Single-stranded siRNAs activate RNAi in animals.

The therapeutic utility of siRNAs is limited by the requirement for complex formulations to deliver them to tissues. If potent single-stranded RNAs could be identified, they would provide a simpler path to pharmacological agents. Here, we describe single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation. Effective ss-siRNAs were identified by iterative design by determining structure-activity relationships correlating chemically modified single strands and Argonaute 2 (AGO2) activities, potency in cells, nuclease stability, and pharmacokinetics. We find that the passenger strand is not necessary for potent gene silencing. The guide-strand activity requires AGO2, demonstrating action through the RNAi pathway. ss-siRNA action requires a 5' phosphate to achieve activity in vivo, and we developed a metabolically stable 5'-(E)-vinylphosphonate (5'-VP) with conformation and sterioelectronic properties similar to the natural phosphate. Identification of potent ss-siRNAs offers an additional option for RNAi therapeutics and an alternate perspective on RNAi mechanism.

GVHD targets organoid-forming bile duct stem cells via a TGF-ß-dependent manner.

Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). While adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) upon injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, significantly reduced in a TGF--dependent manner. Administration of SB-431542, an inhibitor of TGF-ß signaling, from day 14 to day 28 protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.

Neuroblast differentiation during development and in neuroblastoma requires KIF1Bß-mediated transport of TRKA.

We recently identified pathogenic KIF1Bß mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bß in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bß is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bß mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bß-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bß. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bß independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bß loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bß mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Single-cell landscape reveals the immune heterogeneity of bone marrow involvement in peripheral T-cell lymphoma.

The prognosis of patients with peripheral T-cell lymphoma (PTCL) depends on bone marrow involvement (BMI). The bone marrow (BM) tumor microenvironment in PTCL remains unclear. We performed single-cell RNA sequencing (scRNA-seq) on 11 fresh BM samples from patients with BMI to reveal the associations of immune landscape and genetic variations with the prognosis of PTCL patients. Compared with PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL) had a higher number of T cells, lower number of lymphocytes, and greater inflammation. Immune heterogeneity in AITL is associated with prognosis. In particular, specific T-cell receptor (TCR) T cells are enriched in patients with good response to anti-CD30 therapy. We observed RhoA mutation-associated neoantigens. Chidamide-treated patients had a higher number of CD4+ regulatory cells and a better treatment response compared with other patients. In the nonresponder group, T-cell enrichment progressed to secondary B-cell enrichment and subsequently diffuse large B-cell lymphoma. Moreover, AITL patients with lymphoma-associated hemophagocytic syndrome had more T follicular helper (Tfh) cells with copy number variations in CHR5. To our knowledge, this study is the first to reveal the single-cell landscape of BM microenvironment heterogeneity in PTCL patients with BMI. scRNA-seq can be used to investigate the immune heterogeneity and genetic variations in AITL associated with prognosis.

Genome-wide identification and investigation of monosaccharide transporter gene family based on their evolution and expression analysis under abiotic stress and hormone treatments in maize (Zea mays L.).

BACKGROUND: Monosaccharide transporter (MST) family, as a carrier for monosaccharide transport, plays an important role in carbon partitioning and widely involves in plant growth and development, stress response, and signaling transduction. However, little information on the MST family genes is reported in maize (Zea mays), especially in response to abiotic stresses. In this study, the genome-wide identification of MST family genes was performed in maize. RESULT: A total of sixty-six putative members of MST gene family were identified and divided into seven subfamilies (including SPT, PMT, VGT, INT, pGlcT, TMT, and ERD) using bioinformatics approaches, and gene information, phylogenetic tree, chromosomal location, gene structure, motif composition, and cis-acting elements were investigated. Eight tandem and twelve segmental duplication events were identified, which played an important role in the expansion of the ZmMST family. Synteny analysis revealed the evolutionary features of MST genes in three gramineous crop species. The expression analysis indicated that most of the PMT, VGT, and ERD subfamilies members responded to osmotic and cadmium stresses, and some of them were regulated by ABA signaling, while only a few members of other subfamilies responded to stresses. In addition, only five genes were induced by NaCl stress in MST family. CONCLUSION: These results serve to understand the evolutionary relationships of the ZmMST family genes and supply some insight into the processes of monosaccharide transport and carbon partitioning on the balance between plant growth and development and stress response in maize.

