resistant to many kinds of compounds, including PI3Kβ inhibitors, PKC inhibitors, HSP90 inhibitors, and MEK inhibitors. In addition, glioma cells with DLAT silence inhibited proliferation, migration, and invasion ability, and promoted cell apoptosis., Conclusion: We conducted a comprehensive analysis of DLAT in the occurrence and progression of tumors, and its possible functions and mechanisms. DLAT is a potential diagnostic, prognostic, and immunotherapeutic biomarker for cancer patients., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 The Authors.)

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH., (© 2024. The Author(s).)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) maintains the only promising curative option for patients with refractory/relapsed (R/R) acute myeloid leukemia (AML). However, the long-term survival results are suboptimal. Optimization of the conditioning regimen aims to eradicate leukemia blasts and reduce early relapse. Here we reported of the preliminary result of the prospective multicenter single arm study to evaluate the efficacy and safety of a modified dual alkylator-conditioning regimen, MCBC (regimen including Melphalan, Cladribine, Busulfan and Cyclophosphamide) (ChiCTR Registration ID: ChiCTR2000029936). This trial enrolled 56 patients from July 2020 to January 2022. With a median follow-up of 854 days (range 48 to 1343), the 2-year overall survival (OS) and relapse-free survival (RFS) were 60.7 ± 6.5% (95% CI 47.5-73.9) and 57.1 ± 6.6% (95% CI 43.8-70.5), respectively, the estimated 3-year OS and RFS rates were 58.9 ± 6.6% (95% CI 45.6-72.2) and 55.4 ± 6.6% (95% CI 41.9-68.8), respectively. A total of 19 patients experienced relapse, the 2-year cumulative incidence relapse (CIR) rate was 34.2 ± 6.6% (95% CI 19.5-44.8), the estimated 3-year CIR rate was 36.3 ± 6.7% (95% CI 21.1-46.7). Six patients died of severe infection or graft-versus-host disease (GVHD). The non-relapse mortality (NRM) rate was 11.8 ± 4.5% (95% CI 2.4-19.1). Mucositis was the main reported regimen-related toxicity, and it was well controlled. Subgroup analyses illustrated that blasts count ≥ 20% before HSCT and the absence of maintenance treatment after HSCT were poor predictors. Our study confirmed the excellent anti-leukemia activity and acceptable toxicity of the MCBC conditioning regimen in R/R AML. Opportune maintenance treatment after HSCT led to significantly improved OS and RFS., Competing Interests: None., (AJCR Copyright © 2024.)

Histological transformation into an aggressive B-cell lymphoma indicates a poor survival outcome for patients with indolent marginal zone lymphoma (MZL), which has been less studied. Large-scale data with long-term follow-up to investigate MZL transformation is limited. Here, by reporting a US-Nationwide cohort of 30,619 MZL patients diagnosed between 2000 and 2019, we found that transformation occurred in 2.08% (N = 624) of MZL cases, with the transformation incidence of 3.1 per 1,000 person-years. Advanced Ann Arbor stage, nodal MZL (NMZL) and splenic MZL (SMZL) were associated with an elevated risk of transformation. Certain subtype-specific characteristics, such as non-gastric extra-nodal MZL (vs. gastric, HR, 1.51, 95%CI 1.13-2.04; p = 0.006), and receiving splenectomy for SMZL (HR, 2.04, 95%CI 1.28-3.26; p = 0.003), also indicated a higher risk of transformation. Besides, transformation independently increased the overall mortality risk (HR, 1.38, 95%CI 1.24-1.53, p < 0.001), especially the higher lymphoma-caused mortality risk (HR, 3.21, 95%CI 2.81-3.67, p < 0.001). Transformation was also associated with a higher percentage of lymphoma-caused deaths. The post-transformation prognostic analyses demonstrated that female gender and age ≥ 65 years independently affected patients' mortalities. These findings, based on the largest cohort to date, contribute to a better understanding of transformed MZL, and provide valuable reference points for guidelines and patient counseling., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed., (© 2024 Wiley‐VCH GmbH.)

