Insulin signaling establishes a developmental trajectory of adipose regulatory T cells.

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.

Increased infiltration of CD4+ IL-17A+ FOXP3+ T cells in Helicobacter pylori-induced gastritis.

Helicobacter pylori is one of the main predisposing factors for gastric cancer, causing chronic inflammation and proper glands atrophy in the gastric mucosa. Although H. pylori-induced inflammation is a key inducer of precancerous lesions in the gastric mucosa, it remains unclear which precise immune cell subsets are responsible for the progression of H. pylori-induced gastritis. Here, we observed an abundance of CD4+ IL-17A+ FOXP3+ T cells exhibiting a Th17-like phenotype within the microenvironment of H. pylori-induced gastritis. Mechanistically, H. pylori upregulated the expression of IL-6 in Dendritic cells and macrophages, by activating NF-κB signaling through the virulence factor CagA and thus, induced IL-17A expression in FOXP3+ T cells. Moreover, CD4+ IL-17A+ FOXP3+ T cells were positively associated with advanced precancerous lesions. Therefore, these findings offer essential insights into how FOXP3+ T cells sense inflammatory signals from the environment, such as IL-6, during H. pylori infections, thereby guiding the effector immune response and aggravating the gastritis.

Optimization of Minocycline-Containing Bismuth Quadruple Therapy for Helicobacter pylori Rescue Treatment: A Real-World Evidence Study.

BACKGROUND: The optimal dosage of minocycline remains unclear for Helicobacter pylori (H. pylori) eradication. We aimed to evaluate the efficacy and safety of four different regimens with minocycline and metronidazole compared to classical bismuth quadruple therapy for H. pylori rescue treatment. MATERIALS AND METHODS: From March 2021 to March 2024, refractory H. pylori-infected patients with at least two previous treatment failures who received 14-day therapy with b.i.d. proton pump inhibitor 20 mg and bismuth 220 mg, plus tetracycline 400 mg q.i.d and metronidazole 400 mg q.i.d (BQT), or minocycline 50 mg q.i.d and metronidazole 400 mg q.i.d (PBMn4M4), or minocycline 50 mg t.i.d and metronidazole 400 mg t.i.d (PBMn3M3), or minocycline 50 mg b.i.d and metronidazole 400 mg q.i.d (PBMn2M4), or minocycline 50 mg b.i.d and metronidazole 400 mg t.i.d (PBMn2M3) were included in this retrospective study. H. pylori eradication was assessed by 13C-urea breath test at least 6 weeks after treatment. All adverse effects during treatment were recorded. RESULTS: Totally, 823 patients were enrolled: 251 with BQT, 97 with PBMn4M4, 191 with PBMn3M3, 108 with PBMn2M4, and 176 with PBMn2M3. The eradication rates of BQT, PBMn4M4, PBMn3M3, PBMn2M4, and PBMn2M3 were 89.2%, 87.6%, 91.6%, 88.0%, and 91.5%, respectively, by intention-to-treat analysis; 96.1%, 97.7%, 97.8%, 96.9%, and 97.6%, respectively, by modified intention-to-treat analysis; 97.1%, 97.5%, 97.7%, 96.8%, and 97.6%, respectively, by per-protocol analysis. Metronidazole resistance did not affect the efficacy of all groups. PBMn2M3 group achieved the greatest compliance and the fewest moderate and severe adverse events. CONCLUSIONS: The novel bismuth-containing quadruple therapy with a low dose of minocycline and metronidazole is an alternative to classical bismuth quadruple therapy for H. pylori rescue treatment with superior safety and compliance. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06332599.

Vonoprazan-Amoxicillin Dual Therapy With Different Amoxicillin Administration Regimens for Helicobacter pylori Treatment: A Randomized Controlled Trial.

