[Prognostic Significance of Progression of Disease within 24 Months in Mantle Cell Lymphoma].

OBJECTIVE: To investigate the effect of progression of disease within 24 months (POD24) on overall survival (OS) in patients with mantle cell lymphoma (MCL), and compare the clinical characteristics between POD24 and non-POD24 patients. METHODS: A retrospective analysis was performed on 50 MCL patients with treatment indications and regular treatment who were admitted to the Affiliated Hospital of Xuzhou Medical University from January 2010 to August 2020. According to the occurrence of POD24, the patients were grouped for prognostic evaluation and clinical characteristics comparison. RESULTS: Univariate Cox regression analysis showed that POD24, PLT, albumin, MIPI score, ECOG PS score, LDH were the factors influencing OS in newly diagnosed MCL patients (all P < 0.05). The results of multivariate Cox regression analysis showed that POD24ï¼»HR=16.797(95%CI : 3.671-76.861),P < 0.001ï¼½, albumin<40 g/Lï¼»HR=3.238(95%CI :1.095-9.572),P =0.034ï¼½ and ECOG PS score≥2ï¼»HR=4.005(95%CI :1.033-15.521),P =0.045ï¼½ were independent risk factors influencing OS in MCL patients. The incidence of PLT<100×109/L (33.3% vs 5.9%, P =0.033) and ECOG PS score ≥2 (45.5% vs 5.9%, P =0.040) were significantly higher in POD24 patients than those in non-POD24 patients. CONCLUSION: POD24 is an independent poor prognostic factor affecting the OS of MCL patients, and the patients with PLT<100×109/L and ECOG PS score≥2 at diagnosis have a higher probability of POD24.

CD56bright NK cell expansion correlated with EBV reactivation control post allogeneic hematopoietic stem cell transplantation.

Natural killer (NK) cells are equipped with anti-Epstein-Barr virus (EBV) function, however, whether EBV infection will affect NK cells reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. To identify the characteristics of NK cells, we prospectively enrolled 11 patients who occurred EBV reactivation post allo-HSCT and 11 patients without EBV infection as control. We found that that EBV infection induced the expansion of CD56bright and NKG2A+KIR- NK subsets,and decreased the cytotoxicity function of NK cells. The frequency of NKG2A+KIR- NK cells were higher in patients who progressed into post-transplant lymphoproliferative disorder (PTLD) than EBV viremia patients, which also correlated with decreased proliferation and cytotoxic function. By screening the activation receptors of NK cells, we found the DNAM-1+CD56bright NK cells is significantly increased after EBV stimulation, further we demonstrated that DNAM-1 is essential for EBV induced NK cells activation as the cytokine release against EBV-transformed lymphoblastoid cell lines(EBV-LCLs) of CD56bright NK cells were significantly decreased after DNAM-1 blockade. NK cells infusion suppressed the progression of EBV-related tumor mice model. A prospective cohort indicated that old donor age was an independent risk factor for EBV infection. Rapid CD56bri expansion and high expression of DNAM-1 on CD56bri NK cells in response to EBV reactivation correlated with rapid EBV clearance post allo-HSCT in patients with younger donors. In summary, our data showed that high expression of DNAM-1 receptors on NK cell may participate protective CD56bri NK cells response to EBV infection after allo-HSCT.

Adolescent suicidal ideation: dissecting the role of sex in depression and NSSI predictors.

