Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

Association between sleep quality and living environment among Chinese older persons: a cross-sectional study.

Sleep quality significantly affects the quality of life of older persons. Therefore, this study explored the relationship between sleep quality and living environment of older persons in China to provide a theoretical basis for therapies to alleviate sleep disorders in older persons. A total of 6211 subjects > 60 years of age in Anhui Province, China, were evaluated using the Pittsburgh Sleep Quality Index and a self-reported questionnaire. Multivariate logistic regression analysis revealed that living alone (OR = 1.26, 95% CI 1.09-1.46) and living in a rural area (OR = 1.19, 95% CI 1.06-1.34) were significantly associated with a high incidence of sleep disorders in older persons. Living near a park or foot paths suitable for exercise or walking was significantly associated with a lower incidence of sleep disorders in older persons (OR = 0.87, 95% CI 0.77-0.96). Individual factors such as female sex (OR = 1.30, 95% CI 1.14-1.48) and depression (OR = 2.80, 95% CI 2.47-3.19) were also associated with sleep quality in older persons. These data indicate a correlation exists between living environment and sleep quality.

Retraction note to: RNA-binding protein CPSF6 regulates IBSP to affect pyroptosis in gastric cancer.

[This retracts the article on p. 1531 in vol. 15, PMID: 37746647.].

Oncogenic and immunological role of EDIL3 in human tumours: From pan-cancer analysis to validation in gastric cancer.

Background: Epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) is a secreted extracellular matrix protein implicated in diverse physiological and pathological processes including embryonic development, angiogenesis, and anti-inflammatory responses. Recent reports have indicated that EDIL3 play critical roles in carcinogenesis and progression of many cancers. Herein, we performed a pan-cancer investigation to study the potential functions of EDIL3 in various cancers and experimentally validate its function in gastric cancer (GC). Methods: We analysed EDIL3 expression profiles in different tumours using The Cancer Genome Atlas database. The Kaplan-Meier Plotter was used to investigate the prognostic value of EDIL3, while receiver operating characteristic curve was performed to analyze its diagnostic efficacy. Several bioinformatics tools were used to study the association between EDIL3 and promoter methylation, gene enrichment analysis, immune infiltration, immune-related genes, and drug sensitivity. Molecular biology experiments were conducted to validate the tumorigenic effects of EDIL3. Results: EDIL3 is variably expressed in different cancers and is closely associated with clinical outcomes. An inverse correlation between EDIL3 and DNA methylation has been observed in 13 cancers. Enrichment analysis indicated that EDIL3 is correlated with many cellular pathways such as extracellular matrix receptor interactions and focal adhesion. EDIL3 was tightly associated with immune infiltration and immune checkpoints. EDIL3 knockdown can promote GC calls apoptosis while preventing proliferation, migration, and invasion in vitro. Conclusion: EDIL3 is a promising prognostic, diagnostic, and immunological biomarker in various cancers, which could be applied as a new target for cancer therapy.

Comprehensive assessment of refined greenhouse gas emissions from China's livestock sector.

Livestock and poultry products are an essential human food source. However, the rapid development of the livestock sector (LS) has caused it to become a significant source of greenhouse gas (GHG) emissions. Consequently, investigating the spatio-temporal characteristics and evolution of GHG emissions is crucial to facilitate the green development of the LS and achieve "peak carbon and carbon neutrality". This study combined life cycle assessment (LCA) with the IPCC Tier II method to construct a novel GHG emissions inventory. The GHG emissions of 31 provinces in China from 2000 to 2021 were calculated, and their spatio-temporal characteristics were revealed. Then, the stochastic impacts by regression on population, affluence, and technology (STIRPAT) model was used to identify the main driving factors of GHG emissions in six regions of China and explore the emission reduction potential. The results showed that GHG emissions increased and then decreased from 2000 to 2021, following a gradual and steady trend. The peak of 628.55 Mt CO2-eq was reached in 2006. The main GHG-producing segments were enteric fermentation, slaughtering and processing, and manure management, accounting for 45.39 %, 26.34 %, and 23.08 % of total GHG emissions, respectively. Overall, the center of gravity of GHG emissions in China migrated northward, with spatial aggregation observed since 2016. The high emission intensity regions were mainly located west of the "Hu Huanyong line". Economic efficiency and emissions intensity were the main drivers of GHG emissions. Under the baseline scenario, GHG emissions are not projected to peak until 2050. Therefore, urgent action is needed to promote the low-carbon green development of the LS in China. The results can serve as scientific references for the macro-prevention and control of GHG emissions, aiding strategic decision-making. Additionally, they can provide new ideas for GHG accounting in China and other countries around the world.