BACKGROUND: The effect of preprandial or postprandial administration of amoxicillin on the efficacy of vonoprazan-amoxicillin dual therapy (VA-dual therapy) for Helicobacter pylori treatment has not been studied. It is also unclear whether amoxicillin dosing four times daily is more effective than three times daily. We aimed to investigate the effect of different amoxicillin administration regimens on the efficacy of VA-dual therapy. MATERIALS AND METHODS: H. pylori-infected subjects were randomly assigned to three groups in a 1:1:1 ratio to receive a 14-day dual therapy consisting of vonoprazan 20 mg twice daily + amoxicillin 1000 mg three times daily before meals (BM-TID) or 1000 mg three times daily after meals (AM-TID) or 750 mg four times daily after meals (AM-QID). H. pylori eradication rates, adverse events rates, compliance, and antibiotic resistance were compared. RESULTS: Between May 2021 to April 2023, 327 subjects were enrolled. The eradication rates of BM-TID, AM-TID, and AM-QID dual therapy were 88.1%, 89.9%, and 93.6% in intention-to-treat (ITT) analysis, 90.6%, 94.2%, and 99.0% in modified ITT (MITT) analysis, and 90.4%, 94.1%, and 99.0% in per-protocol (PP) analysis. Although there was non-inferiority between BM-TID and AM-TID, as well as between AM-TID and AM-QID, AM-QID was significantly more effective than BM-TID. There were no significant differences in adverse event rates, compliance, and antibiotic resistance among the three groups. CONCLUSIONS: Postprandial administration and the increased frequency of administration of amoxicillin may contribute to a better efficacy of VA-dual therapy, especially for rescue therapy. All VA-dual therapy in our study could achieve good efficacy for first-line treatment. TRIAL REGISTRATION: clinicaltrials.gov: NCT05901051.

Rifabutin-Containing Triple Therapy Versus Bismuth Quadruple Therapy for Helicobacter pylori Rescue Treatment: A Multicenter, Randomized Controlled Trial.

BACKGROUND: We compared the efficacy and safety of rifabutin-containing triple therapy with bismuth quadruple therapy for rescue treatment of Helicobacter pylori. METHODS: This was a noninferiority study trial of H. pylori treatment for subjects who had failed at least 2 prior treatments. Subjects were randomly assigned to receive rifabutin triple therapy with 14-day esomeprazole (20 mg), amoxicillin (1.0 g), and rifabutin (150 mg) twice a day; or bismuth quadruple therapy with esomeprazole (20 mg) and bismuth (220 mg) twice a day, plus metronidazole (400 mg) and tetracycline (500 mg) 4 times a day. Antimicrobial susceptibility was assessed by agar dilution and E-test. RESULTS: From May 2021 to October 2022, a total of 364 subjects were randomized. The eradication rates by intention-to-treat, per-protocol, and modified intention-to-treat were 89.0% (162/182; 95% confidence interval [CI], 83.6%-92.8%), 94.0% (157/167; 95% CI, 89.3%-96.7%), and 93.6% (162/173; 95% CI, 89.0%-96.4%) for rifabutin triple group. For bismuth quadruple group, they were 89.6% (163/182; 95% CI, 84.3%-93.2%), 95.3% (143/150; 95% CI, 90.7%-97.7%), and 93.7% (163/174; 95% CI, 89.0%-96.4%). CONCLUSIONS: The rifabutin triple therapy is an alternative to classical bismuth quadruple therapy for the rescue treatment of H. pylori with fewer side effects and higher compliance. CLINICAL TRIALS REGISTRATION: NCT04879992.

SIGLEC10+ macrophages drive gastric cancer progression by suppressing CD8+ T cell function.

Existing immune checkpoint inhibitors focus on activating T cells and show limited effectiveness in gastric cancer (GC). SIGLEC10 is identified as a novel tumor-associated macrophage-related immune checkpoint in other cancer types. However, its immunosuppressive role and clinical significance in GC remain unclear. In this study, we find a dominant expression of SIGLEC10 on CD68+ macrophages in GC. SIGLEC10 can suppress the proliferation and function of tumor-infiltrating CD8+ T cells in vitro via the Akt/P38/Erk signaling pathway. Furthermore, in ex vivo and in vivo models, SIGLEC10 blockade promotes CD8+ T cell effector function. Finally, SIGLEC10+ macrophages are positively correlated with the adverse prognosis of GC. Our study highlights that SIGLEC10 directly suppresses T cell function and serves as a promising target for immunotherapy and suggests SIGLEC10+ macrophages as a novel potential predictor of the clinical prognosis of GC.

CCL19/CCR7 drives regulatory T cell migration and indicates poor prognosis in gastric cancer.