BACKGROUND: Suicidal ideation (SI) is increasingly prevalent among adolescents, often arising from depression and linked with non-suicidal self-injury (NSSI). Previous studies have noted significant sex differences in the manifestation and predictors of SI, depression, and NSSI. AIM: This study aims to analyze and compare the relationships between SI, depression, and NSSI among male and female adolescents, examining whether these associations differ based on sex. METHODS: A total of 368 adolescents (M = 15.43, SD = 1.22, about 56.2% female participants), both from clinical and school settings, were assessed for SI, depression, NSSI, and other related variables. Network analysis was utilized to explore the interconnections among these variables, focusing on identifying sex-specific patterns. Logistic regression was used to confirm the findings from the network analysis. RESULTS: The network analysis revealed significant sex differences in the relationships between SI, depression, and NSSI. In the female network, the edge weights between SI and NSSI (0.93) and between SI and depression (0.31) were much higher compared to the male network (0.29 and 0, respectively). Centrality indices (strength, betweenness, closeness, and expected influence) for SI, NSSI, and depression were also higher in the female network. Logistic regression confirmed these findings, with depression being a potential predictor of SI only in females (OR = 1.349, p = 0.001) and NSSI having a stronger influence on SI in females (OR = 13.673, p < 0.001) than in males (OR = 2.752, p = 0.037). CONCLUSION: The findings underscore the necessity of considering sex differences when predicting suicidal ideation from depression and NSSI in adolescents. Intervention and prevention strategies should be tailored to address these distinct patterns in male and female adolescents.

[Analysis of chemical compositions in different parts of Isodon japonicus using UPLC-Q-TOF-MS technique combined with chemometrics].

In order to analyze the similarities and differences of chemical compositions between the roots and stems and leaves of Isodon japonicus(IJ), this study utilized UPLC-Q-TOF-MS technology to systematically characterize its chemical compositions, analyzed and identified the structure of its main compounds, and established a method for simultaneous determination of its content by refe-rence substance. A total of 34 major compounds in IJ, including 14 reference compounds, were identified or predicted online. Moreover, an UPLC-UV content determination method was developed for 11 compounds [danshensu, caffeic acid, vicenin-2,(1S,2S)-globoidnan B, rutin,(+)-rabdosiin,(-)-rabdosiin,(1S,2S)-rabdosiin, shimobashiric acid C, rosmarinic acid, and pedalitin]. The method exhibited excellent separation, stability, and repeatability, with a wide linear range(0.10-520.00 µg·mL~(-1)) and high linearity(R~2>0.999). The average recovery rates ranged from 94.72% to 104.2%. The principal component analysis(PCA) demonstrated a clear difference between the roots and stems and leaves of IJ, indicating good separation by cluster. Furthermore, the orthogonal partial least squares discriminant analysis(OPLS-DA) model was employed, and six main differentially identified compounds were identified: rosmarinic acid, shimobashiric acid C, epinodosin, pedalitin, rutin, and(1S,2S)-rabdosiin. In summary, this study established a strategy and method for distinguishing different parts of IJ, providing a valuable tool for quality control of IJ and a basis for the ratio-nal utilization and sustainable development of IJ.

Development and validation of a novel nomogram for predicting good neoangiogenesis after encephaloduroarteriosynangiosis in patients with moyamoya disease and type 2 diabetes mellitus: a case-control study.

OBJECTIVE: Diabetes is often linked to poorer outcomes in patients with moyamoya disease (MMD). However, experience has shown that certain individuals with diabetes have favorable outcomes after encephaloduroarteriosynangiosis (EDAS). The authors aimed to develop a nomogram to predict good neoangiogenesis in patients with MMD and type 2 diabetes mellitus (T2DM) to aid neurosurgeons in the identification of suitable candidates for EDAS. METHODS: Adults with MMD and T2DM who underwent EDAS between June 2004 and December 2018 were included in the analysis. In total, 126 patients (213 hemispheres) with MMD and T2DM from the Fifth Medical Centre of the Chinese PLA General Hospital were included and randomly divided into training (152 hemispheres) and internal validation (61 hemispheres) cohorts at a ratio of 7:3. Univariate logistic and least absolute shrinkage and selection operator regression analyses were used to identify the significant factors associated with good neoangiogenesis, which were used to develop a nomogram. The discrimination, calibration, and clinical utility were assessed. RESULTS: A total of 213 hemispheres in 126 patients were reviewed, including 152 (71.36%) hemispheres with good postoperative collateral formation and 61 (28.64%) with poor postoperative collateral formation. The authors selected 4 predictors (FGD5 rs11128722, VEGFA rs9472135, Suzuki stage, and internal carotid artery [ICA] moyamoya vessels) for nomogram development. The C-indices of the nomogram in the training and internal validation cohorts were 0.873 and 0.841, respectively. The nomogram exhibited a sensitivity of 84.5% and specificity of 81.0%. The positive and negative predictive values were 92.1% and 66.7%, respectively. The calibration curves indicated high predictive accuracy, and receiver operating characteristic curve analysis showed the superiority of the nomogram. The decision-making analysis validated the fitness and clinical application value of this nomogram. Then a web-based calculator to facilitate clinical application was generated. CONCLUSIONS: The nomogram developed in this study accurately predicted neoangiogenesis in patients with MMD and T2DM after EDAS and may assist neurosurgeons in identifying suitable candidates for indirect revascularization surgery.