This study aims to analyze the risk factors for the development of multidrug-resistant (MDR) and carbapenem-resistant (CR) bacteria bloodstream infection (BSI) in a patient with acute leukemia (AL) and the mortality in gram-negative bacteria (GNB) BSI. This is a retrospective study conducted at West China Hospital of Sichuan University, which included patients diagnosed with AL and concomitant GNB BSI from 2016 to 2021. A total of 206 patients with GNB BSI in AL were included. The 30-day mortality rate for all patients was 26.2%, with rates of 25.8% for those with MDR GNB BSI and 59.1% for those with CR GNB BSI. Univariate and multivariate analyses revealed that exposure to quinolones (Odds ratio (OR) = 3.111, 95% confidence interval (95%CI): 1.623-5.964, p = 0.001) within the preceding 30 days was an independent risk factor for MDR GNB BSI, while placement of urinary catheter (OR = 6.311, 95%CI: 2.478-16.073, p < 0.001) and exposure to cephalosporins (OR = 2.340, 95%CI: 1.090-5.025, p = 0.029) and carbapenems (OR = 2.558, 95%CI: 1.190-5.497, p = 0.016) within the preceding 30 days were independently associated with CR GNB BSI. Additionally, CR GNB BSI (OR = 2.960, 95% CI: 1.016-8.624, p = 0.047), relapsed/refractory AL (OR = 3.035, 95% CI: 1.265-7.354, p = 0.013), septic shock (OR = 5.108, 95% CI: 1.794-14.547, p = 0.002), platelets < 30 × 10 9 /L before BSI (OR = 7.785, 95% CI: 2.055-29.492, p = 0.003), and inappropriate empiric antibiotic therapy (OR = 3.140, 95% CI: 1.171-8.417, p = 0.023) were independent risk factors for 30-day mortality in AL patients with GNB BSI. Prior antibiotic exposure was a significant factor in the occurrence of MDR GNB BSI and CR GNB BSI. CR GNB BSI increased the risk of mortality in AL patients with GNB BSI., (© 2024. The Author(s).)

The benefit of high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HDM-ASCT) for multiple myeloma (MM) patients with renal insufficiency (RI) is debated. A systematic review and meta-analysis were conducted to assess the safety and efficacy of HDM-ASCT in MM patients with RIs, and the findings were compared with real-world data. The study included 26 articles, 13 of which were pooled for meta-analysis. We compared three different types of MM patients with RI against MM patients with normal renal function (NRF). These patients were: MM patients with RI at the time of transplantation; MM patients with RI at the time of diagnosis; MM patients with RI at diagnosis but with NRF at transplantation. The meta-analysis indicated that MM patients with RIs conditioned with melphalan ≤ 140 mg/m 2 followed by ASCT had transplant-related mortality rates comparable to those without RIs. The complete response rates post-ASCT were similar between MM patients with RIs and those with NRF. Although progression-free survival (PFS) was statistically similar between the groups, MM patients with RIs had significantly poorer overall survival (OS) than those with NRF. The real-world data supported these findings. With a reduced dose of melphalan, ASCT is safe and effective for MM patients with RI. MM patients with RI have similar complete response rates and PFS after ASCT compared to MM patients with NRF. The lower OS in MM patients with RI indicates the need for further research to improve OS in these patients., (© 2024. The Author(s).)