Aberrancy masquerading as ventricular tachycardia: Importance of invasive electrophysiology study for diagnosis of wide complex tachycardias.

BACKGROUND: Differentiation between ventricular tachycardia (VT) and supraventricular tachycardia (SVT) with aberrancy based on the 12­lead ECG alone can be imprecise. Implantable cardiac defibrillators (ICD) may be inserted for presumed VT, particularly in patients with syncopal presentation or atypical aberrancy patterns. Accurate diagnosis of these patients facilitated by an electrophysiology study (EPS) may alter diagnosis and management. METHODS: We present a prospective collection of cases across 3 cardiac centers of consecutive patients with WCT presumed to be VT who were referred for consideration of an ICD, and in whom further evaluation including an EPS ultimately demonstrated SVT with aberrancy as the culprit arrhythmia. RESULTS: 22 patients were identified (17 male, mean age 50±13 years. Available rhythm data at the time of referral was presumptively diagnosed as monomorphic VT in 16 patients and polymorphic VT in 6 patients. Underlying structural heart disease was present in 20 (91%). EPS resulted in a diagnosis of SVT with aberrancy in all cases: comprising AV nodal re-entry tachycardia (n=10), orthodromic reciprocating tachycardia (n=3), focal atrial tachycardia (n=3), AF/AFL (n=3) and 'double fire' tachycardia (n=2). 21 (95%) patients underwent successful ablation. All patients remained free of arrhythmia recurrence at a median of 3.4 years of follow-up. ICD insertion was obviated in 18 (82%) patients, with 1 patient proceeding to ICD extraction. CONCLUSION: SVT with atypical aberrancy may mimic monomorphic or polymorphic VT. Careful examination of all available rhythm data and consideration of an EPS can confirm SVT and obviate the need for ICD therapy.

Comparison of short­term outcomes and 3-year overall survival between robotic and laparoscopic gastrectomy for gastric cancer: a propensity score matching analysis.

BACKGROUND: Despite the increasing use of robotic gastrectomy (RG) as an alternative to laparoscopic gastrectomy (LG) in treating gastric cancer, controversy remains over the advantages of RG compared to LG and there is a paucity of studies comparing the two techniques regarding patient survival. METHODS: In this retrospective cohort study, 675 patients undergoing minimally invasive gastrectomy were recruited from January 2016 to January 2018 (LG: n = 567; RG: n = 108). A one-to-one propensity score matching (PSM) analysis was applied to minimize the selection bias due to confounding factors, yielding 104 patients in each of the RG and LG groups. After matching, the short-term outcomes and 3-year overall survival were compared in the two groups. RESULTS: The PSM cohort analysis showed a similar 3-year overall survival between RG and LG groups (p = .249). Concerning the short-term outcomes, the RG compared to LG resulted in lower blood loss (p = .01), lower postoperative complications (p = .001), lower postoperative pain (p = .016), earlier initiation of soft diet (p = .011), shorter hospital stay |(p = .012), but higher hospitalization expenses (p = .001). CONCLUSION: Our findings suggest that RG may offer advantages in terms of blood loss, surgical complications, recovery time, and pain management compared to LG while maintaining similar overall survival rates. However, RG is associated with higher hospital costs, potentially limiting its wider adoption. Further research, including large, multi-center randomized controlled trials with longer patient follow-up, particularly for advanced gastric cancer, is needed to confirm these findings.

Catheter ablation for persistent atrial fibrillation: patterns of recurrence and impact on quality of life and health care utilisation.

