Sex disparity, prediagnosis lifestyle factors, and long-term survival of gastric cancer: a multi-center cohort study from China.

BACKGROUND: This multi-center cohort study aimed to investigate whether sex and prediagnosis lifestyle affect the prognosis of gastric cancer. METHODS: Patients with gastric cancer were from four gastric cancer cohorts of the National Cancer Center of China, The First Hospital of Lanzhou University, Lanzhou University Second Hospital, and Gansu Provincial Cancer Hospital. Prediagnosis lifestyle factors in our study included body mass index (BMI) at diagnosis, usual BMI, weight loss, the history of Helicobacter pylori (Hp) infection, and the status of smoking and drinking. RESULTS: Four gastric cancer cohorts with 29,779 gastric cancer patients were included. In total patients, female patients had a better prognosis than male patients (HR = 0.938, 95%CI: 0.881-0.999, P = 0.046). For prediagnosis lifestyle factors, BMI at diagnosis, usual BMI and the amount of smoking were statistically associated with the prognosis of gastric cancer patients. Female patients with smoking history had a poorer survival than non-smoking females (HR = 0.782, 95%CI: 0.616-0.993, P = 0.044). Tobacco consumption > 40 cigarettes per day (HR = 1.182, 95%CI: 1.035-1.350, P = 0.013) was independent adverse prognostic factors in male patients. Obesity paradox was observed only in male patients (BMI < 18.5, HR = 1.145, 95%CI: 1.019-1.286, P = 0.023; BMI: 23-27.4, HR = 0.875, 95%CI: 0.824-0.930, P < 0.001; BMI ≥ 27.5, HR = 0.807, 95%CI: 0.735-0.886, P < 0.001). CONCLUSIONS: Sex and some prediagnosis lifestyle factors, including BMI at diagnosis, usual BMI and the amount of smoking, were associated with the prognosis of gastric cancer.

Trends of older gastric cancer incidence, mortality, and survival in the highest gastric cancer risk area in China: 2010-2019 and prediction to 2024.

BACKGROUND: Gastric cancer is a major health problem worldwide, with a high incidence among older adults. Given the aging overall population, it was crucial to understand the current burden and prospective trend of older gastric cancer. This study aimed to analyze the temporal trends of the incidence, mortality, and survival of older gastric cancer in the highest gastric cancer risk area in China from 2010 to 2019, and to predict the future burden of older gastric cancer up to 2024. METHODS: The study was conducted in Gansu province, an area characterized by the highest gastric cancer incidence and mortality in China. The registration data of gastric cancer incidence and mortality from 2010 to 2019 were pooled from registries in the Gansu Cancer Registration System, while survival data were collected from the First Hospital of Lanzhou University, Lanzhou University Second Hospital, and Gansu Cancer Hospital. Chinese standard population in 2000 and the Segi's world standard population were applied to calculate the age-standardized rate. Joinpoint regression was used to analyze the average annual percentage change (AAPC) in cancer incidence and mortality. Autoregressive Integrated Moving Average (ARIMA) models were employed to generate forecasts for incidence and mortality from 2020 to 2024. RESULTS: Based on registry data from 2010 to 2019, the incidence and mortality rates of gastric cancer among older adults remained stable. The incidence rates declined from 439.65 per 100,000 in 2010 to 330.40 per 100,000 in 2019, with an AAPC of -2.59% (95% confidence interval[CI], -5.14 to 0.04, P = 0.06). Similarly, the mortality rate changed from 366.98 per 100,000 in 2010 to 262.03 per 100,000 in 2019, with an AAPC of -2.55% (95% CI, -8.77-4.08%, P = 0.44). In the hospital-based cohort, the decline in survival rates was reported among older patients with gastric cancer in the highest gastric cancer risk area in China, with the 3-year overall survival (OS) decreasing from 58.5% (95% CI, 53.5-63.2%) in 2010 to 34.4% (95%CI, 32.1-36.7%) in 2019, and the 3-year progression-free survival (PFS) decreasing from 51.3% (95%CI, 47.5-55.1%) in 2010 to 34.2% (95%CI, 32.0-36.3%) in 2019, respectively. Moreover, forecasts generated by ARIMA models revealed a significant decline in the incidence and mortality of older gastric cancer in China from 2020 to 2024. Specifically, the incidence rate of older gastric cancer was expected to decrease from 317.94 per 100,000 population in 2020 to 205.59 per 100,000 population in 2024, while the anticipated mortality rate was estimated to decrease from 222.52 per 100,000 population in 2020 to 186.22 per 100,000 population in 2024. CONCLUSION: From 2010 to 2019, the incidence and mortality of older gastric cancer remained stable in the highest gastric cancer risk area in China, while the survival rates showed a decline. Based on the ARIMA models, it was anticipated that there might be a continued decline in older gastric cancer incidence and mortality in the highest-risk area in China over the next five years.