Development and validation of a novel nomogram for predicting long-term rebleeding risk among patients with hemorrhagic moyamoya disease: a 10-year multicenter retrospective cohort study.

OBJECTIVE: The aim of this study was to develop and validate a predictive nomogram model for long-term rebleeding events in patients with hemorrhagic moyamoya disease (HMMD). METHODS: In total, 554 patients with HMMD from the Fifth Medical Center of the Chinese PLA General Hospital (5-PLAGH cohort) were included and randomly divided into training (390 patients) and internal validation (164 patients) sets. An independent cohort from the First Medical Center and Eighth Medical Center of Chinese PLA General Hospital (the 1-PLAGH and 8-PLAGH cohort) was used for external validation (133 patients). Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression algorithm were used to identify significant factors associated with rebleeding, which were used to develop a nomogram for predicting 5- and 10-year rebleeding. RESULTS: Intraventricular hemorrhage was the most common type of cerebral hemorrhage (39.0% of patients in the 5-PLAGH cohort and 42.9% of the 1-PLAGH and 8-PLAGH cohort). During the mean ± SD follow-up period of 10.4 ± 2.9 years, 91 (16.4%) patients had rebleeding events in the 5-PLAGH cohort. The rebleeding rates were 12.3% (68 patients) at 5 years and 14.8% (82 patients) at 10 years. Rebleeding events were observed in 72 patients (14.3%) in the encephaloduroarteriosynangiosis (EDAS) surgery group, whereas 19 patients (37.3%) experienced rebleeding events in the conservative treatment group. This difference was statistically significant (p < 0.001). We selected 4 predictors (age at onset, number of episodes of bleeding, posterior circulation involvement, and EDAS surgery) for nomogram development. The concordance index (C-index) values of the nomograms of the training cohort, internal validation cohort, and the external validation cohort were 0.767 (95% CI 0.704-0.830), 0.814 (95% CI 0.694-0.934), and 0.718 (95% CI 0.661-0.775), respectively. The nomogram at 5 years exhibited a sensitivity of 48.1% and specificity of 87.5%. The positive and negative predictive values were 38.2% and 91.3%, respectively. The nomogram at 10 years exhibited a sensitivity of 47.1% and specificity of 89.1%. The positive and negative predictive values were 48.5% and 88.5%, respectively. CONCLUSIONS: EDAS may prevent rebleeding events and improve long-term clinical outcomes in patients with HMMD. The nomogram accurately predicted rebleeding events and assisted clinicians in identifying high-risk patients and devising individual treatments. Simultaneously, comprehensive and ongoing monitoring should be implemented for specific patients with HMMD throughout their entire lifespan.

The transgenerational effects of maternal low-protein diet during lactation on offspring.