BACKGROUND: Gastric cancer is associated with significant morbidity and mortality in the world. Blocking programmed cell death protein 1 pathway have been approved for the treatment of a variety of tumors and have achieved remarkable clinical therapeutic effects. However, immune checkpoint inhibitors failed to achieve satisfactory results in gastric cancer. There is a need to identify novel immunotherapy targets in gastric cancer. METHODS: We analysed the correlation between Treg cells and CD8 + T cells in gastric cancer samples. We studied the relationship between chemokines and Treg cells or CD8 + T cells in gastric cancer. We compared CCL19/CCR7 expression in gastric cancer patients in TCGA database. We performed transwell experiments to determine the influence of CCL19 on Treg cells and CD8 + T cells migratory capacity. We conducted survival analysis of CCL19 and CCR7 in gastric cancer database. RESULTS: Treg cells show positive correlation with CD8 + T cells in gastric cancer. Treg cell expression was significantly upregulated in tumor tissues. Patients with high FOXP3 expression had worse overall survival than those with low FOXP3 expression. CCL19 had strong correlation with FOXP3 and weak correlation with CD8A. CCL19 had strong impact on the migratory capacity of Treg cells but weak impact on the migratory capacity of CD8 + T cells. Both CCL19 and CCR7 expression were significantly upregulated in gastric cancer tissues. Survival analysis demonstrated that both CCL19 and CCR7 indicate poor prognosis in gastric cancer. CONCLUSIONS: CCL19/CCR7 may be a potential novel therapeutic target in gastric cancer.

A retrospective assessment of real-world experience with venetoclax and azacitidine therapy in elderly acute myeloid leukemia.

This study aimed to examine the effect of venetoclax coupled with azacytidine in treating older adults with relapsed and refractory (R/R) acute myeloid leukemia (AML). The clinical data of 10 senior patients with AML over 65 years old who were treated with venetoclax and azacytidine, including six patients with R/R AML, were retrospectively evaluated. This study comprised seven males and three females with a median age of 71 years. Five patients had at least one relapse, and one patient did not achieve remission after four cycles of azacytidine monotherapy, considering it resistant. AML with myelodysplasia-related changes was found in four cases. One of the 10 patients died early after 1-13 cycles of venetoclax plus azacytidine treatment due to a protracted period of neutropenia and severe lung infection induced by medications. Six of the remaining nine patients, including six R/R patients, achieved a complete remission (CR) or a CR with incomplete hematologic recovery (CRi). After two cycles of therapy, one patient did not react. Neutropenia lasted an average of 10.5 (6-15) days in all patients, with the most severe cases occurring in the second and third weeks of therapy. Three patients who tested positive for the TP53 gene mutation had the following outcomes: One relapsed patient has been in progression-free remission (PFS) for the past 24 months, whereas another has been in full remission but relapsed 2 months later. Another patient experienced complete remission in myelology for 4 months, but the variable allele fraction (VAF) value steadily rose, suggesting that the illness was on the verge of progressing. IDH2 gene alterations were found in three of four patients who obtained maintained CR for more than 18 months following recurrence. Venetoclax in combination with azacytidine is a successful and well-tolerated therapy for R/R AML in the elderly. Venetoclax and azacytidine may help patients with TP53 mutations and reduce VAF. The IDH2 mutation might be a good predictor of veneclax sensitivity. A notable adverse response in the treatment phase of the regimen is severe infection induced by neutropenia.

Evolution and Expression of the Meprin and TRAF Homology Domain-Containing Gene Family in Solanaceae.

Meprin and TRAF homology (MATH)-domain-containing proteins are pivotal in modulating plant development and environmental stress responses. To date, members of the MATH gene family have been identified only in a few plant species, including Arabidopsis thaliana, Brassica rapa, maize, and rice, and the functions of this gene family in other economically important crops, especially the Solanaceae family, remain unclear. The present study identified and analyzed 58 MATH genes from three Solanaceae species, including tomato (Solanum lycopersicum), potato (Solanum tuberosum), and pepper (Capsicum annuum). Phylogenetic analysis and domain organization classified these MATH genes into four groups, consistent with those based on motif organization and gene structure. Synteny analysis found that segmental and tandem duplication might have contributed to MATH gene expansion in the tomato and the potato, respectively. Collinearity analysis revealed high conservation among Solanaceae MATH genes. Further cis-regulatory element prediction and gene expression analysis showed that Solanaceae MATH genes play essential roles during development and stress response. These findings provide a theoretical basis for other functional studies on Solanaceae MATH genes.