Perioperative Chemotherapy Could Not Improve the Prognosis of Gastric Cancer Patients With Mismatch Repair Deficiency: A Multicenter, Real-World Study.

INTRODUCTION: To date, the role of deficient mismatch repair (dMMR) remains to be proven in gastric cancer, and it is difficult to judge its value in clinical application. Our study aimed to investigate how MMR status affected the prognosis in patients with gastrectomy, as well as the efficacy of neoadjuvant chemotherapy and adjuvant chemotherapy in patients with dMMR with gastric cancer. MATERIALS AND METHODS: Patients with gastric cancer with certain pathologic diagnosis of dMMR or proficient MMR (pMMR) using immunohistochemistry from 4 high-volume hospitals in China were included. Propensity score matching was used to match patients with dMMR or pMMR in 1:2 ratios. Overall survival (OS) and progression-free survival (PFS) curves were plotted using the Kaplan-Meier method and compared statistically using the log-rank test. Univariate and multivariate Cox proportional hazards models based on hazard ratios (HRs) and 95% confidence intervals (CIs) were used to determine the risk factors for survival. RESULTS: In total, data from 6176 patients with gastric cancer were ultimately analyzed, and loss of expression of one or more MMR proteins was observed in 293 patients (293/6176, 4.74%). Compared to patients with pMMR, patients with dMMR are more likely to be older (≥66, 45.70% vs. 27.94%, P < .001), distal location (83.51% vs. 64.19%, P < .001), intestinal type (42.21% vs. 34.46%, P < .001), and in the earlier pTNM stage (pTNM I, 32.79% vs. 29.09%, P = .009). Patients with gastric cancer with dMMR showed better OS than those with pMMR before PSM (P = .002); however, this survival advantage was not observed for patients with dMMR after PSM (P = .467). As for perioperative chemotherapy, results of multivariable Cox regression analysis showed that perioperative chemotherapy was not an independent prognostic factor for PFS and OS in patients with dMMR with gastric cancer (HR = 0.558, 95% CI, 0.270-1.152, P = .186 and HR = 0.912, 95% CI, 0.464-1.793, P = .822, respectively). CONCLUSION: In conclusion, perioperative chemotherapy could not prolong the OS and PFS of patients with dMMR with gastric cancer.

Concurrent clinical and pathological response predicts favorable prognosis of patients with gastric cancer after neoadjuvant therapy: a real-world study.

BACKGROUND: Response of locally advanced gastric cancer (LAGC) to neoadjuvant therapy (NAT) may be associated with prognosis, but which of the clinical or pathological evaluation can accurately predict a favorable prognosis is still controversial. This study aims to compare the effect of clinical and pathological response on the prognosis of patients with gastric cancer. METHODS: This study retrospectively analyzed LAGC patients who underwent NAT followed by surgery in the China National Cancer Center from January 2004 to January 2021. Clinical and pathological responses after NAT were evaluated using RECIST 1.1 and Mandard tumor regression grade system (TRG) respectively. Complete response (CR) and partial response (PR) assessed by computed tomography were regarded as clinical response. For histopathology regression assessment, response was defined as Mandard 1, 2, 3 and non-response as Mandard 4, 5. Furthermore, we combined clinical and pathological evaluation results into a variable termed "comprehensive assessment" and divided it into four groups based on the presence or absence of response (concurrent response, only clinical response, only pathological response, both non-response). The association between the prognosis and clinicopathological factors was assessed in univariate and multivariate Cox regression analysis. RESULTS: In total, 238 of 1073 patients were included in the study after screening. The postoperative pathological response rate and clinical response rate were 50.84% (121/238) and 39.92% (95/238), respectively. 154 patients got consistent results in clinical and pathological evaluation (66 were concurrent response and 88 were both non-response), while the other 84 patients did not. The kappa value was 0.297(p < 0.001), which showed poor consistency. Multivariate Cox regression analysis revealed that comprehensive assessment (P = 0.03), clinical N stage(P < 0.001), vascular or lymphatic invasion (VOLI) (HR 2.745, P < 0.001), and pre-CA724(HR 1.577, P = 0.047) were independent factors for overall survival in patients with gastric cancer. Among four groups in the comprehensive assessment, concurrent response had significantly better survival (median OS: 103.5 months) than the other groups (P = 0.008). CONCLUSION: Concurrent clinical and pathological response might predict a favorable prognosis of patients with gastric cancer after neoadjuvant therapy, further validation is needed in prospective clinical trials with larger samples.

The minimum number of examined lymph nodes was 24 for optimal survival of pathological T2-4 gastric cancer: a multi-center, hospital-based study covering 20 years of data.

INTRODUCTION: The current National Comprehensive Cancer Network (NCCN) guidelines recommend that at least 16 lymph nodes should be examined for gastric cancer patients to reduce staging migration. However, there is still debate regarding the optimal management of examined lymph nodes (ELNs) for gastric cancer patients. In this study, we aimed to develop and test the minimum number of ELNs that should be retrieved during gastrectomy for optimal survival in patients with gastric cancer. METHODS: We used the restricted cubic spline (RCS) to identify the optimal threshold of ELNs that should be retrieved during gastrectomy based on the China National Cancer Center Gastric Cancer (NCCGC) database. Northwest cohort, which sourced from the highest gastric cancer incidence areas in China, was used to verify the optimal cutoff value. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: In this study, 12,670 gastrectomy patients were included in the NCCGC cohort and 4941 patients in the Northwest cohort. During 1999-2019, the average number of ELNs increased from 17.88 to 34.45 nodes in the NCCGC cohort, while the number of positive lymph nodes remained stable (5-6 nodes). The RCS model showed a U-curved association between ELNs and the risk of all-cause mortality, and the optimal threshold of ELNs was 24 [Hazard ratio (HR) = 1.00]. The ELN ≥ 24 group had a better overall survival (OS) than the ELN < 24 group clearly (P = 0.003), however, with respect to the threshold of 16 ELNs, there was no significantly difference between the two groups (P = 0.101). In the multivariate analysis, ELN ≥ 24 group was associated with improved survival outcomes in total gastrectomy patients [HR = 0.787, 95% confidence interval (CI): 0.711-0.870, P < 0.001], as well as the subgroup analysis of T2 patients (HR = 0.621, 95%CI: 0.399-0.966, P = 0.035), T3 patients (HR = 0.787, 95%CI: 0.659-0.940, P = 0.008) and T4 patients (HR = 0.775, 95%CI: 0.675-0.888, P < 0.001). CONCLUSION: In conclusion, the minimum number of ELNs for optimal survival of gastric cancer with pathological T2-4 was 24.

Design, synthesis, and biological evaluation of novel N-Benzyl piperidine derivatives as potent HDAC/AChE inhibitors for Alzheimer's disease.

The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDACIC50 = 0.17 µM, AChEIC50 = 6.89 µM, d10: HDACIC50 = 0.45 µM, AChEIC50 = 3.22 µM), and both compounds showed activities on scavenging free radical, metal chelating, and inhibiting Aß aggregations. More importantly, both compounds exhibited promising neuroprotective activities in PC-12 cells and good AChE selectivity. Collectively, the multifunctional profiles of compound d5 and d10 encourage further optimization and exploration to develop more potent analogues as potential treatments for AD.

A Mulberry Diels-Alder-Type Adduct, Kuwanon M, Triggers Apoptosis and Paraptosis of Lung Cancer Cells through Inducing Endoplasmic Reticulum Stress.

The mulberry tree (Morus alba) has been cultivated in China for thousands of years. Mulberry Diels-Alder-type adducts (MDAAs) are characteristic constituents of the genus Morus. The unique structure and diverse bioactivities of MDAAs have attracted the attention of researchers. Kuwanon M (KWM) is an MDAA isolated from the root bark of Morus alba. This research reports the growth inhibitory effects of KWM on human lung cancer cells and its possible mechanism. In A549 and NCI-H292 cells, KWM treatment induced suppression of cell proliferation and migration. The appearance of chromatin condensation, phosphatidyl serine exposure and caspase cleavage indicated the arising of apoptosis. The loss of mitochondrial membrane potential (MMP), release of cytochrome c and dysregulation of Bax/Bcl-2 demonstrated that the KWM-induced apoptosis was through the mitochondrial pathway. Paraptosis was simultaneously detected under KWM treatment, as evidenced by the exhibition of cytoplasmic vacuolation, down-regulation of Alix and up-regulation of endoplasmic reticulum (ER) stress-related proteins. Mechanistically, ER stress induced activation of unfolded protein response (UPR) pathways and activation of the MAPK (JNK and ERK) pathway, all of which were critical for KWM-induced apoptosis and paraptosis. These findings suggested the possibility that KWM might be considered as a potential lung cancer therapeutic agent.

Palmarumycin P3 Reverses Mrr1-Mediated Azole Resistance by Blocking the Efflux Pump Mdr1.

Palmarumycin P3 (PP3) reduces fluconazole-induced MDR1 transcription to reverse azole resistance in clinical Candida strains. Here, we demonstrated that PP3 restores the susceptibility to several antifungal drugs for Candida albicans strains with gain-of-function mutations in the transcription factor Mrr1. In addition, PP3 inhibits the efflux of Mdr1 substrates by C. albicans strains harboring hyperactive MRR1 alleles. Molecular docking revealed that PP3 is a potential Mdr1 blocker that binds to the substrate binding pocket of Mdr1.

Recent advances of small molecule JNK3 inhibitors for Alzheimer's disease.

C-Jun N-terminal kinase (JNK) is a member of mitogen-activated protein kinases (MAPKs) family, with three isoforms, JNK1, JNK2 and JNK3. Alzheimer's disease (AD) is a neurological disorder and the most common type of dementia. Two well-established AD pathologies are the deposition of Aß amyloid plaques and neurofibrillary tangles caused by Tau hyperphosphorylation. JNK3 is involved in forming amyloid Aß and neurofibrillary tangles, suggesting that JNK3 may represent a target to develop treatments for AD. Therefore, this review will discuss the roles of JNK3 in the pathogenesis and treatment of AD, and the latest progress in the development of JNK3 inhibitors.

Cytotoxic Heptaketides from the Endolichenic Fungus Ulospora bilgramii.

Eleven new metabolites including nine heptaketides, ulosporin A-G (1a-7b), one diphenyl compound, ulophenol (8), and one spirobisnaphthalene, palmarumycin P5 (9), were isolated from the endolichenic fungus Ulospora bilgramii, which inhabits the lichen Umbilicaria sp. The structures of these compounds were elucidated based on comprehensive analysis of their spectroscopic, electronic circular dichroism (ECD), and single-crystal X-ray diffraction data. Ulosporin G (7) inhibited the growth of the human cancer cell lines A549, MCF-7, and KB with IC50 values of 1.3, 1.3, and 3.0 µM, respectively. Additionally, it induced A549 cell apoptosis through G0/G1 cell cycle arrest caused by DNA damage.

Application of Survival Quilts for prognosis prediction of gastrectomy patients based on the Surveillance, Epidemiology, and End Results database and China National Cancer Center Gastric Cancer database.