Environmental factors such as diet and lifestyle can influence the health of both mothers and offspring. However, its transgenerational transmission and underlying mechanisms remain largely unknown. Here, using a maternal lactation-period low-protein diet (LPD) mouse model, we show that maternal LPD during lactation causes decreased survival and stunted growth, significantly reduces ovulation and litter size, and alters the gut microbiome in the female LPD-F1 offspring. The transcriptome of LPD-F1 metaphase II (MII) oocytes shows that differentially expressed genes are enriched in female pregnancy and multiple metabolic processes. Moreover, maternal LPD causes early stunted growth and impairs metabolic health, which is transmitted over two generations. The methylome alteration of LPD-F1 oocytes can be partly transmitted to the F2 oocytes. Together, our results reveal that LPD during lactation transgenerationally affects offspring health, probably via oocyte epigenetic changes.

Association between polymorphism in the MTHFR gene and encephaloduroarteriosynangiosis-induced collateral circulation formation.

OBJECTIVE: This study aimed to investigate whether high homocysteine (Hcy) levels associated with the MTHFR gene influence the formation of the collateral vascular network in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis (EDAS) by influencing the number of endothelial progenitor cells (EPCs) in peripheral blood. METHODS: A total of 118 Chinese patients with bilateral primary MMD were prospectively included. Blood samples were collected from the anterior cubital vein before surgery, and MTHFR rs9651118 was genotyped using high-throughput mass spectrometry to determine the genotype of the test specimen. Serum Hcy and EPC levels were measured, the latter with flow cytometry. Digital subtraction angiography was performed 6 months after EDAS, and the formation of collateral circulation was evaluated using the Matsushima grade system. The correlations between MTHFR rs9651118 genotype, Hcy and EPC levels, and Matsushima grade were compared. RESULTS: Among the 118 patients, 53 had the TT genotype (wild type) of MTHFR rs9651118, 33 TC genotype (heterozygous mutation), and 32 CC genotype (homozygous mutation). The mean ± SD Hcy level was 13.4 ± 9.5 µmol/L in TT patients, 9.8 ± 3.2 µmol/L in TC patients, and 8.9 ± 2.9 µmol/L in CC patients (p < 0.001). The level of EPCs in the venous blood of TT patients was 0.039% ± 0.016%, that of TC patients 0.088% ± 0.061%, and that of CC patients 0.103% ± 0.062% (p < 0.001). When the rs9651118 gene locus was mutated, Matsushima grade was better (p < 0.001) but there was no difference between heterozygous and homozygous mutations. CONCLUSIONS: The results suggest that the MTHFR rs9651118 polymorphism is a good biomarker for collateral vascular network formation after EDAS in MMD patients.

Neuropathological characteristics of abnormal white matter functional signaling in adolescents with major depression.

BACKGROUND: Major depression disorder (MDD) constitutes a significant mental health concern. Epidemiological surveys indicate that the lifetime prevalence of depression in adolescents is much higher than that in adults, with a corresponding increased risk of suicide. In studying brain dysfunction associated with MDD in adole-scents, research on brain white matter (WM) is sparse. Some researchers even mistakenly regard the signals generated by the WM as noise points. In fact, studies have shown that WM exhibits similar blood oxygen level-dependent signal fluctuations. The alterations in WM signals and their relationship with disease severity in adolescents with MDD remain unclear. AIM: To explore potential abnormalities in WM functional signals in adolescents with MDD. METHODS: This study involved 48 adolescent patients with MDD and 31 healthy controls (HC). All participants were assessed using the Patient Health Questionnaire-9 Scale and the mini international neuropsychiatric interview (MINI) suicide inventory. In addition, a Siemens Skyra 3.0T magnetic resonance scanner was used to obtain the subjects' image data. The DPABI software was utilized to calculate the WM signal of the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity, followed by a two-sample t-test between the MDD and HC groups. Independent component analysis (ICA) was also used to evaluate the WM functional signal. Pearson's correlation was performed to assess the relationship between statistical test results and clinical scales. RESULTS: Compared to HC, individuals with MDD demonstrated a decrease in the fALFF of WM in the corpus callosum body, left posterior limb of the internal capsule, right superior corona radiata, and bilateral posterior corona radiata [P < 0.001, family-wise error (FWE) voxel correction]. The regional homogeneity of WM increased in the right posterior limb of internal capsule and left superior corona radiata, and decreased in the left superior longitudinal fasciculus (P < 0.001, FWE voxel correction). The ICA results of WM overlapped with those of regional homo-geneity. The fALFF of WM signal in the left posterior limb of the internal capsule was negatively correlated with the MINI suicide scale (P = 0.026, r = -0.32), and the right posterior corona radiata was also negatively correlated with the MINI suicide scale (P = 0.047, r = -0.288). CONCLUSION: Adolescents with MDD involves changes in WM functional signals, and these differences in brain regions may increase the risk of suicide.