Background: Chromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high-risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively., Methods: In a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the β-value of the corresponding regression coefficient. A predictive risk-scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21-involved risk with the established R-ISS and R2-ISS models., Results: Upon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p < 0.05), which could be effectively mitigated by ASCT. The +1q21-involved risk model, with an AUC of 0.697 in the training set and 0.725 in the validation set, was constructed including Gain(1q21), Amp(1q21), no-ASCT, and TP53 deletion. This model, termed the ultra-high-risk (UHR) model, demonstrated superior performance in predicting shorter PFS compared to the R-ISS stage 3 and R2-ISS stage 4., Conclusion: The UHR model, which integrates the presence of +1q21 with no-ASCT and TP53 deletion, is designed to identify the early relapse subgroup among patients with +1q21 in NDMM., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Clinical trials of Chimeric Antigen Receptor T-cell (CAR-T) therapy have demonstrated remarkable success in treating both solid tumors and hematological malignancies. Nanobodies (Nbs) have emerged as promising antigen-targeting domains for CARs, owing to their high specificity, robust stability, and strong affinity, leading to significant advancements in the field of Nb-CAR-T. In the realm of T-cell acute lymphoblastic leukemia (T-ALL) targets, CD5 stands out as a potentially excellent candidate for T-cell-based CAR therapy, due to its distinct expression on the surface of malignant T-ALL cells. To mitigate graft-versus-host disease associated with allogeneic CAR-T, γδT cells are selected and stimulated from peripheral blood mononuclear cells, and γδT cells are engineered via CRISPR/Cas9 to eliminate fratricide, enabling the creation of fratricide-resistant CAR-γδT CD5- cells. In vitro transcribed (IVT) mRNA is used to construct CAR-T, presenting a safer, faster, and cost-effective method compared to traditional viral vector approaches. In this study, a CD5-VHH library is constructed, and specific CD5-nanobodies are screened for subsequent use in CD5-CAR-γδT CD5- therapy. IVT-mRNA-CD5-CAR-γδT CD5- cells exhibited favorable functional characteristics and demonstrated antitumor efficacy against malignant T cell lines, underlining the potential for advancing mRNA-CD5-CAR-γδT CD5- therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Proteasome inhibitors (PIs), such as bortezomib and calfizomib, were backbone agents in the treatment of multiple myeloma (MM). In this study, we investigated bortezomib interactors in MM cells and identified dihydrolipoamide dehydrogenase (DLD) as a molecular target of bortezomib. DLD catalyzes the oxidation of dihydrolipoamide to form lipoamide, a reaction that also generates NADH. Our data showed that bortezomib bound to DLD and inhibited DLD's enzymatic function in MM cells. DLD knocked down MM cells (DLD-KD) had decreased levels of NADH. Reduced NADH suppressed assembly of proteasome complex in cells. As a result, DLD-KD MM cells had decreased basal-level proteasome activity and were more sensitive to bortezomib. Since PIs were used in many anti-MM regimens in clinics, we found that high expression of DLD correlated with inferior prognosis of MM. Considering the regulatory role of DLD in proteasome assembly, we evaluated DLD targeting therapy in MM cells. DLD inhibitor CPI-613 showed a synergistic anti-MM effect with bortezomib in vitro and in vivo. Overall, our findings elucidated DLD as an alternative molecular target of bortezomib in MM. DLD-targeting might increase MM sensitivity to PIs., (© 2024. The Author(s).)

Although the significant strides in novel therapeutic approaches have prolonged the survival of multiple myeloma (MM) patients, the unfavorable prognosis of cytogenetically high-risk newly diagnosed MM (NDMM) remains intractable with the lack of consensus regarding the choice of maintenance regimens. Therefore, this study was initiated with the aim of examining the effectiveness of various maintenance treatments for this group of patients in jeopardy. Overall, 17 studies with 1937 high-risk NDMM patients were included in the network meta-analysis. Combination therapies involving novel drugs presented encouraging prospects in the maintenance phase, while the patients and circumstances for the application of different regimens still needed to be further distinguished and clarified. To investigate the current status of maintenance therapy of high-risk NDMM patients in clinical practice, a real-world cohort of high-risk NDMM was retrospectively incorporated 80 patients with lenalidomide maintenance and 53 patients with bortezomib maintenance, presenting the median PFS of 31.7 months and 30.4 months, respectively (p = 0.874, HR = 0.966, 95% CI: 0.628-1.486). Collectively, this study illuminated the present constraints of conventional approaches during the maintenance phase for high-risk NDMM patients while highlighting the future potential associated with enhanced regimens integrating novel medications., (© 2024. The Author(s).)

Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPU Low MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3'-untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU-binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn-humanized murine 5TGM1 cells into Crbn I391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (MMACHC) c.482G > A mutation in 195 Chinese cases with CblC disease., Methods: We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months., Results: Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group)., Conclusions: The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. Video Abstract (MP4 136794 kb)., (© 2023. The Author(s).)

Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug-based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus-responsive CPT nano-prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus-responsive CPT nano-prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus-responsive CPT nano-prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano-prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected., (© 2023 Wiley‐VCH GmbH.)

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting., Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut , azacytidine if TET2/KMT2D mut , tucidinostat if CREBBP/EP300 mut , and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099., Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p  = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p  = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p  = 0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%)., Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL., Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400)., Competing Interests: All authors declare no conflict of interest., (© 2024 The Author(s).)

Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes., (© 2024. The Author(s).)