BACKGROUND AND AIMS: Patterns of atrial fibrillation (AF) recurrence post catheter ablation for persistent AF are not well described. This study aimed to describe the pattern of AF recurrence seen following catheter ablation for persistent AF (PsAF) and the implications for healthcare utilisation and quality of life. METHODS: This was a post-hoc analysis of the CAPLA study, an international, multi-centre study that randomised patients with symptomatic PsAF to pulmonary vein isolation plus posterior wall isolation or pulmonary vein isolation alone. Patients underwent twice daily single lead ECG, implantable device monitoring or three monthly Holter monitoring. RESULTS: 154 of 333 (46.2%) patients (median age 67.3 years, 28% female) experienced AF recurrence at 12-month follow-up. Recurrence was paroxysmal in 97 (63%) patients and persistent in 57 (37%). Recurrence type did not differ between randomisation groups (p=0.508). Median AF burden was 27.4% in PsAF recurrence and 0.9% in paroxysmal AF (PAF) recurrence (p<0.001). Patients with PsAF recurrence had lower baseline left ventricular ejection fraction (PsAF 50% vs PAF 60%, p<0.001) and larger left atrial volume (PsAF 54.2±19.3 ml/m² vs PAF 44.8±11.6 ml/m², p=0.008). Healthcare utilisation was significantly higher in PsAF (45 patients [78.9%]) vs PAF recurrence (45 patients [46.4%], p<0.001) and lowest in those without recurrence (17 patients [9.5%], p<0.001). Patients without AF recurrence had greater improvements in quality of life as assessed by the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire (Δ33.3±25.2 points) compared to those with PAF (Δ24.0±25.0 points, p=0.012) or PsAF (Δ13.4±22.9 points, p<0.001) recurrence. CONCLUSIONS: AF recurrence is more often paroxysmal after catheter ablation for PsAF irrespective of ablation strategy. Recurrent PsAF was associated with higher AF burden, increased healthcare utilisation and antiarrhythmic drug use. The type of AF recurrence and AF burden may be considered important endpoints in clinical trials investigating ablation of PsAF.

Circulating long noncoding RNA, Zfpm2-As1, and XIST based on medical data analysis are potential plasma biomarkers for gastric cancer diagnosis.

BACKGROUND: Long noncoding RNAs (lncRNAs) participate in diseases, especially tumorigenesis, including gastric cancer (GC). Although lncRNAs in GC tissues have been extensively studied in previous research, the possible significance of circulating lncRNAs in diagnosing GC is still unknown. OBJECTIVE: The present work investigated lncRNAs ZFPM2-AS1 and XIST with high expression in GC tissues proved as potential plasma biomarkers from 20 early GC cases, 100 GC cases, and 90 normal subjects. METHODS: The possible correlation between ZFPM2-AS1 and XIST expression levels was analyzed with general characteristics and clinicopathological features. The performance in diagnosis was assessed according to receiver operating characteristic (ROC) analysis. RESULTS: According to the results, XIST and ZFPM2-AS1 expression remarkably increased within GC plasma relative to normal subjects (P< 0.01); besides, lncRNA XIST expression after surgery had a tendency of downregulation compared with preoperative levels (P< 0.05). Moreover, the area under ROC curve (AUC) values were 0.62 for ZFPM2-AS1 and 0.68 for XIST, while the pooled AUC value of CA-724 and two lncRNAs was 0.751. CONCLUSION: Circulating lncRNAs ZFPM2-AS1 and XIST can serve as the candidate plasma biomarkers used to diagnose GC.

Establishment and validation of a risk score model based on EUS: assessment of lymph node metastasis in early gastric cancer.

BACKGROUND AND AIMS: Lymph node metastasis significantly affects the prognosis of early gastric cancer patients. EUS plays a crucial role in the preoperative assessment of early gastric cancer. This study evaluated the efficacy of EUS in identifying lymph node metastasis in early gastric cancer patients and developed a risk score model to aid in choosing the best treatment options. METHODS: We retrospectively analyzed the effectiveness of EUS for detecting lymph node metastasis in early gastric cancer patients. A risk score model for predicting lymph node metastasis preoperatively was created using independent risk factors identified through binary logistic regression analysis and subsequently validated. Receiver operating characteristic curves were generated for both the development and validation cohorts. RESULTS: The overall accuracy of EUS in identifying lymph node metastasis was 85.3%, although its sensitivity (29.2%) and positive predictive value (38.7%) were relatively low. Patients were categorized based on preoperative risk factors for lymph node metastasis, including tumor size of ≥20 mm, lymph nodes of ≥10 mm, body mass index of ≥24 kg/m2, and lymph node metastasis on CT scans. A 7-point risk score model was developed to assess the likelihood of lymph node metastasis. The areas under the receiver operating characteristic curve for the development and validation sets were 0.842 and 0.837, respectively, with sensitivities of 64% and 79%, respectively. CONCLUSIONS: We developed a practical risk score model based on preoperative factors to help EUS predict lymph node metastasis in early gastric cancer patients, guiding the selection of optimal treatment approaches for these patients.