Genetic variation in ZmKW1 contributes to kernel weight and size in dent corn and popcorn.

Kernel weight is a critical factor that essentially affects maize (Zea mays) yield. In natural inbred lines, popcorn kernels exhibit overtly smaller sizes compared to dent corn kernels, and kernel weight, which is controlled by multiple genetic loci, varies widely. Here, we characterized a major quantitative trait locus on chromosome 1, responsible for controlling kernel weight (qKW1) and size. The qKW1 locus encodes a protein containing a seven in absentia domain with E3 ubiquitin ligase activity, expressed prominently from the top to the middle region of the endosperm. The presence and function of qKW1 were confirmed through ZmKW1 gene editing, where the mutations in ZmKW1 within dent corn significantly increased kernel weight, consistent with alterations in kernel size, while overexpression of ZmKW1 had the opposite effect. ZmKW1 acts as a negative regulator of kernel weight and size by reducing both the number and size of the endosperm cells and impacting endosperm filling. Notably, the popcorn allele qKW1N and the dent corn allele qKW1D encode identical proteins; however, the differences in promoter activity arise due to the insertion of an Indel-1346 sequence in the qKW1N promoter, resulting in higher expression levels compared to qKW1D, thus contributing to the variation in kernel weight and size between popcorn and dent corn kernels. Linkage disequilibrium analysis of the 2.8 kb promoter region of ZmKW1 in a dataset comprising 111 maize association panels identified two distinct haplotypes. Our results provide insight into the mechanisms underlying kernel development and yield regulation in dent corn and popcorn, with a specific focus on the role of the ubiquitination system.

The relative and combined ability of stress hyperglycemia ratio and N-terminal pro-B-type natriuretic peptide to predict all-cause mortality in diabetic patients with multivessel coronary artery disease.

BACKGROUND: Stress hyperglycemia ratio (SHR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are independently associated with increased mortality risk in diabetic patients with coronary artery disease (CAD). However, the role of these biomarkers in patients with diabetes and multivessel disease (MVD) remains unknown. The present study aimed to assess the relative and combined abilities of these biomarkers to predict all-cause mortality in patients with diabetes and MVD. METHODS: This study included 1148 diabetic patients with MVD who underwent coronary angiography at Tianjin Chest Hospital between January 2016 and December 2016. The patients were divided into four groups according to their SHR (SHR-L and SHR-H) and NT-proBNP (NT-proBNP-L and NT-proBNP-H) levels. The primary outcome was all-cause mortality. Multivariate Cox regression analyses were performed to evaluate the association of SHR and NT-proBNP levels with all-cause mortality. RESULTS: During a mean 4.2 year follow-up, 138 patients died. Multivariate analysis showed that SHR and NT-proBNP were strong independent predictors of all-cause mortality in diabetic patients with MVD (SHR: HR hazard ratio [2.171; 95%CI 1.566-3.008; P < 0.001; NT-proBNP: HR: 1.005; 95%CI 1.001-1.009; P = 0.009). Compared to patients in the first (SHR-L and NT-proBNP-L) group, patients in the fourth (SHR-H and NT-proBNP-H) group had the highest mortality risk (HR: 12.244; 95%CI 5.828-25.721; P < 0.001). The areas under the curve were 0.615(SHR) and 0.699(NT-proBNP) for all-cause mortality. Adding either marker to the original models significantly improved the C-statistic and integrated discrimination improvement values (all P < 0.05). Moreover, combining SHR and NT-proBNP levels into the original model provided maximal prognostic information. CONCLUSIONS: SHR and NT-proBNP independently and jointly predicted all-cause mortality in diabetic patients with MVD, suggesting that strategies to improve risk stratification in these patients should incorporate SHR and NT-porBNP into risk algorithms.

ZmMPK6, a mitogen-activated protein kinase, regulates maize kernel weight.

Kernel weight is a critical agronomic trait in maize production. Many genes are related to kernel weight but only a few of them have been applied to maize breeding and cultivation. Here, we identify a novel function of maize mitogen-activated protein kinase 6 (ZmMPK6) in the regulation of maize kernel weight. Kernel weight was reduced in zmmpk6 mutants and increased in ZmMPK6-overexpressing lines. In addition, starch granules, starch content, protein content, and grain-filling characteristics were also affected by the ZmMPK6 expression level. ZmMPK6 is mainly localized in the nucleus and cytoplasm, widely distributed across various tissues, and is expressed during kernel development, which is consistent with its role in kernel weight. Thus, these results provide new insights into the role of ZmMPK6, a mitogen-activated protein kinase, in maize kernel weight, and could be applied to further molecular breeding for kernel quality and yield in maize.

Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor 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 B-cell 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 II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). 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% confidence interval: 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 dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Development of IL-17A inhibitor-induced atopic dermatitis-like rash in psoriasis patients: Insights into immune shift.

Cases of atopic dermatitis (AD)-like rash induced by IL-17A inhibitor secukinumab treatment (SI-AD) have been recently reported in psoriasis patients. To identify immune and inflammatory factors expression in SI-AD. A panel of 15 immune and inflammatory factors in peripheral blood samples from various groups, including patients with patients with SI-AD, psoriasis with secukinumab (S-stable), advanced psoriasis patients (Advanced) and healthy controls (HC). Interleukin-10 (IL-10), IL-4 and IL-17A were detected in skin tissue biopsy samples by immunohistochemistry and real-time quantitative polymerase chain reaction. The immunoglobulin E levels in the SI-AD patients exceeded normal values. The IL-10 levels in SI-AD patients were higher than those in S-stable patients, advanced patients and HC. The IL-4 levels in SI-AD patients were higher than that in S-stable patients and HC. The IL-17A levels in SI-AD patients were higher than those in advanced psoriasis patients and HC, but no significant differences were observed between SI-AD patients and S-stable patients. IL-10 and IL-4 levels were higher in AD-like rashes than in healthy skin, while IL-17A did not differ significantly between the two. Upon discontinuing secukinumab, and switching to oral cyclosporine, antihistamines, Janus kinase 1 inhibitor and topical glucocorticoids, SI-AD patients experienced significant improvement in their skin lesions. Upon reexamination, all 15 immune and inflammatory factors returned to normal levels. Immune shift from Th17 towards Th2 may occur in SI-AD, as indicated by abnormal expression of multiple immune and inflammatory factors observed in peripheral blood and skin tissues.

Tailoring Charge Separation in ZnIn2S4@CdS Hollow Nanocages for Simultaneous Alcohol Oxidation and CO2 Reduction under Visible Light.

Artificial photosynthesis provides a sustainable strategy for producing usable fuels and fine chemicals and attracts broad research interest. However, conventional approaches suffer from low reactivity or low selectivity. Herein, we demonstrate that photocatalytic reduction of CO2 coupled with selective oxidation of aromatic alcohol into corresponding syngas and aromatic aldehydes can be processed efficiently and fantastically over the designed S-scheme ZnIn2S4@CdS core-shell hollow nanocage under visible light. In the ZnIn2S4@CdS heterostructure, the photoexcited electrons and holes with weak redox capacities are eliminated, while the photoexcited electrons and holes with powder redox capacities are separated spatially and preserved on the desired active sites. Therefore, even if there are no cocatalysts and no vacancies, ZnIn2S4@CdS exhibits high reactivity. For instance, the CO production of ZnIn2S4@CdS is about 3.2 and 3.4 times higher than that of pure CdS and ZnIn2S4, respectively. More importantly, ZnIn2S4@CdS exhibits general applicability and high photocatalytic stability. Trapping agent experiments, 13CO2 isotopic tracing, in situ characterizations, and theoretical calculations reveal the photocatalytic mechanism. This study provides a new strategy to design efficient and selective photocatalysts for dual-function redox reactions by tailoring the active sites and regulating vector separation of photoexcited charge carriers.

The STAT3 inhibitor stattic overcome bortezomib-resistance in multiple myeloma via decreasing PSMB6.

Bortezomib, an FDA approved drug in 2003 for newly diagnosed and relapsed/refractory MM, had showed great efficacy in different clinical settings. However, many patients still developed resistance to Bortezomib, and the mechanism of action remains unelucidated. Here, we showed that Bortezomib resistance can be partially overcome by targeting a different subunit of 20 S complex - PSMB6. PSMB6 knock down by shRNA increased sensitivity to Bortezomib in resistant and sensitive cell line. Interestingly, a STAT3 inhibitor, Stattic, is shown to selectively inhibit PSMB6 and induce apoptosis in Bortezomib resistant and sensitive MM cells, even with IL-6 induction. Therefore, PSMB6 is a novel target for Bortezomib resistance and Stattic may offer a potential therapeutic strategy.

An endoplasmic reticulum-localized cytochrome b5 regulates high-affinity K+ transport in response to salt stress in rice.

Potassium (K+) is an essential element for growth and development in both animals and plants, while high levels of environmental sodium (Na+) represent a threat to most plants. The uptake of K+ from high-saline environments is an essential mechanism to maintain intracellular K+/Na+ homeostasis, which can help reduce toxicity caused by Na+ accumulation, thereby improving the salt tolerance of plants. However, the mechanisms and regulation of K+-uptake during salt stress remain poorly understood. In this study, we identified an endoplasmic reticulum-localized cytochrome b5 (OsCYB5-2) that interacted with a high-affinity K+ transporter (OsHAK21) at the plasma membrane. The association of OsCYB5-2 with the OsHAK21 transporter caused an increase in transporter activity by enhancing the apparent affinity for K+-binding but not Na+-binding. Heme binding to OsCYB5-2 was essential for the regulation of OsHAK21. High salinity directly triggered the OsHAK21-OsCYB5-2 interaction, promoting OsHAK21-mediated K+-uptake and restricting Na+ entry into cells; this maintained intracellular K+/Na+ homeostasis in rice cells. Finally, overexpression of OsCYB5-2 increased OsHAK21-mediated K+ transport and improved salt tolerance in rice seedlings. This study revealed a posttranslational regulatory mechanism for HAK transporter activity mediated by a cytochrome b5 and highlighted the coordinated action of two proteins to perceive Na+ in response to salt stress.

The OsWRKY72-OsAAT30/OsGSTU26 module mediates reactive oxygen species scavenging to drive heterosis for salt tolerance in hybrid rice.

Hybrid rice (Oryza sativa) generally outperforms its inbred parents in yield and stress tolerance, a phenomenon termed heterosis, but the underlying mechanism is not completely understood. Here, we combined transcriptome, proteome, physiological, and heterosis analyses to examine the salt response of super hybrid rice Chaoyou1000 (CY1000). In addition to surpassing the mean values for its two parents (mid-parent heterosis), CY1000 exhibited a higher reactive oxygen species scavenging ability than both its parents (over-parent heterosis or heterobeltiosis). Nonadditive expression and allele-specific gene expression assays showed that the glutathione S-transferase gene OsGSTU26 and the amino acid transporter gene OsAAT30 may have major roles in heterosis for salt tolerance, acting in an overdominant fashion in CY1000. Furthermore, we identified OsWRKY72 as a common transcription factor that binds and regulates OsGSTU26 and OsAAT30. The salt-sensitive phenotypes were associated with the OsWRKY72paternal genotype or the OsAAT30maternal genotype in core rice germplasm varieties. OsWRKY72paternal specifically repressed the expression of OsGSTU26 under salt stress, leading to salinity sensitivity, while OsWRKY72maternal specifically repressed OsAAT30, resulting in salinity tolerance. These results suggest that the OsWRKY72-OsAAT30/OsGSTU26 module may play an important role in heterosis for salt tolerance in an overdominant fashion in CY1000 hybrid rice, providing valuable clues to elucidate the mechanism of heterosis for salinity tolerance in hybrid rice.

Risk factors for converting traditional wards to temporary intensive care units during the COVID-19 pandemic: Insights from nurses' perspectives.

BACKGROUND: The surge in critically ill COVID-19 patients caused a shortage of intensive care unit (ICU) beds. Some hospitals temporarily transformed general wards into ICUs to meet this pressing health care demand. AIM: This study aims to evaluate and analyse the risk factors in temporary ICU from the perspective of nurses. By identifying these factors, the goal is to provide actionable insights and recommendations for effectively establishing and managing temporary ICUs in similar crisis scenarios in the future. STUDY DESIGN: The study was conducted in China within a public hospital. Specifically, it focused on examining 62 nurses working in a temporary ICU that was converted from an infectious disease ward. The research utilized the Hazard Vulnerability Analysis (HVA) scoring method to identify potential threats, evaluate their probability, estimate their impact on specific organizations or regions and calculate the relative risk associated with such occurrences. RESULTS: Staff demonstrated the highest risk percentage (32.74%), with Stuff (16.11%), Space (15.19%) and System (11.30%) following suit. The most critical risk factors included insufficient knowledge and decision-making competence in critical care (56.14%), lacking decision-making abilities and skills in renal replacement therapy care (55.37%), inadequate decision-making capacity and relevant skills in respiratory support care (50.64%), limited decision-making capability in circulatory support care (45.73%) and unfamiliarity with work procedures or systems (42.09%). CONCLUSIONS: Urgent implementation of tailored training and support for temporary ICU nurses is paramount. Addressing capability and skill-related issues among these nurses supersedes resource availability, infrastructure, equipment and system considerations. Essential interventions must target challenges encompassing nurses' inability to perform critical treatment techniques autonomously and ensure standardized care. These measures are designed to heighten patient safety and elevate care quality during emergencies. These findings offer a viable avenue to mitigate potential moral distress, anxiety and depression among nurses, particularly those transitioning from non-critical care backgrounds. These nurses swiftly assimilate into temporary ICUs, and the study's insights offer practical guidance to alleviate their specific challenges. RELEVANCE TO CLINICAL PRACTICE: The study on risk factors for converting traditional wards into temporary ICU during the COVID-19 pandemic, especially from the perspective of nurses, provides crucial insights into the challenges and requirements for effectively establishing and managing these emergency settings. The findings highlight several key areas of concern and opportunities for improvement directly related to clinical practice, particularly in situations where there is a rapid need to adapt to increased demands for critical care. By addressing the identified risk factors through enhanced training, support systems, resource management, process improvements and cultivating a culture of adaptability, not only can the quality of care in temporary ICUs be improved, but also can the health care system be better prepared for future emergencies. These actions will help mitigate the risks associated with such conversions, ultimately benefiting patient safety, staff well-being and the overall effectiveness of health care services in crises.

Co-Immobilization of GOD & HRP on Y-Shaped DNA Scaffold and the Regulation of Inter-Enzyme Distance.

In multienzymes cascade reaction, the inter-enzyme spacing is supposed to be a factor affecting the cascade activity. Here, a simple and efficient Y-shaped DNA scaffold is assembled using two partially complementary DNA single strands on magnetic microspheres, which is used to coimmobilize glucose oxidase (GOD) and horseradish peroxidase (HRP). As a result, on poly(vinyl acetate) magnetic microspheres (PVAC), GOD/HRP-DNA@PVAC multienzyme system is obtained, which can locate GOD and HRP accurately and control the inter-enzyme distance precisely. The distance between GOD and HRP is regulated by changing the length of DNA strand. It showed that the cascade activity is significantly distance-dependent. Moreover, the inter-enzyme spacing is not the closer the better, and too short distance would generate steric hindrance between enzymes. The cascade activity reached the maximum value of 967 U mg-1 at 13.6 nm, which is 3.5 times higher than that of free enzymes. This is ascribed to the formation of substrate channeling.

Long-term outcomes of relmacabtagene autoleucel in Chinese patients with relapsed/refractory large B-cell lymphoma: Updated results of the RELIANCE study.

BACKGROUND AIMS: The RELIANCE study has demonstrated the activity and safety of relmacabtagene autoleucel (relma-cel) (JW Therapeutics [Shanghai] Co, Ltd, Shanghai, China), a CD19-targeted chimeric antigen receptor T-cell product, in patients with heavily pre-treated relapsed/refractory large B-cell lymphoma (r/r LBCL). This study aimed to report the updated 2-year data of the RELIANCE study. METHODS: The RELIANCE study (NCT04089215) was an open-label, multi-center, randomized, phase 1/2 registrational clinical trial conducted at 10 clinical sites in China. Adult patients with heavily pre-treated r/r LBCL were enrolled and received lymphodepletion chemotherapy followed by infusion of 100 × 106 or 150 × 106 relma-cel. The primary endpoint was objective response rate (ORR) at 3 months, as assessed by investigators. Secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety profiles. RESULTS: From November 2017 to January 2022, a total of 68 patients were enrolled, and 59 patients received relma-cel infusion. As of March 29, 2022, a total of 59 patients had a median follow-up of 17.9 months (range, 0.3-25.6). ORR was 77.59% (95% confidence interval [CI], 64.73-87.49) and complete response rate was 53.45% (95% CI, 39.87-66.66). Median DoR was 20.3 months (95% CI, 4.86-not reached [NR]) and median PFS was 7.0 months (95% CI, 4.76-24.15). Median OS was NR and 1-year and 2-year OS rates were 75.0% and 69.3%, respectively. Three (5.1%) patients experienced grade ≥3 cytokine release syndrome and two (3.4%) patients had grade ≥3 neurotoxicity. CONCLUSIONS: The updated data of the RELIANCE study demonstrate durable response with and manageable safety profile of relma-cel in patients with heavily pre-treated r/r LBCL.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

Genome-wide identification and characterization of tomato 14-3-3 (SlTFT) genes and functional analysis of SlTFT6 under heat stress.

The plant 14-3-3 proteins are essential for many biological processes and responses to abiotic stress. We performed genome-wide identification and analysis of the 14-3-3 family genes in tomato. To explore the properties of the thirteen Sl14-3-3 found in the tomato genome, their chromosomal location, phylogenetic, and syntenic relationships were analyzed. The Sl14-3-3 promoters were found to have a number of growth-, hormone-, and stress-responsive cis-regulatory elements. Moreover, the qRT-PCR assay revealed that Sl14-3-3 genes are responsive to heat and osmotic stress. Subcellular localization experiments evidenced that the SlTFT3/6/10 proteins occur in the nucleus and cytoplasm Additional analysis on Sl14-3-3 putative interactor proteins revealed a number of prospective clients that potentially participate in stress reactions and developmental processes. Furthermore, overexpression of an Sl14-3-3 family gene, SlTFT6, improved tomato plants thermotolerance. Taken together, the study provides basic information on tomato 14-3-3 family genes in plant growth and abiotic stress response (high temperature stress), which can be helpful to further study the underlying molecular mechanisms.