Genome-Wide Analysis of the Membrane Attack Complex and Perforin Genes and Their Expression Pattern under Stress in the Solanaceae.

The Membrane Attack Complex and Perforin (MACPF) proteins play a crucial role in plant development and adaptation to environmental stresses. Heretofore, few MACPF genes have been functionally identified, leaving gaps in our understanding of MACPF genes in other plants, particularly in the Solanaceae family, which includes economically and culturally significant species, such as tomato, potato, and pepper. In this study, we have identified 26 MACPF genes in three Solanaceae species and in the water lily, which serves as the base group for angiosperms. Phylogenetic analysis indicates that angiosperm MACPF genes could be categorized into three distinct groups, with another moss and spikemoss lineage-specific group, which is further supported by the examination of gene structures and domain or motif organizations. Through inter-genome collinearity analysis, it is determined that there are 12 orthologous SolMACPF gene pairs. The expansion of SolMACPF genes is primarily attributed to dispersed duplications, with purifying selection identified as the principal driving force in their evolutionary process, as indicated by the ω values. Furthermore, the analysis of expression patterns revealed that Solanaceae genes are preferentially expressed in reproductive tissues and regulated by various environmental stimuli, particularly induced by submergence. Taken together, these findings offer valuable insights into and a fresh perspective on the evolution and function of SolMACPF genes, thereby establishing a foundation for further investigations into their phenotypic and functional characteristics.

Prognostic prediction of systemic immune-inflammation status for patients with colorectal cancer: a novel pyroptosis-related model.

Pyroptosis and related gasdermin family proteins play an important role in the tumorigenesis of colorectal cancer (CRC). However, the prognostic roles of pyroptosis-related genes (PRGs) and their relation to infiltrates of immune cells in the pathogenesis of CRC remain unclear. Using this study, we set up a prognostic gene pattern on the basis of 13 PRGs (AIM2, CASP1, CASP5, CASP6, CASP8, CASP9, ELANE, GPX4, GSDMD, NLRP7, NOD2, PJVK, and PRKACA) for CRC patients. A comprehensive bioinformatics analysis based on these genes was then performed. With the good AUC prediction value of the ROC curves, the group with high hazard first had a poorer survival prognosis than the group with low hazard. Second, we found that PRGs were significantly related to inflammation-associated genes and immune-associated genes in CRC. Then, we identified a correlation of PRGs with immune infiltrations in CRC. For instance, the abundances of resting NK cells resting and neutrophils were higher in the low hazard group than in the high hazard group. Overall, this work indicated that PRGs contributed to generate heterogeneity of the tumor microenvironment (TME) in CRC. This prognostic PRG model may provide a starting point for the early diagnosis and medication use of CRC.

Hepatocellular carcinoma with right atrial tumor thrombus.

BACKGROUND: Hepatocellular carcinoma with right atrial tumor thrombus is uncommon but with a dismal prognosis. METHODS: By comprehensive retrieval of literature published between 2000 and 2019, 53 reports were obtained with 187 patients recruited into this study. The extracted data included patient characteristics, tumor characteristics, treatment, follow-up and outcomes. Statistical analyses applied were student t, Fisher exact and I2 tests. Patients were devided into 6 groups according to treatment of choices: transarterial chemoembolization (TACE), surgery, radiotherapy, chemotherapy, interventional treatment and supportive care. RESULTS: The overall survival rate of this cohort was 40.8 %. The survival rate of patients receiving TACE was 33.3 % and that of surgical patients was 41.9 %. The survival time of patients with TACE was longer than surgical patients, but lack of a statistical significance. Patients had a follow-up of 15.7 ±â€Š16.6 (median 10) months. The patients receiving radiotherapy had the longest follow-up among all groups. Intra- and/or extrahepatic recurrence of hepatocellular carcinoma was the major morbidity. The mortality rates in a decremental sequence for patients receiving different treatments were supportive care > radiotherapy > surgery > TACE > interventional treatment. No difference was found in mortality between patients reported from case reports and those from non-case reports. CONCLUSIONS: Advanced hepatocellular carcinoma with right atrial thrombus is an aggressive malignancy. Based on the results of median survival time, radiotherapy and TACE seemed to be associated with an improved prognosis and possible better survival.

Regulatory T cells and M2 macrophages present diverse prognostic value in gastric cancer patients with different clinicopathologic characteristics and chemotherapy strategies.

BACKGROUND: Gastric cancer (GC) remains a refractory cancer worldwide. Currently, exploring the differences of the immune status in GC patients with different subgroups might provide promising immunotherapeutic approaches for the treatment of GC. METHODS: In this study, a total of 598 surgically resected FFPE primary gastric cancer samples were assessed for FOXP3, CD163, CD3, CD8, and PD-L1 markers. The correlations between the immune markers expression and clinicopathological features and prognosis were investigated retrospectively. RESULTS: In general, PD-L1, CD3, and CD8 could be regarded as favorable prognostic factors. Our data demonstrated that high infiltration of FOXP3+ Treg indicates better prognosis in stage I-II patients, while the converse outcome was noted in stage III-IV patients. Our data also confirmed different prognostic value in different pathological classifications, chemotherapy strategies, and locations, with or without lymph node metastasis. Also, M2 macrophages indicated poor prognosis in general. However, high M2 macrophage infiltration suggests a favorable prognosis in signet ring cell carcinoma and mucinous adenocarcinoma. Moreover, the prognostic value of the two indices when they are combined is reported. CONCLUSIONS: These results suggested that different immune statuses are exhibited in different subgroups of GC, which may direct further understanding of the immune status of GC as well as provide a further theoretical basis and potential targets for GC immunotherapy.

Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice.

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H×Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT.

Variation characteristics and clinical significance of TP53 in patients with myeloid neoplasms.

Objectives: MDS and AML characterized by TP53 variations have a poor prognosis in general. However, specifically, differences in prognosis have also been observed in patients with different TP53 variants and VAFs.Methods: Here, we retrospectively analyzed datasets of patients with MDS, MPN, and AML who underwent targeted DNA sequencing from February 2018 to December 2023, and patients with reportable TP53 variations were screened. Demographic data and clinical data were collected, and the relationship between TP53 alterations and patient prognosis (AML/MDS) was analyzed using the cBioPortal and Kaplan-Meier Plotter databases. The relationship between the VAFs of TP53 variations and prognoses was analyzed using data from the present study.Results: Sixty-two variants of TP53 were identified in 58 patients. We mainly identified single mutations (79.31%, 46/58), followed by double (17.24%, 10/58) and triple (3.45%, 2/58) mutations. The variations were mainly enriched in exon4-exon8 of TP53. Missense (72.58%, 45/62) mutations were the main type of variations, followed by splice-site (9.68%, 6/62), nonsense (9.68%, 6/62), frameshift (6.45%, 4/62), and indel (1.61%, 1/62) mutations. In this study, p.Arg175His and p.Arg273His were high-frequency TP53 mutations, and DNMT3A and TET2 were commonly co-mutated genes in the three types of myeloid neoplasms; However, we reported some new TP53 variants in MPN that have not been found in the public database. Moreover, MDS or AML characterized by altered TP53 had a shorter OS than patients in the unaltered group (P<0.01), low TP53 mRNA levels were associated with shorter OS in patients with AML (P<0.01). Data from our center further found higher VAF (≥10%) associated with shorter OS in patients with MDS (median 2.75 vs. 24 months) (P<0.01).Conclusion: TP53 mutations are mainly enriched in exon4-exon8, are missense and single mutations in myeloid neoplasms, and are associated with poor prognosis of MDS/AML, and higher VAF (≥10%) of TP53 mutations associated with a shorter OS in patients with MDS.

Magnetic anchoring device assisted-laparoscopic sleeve gastrectomy versus conventional laparoscopic sleeve gastrectomy: A retrospective cohort study.