High-throughput prediction of enzyme promiscuity based on substrate-product pairs.

The screening of enzymes for catalyzing specific substrate-product pairs is often constrained in the realms of metabolic engineering and synthetic biology. Existing tools based on substrate and reaction similarity predominantly rely on prior knowledge, demonstrating limited extrapolative capabilities and an inability to incorporate custom candidate-enzyme libraries. Addressing these limitations, we have developed the Substrate-product Pair-based Enzyme Promiscuity Prediction (SPEPP) model. This innovative approach utilizes transfer learning and transformer architecture to predict enzyme promiscuity, thereby elucidating the intricate interplay between enzymes and substrate-product pairs. SPEPP exhibited robust predictive ability, eliminating the need for prior knowledge of reactions and allowing users to define their own candidate-enzyme libraries. It can be seamlessly integrated into various applications, including metabolic engineering, de novo pathway design, and hazardous material degradation. To better assist metabolic engineers in designing and refining biochemical pathways, particularly those without programming skills, we also designed EnzyPick, an easy-to-use web server for enzyme screening based on SPEPP. EnzyPick is accessible at http://www.biosynther.com/enzypick/.

Sporadic gastrinoma with refractory benign esophageal stricture: A case report.

BACKGROUND: Gastrinoma is characterized by an excessive release of gastrin, leading to hypersecretion of gastric acid, subsequently resulting in recurrent peptic ulcers, chronic diarrhea, and even esophageal strictures. This case report aims to improve awareness and facilitate early diagnosis and treatment of gastrinoma by presenting a rare case of gastrinoma with refractory benign esophageal stricture (RBES). Additionally, it highlights the persistent challenges that gastroenterologists encounter in managing RBES. CASE SUMMARY: This case demonstrates a patient with gastrinoma who developed RBES and complete esophageal obstruction despite management with maximal acid suppressive therapy, multiple endoscopic bougie dilations and endoscopic incisional therapy (EIT). CONCLUSION: It is essential to diagnose gastrinoma as early as possible, as inadequately controlled acid secretion over an extended period increases the risk of developing severe esophageal strictures. In patients with esophageal strictures causing complete luminal obstruction, blind reopening EIT presents challenges and carries a high risk of perforation.

Early-onset Marfan syndrome with aortic dilatation and giant pulmonary artery aneurysm: A case report.

A 30-year-old woman with ankylosing spondylitis was referred to our clinic with abnormal fetal echocardiography findings, including ascending aortic dilatation, giant main pulmonary artery aneurysm, and aortic and pulmonary valve stenosis at 22 weeks of gestation. The full-term male neonate was born by cesarean section and was transferred to the cardiac intensive care unit soon after delivery for respiratory distress with low percutaneous oxygen saturation. Based on cardiovascular and genetic analysis findings, the patient was diagnosed with Marfan syndrome. Surgery was performed; however, the patient died due to cardiac arrest. In conclusion, main pulmonary artery dilatation and aneurysms are uncommon in Marfan syndrome; therefore, presentation with these findings during the fetal life, as in the present case, is likely a sign of severe Marfan syndrome-related cardiac involvement.