Salvaging donated kidneys from prolonged warm ischemia during ex vivo hypothermic oxygenated perfusion.

Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated intravascular coagulation and severe capillary vasospasm after cardiac death of rat kidneys. Additionally, we found a significant accumulation of fibrinogen in a hypoxic cell culture of human umbilical vein epithelial cells and in isolated kidneys exposed to prolonged warm ischemic following flushing out of blood. However, pre-flushing the kidney with snake venom plasmin in a 90-minute warm ischemic model maximized removal of micro thrombi and facilitated the delivery of oxygen and therapeutic agents. Application of carbon monoxide-releasing CORM-401 during ex vivo hypothermic oxygenated perfusion achieved multipath protective effects in prolonged warm ischemic kidneys. This led to significant improvements in perfusion parameters, restoration of the microcirculation, amelioration of mitochondrial injury, oxidative stress, and apoptosis. This benefit resulted in significantly prolonged warm ischemic kidney recipient survival rates of 70%, compared with none in those receiving ex vivo hypothermic oxygenated perfusion alone. Significantly, ex vivo hypothermic oxygenated perfusion combined with cytoprotective carbon monoxide releasing CORM-401 treatment meaningfully protected the donated kidney after cardiac death from ischemia-reperfusion injury by reducing inflammation, oxidative stress, apoptosis, and pathological damage. Thus, our study suggests a new combination treatment strategy to potentially expand the donor pool by increasing use of organs after cardiac death and salvaging prolonged warm ischemic kidneys.

2023 Cardiac Society of Australia and New Zealand Expert Position Statement on Catheter and Surgical Ablation for Atrial Fibrillation.

Catheter ablation for atrial fibrillation (AF) has increased exponentially in many developed countries, including Australia and New Zealand. This Expert Position Statement on Catheter and Surgical Ablation for Atrial Fibrillation from the Cardiac Society of Australia and New Zealand (CSANZ) recognises healthcare factors, expertise and expenditure relevant to the Australian and New Zealand healthcare environments including considerations of potential implications for First Nations Peoples. The statement is cognisant of international advice but tailored to local conditions and populations, and is intended to be used by electrophysiologists, cardiologists and general physicians across all disciplines caring for patients with AF. They are also intended to provide guidance to healthcare facilities seeking to establish or maintain catheter ablation for AF.

Critical Role of Configurational Disorder in Stabilizing Chemically Unfavorable Coordination in Complex Compounds.

The crystal structure of a material is essentially determined by the nature of its chemical bonding. Consequently, the atomic coordination intimately correlates with the degree of ionicity or covalency of the material. Based on this principle, materials with similar chemical compositions can be successfully categorized into different coordination groups. However, counterexamples have recently emerged in complex ternary compounds. For instance, covalent IB-IIIA-VIA2 compounds, such as AgInS2, prefer a tetrahedrally coordinated structure (TCS), while ionic IA-VA-VIA2 compounds, such as NaBiS2, would favor an octahedrally coordinated structure (OCS). One naturally expects that IB-VA-VIA2 compounds with intermediate ionicity or covalency, such as AgBiS2, should then have a mix-coordinated structure (MCS) consisting of covalent AgS4 tetrahedra and ionic BiS6 octahedra. Surprisingly, only the experimental presence of the OCS was observed for AgBiS2. To resolve this puzzle, we perform first-principles studies of the phase stabilities of ternary compounds at finite temperatures. We find that AgBiS2 indeed prefers MCS at the ground state, in agreement with the typical expectation, but under experimental synthesis conditions, disordered OCS becomes energetically more favorable because of its low mixing energy and high configurational entropy. Our work elucidates the critical role of configurational disorder in stabilizing chemically unfavorable coordination, providing a rigorous rationale for the anomalous coordination preference in IB-VA-VIA2 compounds.

State of mental health, sleep status, and the interaction with health-related quality of life in HIV-infected Chinese patients during the COVID-19 pandemic.