Background: Bariatric surgeries, including the sleeve gastrectomy, have been recognized as the most effectively treatment strategy for severe obesity. Magnetic devices have been successfully used in bariatric surgeries. Here, we intended to evaluate the safety and efficiency of magnetic anchoring device assisted-laparoscopic sleeve gastrectomy (MLSG), and to make a comparison of the short-term results between conventional laparoscopic sleeve gastrectomy (CLSG) and MLSG. Methods: The retrospective cohort study was carried out by analyzing and summarizing the data from a database of routinely collected data. The cohort included the patients who underwent either CLSG (n = 120) or MLSG (n = 115) at a single center between January 2018 and December 2020 with a two-year follow-up. The effects of these two surgeries on the weight loss, resolution of comorbidities and quality of life (QOL) were analyzed. Results: The two groups were similar in gender, age, body mass index, abdominal girth, as well as the type and proportion of comorbidities. And the cases in MLSG group had a markedly shorter time of operation (MLSG, 72.59 min vs. CLSG, 76.67 min; P = 0.003). Length of stay in hospital was significantly shorter in the MLSG group than that in the CLSG group (MLSG, 5.59 days vs. CLSG, 5.96 days; P = 0.016). Neither fatal event nor conversion to open surgery happened among all cases. There were no differences in terms of the postoperative complications between the two groups. Magnetic device-related mild hepatic lacerations occurred and were handled by hemostatic treatments in 3 cases. The QOL of patients in MLSG was better at 6-month after surgery, but there was no significant difference between the two groups at 1-year or 2-year after surgery. Conclusion: Both MLSG and CLSG prove safe and effective, and the patients underwent MLSG have a shorter length of stay in hospital, and a better QOL during 6 months after surgery.

Comprehensive Identification and Expression Analysis of the Multidrug and Toxic Compound Extrusion (MATE) Gene Family in Brachypodium distachyon.

The Multidrug and Toxic Compound Extrusion (MATE) proteins serve as pivotal transporters responsible for the extrusion of metabolites, thereby playing a significant role in both plant development and the detoxification of toxins. The MATE gene family within the Brachypodium distachyon, which is an important model organism of the Poaceae family, remains largely unexplored. Here, a comprehensive identification and analysis of MATE genes that complement B. distachyon were conducted. The BdMATE genes were systematically categorized into five distinct groups, predicated on an assessment of their phylogenetic affinities and protein structure. Furthermore, our investigation revealed that dispersed duplication has significantly contributed to the expansion of the BdMATE genes, with tandem and segmental duplications showing important roles, suggesting that the MATE genes in Poaceae species have embarked on divergent evolutionary trajectories. Examination of ω values demonstrated that BdMATE genes underwent purifying selection throughout the evolutionary process. Furthermore, collinearity analysis has confirmed a high conservation of MATE genes between B. distachyon and rice. The cis-regulatory elements analysis within BdMATEs promoters, coupled with expression patterns, suggests that BdMATEs play important roles during plant development and in response to phytohormones. Collectively, the findings presented establish a foundational basis for the subsequent detailed characterization of the MATE gene family members in B. distachyon.

[Genetic Variation of SH2B3 in Patients with Myeloid Neoplasms].

OBJECTIVE: To observe the genetic variation of SH2B3 in patients with myeloid neoplasms. METHODS: The results of targeted DNA sequencing associated with myeloid neoplasms in the Department of Hematology, Xuanwu Hospital, Capital Medical University from November 2017 to November 2022 were retrospectively analyzed, and the patients with SH2B3 gene mutations were identified. The demographic and clinical data of these patients were collected, and characteristics of SH2B3 gene mutation, co-mutated genes and their correlations with diseases were analyzed. RESULTS: The sequencing results were obtained from 1 005 patients, in which 19 patients were detected with SH2B3 gene mutation, including 18 missense mutations (94.74%), 1 nonsense mutation (5.26%), and 10 patients with co-mutated genes (52.63%). Variant allele frequency (VAF) ranged from 0.03 to 0.66. The highest frequency mutation was p.Ile568Thr (5/19, 26.32%), with an average VAF of 0.49, involving 1 case of MDS/MPN-RS (with SF3B1 mutation), 1 case of MDS-U (with SF3B1 mutation), 1 case of aplastic anemia with PNH clone (with PIGA and KMT2A mutations), 2 cases of MDS-MLD (1 case with SETBP1 mutation). The other mutations included p.Ala567Thr in 2 cases (10.53%), p.Arg566Trp, p.Glu533Lys, p.Met437Arg, p.Arg425Cys, p.Glu314Lys, p.Arg308*, p.Gln294Glu, p.Arg282Gln, p.Arg175Gln, p.Gly86Cys, p.His55Asn and p.Gln54Pro in 1 case each. CONCLUSION: A wide distribution of genetic mutation sites and low recurrence of SH2B3 is observed in myeloid neoplasms, among of them, p.Ile568Thr mutation is detected with a higher incidence and often coexists with characteristic mutations of other diseases.

Establishment of a prognosis predictive model for liver cancer based on expression of genes involved in the ubiquitin-proteasome pathway.

BACKGROUND: The ubiquitin-proteasome pathway (UPP) has been proven to play important roles in cancer. AIM: To investigate the prognostic significance of genes involved in the UPP and develop a predictive model for liver cancer based on the expression of these genes. METHODS: In this study, UPP-related E1, E2, E3, deubiquitylating enzyme, and proteasome gene sets were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, aiming to screen the prognostic genes using univariate and multivariate regression analysis and develop a prognosis predictive model based on the Cancer Genome Atlas liver cancer cases. RESULTS: Five genes (including autophagy related 10, proteasome 20S subunit alpha 8, proteasome 20S subunit beta 2, ubiquitin specific peptidase 17 like family member 2, and ubiquitin specific peptidase 8) were proven significantly correlated with prognosis and used to develop a prognosis predictive model for liver cancer. Among training, validation, and Gene Expression Omnibus sets, the overall survival differed significantly between the high-risk and low-risk groups. The expression of the five genes was significantly associated with immunocyte infiltration, tumor stage, and postoperative recurrence. A total of 111 differentially expressed genes (DEGs) were identified between the high-risk and low-risk groups and they were enriched in 20 and 5 gene ontology and KEGG pathways. Cell division cycle 20, Kelch repeat and BTB domain containing 11, and DDB1 and CUL4 associated factor 4 like 2 were the DEGs in the E3 gene set that correlated with survival. CONCLUSION: We have constructed a prognosis predictive model in patients with liver cancer, which contains five genes that associate with immunocyte infiltration, tumor stage, and postoperative recurrence.

Efficacy of bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed POEMS syndrome patients.

Background: Due to the rarity of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, the best first-line treatment has not been established, although there are several options in guidelines. The preferred treatments vary according to the preference of the physician and anecdote. Objectives: First, to analyze the efficacy of a new treatment mode in POEMS syndrome that uses the four-cycle treatment as the induction regimen, followed by sequential transplantation as the consolidation regimen for transplantation-eligible patients, or received another two-cycle treatment for transplantation-ineligible patients. Second, to compare the efficacy and safety of regimens with a proteasome inhibitor (bortezomib-cyclophosphamide-dexamethasone, BCD) or without a proteasome inhibitor (cyclophosphamide-dexamethasone ± thalidomide, CD ± T). Design: We conducted a retrospective study using real-world data from Capital Medical University, Xuanwu Hospital. Methods: A total of 34 newly diagnosed POEMS syndrome patients met Dispenzieri's diagnostic criteria, and those who completed at least four cycles of treatment from July 2013 to March 2021 were included. Results: The overall vascular endothelial growth factor (VEGF) response rate of this new treatment mode was 100%. The cumulative VEGF complete remission (CRV) rate was 67.9%, and the cumulative complete hematological response (CRH) rate was 55.6%. During the median 49-month follow-up, the 5-year-overall survival (OS) rate was 90.7%, the 3-year-progression-free survival (PFS) rate was 78.4%, and the 5-year-PFS rate was 73.8%. The BCD regimen achieved a 75% CRV rate (median time from diagnosis to CRV = 130 days) and 66.7% CRH rate (median time from diagnosis to CRH = 218 days). In addition, the VEGF response was less than the partial remission (PRV) after four-cycle induction treatment, which, together with a decrease on the Overall Neurological Limitation Scale of less than three points 1 year after consolidation treatment, was an independent poor prognostic factor. Conclusion: Bortezomib was well-tolerated by patients with POEMS syndrome. Compared with CD ± T regimen, BCD as the induction regimen achieved better VEGF response and earlier hematological remission. Autologous stem cell transplantation used as consolidation therapy further improved the neurological and hematological remission rates, resulting in better OS and PFS.