[Buyang Huanwu Decoction promotes arteriogenesis after hindlimb ischemia in mice by activating PDGF signaling pathway].

This study aims to investigate the effect of Buyang Huanwu Decoction on blood flow recovery and arteriogenesis after hindlimb ischemia in mice via the platelet-derived growth factor(PDGF) signaling pathway. Forty C57BL/6 mice were randomized into model(clean water, 10 mL·kg~(-1)·d~(-1)), beraprost sodium(positive control, 18 µg·kg~(-1)·d~(-1)), and low-, medium-, and high-dose(10, 20, and 40 g·kg~(-1)·d~(-1), respectively) Buyang Huanwu Decoction groups(n=8). The hindlimb ischemia model was established by femoral artery ligation. The mice were administrated with corresponding agents by gavage daily for 14 days after ligation. For laser Doppler perfusion imaging, the mice were anesthetized and measured under a Periscan PSI imager. The density of capillary and arterio-le in the ischemic gastrocnemius was measured using immunofluorescence staining of the frozen tissue sections. Western blot was employed to determine the expression of PDGF subunit B(PDGFB), phosphorylated mitogen extracellular kinase(p-MEK), MEK, phosphorylated extracellular signal-regulated kinase(p-ERK), and ERK. Real-time PCR was employed to determine the mRNA level of PDGFB. The Buyang Huanwu Decoction-containing serum was used to treat the vascular smooth muscle cells(VSMCs) in hypoxia at doses of 10% and 20%. The proliferation and migration of VSMCs was assessed in vitro. The results showed that compared with the model group, beraprost sodium and Buyang Huanwu Decoction enhanced the blood flow recovery, increased the capillary and arteriole density, and up-regulated the protein levels of PDGFB, p-MEK, p-ERK, and mRNA levels of PDGFB, with the medium-dose Buyang Huanwu Decoction demonstrating the most significant effect. The 10% Buyang Huanwu Decoction-containing serum enhanced the proliferation and migration of VSMCs. Our findings demonstrate that Buyang Huanwu Decoction up-regulates PDGFB transcription and activates PDGF signaling pathway to promote arteriogenesis and blood flow recovery in ischemic gastrocnemius.

Clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease: Longitudinal and Cross-Sectional Study.

Objective: This study aimed to explore the long-term outcome of unilateral moyamoya disease and predict the clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease. Methods: We retrospectively recruited unilateral moyamoya disease patients with available genetic data who underwent encephaloduroarteriosynangiosis (EDAS) surgery at our institution from January 2009 to November 2017. Long-term follow-up data, including clinical outcomes, angiographic features, and genetic information, were analyzed. Results: A total of 83 unilateral moyamoya disease patients with available genetic data were enrolled in our study. The mean duration of clinical follow-up was 7.9 ± 2.0 years. Among all patients, 19 patients demonstrated contralateral progression to bilateral disease. Heterozygous Ring Finger Protein 213 p.R4810K mutations occurred significantly more frequently in unilateral moyamoya disease patients with contralateral progression. Furthermore, patients with contralateral progression typically demonstrated an earlier age of onset than those with non-progressing unilateral moyamoya disease. In the contralateral progression group, posterior circulation involvement was observed in 11 (11/19, 57.9%) patients compared to 12 (12/64, 18.8%) in the non-contralateral progression group (P = 0.001). The time to peak of cerebral perfusion and neurological status showed significant postoperative improvement. Conclusion: Long-term follow-up revealed that the EDAS procedure might provide benefits for unilateral moyamoya disease patients. Ring Finger Protein 213 p.R4810K mutations, younger age, and posterior circulation involvement might predict the contralateral progression of unilateral moyamoya disease.

Alexithymia and peer victimisation: interconnected pathways to adolescent non-suicidal self-injury.