Objective: Accurate prognosis prediction is critical for individualized-therapy making of gastric cancer patients. We aimed to develop and test 6-month, 1-, 2-, 3-, 5-, and 10-year overall survival (OS) and cancer-specific survival (CSS) prediction models for gastric cancer patients following gastrectomy. Methods: We derived and tested Survival Quilts, a machine learning-based model, to develop 6-month, 1-, 2-, 3-, 5-, and 10-year OS and CSS prediction models. Gastrectomy patients in the development set (n = 20,583) and the internal validation set (n = 5,106) were recruited from the Surveillance, Epidemiology, and End Results (SEER) database, while those in the external validation set (n = 6,352) were recruited from the China National Cancer Center Gastric Cancer (NCCGC) database. Furthermore, we selected gastrectomy patients without neoadjuvant therapy as a subgroup to train and test the prognostic models in order to keep the accuracy of tumor-node-metastasis (TNM) stage. Prognostic performances of these OS and CSS models were assessed using the Concordance Index (C-index) and area under the curve (AUC) values. Results: The machine learning model had a consistently high accuracy in predicting 6-month, 1-, 2-, 3-, 5-, and 10-year OS in the SEER development set (C-index = 0.861, 0.832, 0.789, 0.766, 0.740, and 0.709; AUC = 0.784, 0.828, 0.840, 0.849, 0.869, and 0.902, respectively), SEER validation set (C-index = 0.782, 0.739, 0.712, 0.698, 0.681, and 0.660; AUC = 0.751, 0.772, 0.767, 0.762, 0.766, and 0.787, respectively), and NCCGC set (C-index = 0.691, 0.756, 0.751, 0.737, 0.722, and 0.701; AUC = 0.769, 0.788, 0.790, 0.790, 0.787, and 0.788, respectively). The model was able to predict 6-month, 1-, 2-, 3-, 5-, and 10-year CSS in the SEER development set (C-index = 0.879, 0.858, 0.820, 0.802, 0.784, and 0.774; AUC = 0.756, 0.827, 0.852, 0.863, 0.874, and 0.884, respectively) and SEER validation set (C-index = 0.790, 0.763, 0.741, 0.729, 0.718, and 0.708; AUC = 0.706, 0.758, 0.767, 0.766, 0.766, and 0.764, respectively). In multivariate analysis, the high-risk group with risk score output by 5-year OS model was proved to be a strong survival predictor both in the SEER development set (hazard ratio [HR] = 14.59, 95% confidence interval [CI]: 1.872-2.774, P < 0.001), SEER validation set (HR = 2.28, 95% CI: 13.089-16.293, P < 0.001), and NCCGC set (HR = 1.98, 95% CI: 1.617-2.437, P < 0.001). We further explored the prognostic value of risk score resulted 5-year CSS model of gastrectomy patients, and found that high-risk group remained as an independent CSS factor in the SEER development set (HR = 12.81, 95% CI: 11.568-14.194, P < 0.001) and SEER validation set (HR = 1.61, 95% CI: 1.338-1.935, P < 0.001). Conclusion: Survival Quilts could allow accurate prediction of 6-month, 1-, 2-, 3-, 5-, and 10-year OS and CSS in gastric cancer patients following gastrectomy.

Structure-Based Optimization of Novel Sterol 24-C-Methyltransferase Inhibitors for the Treatment of Candida albicans Infections.

Interfering with sterol biosynthesis is an important strategy for developing safe and effective antifungal drugs. We previously identified compound H55 as an allosteric inhibitor of the fungal-specific C-24 sterol methyltransferase Erg6 for treating Candida albicans infections. Herein, 62 derivatives of H55 were designed and synthesized based on target-ligand interactions to identify more active candidates. Among them, d28 displayed the most potent antivirulence ability (MHIC50 = 0.25 µg/mL) by targeting Erg6, exhibiting an 8-fold increase in potency compared with H55. Moreover, d28 significantly outperformed H55 in inhibiting cell adhesion and biofilm formation, and exhibited minimal cytotoxicity and negligible potential to induce drug resistance. Of note, the coadministration of d28 and other sterol biosynthesis inhibitors, such as tridemorph or terbinafine, demonstrated a strong synergistic antifungal action in vitro and in vivo in a murine skin infection model. These results support the potential application of d28 in the treatment of C. albicans infections.

Chemical constituents with antioxidant activity from the branches and leaves of Hultholia mimosoides.

Four undescribed homoisoflavanoids (1-4), one homoflavonoid (5), ten dibenzoxocin derivatives (6a-10a and 6b-10b), one dibenzoxocin-derived phenolic compound (11), one diterpenoid (13), three aliphatic dicarboxylic acid derivatives (14-16), together with the known diterpenoid 12-O-ethylneocaesalpin B (12) were obtained from the branches and leaves of Hultholia mimosoides. Their structures were elucidated by extensive spectroscopic techniques. Notably, each of the dibenzoxocins 6-10 existed as a pair of interconvertible atropisomers and the conformation for these compounds was clarified by NMR and ECD analyses. Protosappanin F (11) was a previously undescribed dibenzoxocin-derived compound in which one of the benzene rings was hydrogenated to a polyoxygenated cyclohexane ring and an ether linkage was established between C-6 and C-12a. The isolated polyphenols were tested for induction of quinone reductase and compounds 3 and 8 showed potent QR-inducing activity in Hepa-1c1c7 cells.

Blood transfusion might not be recommended for gastric cancer patients with pretransfusion minimum hemoglobin values higher than 90 g/L: a real-world study covering 20 years of 13470 patients.

BACKGROUND: There was no consistent evidence whether perioperative blood transfusion (PBT) affects the long-term survival of gastric cancer (GC) patients after undergoing gastrectomy. This study aimed to investigate the effects of PBT on long-term survival of GC patients, as well as to determine the threshold of PBT and provide evidence for future surgical practice. METHODS: We performed this real-world study of GC patients undergoing gastrectomy in China National Cancer Center from January 1, 2000 to December 30, 2019. Overall survival (OS) curves were plotted using the Kaplan-Meier method and compared statistically using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to determine the risk factors for OS. RESULTS: In total, 13470 GC patients undergoing gastrectomy from 2000 to 2019 was included, of whom 3465 (34.6%) GC patients received PBT. PBT ratios declined from 29.1% (114/392) in 2000 to 11.2% in 2019 (149/1178), with the highest blood transfusion ratio in 2005 at 43.7% (220/504). For patients transfused with red blood cells, the median value of hemoglobin (Hb) before transfusion in the PBT group decreased from 110 g/L in 2000 to 87 g/L in 2019. Compared with patients who not receiving perioperative blood transfusion (NPBT), PBT group are more likely to be older (≥65, 39.1% vs. 30.1%, P<0.001), open operation (89.7% vs. 78.1%, P<0.001), higher ASA score (>2, 25.3% vs. 14.9%, P<0.001) and in the later pTNM stage (pTNM stage III, 68.5% vs. 51.5%, P<0.001). Results of multivariable Cox regression analysis showed that PBT was an independent prognostic factor for worse OS in GC patients undergoing gastrectomy (HR=1.106, 95% CI, 1.01-1.211, P=0.03). After stratified according to tumor stage, we found that PBT group had a worse prognosis only in pTNM stage III (HR=1.197, 95% CI, 1.119-1.281, P<0.001). OS was obviously poor in the PBT group when Hb levels were higher than 90 g/L (90 g/L120 g/L:HR= 1.207, 95% CI, 1.098-1.327, P<0.001), while there was no difference between the two groups when Hb levels were lower than or equal to 90 g/L (Hb≤90 g/L: HR=1.162, 95% CI, 0.985-1.370, P=0.075). CONCLUSION: In conclusion, PBT was an independent prognostic factor for worse OS. Blood transfusion might not be recommended for gastric cancer patients with perioperative minimum Hb values higher than 90 g/L.

Erg6 Acts as a Downstream Effector of the Transcription Factor Flo8 To Regulate Biofilm Formation in Candida albicans.

The yeast-to-hyphal morphotype transition and subsequent biofilm formation are important virulence factors of Candida albicans and are closely associated with ergosterol biosynthesis. Flo8 is an important transcription factor that determines filamentous growth and biofilm formation in C. albicans. However, the relationship between Flo8 and regulation of the ergosterol biosynthesis pathway remains elusive. Here, we analyzed the sterol composition of a flo8-deficient C. albicans strain by gas chromatography-mass spectrometry and observed the accumulation of the sterol intermediate zymosterol, the substrate of Erg6 (C-24 sterol methyltransferase). Accordingly, the transcription level of ERG6 was reduced in the flo8-deficient strain. Yeast one-hybrid experiments revealed that Flo8 physically interacted with the ERG6 promoter. Ectopic overexpression of ERG6 in the flo8-deficient strain partially restored biofilm formation and in vivo virulence in a Galleria mellonella infection model. These findings suggest that Erg6 is a downstream effector of the transcription factor Flo8 that mediates the cross talk between sterol synthesis and virulence factors in C. albicans. IMPORTANCE Biofilm formation by C. albicans hinders its eradication by immune cells and antifungal drugs. Flo8 is an important morphogenetic transcription factor that regulates the biofilm formation and in vivo virulence of C. albicans. However, little is known about how Flo8 regulates biofilm formation and fungal pathogenicity. Here, we determined that Flo8 directly binds to the promoter of ERG6 to positively regulate its transcriptional expression. Consistently, loss of flo8 results in the accumulation of the substrate of Erg6. Moreover, ectopic overexpression of ERG6 at least partially restores the biofilm formation and virulence of the flo8-deficient strain both in vitro and in vivo. This work provides a new perspective on the metabolic link between transcription factors and morphotypes in C. albicans.

Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi.

Fungal infections present a growing global public health concern, necessitating the development of novel antifungal drugs. However, many potential antifungals, particularly the expelled potential active agents (EPAAs), are often underestimated owing to their limitations in cellular entry or expulsion by efflux pumps. Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the obtained EPAA-BM conjugates, IS-2-BM (11) exhibited excellent antifungal activities and induced negligible drug resistance. Furthermore, IS-2-BM prevented biofilm formation, eradicated mature biofilms, and exhibited excellent therapeutic effects in a murine model of systemic candidiasis. These findings provide a promising strategy for increasing the possibilities of discovering more antifungals.

Survival benefit of younger gastric cancer patients in China and the United States: A comparative study.

BACKGROUND: The impact of racial and regional disparity on younger patients with gastric cancer (GC) remains unclear. AIM: To investigate the clinicopathological characteristics, prognostic nomogram, and biological analysis of younger GC patients in China and the United States. METHODS: From 2000 to 2018, GC patients aged less than 40 years were enrolled from the China National Cancer Center and the Surveillance Epidemiology and End Results database. Biological analysis was performed based on the Gene Expression Omnibus database. Survival analysis was conducted via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: A total of 6098 younger GC patients were selected from 2000 to 2018, of which 1159 were enrolled in the China National Cancer Center, and 4939 were collected from the Surveillance Epidemiology and End Results database. Compared with the United States group, younger patients in China revealed better survival outcomes (P < 0.01). For race/ethnicity, younger Chinese cases also enjoyed a better prognosis than that in White and Black datasets (P < 0.01). After stratification by pathological Tumor-Node-Metastasis (pTNM) stage, a survival advantage was observed in China with pathological stage I, III, and IV (all P < 0.01), whereas younger GC patients with stage II showed no difference (P = 0.16). In multivariate analysis, predictors in China involved period of diagnosis, linitis plastica, and pTNM stage, while race, diagnostic period, sex, location, differentiation, linitis plastica, signet ring cell, pTNM stage, surgery, and chemotherapy were confirmed in the United States group. Prognostic nomograms for younger patients were established, with the area under the curve of 0.786 in the China group and of 0.842 in the United States group. Moreover, three gene expression profiles (GSE27342, GSE51105, and GSE38749) were enrolled in further biological analysis, and distinctive molecular characteristics were identified in younger GC patients among different regions. CONCLUSION: Except for younger cases with pTNM stage II, a survival advantage was observed in the China group with pathological stage I, III, and IV compared to the United States group, which might be partly due to differences in surgical approaches and the improvement of the cancer screening in China. The nomogram model provided an insightful and applicable tool to evaluate the prognosis of younger patients in China and the United States. Furthermore, biological analysis of younger patients was performed among different regions, which might partly explain the histopathological behavior and survival disparity in the subpopulations.

Perylenequinone derivatives from the endolichenic fungus Phialocephala fortinii.

Five undescribed perylenequinone derivatives (PQDs) phialocephalarins H - L (1 - 5), together with two known PQDs phialocephalarins A - B (6, 7) and one known spirobisnaphthalene palmarumycin P3 (8) were isolated from the endolichenic fungus Phialocephala fortinii. Their structures were elucidated on the basis of NMR and HRESIMS data as well as electronic circular dichroism (ECD) calculations. Compounds 1, 2, 4, and 6 - 8 were evaluated for cytotoxic activities against NCI-H460, NCI-H446, PC3, and EC109 cell lines. The results showed that compounds 1, 2, 6, and 8 showed cytotoxic activities against EC109 cells with IC50 values ranging from 24.5 to 33.3 µM.

Using nomogram, decision tree, and deep learning models to predict lymph node metastasis in patients with early gastric cancer: a multi-cohort study.

The accurate assessment of lymph node metastasis (LNM) in patients with early gastric cancer is critical to the selection of the most appropriate surgical treatment. This study aims to develop an optimal LNM prediction model using different methods, including nomogram, Decision Tree, Naive Bayes, and deep learning methods. In this study, we included two independent datasets: the gastrectomy set (n=3158) and the endoscopic submucosal dissection (ESD) set (n=323). The nomogram, Decision Tree, Naive Bayes, and fully convolutional neural networks (FCNN) models were established based on logistic regression analysis of the development set. The predictive power of the LNM prediction models was revealed by time-dependent receiver operating characteristic (ROC) curves and calibration plots. We then used the ESD set as an external cohort to evaluate the models' performance. In the gastrectomy set, multivariate analysis showed that gender (P=0.008), year when diagnosed (2006-2010 year, P=0.265; 2011-2015 year, P=0.001; and 2016-2020 year, P<0.001, respectively), tumor size (2-4 cm, P=0.001; and ≥4 cm, P<0.001, respectively), tumor grade (poorly-moderately, P=0.016; moderately, P<0.001; well-moderately, P<0.001; and well, P<0.001, respectively), vascular invasion (P<0.001), and pT stage (P<0.001) were independent risk factors for LNM in early gastric cancer. The area under the curve (AUC) for the validation set using the nomogram, Decision Tree, Naive Bayes, and FCNN models were 0.78, 0.76, 0.77, and 0.79, respectively. In conclusion, our multi-cohort study systematically investigated different LNM prediction methods for patients with early gastric cancer. These models were validated and shown to be reliable with AUC>0.76 for all. Specifically, the FCNN model showed the most accurate prediction of LNM risks in early gastric cancer patients with AUC=0.79. Based on the FCNN model, patients with LNM rates of >4.77% are strong candidates for gastrectomy rather than ESD surgery.

Effects of perioperative blood transfusion in gastric cancer patients undergoing gastrectomy: A systematic review and meta-analysis.

Background: The short-term and long-term effects of perioperative blood transfusion (PBT) on patients with gastric cancer are still intriguing. This systematic review and meta-analysis aimed to investigate the effects of blood transfusion on clinical outcomes in patients with gastric cancer undergoing gastrectomy. Methods: We searched PubMed, Web of Science, Embase, and The Cochrane Library on December 31th 2021. The main outcomes were overall survival (OS), disease-free survival (DFS), disease-specific survival (DFS), and postoperative complications. A fixed or random-effects model was used to calculate the hazard ratio (HR) with 95% confidence intervals (CIs). Results: Fifty-one studies with a total of 41,864 patients were included for this review and meta-analysis. Compared with patients who did not receive blood transfusions (NPBT), PBT was associated with worse 5-year OS (HR = 2.39 [95%CI: 2.00, 2.84]; p < 0.001; Multivariate HR = 1.43 [95%CI: 1.24, 1.63]; p < 0. 001), worse 5-year DFS (HR = 2.26 [95%CI: 1.68, 3.05]; p < 0.001; Multivariate HR = 1.45 [95%CI: 1.16, 1.82]; p < 0. 001), and worse 5-year DSS (HR = 2. 23 [95%CI: 1.35, 3.70]; p < 0.001; Multivariate HR = 1.24 [95%CI: 0.96, 1.60]; p < 0.001). Moreover, The PBT group showed a higher incidence of postoperative complications [OR = 2.30 (95%CI:1.78, 2. 97); p < 0.001] than that in the NPBT group, especially grade III-V complications, according to the Clavien-Dindo classification. [OR = 2.50 (95%CI:1.71, 3.63); p < 0.001]. Conclusion: In patients who underwent gastrectomy, PBT was associated with negative survival effects (OS, DFS, DSS) and a higher incidence of perioperative complications. However, more research was expected to further explore the impact of PBT. Meanwhile, strict blood transfusion management should be implemented to minimize the use of PBT.