OBJECTIVE: To describe how mental health and sleep status influence the health-related quality of life (HRQOL) of people living with HIV/AIDS (PLWHA) during the novel coronavirus disease 2019 (COVID-19) pandemic, and to apply targeted interventions to improve the HRQOL. METHODS: A web-based online questionnaire survey was administered. Descriptive analysis was used to depict the mental health and sleep status. Correlation analysis and the structural equation model (SEM) method were used to analyze the influence of mental health and sleep status on HRQOL in PLWHA. RESULTS: After excluding 24 unqualified questionnaires, a total of 490 participants in this survey were included in the statistical analysis. Of the participants, 66.1% and 55.1% reported mild or worse symptoms of depression and anxiety, respectively. Overall, 70.0% had varying degrees of sleep problems. Correlation analysis showed that anxiety had the strongest correlation with sleep disturbances and sleep quality (R = 0.588 and 0.551, respectively), while depression had the strongest correlation with the HRQOL psychological and physical domains (R = - 0.759 and - 0.682, respectively). SEM analysis showed that depression, sleep quality, and psychological domains had the greatest item load on mental health, sleep status, and HRQOL (093, 0.82, and 0.89, respectively). Mental health had a more significant influence than sleep status on HRQOL, as indicated by factor loading (- 0.75 and - 0.15, respectively). CONCLUSIONS: There were more severe mental health and sleep problems among PLWHA during the COVID-19 pandemic, thus, mental health intervention, especially to relieve depression symptoms, may be the most important approach to improve the HRQOL among PLWHA.

Impact of Posterior Wall Isolation During AF Ablation on the Incidence of Left Atrial Flutter.

BACKGROUND: Linear and complex electrogram ablation (LCEA) beyond pulmonary vein isolation (PVI) is associated with an increase in left atrial macro-re-entrant tachycardias (LAMTs). Posterior wall isolation (PWI) is increasingly performed to improve AF ablation outcomes. However, the impact of PWI on the incidence of LAMT is unknown. OBJECTIVES: The purpose of this study was to establish the incidence of LAMT following PVI alone vs PVI + PWI vs PVI + PWI + LCEA. METHODS: Consecutive patients undergoing catheter ablation for AF or LAMT post-AF ablation between 2008 and 2022 from 4 electrophysiology centers were reviewed with a minimum follow-up of 12 months. RESULTS: In total, 5,619 (4,419 index, 1,100 redo) AF ablation procedures were performed in 4,783 patients (mean age 60.9 ± 10.6 years, 70.7% men). Over a mean follow-up of 6.4 ± 3.8 years, 246 procedures for LAMT were performed in 214 patients at a mean of 2.6 ± 0.6 years post-AF ablation. Perimitral (52.8% of patients), roof-dependent (27.1%), PV gap-related (17.3%), and anterior circuits (8.9%) were most common, with 16.4% demonstrating multiple circuits. The incidence of LAMT was significantly higher following PVI + PWI (6.2%) vs PVI alone (3.0%; P < 0.0001) and following PVI + PWI + LCEA vs PVI + PWI (12.5%; P = 0.019). Conduction gaps in previous ablation lines were responsible for LAMT in 28.4% post-PVI alone, 35.3% post-PVI + PWI (P = 0.386), and 81.8% post-PVI + PWI + LCEA (P < 0.005). CONCLUSIONS: The incidence of LAMT following PVI + PWI is higher than with PVI alone but significantly lower than with more extensive atrial substrate modification. Given a low frequency of LAMT following PWI, empiric mitral isthmus ablation is not justified and may be proarrhythmic.

Association between repeat imaging and readmission in patients with acute ischaemic stroke: a 16-year nationwide population-based study.

OBJECTIVES: This study aims to evaluate such usage patterns and identify factors that may contribute to the need for repeat imaging in acute ischaemic stroke patients and determine the association between repeat imaging and readmission in Taiwan. METHODS: We searched and analysed data from the Taiwan National Health Insurance Research Database for patients admitted for acute ischaemic stroke between 2002 and 2017. Cases where repeat brain imaging during the initial hospital admission occurred and where patients were readmitted within 30 days following discharge were documented. RESULTS: Of a total of 195 016 patients with new onset ischaemic stroke, 51 798 (26.6%) underwent repeat imaging during their initial admission. Factors associated with repeat brain imaging included younger age, longer hospital stay, use of recombinant tissue plasminogen activator (rt-PA) therapy (odds ratio = 2.10 [95% CI, 1.98-2.22]), more recent year of diagnosis, higher National Institutes of Health Stroke Scale (NIHSS) score, and admission to a hospital offering a higher level of care. Repeat imaging was also associated with an increased risk of ischaemic stroke and all types of stroke readmission. CONCLUSIONS: Repeat brain imaging of patients with stroke has increased in recent years, and it is associated with certain factors including age, length of stay, use of rt-PA, hospital level of care, and NIHSS score. It is also associated with increased readmission. ADVANCES IN KNOWLEDGE: Knowledge of the associations of repeat imaging may help clinicians use repeat imaging more carefully and efficaciously.

Enhanced plant-derived vesicles for nucleotide delivery for cancer therapy.

Small RNAs (microRNAs [miRNAs] or small interfering RNAs [siRNAs]) are effective tools for cancer therapy, but many of the existing carriers for their delivery are limited by low bioavailability, insufficient loading, impaired transport across biological barriers, and low delivery into the tumor microenvironment. Extracellular vesicle (EV)-based communication in mammalian and plant systems is important for many physiological and pathological processes, and EVs show promise as carriers for RNA interference molecules. However, some fundamental issues limit their use, such as insufficient cargo loading and low potential for scaling production. Plant-derived vesicles (PDVs) are membrane-coated vesicles released in the apoplastic fluid of plants that contain biomolecules that play a role in several biological mechanisms. Here, we developed an alternative approach to deliver miRNA for cancer therapy using PDVs. We isolated vesicles from watermelon and formulated a hybrid, exosomal, polymeric system in which PDVs were combined with a dendrimer bound to miRNA146 mimic. Third generation PAMAM was chosen due to its high branching structure and versatility for loading molecules of interest. We performed several in vivo experiments to demonstrate the therapeutic efficacy of our compound and explored in vitro biological mechanisms underlying the anti-tumor effects of miRNA146, which are mostly related to its anti-angiogenic activity.

Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial.

Evidence from Europe shows that perioperative chemotherapy may be beneficial for the treatment of locally advanced gastric cancer, but reliable and robust data is lacking. To rectify this, the phase 3 RESONANCE trial investigated the efficacy and safety of S-1 plus oxaliplatin (SOX) as a perioperative chemotherapy regimen for gastric cancer. This randomized, open-label trial enrolled patients from 19 medical centers with stage II/III resectable gastric cancer who were centrally randomly assigned to either perioperative chemotherapy (PC) arm or adjuvant chemotherapy (AC) arm. Patients in the PC arm received two to four cycles of SOX followed by surgery and four to six cycles of SOX. Patients in the AC arm received upfront surgery and eight cycles of SOX. 386 patients in each group were enrolled and 756 (382 in PC and 374 in AC) were included in the mITT population. The three-year DFS rate was 61.7% in the PC arm and 53.8% in the AC arm (log-rank p = 0.019). The R0 resection rate in the PC arm was significantly higher than that in the AC arm (94.9% vs. 83.7%, p < 0.0001). There was no difference between two arms in surgical outcomes or postoperative complications. Safety-related data were like the known safety profile. In conclusion, from a clinical perspective, this trial indicated a trend towards higher three-year disease-free survival rate with perioperative SOX in stage II/III resectable gastric cancer with well-tolerated toxicity compared to adjuvant SOX, which might provide a theoretical basis for applying perioperative SOX in advanced gastric cancer patients. (ClinicalTrials.gov NCT01583361).

Ketohexokinase-A deficiency attenuates the proliferation via reducing ß-catenin in gastric cancer cells.

Overconsumption of fructose is closely related to cancer. Ketohexokinase (KHK) catalyzes the conversion from fructose to fructose-1-phosphate (F1P), which is the first and committed step of fructose metabolism. Recently, aberrant KHK activation has been identified in multiple malignancies. However, the roles of KHK in gastric cancer (GC) cells are largely unclear. Herein, we reveal that the expression of ketohexokinase-A (KHK-A), one alternatively spliced KHK isoform that possesses low affinity for fructose, was markedly increased in GC cells. Depletion of endogenous KHK-A expression using lentiviruses encoding short hairpin RNAs (shRNAs) or pharmaceutical disruption of KHK-A activity using KHK-IN-1 hydrochloride in GC NCI-N87 and HGC-27 cells inhibited the proliferation in vitro and in vivo. Additionally, the mitochondrial respiration in the GC cells with KHK-A deficiency compared with the control cells was significantly impaired. One commercially-available antibody array was used to explore the effects of KHK-A knockdown on signaling pathways, showing that ß-catenin was remarkably reduced in the KHK-A deficient GC cells compared with the control ones. Pharmaceutical reduction in ß-catenin levels slowed down the proliferation of GC cells. These data uncover that KHK-A promotes the proliferation in GC cells, indicating that this enzyme might be a promising therapeutical target for GC treatment.