Aggrephagy, a type of autophagy, degrades the aggregation of misfolded protein in cells. However, the role of aggrephagy in multiple myeloma (MM) has not been fully demonstrated. In this study, we first investigated the correlation between aggrephagy signaling, MM immune microenvironment composition and disease prognosis. Single-cell RNA-seq data, including the expression profiles of 12,187 single cells from seven MM bone marrow (BM) and seven healthy BM samples, were analyzed by non-negative matrix factorization for 44 aggrephagy-related genes. Bulk RNA-seq cohorts from the Gene Expression Omnibus database were used to evaluate the prognostic value of aggrephagy-related immune cell subtypes and predict immune checkpoint blockade immunotherapeutic response in MM. Compared with healthy BM, MM BM exhibited different patterns of aggrephagy-related gene expression. In MM BM, macrophages, CD8 + T cells, B cells and natural killer cells could be grouped into four to nine aggrephagy-related subclusters. The signature of aggrephagy signaling molecule expression in the immune cells correlates with the patient's prognosis. Our investigation provides a novel view of aggrephagy signaling in MM tumor microenvironment cells, which might be a prognostic indicator and potential target for MM treatment., (© 2024 John Wiley & Sons Ltd.)

Objective: TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first-in-human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM)., Methods: This is a multicenter phase I clinical trial consisting of the 3+3 dose-escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28-day cycle., Results: Twenty-five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose-limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any-grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time-to-plasma peak concentration of 0.8-1.5 h. The mean half-life was approximately 82 h. The AUC last and C max were approximately 1.9 times higher on day 15 than on day 1. Among 22 response-evaluable patients, 63.7% achieved stable disease or better., Conclusions: TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose-expansion phase., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 10 9 /L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 10 9 /L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 10 9 /L and 50 × 10 9 /L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials., (© 2024. The Author(s).)

Inflammation-associated diseases are very common clinically with a high incidence; however, there is still a lack of effective treatments. Cell-biomimetic nanoplatforms have led to many breakthroughs in the field of biomedicine, significantly improving the efficiency of drug delivery and its therapeutic implications especially for inflammation-associated diseases. Macrophages are an important component of immune cells and play a critical role in the occurrence and progression of inflammation-associated diseases while simultaneously maintaining homeostasis and modulating immune responses. Therefore, macrophage-biomimetic nanoplatforms not only inherit the functions of macrophages including the inflammation tropism effect for targeted delivery of drugs and the neutralization effect of pro-inflammatory cytokines and toxins via membrane surface receptors or proteins, but also maintain the functions of the inner nanoparticles. Macrophage-biomimetic nanoplatforms are shown to have remarkable therapeutic efficacy and excellent application potential in inflammation-associated diseases. In this review, inflammation-associated diseases, the physiological functions of macrophages, and the classification and construction of macrophage-biomimetic nanoplatforms are first introduced. Next, the latest applications of different macrophage-biomimetic nanoplatforms for the treatment of inflammation-associated diseases are summarized. Finally, challenges and opportunities for future biomedical applications are discussed. It is hoped that the review will provide new ideas for the further development of macrophage-biomimetic nanoplatforms., (© 2023 Wiley‐VCH GmbH.)

Objective: Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ&#95;0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition., Methods: Circ&#95;0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets., Results: Circ&#95;0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258-4.415). The circ&#95;0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ&#95;0012152. Cell growth inhibition by circ&#95;0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ&#95;0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells., Conclusion: Circ&#95;0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p., (© 2024. Huazhong University of Science and Technology.)

Splenectomy is an effective treatment for immune thrombocytopenia (ITP). The effect of COVID-19 vaccination on splenectomized patients with ITP during the COVID-19 pandemic has not been reported. Therefore, this study aimed to investigate the effect of COVID-19 vaccination on clinical outcomes in these patients. This was a longitudinal study of splenectomized patients with ITP. A total of 191 splenectomized patients were included in this study. After a median follow-up of 114 months, 146 (76.4%) patients had a sustained response to splenectomy. During COVID-19 infection, vaccinated patients showed a lower risk of severe infections (odds ratio [OR], 0.13; 95% confidence interval [CI]: 0.05-0.36; p < 0.001), hospitalization (OR, 0.13; 95% CI, 0.04-0.48; p = 0.002), and ITP exacerbation (OR, 0.16; 95% CI, 0.04-0.67; p = 0.012). These findings indicate that COVID-19 vaccination plays a protective role in splenectomized patients with ITP., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Relapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready process developed in China, demonstrated remarkable efficacy and manageable safety in the pivotal RELIANCE study. However, no published data are available on the "real-world" use of relma-cel, especially for patients with CNS involvement., Patients and Methods: Retrospective analyses were conducted for commercial relma-cel used in patients with R/R CNSL at 12 clinics. The primary endpoint was to evaluate the proportion of patients who achieved complete response (CR) at 3 months. Secondary endpoints included best complete response (BCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the incidence of adverse events., Results: Among the 22 CNSL patients (12 primary CNSLs; 10 secondary CNSLs), the best overall response rate was 90.9% and the BCR rate was 68.2%. With median follow-up of 316 days (range, 55-618 days), the estimated 1-year PFS rate, DOR, and OS rate were 64.4%, 71.5%, and 79.2%, respectively. Significant clinical benefits were observed in patients who were in durable CR or partial response to the most recent prior therapy preleukapheresis and received relma-cel as consolidation therapy (n=8), with 1-year PFS rate of 100.0% versus 41.7% (p=0.02). In addition, in terms of primary endpoint, non-CR at 3 months postinfusion seemed to be predictive of a worse prognosis, with an estimated 1-year PFS of 83.3% versus 37.0% (p=0.03), respectively. CRS occurred in 72.9% of patients (grade 3: 4.5%) and immune effector cell-associated neurotoxicity syndrome in 36.4% of patients (grade 3: 4.5%). With the add-on agent PD-1 inhibitor (tislelizumab) to the ongoing BTKi, significant re-expansions of CAR T-cell were detected by quantitative PCR or flow cytometry after a median of 2 weeks (range, 12-32 days)., Conclusions: This study was the first and largest real-world study of commercial relma-cel for R/R CNSL, demonstrating promising efficacy and acceptable safety. We reaffirmed the benefit of immuno-agents such as BTKi or PD-1 inhibitor on CAR T-cell re-expansion and hypothesized a dual-agent CAR-T related combinatorial therapies, which warrants further validation. Most importantly, we highlighted the earlier use of CAR T-cell therapy as a consolidative therapy for patients sensitive to salvage therapy, which provided an impetus and inspired-future strategy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Angioimmunoblastic T-cell lymphoma (AITL) is characterized by high recurrence rates and poor prognosis, and effective first-line treatment is lacking. Recently, histone deacetylase inhibitors (HDACi), such as chidamide, have been found to induce durable remissions in AITL patients., Methods: Patients with untreated AITL from March 2015 to March 2023 were retrospectively collected and divided into chemotherapy (ChT) group and chidamide combined with chemotherapy (C-ChT) group based on the first-line treatment received. The comparison of efficacy and safety between the two groups was conducted., Results: 86 patients with newly diagnosed AITL were enrolled, in which 35 patients were in the ChT group and 51 in the C-ChT group. The objective response rate (ORR) of C-ChT group was significantly higher than that of ChT group (84.3% vs. 60%, P = 0.011), and had superior progression-free survival (PFS) (27 months vs. 12 months, P = 0.025). However, no significant difference in overall survival (OS) was observed between the two groups ( P = 0.225). In addition, the responding patients who received autologous stem cell transplantation (ASCT) had superior PFS compared to those who did not ( P = 0.015)., Conclusions: Compared with ChT regimen, C-ChT regimen was well tolerated and had superior ORR and PFS in patients with untreated AITL. ASCT may contribute to longer PFS in remission patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gu, Wang, Zhou, Du and Niu.)

BackgroundEndovascular thrombectomy is the recommended treatment for acute ischaemic stroke, but the optimal blood pressure management strategy during the procedure under general anaesthesia remains controversial. In this study protocol, we propose an intraoperative intensive blood pressure range (110-140 mm Hg systolic blood pressure) based on a retrospective analysis and extensive literature review. By comparing the outcomes of patients who had an acute ischaemic stroke undergoing mechanical thrombectomy under general anaesthesia with standard blood pressure management (140-180 mm Hg systolic blood pressure) versus intensive blood pressure management, we aim to determine the impact of intraoperative intensive blood pressure management strategy on patient prognosis., Methods and Analysis: The study is a double-blinded, randomised, controlled study, with patients randomised into either the standard blood pressure management group or the intensive blood pressure management group. The primary endpoint of the study will be the sequential analysis of modified Rankin Scale scores at 90 days after mechanical thrombectomy., Ethics and Dissemination: The study has been approved by the ethics committee of Shanghai Changhai Hospital with an approval number CHEC2023-015. The results of the study will be published in peer-reviewed international journals., Trial Registration Number: ChiCTR2300070764., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Venetoclax (VEN), a BCL-2 inhibitor, has transformed treatment strategies for elderly and unfit acute myeloid leukemia (AML) patients by significantly improving response rates and survival. However, the predictive factors for VEN efficacy differ from traditional chemotherapy. The clinical relevance of the FAB (French-American-British) monocytic subtype, including M4 and M5, has been debated as a marker for VEN resistance. This real-world study examined 162 newly diagnosed (ND) and 85 relapsed/refractory (R/R) AML patients who received VEN-based therapy at West China Hospital, Sichuan University, from January 2019 to January 2023. We retrospectively collected clinical and treatment data from electronic medical records. The median age of the cohort was 55.5 years (range: 16.5-83.5). The composite complete remission (cCR) rate in the entire cohort was 60.7%. Specifically, among newly diagnosed (ND) patients, FAB monocytic subtypes exhibited lower cCR compared to non-monocytic subtypes (55.1% vs. 76.3%, P = 0.007). Additionally, there were no significant differences observed between M4 and M5 subtypes, both in the ND group (61.7% vs. 40.9%, p = 0.17) and the R/R group (38.2% vs. 40%, p > 0.9). Furthermore, the median follow-up was 238 (range: 7-1120) days. ND patients with monocytic subtypes had shorter overall survival compared to non-monocytic subtypes (295 days vs. not reached, p = 0.0017). Conversely, R/R patients showed no such difference (204 vs. 266 days, p = 0.72). In summary, our study suggests that the FAB monocytic subtype can predict VEN resistance and shorter survival in ND AML patients. Moreover, there is no significant distinction between M4 and M5 subtypes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute promyelocytic leukemia (APL) is generally driven by PML::RARA, but approximately 2% of variant APL patients do not contain this fusion gene and pose challenges in diagnosis and treatment. Here, we reported an aggressive APL patient with variant TNRC18::RARA fusion gene, who was resistant to standard differentiation induction therapy consisting of all-trans retinoic acid (ATRA) and arsenic trioxide but achieved complete remission with venetoclax plus ATRA. Mechanistically, venetoclax possesses synergistic effects in ATRA-induced TNRC18::RARA-positive cell differentiation., (© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)

In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRPα ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRPα blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma., Competing Interests: Declaration of competing interest APT, QZL, HXL and ZXZ have filed patents related to this work. The other authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) is a hematologic malignancy notorious for its high relapse rate and development of drug resistance, in which cell adhesion-mediated drug resistance plays a critical role. This study integrated four RNA sequencing datasets (CoMMpass, GSE136337, GSE9782, and GSE2658) and focused on analyzing 1706 adhesion-related genes. Rigorous univariate Cox regression analysis identified 18 key prognosis-related genes, including KIF14, TROAP, FLNA, MSN, LGALS1, PECAM1, and ALCAM, which demonstrated the strongest associations with poor overall survival (OS) in MM patients. To comprehensively evaluate the impact of cell adhesion on MM prognosis, an adhesion-related risk score (ARRS) model was constructed using Lasso Cox regression analysis. The ARRS model emerged as an independent prognostic factor for predicting OS. Furthermore, our findings revealed that a heightened cell adhesion effect correlated with tumor resistance to DNA-damaging drugs, protein kinase inhibitors, and drugs targeting the PI3K/Akt/mTOR signaling pathway. Nevertheless, we identified promising drug candidates, such as tirofiban, pirenzepine, erlotinib, and bosutinib, which exhibit potential in reversing this resistance. In vitro , experiments employing NCIH929, RPMI8226, and AMO1 cell lines confirmed that MM cell lines with high ARRS exhibited poor sensitivity to the aforementioned candidate drugs. By employing siRNA-mediated knockdown of the key ARRS model gene KIF14, we observed suppressed proliferation of NCIH929 cells, along with decreased adhesion to BMSCs and fibronectin. This study presents compelling evidence establishing cell adhesion as a significant prognostic factor in MM. Additionally, potential molecular mechanisms underlying adhesion-related resistance are proposed, along with viable strategies to overcome such resistance. These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 Hu et al.)

Objectives: This meta-analysis focused on systematically assessing the clinical value of mNGS for infection in hematology patients., Methods: We searched for studies that assessed the clinical value of mNGS for infection in hematology patients published in Embase, PubMed, Cochrane Library, Web of Science, and CNKI from inception to August 30, 2023. We compared the detection positive rate of pathogen for mNGS and conventional microbiological tests (CMTs). The diagnostic metrics, antibiotic adjustment rate and treatment effective rate were combined., Results: Twenty-two studies with 2325 patients were included. The positive rate of mNGS was higher than that of CMT (blood: 71.64% vs. 24.82%, P < 0.001; BALF: 89.86% vs. 20.78%, P < 0.001; mixed specimens: 82.02% vs. 28.12%, P < 0.001). The pooled sensitivity and specificity were 87% (95%CI: 81-91%) and 59% (95%CI: 43-72%), respectively. The reference standard/neutropenia and research type/reference standard may be sources of heterogeneity in sensitivity and specificity, respectively. The pooled antibiotic adjustment rate according to mNGS was 49.6% (95% CI: 41.8-57.4%), and the pooled effective rate was 80.9% (95% CI: 62.4-99.3%)., Conclusion: mNGS has high positive detection rates in hematology patients. mNGS can guide clinical antibiotic adjustments and improve prognosis, especially in China., (© 2024. The Author(s).)

Introduction: Metagenomic next-generation sequencing (mNGS) is a novel technique for detecting pathogens. This retrospective study evaluated the diagnostic value of mNGS using plasma for infections in hematology patients and its impact on clinical treatment and prognosis in different subgroups of hematology patients., Methods: A total of 153 hematology patients with suspected infection who underwent mNGS using plasma were enrolled in the study. Their clinical histories, conventional microbiological test (CMT) results, mNGS results, treatment and prognosis were retrospectively analyzed., Results: In 153 plasma samples, mNGS yielded a higher positivity rate than CMT (total: 88.24% vs. 40.52%, P<0.001; bacteria: 35.95% vs. 21.57%, P < 0.01; virus: 69.93% vs. 21.57%, P<0.001; fungi: 20.26% vs. 7.84%, P<0.01). mNGS had a higher positivity rate for bacteria and fungi in the neutropenia group than in the non-neutropenia group (bacteria: 48.61% vs. 24.69%, P<0.01; fungi: 27.78% vs. 13.58%, P<0.05). mNGS demonstrated a greater advantage in the group of patients with hematopoietic stem cell transplantation (HSCT). Both the 3-day and 7-day efficacy rates in the HSCT group were higher than those in the non-HSCT group (3-day: 82.22% vs. 58.65%, P < 0.01; 7-day: 88.89% vs. 67.31%, P < 0.01), and the 28-day mortality rate was lower in the HSCT group than in the non-HSCT group (6.67% vs. 38.89%, P < 0.000). The neutropenia group achieved similar efficacy and mortality rates to the non-neutropenia group (7-day efficiency rate: 76.39% vs. 71.43%, P > 0.05; mortality rate: 29.17% vs. 29.63%, P > 0.05) with more aggressive antibiotic adjustments (45.83% vs. 22.22%, P < 0.01)., Conclusion: mNGS can detect more microorganisms with higher positive rates, especially in patients with neutropenia. mNGS had better clinical value in patients with hematopoietic stem cell transplantation (HSCT) or neutropenia, which had a positive effect on treatment and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Wang, Gan, Li, Liao, Zhou and Niu.)

Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment., (© 2023. The Author(s).)

StemDriver is a comprehensive knowledgebase dedicated to the functional annotation of genes participating in the determination of hematopoietic stem cell fate, available at http://biomedbdc.wchscu.cn/StemDriver/. By utilizing single-cell RNA sequencing data, StemDriver has successfully assembled a comprehensive lineage map of hematopoiesis, capturing the entire continuum from the initial formation of hematopoietic stem cells to the fully developed mature cells. Extensive exploration and characterization were conducted on gene expression features corresponding to each lineage commitment. At the current version, StemDriver integrates data from 42 studies, encompassing a diverse range of 14 tissue types spanning from the embryonic phase to adulthood. In order to ensure uniformity and reliability, all data undergo a standardized pipeline, which includes quality data pre-processing, cell type annotation, differential gene expression analysis, identification of gene categories correlated with differentiation, analysis of highly variable genes along pseudo-time, and exploration of gene expression regulatory networks. In total, StemDriver assessed the function of 23 839 genes for human samples and 29 533 genes for mouse samples. Simultaneously, StemDriver also provided users with reference datasets and models for cell annotation. We believe that StemDriver will offer valuable assistance to research focused on cellular development and hematopoiesis., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A new scoring system termed sepsis-induced coagulopathy (SIC) has been proposed to diagnose early sepsis-induced disseminated intravascular coagulation (DIC). This study performed DIC-related analyses in patients with confirmed SIC. Data from the intensive care unit (ICU) departments of the three hospitals between 2020 and 2022 were retrospectively analyzed. Finally, 125 patients with confirmed SIC were enrolled in the study. The diagnostic value of three widely used DIC criteria was assessed in patients with newly diagnosed SIC. In addition, the diagnostic and prognostic value of antithrombin (AT) was analyzed in patients with SIC. The Japanese Association for Acute Medicine DIC criteria (JAAM) exhibited the highest DIC diagnostic rate, while the mortality risk of SIC patients demonstrated a proportional increase with higher International Society on Thrombosis and Haemostasis (ISTH) and Chinese DIC scoring system (CDSS) scores. Low AT activity (<70%) in septic patients upon SIC diagnosis predicted a very high 28-day mortality rate, almost twice as high as in the normal AT activity (≥70%) group. A decreasing tendency in AT activity after clinical interventions was correlated with increased mortality. The area under the ROC curve (AU-ROC) of AT in DIC diagnosis was statistically significant when CDSS and ISTH were used as diagnostic criteria, but not JAAM. Each of the three DIC diagnostic criteria showed diagnostic and prognostic advantages for SIC. AT could be an independent prognostic indicator for SIC but demonstrated a relatively limited DIC diagnostic value. Adding AT to the SIC scoring system may increase its prognostic power., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Multiple myeloma (MM) is an incurable haematological cancer. Selinexor is the first-in-class selective inhibitor of nuclear export (SINE) and was newly approved for the treatment of MM. Until now, very few studies have investigated selinexor resistance in MM. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is an RNA-binding protein and a component of hnRNP complexes. Here we found that hnRNPU regulates MM sensitivity to selinexor. Cell apoptosis assays were performed to compare selinexor-induced cell death in control knockdown (CTR-KD) and hnRNPU knockdown (hnR-KD) MM cells. HnRNPU knockdown-induced nuclear protein retention was examined by proteomics array. HnRNPU-conferred mRNA translation regulation was evaluated by sucrose gradient assay, RNA electrophoresis mobility shift assay, and RNA pull-down assay. We found that hnR-KD MM cells were more sensitive to selinexor-induced cell death in vitro and in mouse model. MM patients who responded to selinexor had relatively low hnRNPU expression. In brief, hnRNPU comprehensively regulated MM sensitivity to selinexor by affecting the localization of LTV1 and NMD3, and mRNA translation of MDM2 and RAN, which were involved in XPO1-mediated nuclear export of ribosome subunits and tumor suppressors. Our discoveries indicate that hnRNPU might be a possible marker to categorize MM patients for the use of Selinexor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: The clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11 mut ) in acute myeloid leukemia (AML) is underestimated., Methods: We collected the data of AML patients with mutated PTPN11 and wild-type PTPN11 (PTPN11 wt ) treated at our hospital and analyzed their clinical characteristics and prognosis., Results: Fifty-nine PTPN11 mut and 124 PTPN11 wt AML patients were included. PTPN11 mut was more common in myelomonocytic and monocytic leukemia, and was more likely to co-mutate with KRAS, KMT2C, NRAS, U2AF1, NOTCH1, IKZF1, and USH2A mutations than PTPN11 wt . The overall survival for AML patients with PTPN11 mut was significantly shorter than that for those with PTPN11 wt (p = 0.03). The negative impact of PTPN11 mut on overall survival was pronounced in the "favorable" and "intermediate" groups of ELN2017 risk stratification, as well as in the wild-type NPM1 group (p = 0.01, p = 0.01, and p = 0.04)., Conclusion: PTPN11 mut is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Our objective is to compare the early outcomes associated with passive (gravity) drainage (PG) and active drainage (AD) after surgery., Methods: Studies published until April 28, 2022 were retrieved from the PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science databases., Results: Nine studies with 14,169 patients were identified. Two groups had the same intra-abdominal infection rate (RR: 0.55; P  = 0.13); In subgroup analysis of pancreaticoduodenectomy, active drainage had no significant effect on postoperative pancreatic fistula (POPF) rate (RR: 1.21; P  = 0.26) and clinically relevant POPF (CR-POPF) (RR: 1.05; P  = 0.72); Active drainage was not associated with lower percutaneous drainage rate (RR: 1.00; P  = 0.96), incidence of sepsis (RR: 1.00; P  = 0.99) and overall morbidity (RR: 1.02; P  = 0.73). Both groups had the same POPF rate (RR: 1.20; P  = 0.18) and CR-POPF rate (RR: 1.20; P  = 0.18) after distal pancreatectomy. There was no difference between two groups on the day of drain removal after pancreaticoduodenectomy (Mean difference: -0.16; P  = 0.81) and liver surgery (Mean difference: 0.03; P  = 0.99)., Conclusions: Active drainage is not superior to passive drainage and both drainage methods can be considered.