BACKGROUND: The prevalence of non-suicidal self-injury (NSSI) among adolescents underscores the importance of understanding the complex factors that drive this behaviour. Framed within broader constructs of emotional regulation theories, alexithymia and peer victimisation are thought to interact to influence NSSI behaviours. AIM: This research addresses whether alexithymia and peer victimisation serve as risk factors for NSSI and, if so, how these factors interact with each other. METHOD: This quantitative study analysed data from 605 adolescents, using a range of validated self-report measures including the Toronto Alexithymia Scale. Statistical analyses including one-way analysis of variance, multiple regression and structural equation modelling were employed to scrutinise the relationships among the variables. RESULTS: Alexithymia and peer victimisation significantly predicted NSSI behaviours. Specifically, the 'difficulty in identifying feelings' subscale of alexithymia emerged as a noteworthy predictor of NSSI (P < 0.001). Peer victimisation mediated the relationship between alexithymia and NSSI, explaining approximately 24.50% of alexithymia's total effect on NSSI. In addition, age was a significant predictor of NSSI, but gender and education years were not (P > 0.05). These relationships were found to be invariant across genders. CONCLUSIONS: This study enriches our understanding of the interplay between alexithymia, peer victimisation and NSSI, particularly within the Chinese context. Its findings have significant implications for a rethinking of alexithymia's theoretical construct and interventions targeting emotional literacy and peer dynamics among adolescents. Future research could benefit from a longitudinal design to establish causality.

Laparoscopic versus open distal gastrectomy for advanced gastric cancer in elderly patients: a propensity-score matched analysis.

BACKGROUND: Scarce research has reported the efficacy and safety of laparoscopic distal gastrectomy in elderly patients. This retrospective study aimed to compare the outcomes of laparoscopic and open distal gastrectomy for advanced gastric cancer in elderly patients. METHODS: A total of 303 elderly patients who underwent distal gastrectomy for advanced gastric cancer from June 2017 to June 2021 were enrolled. Variables used to calculate propensity score matching included sex, age, body mass index, American Society of Anesthesiologists, history of diabetes, and history of hypertension. The statistical significance of continuous variables was tested using an independent sample t test. chi-square or Fisher's exact tests were used for categorical variables. Kaplan-Meier curve and log-rank test were used for the evaluation of 3-year overall survival and recurrence-free survival. RESULTS: After performing 1:1 propensity score matching, 248 patients were included for analysis (laparoscopic = 124, open = 124). Compared with the open group, the laparoscopic group showed significant advantages in estimated blood loss (P < 0.001), pain scale on the first postoperative day (P = 0.002), time to first flatus (P = 0.004), time to first liquid diet (P = 0.005), hospital stays (P < 0.001), and total complications (P = 0.011), but devoted much more operation time (P < 0.001). No statistical difference was observed between the two groups in 3-year recurrence-free survival (P = 0.315) or overall survival (P = 0.159). CONCLUSIONS: Our analysis demonstrated that laparoscopic surgery had the advantages of less intraoperative blood loss, fewer postoperative complications, and faster postoperative recovery in distal gastrectomy for advanced gastric, indicating that laparoscopic distal gastrectomy is safe and effective for treating elderly patients with distal gastric cancer.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma.

The androgen receptor (AR) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis. However, the role of hepatic acquired somatic mutations of AR remains unknown. In this study, we identify two crucial acquired somatic mutations, Q62L and E81Q, situated close to the N-terminal activation function domain-1 of AR. These mutations lead to constitutive activation of AR, both independently and synergistically with androgens, making them potent driver oncogene mutations. Mechanistically, these N-terminal AR somatic mutations enhance de novo lipogenesis by activating sterol regulatory element-binding protein-1 and promote glycogen accumulation through glycogen phosphorylase, brain form, thereby disrupting the AMPK pathway and contributing to tumorigenesis. Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations.