Terlipressin versus placebo or noradrenalin in the treatment of hepatorenal syndrome: a systematic review and meta-analysis.

Background: Hepatorenal syndrome (HRS) bears a very poor prognosis with unmet need for safe and effective therapies. This systematic review and meta-analysis aimed to re-assess safety and efficacy of terlipressin versus placebo or noradrenaline for HRS, based on previous randomized controlled trials (RCTs). Methods: PubMed, EMBASE, MEDLINE (OvidSP) and Cochrane registers were searched for trials reporting HRS treatment by terlipressin or noradrenaline. Search terms included: "hepatorenal syndrome", "terlipressin", "noradrenaline", and corresponding synonyms. Comparisons between terlipressin, noradreanaline, placebo and albumin were included. Meta-analysis was conducted for treatment response (both HRS reversal and complete response), mortality and adverse events. Results: 15 RCTs were included, enrolling 1236 HRS patients (type 1: 1166, type 2: 70). Treatment with terlipressin+albumin resulted in significantly higher treatment response than placebo+albumin or albumin alone (risk ratio [RR]:2.75, 95% confidence interval [CI]:1.96 to 3.84; I2 = 28%, p = 0.23; n = 6). Noradrenaline was equally effective in treatment response compared to terlipressin (RR:1.19, 95% CI:0.96 to 1.46; I2 = 16%, p = 0.31; n = 7), but trials were limited by its non-blind design and small size. Sensitivity analysis showed no survival benefit with terlipressin compared to either placebo (RR:1.03, 95% CI:0.83 to 1.28; I2 = 0%, p = 0.72; n = 3) or noradreanline (RR:0.83, 95% CI:0.69 to 1.00; I2 = 4%, p = 0.39; n = 7) at 30 days of follow-up. Terlipressin carried higher risk of treatment-related adverse events compared to either placebo (RR:2.92, 95% CI:1.48 to 5.77; I2 = 0%, p = 0.75; n = 3) or noradrenaline (RR:2.45, 95% CI:1.37 to 4.37; I2 = 0%, p = 0.92; n = 5). Conclusion: Terlipressin is superior to placebo, and comparable to noradreanline in treatment response, but survival benefit is lacking. Noradrenaline, with low certainty, may be a better alternative for HRS.

Pan-cancer analysis suggests that LY6H is a potential biomarker of diagnosis, immunoinfiltration, and prognosis.

LY6H, a member of the lymphocyte antigen-6(LY6) gene family, is located on human chromosomes 6, 8, 11 and 19. This superfamily is characterized by the presence of LU domains. It has demonstrated its emerging significance in various cancers including adenocarcinoma, bladder cancer, ovarian cancer and skin cancer. However, comprehensive pan-cancer analyses have not been conducted to investigate its role in diagnosis, prognosis and immunological prediction. By conducting comprehensive analysis of patient data obtained from publicly available databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), University of Alabama at Birmingham (UALCAN), The Comparative Toxicological Genomics Database (CTD), cBioportal, cancerSEA, and UCSC, we systematically investigated the differential expression of LY6H in 33 different types of human tumors. Additionally, we thoroughly analyzed the diagnostic, prognostic, and immunoinfiltration value of LY6H. Simultaneously, we examined the correlation between LY6H and tumor stemness, methylation patterns, drug sensitivity, gene alterations as well as single cell functions. Furthermore, protein-protein interaction networks and gene-gene interaction networks for LY6H were constructed. Moreover, we also explored the network relationship between LY6H and chemical compounds or genes. The results revealed that LY6H exhibited high expression levels in most cancers which were further validated through Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Immunohistochemistry (IHC) analysis using Hepatocellular carcinoma (HCC) samples. Moreover, LY6H displayed early diagnostic potential in 12 tumors while also showing positive or negative correlations with prognosis across different tumor types. Additionally, it was found that LY6H played a pivotal role in regulating immune-infiltrating cells across multiple cancers whereas the correlation between LY6H expression and immune-related genes varied depending on their specific types. Furthermore, the expression of LY6H was significantly associated with DNA methylation patterns in 21 cancers. Therefore, LY6H could serve as an adjunctive biomarker for early tumor detection as well as a prognostic indicator for diverse malignancies.

Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy.

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

Inhibition of Tumoral VISTA to Overcome TKI Resistance via Downregulation of the AKT/mTOR and JAK2/STAT5 Pathways in Chronic Myeloid Leukemia.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

Spectral Decomposition and Transformation for Cross-domain Few-shot Learning.

Cross-domain few-shot Learning (CDFSL) is proposed to first pre-train deep models on a source domain dataset where sufficient data is available, and then generalize models to target domains to learn from only limited data. However, the gap between the source and target domains greatly hampers the generalization and target-domain few-shot finetuning. To address this problem, we analyze the domain gap from the aspect of frequency-domain analysis. We find the domain gap could be reflected by the compositions of source-domain spectra, and the lack of compositions in the source datasets limits the generalization. Therefore, we aim to expand the coverage of spectra composition in the source datasets to help the source domain cover a larger range of possible target-domain information, to mitigate the domain gap. To achieve this goal, we propose the Spectral Decomposition and Transformation (SDT) method, which first randomly decomposes the spectrogram of the source datasets into orthogonal bases, and then randomly samples different coordinates in the space formed by these bases. We integrate the above process into a data augmentation module, and further design a two-stream network to handle augmented images and original images respectively. Experimental results show that our method achieves state-of-the-art performance in the CDFSL benchmark dataset.

Scinderin is a potential prognostic biomarker and correlated with immunological regulation: from pan-cancer analysis to liver hepatocellular carcinoma.

Aim: This study aimed to systematically dissect the role of Scinderin (SCIN) in tumorigenesis. Methods: Bioinformatics techniques were employed based on cancer data from TCGA, ENCORI, HPA, GEPIA2, UALCAN, Kaplan-Meier plotter, TIMER, TISIDB, cBioPortal, HCCDB, GeneMANIA and LinkedOmics database. Experiments in vitro and in vivo were conducted to dissect the role of SCIN in liver hepatocellular carcinoma (LIHC). Results: Significantly differential expression of SCIN was found in nine types of cancers, including LIHC. Through pan-cancer analysis, the correlations between SCIN expression with prognosis and immune cell infiltration were proven, especially in LIHC, ovarian serous cystadenocarcinoma and lung adenocarcinoma. The highest frequency of alteration in SCIN (6.81%) was seen in patients with uterine corpus endometrial carcinoma, in which "mutation" was the predominant type, with a frequency of about 5.29%; meanwhile, S673F and S381Y were the two most frequent mutation sites. Furthermore, the abnormal expression of SCIN exhibited a strong relationship with immune cell subtypes, immune checkpoint genes, tumor mutation burden, microsatellite instability, neoantigen, molecular subtypes, mismatch repair signatures and DNA methyl-transferase in different cancer types. Through comparative analysis, we discovered that SCIN was dramatically up-regulated in LIHC, and associated with poor survival. Experiments in vitro and in vivo suggested the knockdown of SCIN could suppress tumor cell proliferation and improve the survival rate partly in animal models. Conclusion: This study reveals SCIN may be a promising biomarker for prognosis and treatment in certain cancers, especially in LIHC.

Prevalence and Diagnostic Agreement of Sarcopenia Based on Handgrip Strength and 5-Time Chair-Stand Test Among Chinese Community-Dwelling Older Adults.

INTRODUCTION: Handgrip strength and the 5-time chair-stand test are the two important muscle strength measures run through the whole sarcopenia diagnosis algorithm. There is a lack of evidence to confirm which muscle strength measures have a higher detection rate of sarcopenia among Chinese older adults, which is a challenge for community workers to choose the muscle strength measures and to identify more sarcopenia in clinical practice. OBJECTIVE: We aimed to investigate the prevalence and diagnostic agreement of sarcopenia based on handgrip strength and the 5-time chair-stand test among Chinese community-dwelling older adults. METHODS: This cross-sectional study sampled 1027 community-dwelling older adults from Hunan, China. We used handgrip strength and the 5-time chair-stand test to assess participants' muscle strength and used gait speed and bioimpedance analysis (BIA) to assess physical performance and skeletal muscle mass, respectively. The kappa values of the agreement test were used to evaluate the agreement of handgrip strength and 5-time chair-stand tests in the assessment of sarcopenia. RESULTS: A total of 1027 participants were included in this analysis including 337 males and 690 females with an average age of 70.35 ± 7.24 years. The prevalence of possible sarcopenia, confirmed sarcopenia and severe sarcopenia based on handgrip strength was 50.8%, 20.3% and 14.5% respectively, while the corresponding prevalence for using the 5-time chair-stand test was 27.6%, 10.8% and 10.9%. The kappa value of the consistency test between handgrip strength and 5-time chair-stand test in the assessment of possible sarcopenia, confirmed and severe sarcopenia was 0.26, 0.51 and 0.62, respectively (p < 0.001 for all). CONCLUSIONS: The prevalence of possible sarcopenia, confirmed sarcopenia and severe sarcopenia based on handgrip strength was significantly higher than that of the 5-time chair-stand test. We recommend handgrip strength as the preferred method of muscle strength measurement for Chinese community-dwelling older adults and use 5-time chair-stand tests when handgrip strength is not available. IMPLICATIONS FOR PRACTICE: The findings provide information and suggestions to healthcare providers for choosing the muscle strength measures to detect more sarcopenia in clinical practice. Compared with the 5-time chair-stand test, handgrip strength has a better performance to identify sarcopenia in Chinese community-dwelling older adults.

A method for predicting needle insertion deflection in soft tissue based on cutting force identification.

The deflection modeling during the insertion of bevel-tipped flexible needles into soft tissues is crucial for robot-assisted flexible needle insertion into specific target locations within the human body during percutaneous biopsy surgery. This paper proposes a mechanical model based on cutting force identification to predict the deflection of flexible needles in soft tissues. Unlike other models, this method does not require measuring Young's modulus (E) and Poisson's ratio (ν) of tissues, which require complex hardware to obtain. In the model, the needle puncture process is discretized into a series of uniform-depth puncture steps. The needle is simplified as a cantilever beam supported by a series of virtual springs, and the influence of tissue stiffness on needle deformation is represented by the spring stiffness coefficient of the virtual spring. By theoretical modeling and experimental parameter identification of cutting force, the spring stiffness coefficients are obtained, thereby modeling the deflection of the needle. To verify the accuracy of the proposed model, the predicted model results were compared with the deflection of the puncture experiment in polyvinyl alcohol (PVA) gel samples, and the average maximum error range predicted by the model was between 0.606 ± 0.167 mm and 1.005 ± 0.174 mm, which showed that the model can successfully predict the deflection of the needle. This work will contribute to the design of automatic control strategies for needles.

Integrated Metabolomics and Transcriptomics Reveal the Key Role of Flavonoids in the Cold Tolerance of Chrysanthemum.

Chrysanthemum (Chrysanthemum morifolium, ground-cover Chrysanthemums), one of the important garden flowers, has a high ornamental and economic value. However, its ornamental value is significantly diminished by the low temperature experienced in northeastern China. Here, metabolomics and transcriptomics were performed on three Chrysanthemum cultivars before and after a low temperature to investigate the dynamic metabolite changes and the molecular regulatory mechanisms. The results showed that 1324 annotated metabolites were detected, among which 327 were identified as flavonoids derived from Chrysanthemum. The accumulation of metabolites and gene expression related to the flavonoid biosynthesis pathway significantly increased in the three cultivars under the low temperature, indicating flavonoid metabolism actively participates in the Chrysanthemum cold response. Specifically, the content of cyanidin and pelargonidin derivatives and the expression of anthocyanin biosynthesis genes significantly increases in XHBF, providing a reasonable explanation for the change in petal color from white to purple under the low temperature. Six candidate UDP-glycosyltransferase genes involved in the glycosylation of flavonoids were identified through correlation networks and phylogenetic analysis. CmNAC1, CmbZIP3, and other transcription factors potentially regulating flavonoid metabolism and responding to low temperatures were discovered by correlation analysis and weighted gene co-expression network analysis (WGCNA). In conclusion, this study elucidated the specific response of flavonoids to low temperatures in Chrysanthemums, providing valuable insights and metabolic data for investigating cold tolerance.

Associations of sex-related and thyroid-related hormones with risk of metabolic dysfunction-associated fatty liver disease in T2DM patients.

BACKGROUND: We aimed to examine sex-specific associations between sex- and thyroid-related hormones and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Cross-sectional analyses of baseline information from an ongoing cohort of 432 T2DM patients (185 women and 247 men) in Xiamen, China were conducted. Plasma sex-related hormones, including estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone, and total testosterone (TT), and thyroid-related hormones, including free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and parathyroid hormone (PTH), were measured using chemiluminescent immunoassays. MAFLD was defined as the presence of hepatic steatosis (diagnosed by either hepatic ultrasonography scanning or fatty liver index (FLI) score > 60) since all subjects had T2DM in the present study. RESULTS: Prevalence of MAFLD was 65.6% in men and 61.1% in women with T2DM (P = 0.335). For men, those with MAFLD showed significantly decreased levels of FSH (median (interquartile range (IQR)):7.2 (4.9-11.1) vs. 9.8 (7.1-12.4) mIU/ml) and TT (13.2 (10.4-16.5) vs. 16.7 (12.8-21.6) nmol/L) as well as increased level of FT3 (mean ± standard deviation (SD):4.63 ± 0.68 vs. 4.39 ± 0.85 pmol/L) than those without MAFLD (all p-values < 0.05). After adjusting for potential confounding factors, FSH and LH were negative, while progesterone was positively associated with the risk of MAFLD in men, and the adjusted odds ratios (ORs) (95% confidence intervals (CIs)) were 0.919 (0.856-0.986), 0.888 (0.802-0.983), and 8.069 (2.019-32.258) (all p-values < 0.05), respectively. In women, there was no statistically significant association between sex- or thyroid-related hormones and the risk of MAFLD. CONCLUSION: FSH and LH levels were negative, whereas progesterone was positively associated with the risk of MAFLD in men with T2DM. Screening for MAFLD and monitoring sex-related hormones are important for T2DM patients, especially in men.

Scriptaid is a prospective agent for improving human asthenozoospermic sample quality and fertilization rate in vitro.

ABSTRACT: Male infertility is a global issue caused by poor sperm quality, particularly motility. Enhancement of the sperm quality may improve the fertilization rate in assisted reproductive technology (ART) treatment. Scriptaid, with a novel human sperm motility-stimulating activity, has been investigated as a prospective agent for improving sperm quality and fertilization rate in ART. We evaluated the effects of Scriptaid on asthenozoospermic (AZS) semen, including its impact on motility stimulation and protective effects on cryopreservation and duration of motility, by computer-aided sperm analysis (CASA). Sperm quality improvement by Scriptaid was characterized by increased hyaluronan-binding activity, tyrosine phosphorylation, adenosine triphosphate (ATP) concentration, mitochondrial membrane potential, and an ameliorated AZS fertilization rate in clinical intracytoplasmic sperm injection (ICSI) experiments. Furthermore, our identification of active Scriptaid analogs and different metabolites induced by Scriptaid in spermatozoa lays a solid foundation for the future biomechanical exploration of sperm function. In summary, Scriptaid is a potential candidate for the treatment of male infertility in vitro as it improves sperm quality, prolongs sperm viability, and increases the fertilization rate.

[Advances in paclitaxel biosynthesis and transcriptional regulation mechanisms].

Paclitaxel, a rare diterpene extracted from the bark of Chinese yew (Taxus chinensis), is renowned for its anti-cancer activity and serves as a primary drug for treating cancers. Due to the exceptionally low content of paclitaxel in the bark, a semi-synthetic method that depletes Chinese yew resources is used in the production of paclitaxel, which, however, fails to meet the escalating clinical demand. In recent years, researchers have achieved significant progress in heterologous biosynthesis and metabolic engineering for the production of paclitaxel. This article comprehensively reviews the advancements in paclitaxel production, encompassing chemical synthesis, heterologous biosynthesis, and cell engineering. It provides an in-depth introduction to the biosynthetic pathway and transcriptional regulation mechanisms of paclitaxel, aiming to provide a valuable reference for further research on paclitaxel biosynthesis.

Development of a community intervention combining social media-based health education plus exercise programme (SHEEP) to improve muscle function among young-old adults with possible sarcopenia: Co-design approach.

OBJECTIVES: There is no precedent for the use of social media in preventing sarcopenia. The aim of this study is to develop a social media-based intervention programme for the young-old population in the community in China to improve their awareness and behaviours regarding sarcopenia prevention. STUDY DESIGN: Using guidelines for developing complex interventions, this study was divided into two main phases: a co-development phase and a preliminary test phase. Both were carried out in Changsha, China. The development phase employed co-design methodology with relevant stakeholders, including two rounds of consultation with patient and public involvement (12 members) and two rounds of focus groups (30 participants); this was followed by the three-week preliminary test phase (22 participants). MAIN OUTCOME MEASURES: This study evaluated the consultation with patient and public involvement, and mainly collected qualitative data from the two rounds of focus group interviews and a final semi-structured interview following the preliminary test, so as to explore the participants' experiences, comments, and suggestions for revising the social media-based intervention. Handgrip strength was also evaluated. RESULTS: The health education included seven videos of 4-6 min each related to sarcopenia, including information on the concept, influencing factors, adverse effects, manifestations, screening methods, and preventions. The exercise video consisted of four types of training (warm-up, aerobic, resistance, and flexibility training) and lasted 30 min, with a suggested engagement of at least 3 days/week. The specific contents and "dosage" of the final intervention were unanimously favourable to the diverse stakeholders involved (older adults with possible sarcopenia, experts, researchers). After the preliminary test, an improvement in handgrip strength was observed, from M15.92±SD5.22 kg to M19.13±SD5.44 kg (T = -5.44, P < 0.001). Subgroup analysis revealed that this improvement was evident in both men and women. CONCLUSIONS: The social media-based intervention was universally endorsed by the participants and showed indications of a positive influence on sarcopenia. A feasibility study is now needed.

A back propagation neural network based respiratory motion modelling method.

BACKGROUND: This study presents the development of a backpropagation neural network-based respiratory motion modelling method (BP-RMM) for precisely tracking arbitrary points within lung tissue throughout free respiration, encompassing deep inspiration and expiration phases. METHODS: Internal and external respiratory data from four-dimensional computed tomography (4DCT) are processed using various artificial intelligence algorithms. Data augmentation through polynomial interpolation is employed to enhance dataset robustness. A BP neural network is then constructed to comprehensively track lung tissue movement. RESULTS: The BP-RMM demonstrates promising accuracy. In cases from the public 4DCT dataset, the average target registration error (TRE) between authentic deep respiration phases and those forecasted by BP-RMM for 75 marked points is 1.819 mm. Notably, TRE for normal respiration phases is significantly lower, with a minimum error of 0.511 mm. CONCLUSIONS: The proposed method is validated for its high accuracy and robustness, establishing it as a promising tool for surgical navigation within the lung.

A universal recombinant adenovirus type 5 vector-based COVID-19 vaccine.

A universal recombinant adenovirus type-5 (Ad5) vaccine against COVID19 (Ad-US) was constructed, and immunogenicity and broad-spectrum of Ad5-US were evaluated with both intranasal and intramuscular immunization routes. The humoral immune response of Ad5-US in serum and bronchoalveolar lavage fluid were evaluated by the enzyme-linked immunosorbent assay (ELISA), recombinant vesicular stomatitis virus based pseudovirus neutralization assay, and angiotensin-converting enzyme-2 (ACE2) -binding inhibition assay. The cellular immune response and Th1/Th2 biased immune response of Ad5-US were evaluated by the IFN-γ ELISpot assay, intracellular cytokine staining, and Meso Scale Discovery (MSD) profiling of Th1/Th2 cytokines. Intramuscular priming followed by an intranasal booster with Ad5-US elicited the broad-spectrum and high levels of IgG, IgA, pseudovirus neutralizing antibody (PNAb), and Th1-skewing of the T-cell response. Overall, the adenovirus type-5 vectored universal SARS-CoV-2 vaccine Ad5-US was successfully constructed, and Ad5-US was highly immunogenic and broad spectrum. Intramuscular priming followed by an intranasal booster with Ad5-US induced the high and broad spectrum systemic immune responses and local mucosal immune responses.

Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China.

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.

Prognosis and immunotherapy efficacy in dMMR&MSS colorectal cancer patients and an MSI status predicting model.

The inconsistency between mismatch repair (MMR) protein immunohistochemistry (IHC) and microsatellite instability PCR (MSI-PCR) methods has been widely reported. We aim to investigate the prognosis and the effect of immunotherapy in dMMR by IHC but MSS by MSI-PCR (dMMR&MSS) colorectal cancer (CRC) patients. A microsatellite instability (MSI) predicting model was established to help find dMMR&MSS patients. MMR and MSI states were detected by the IHC and MSI-PCR in 1622 CRC patients (ZS6Y-1 cohort). Logistic regression analysis was used to screen clinical features to construct an MSI-predicting nomogram. We propose a new nomogram-based assay to find patients with dMMR&MSS, in which the MSI-PCR assay only detects dMMR patients with MSS predictive results. We applied the new strategy to a random cohort of 248 CRC patients (ZS6Y-2 cohort). The consistency of MMR IHC and MSI-PCR in the ZS6Y-1 cohort was 95.7% (1553/1622). Both pMMR&MSS and dMMR&MSS groups experienced significantly shorter overall survival (OS) than those in dMMR by IHC and MSI-H by MSI-PCR (dMMR&MSI-H) group (hazard ratio [HR] = 2.429, 95% confidence interval [CI]: 1.89-3.116, p < .01; HR = 21.96, 95% CI: 7.24-66.61, p < .01). The dMMR&MSS group experienced shorter OS than the pMMR&MSS group, but the difference did not reach significance (log rank test, p = .0686). In the immunotherapy group, the progression-free survival of dMMR&MSS patients was significantly shorter than that of dMMR&MSI-H patients (HR = 13.83, 95% CI: 1.508-126.8, p < .05). The ZS6Y-MSI-Pre nomogram (C-index = 0.816, 95% CI: 0.792-0.841, already online) found 66% (2/3) dMMR&MSS patients in the ZS6Y-2 cohort. There are significant differences in OS and immunotherapy effect between dMMR&MSI-H and dMMR&MSS patients. Our prediction model provides an economical way to screen dMMR&MSS patients.

Climate-related naturally occurring epimutation and their roles in plant adaptation in A. thaliana.

DNA methylation has been proposed to be an important mechanism that allows plants to respond to their environments sometimes entirely uncoupled from genetic variation. To understand the genetic basis, biological functions and climatic relationships of DNA methylation at a population scale in Arabidopsis thaliana, we performed a genome-wide association analysis with high-quality single nucleotide polymorphisms (SNPs), and found that ~56% on average, especially in the CHH sequence context (71%), of the differentially methylated regions (DMRs) are not tagged by SNPs. Among them, a total of 3235 DMRs are significantly associated with gene expressions and potentially heritable. 655 of the 3235 DMRs are associated with climatic variables, and we experimentally verified one of them, HEI10 (HUMAN ENHANCER OF CELL INVASION NO.10). Such epigenetic loci could be subjected to natural selection thereby affecting plant adaptation, and would be expected to be an indicator of accessions at risk. We therefore incorporated these climate-related DMRs into a gradient forest model, and found that the natural A. thaliana accessions in Southern Europe that may be most at risk under future climate change. Our findings highlight the importance of integrating DNA methylation that is independent of genetic variations, and climatic data to predict plants' vulnerability to future climate change.