Genomic Alterations Correlated to Trastuzumab Resistance and Clinical Outcomes in HER2+/HR- Breast Cancers of Patients Living in Northwestern China.

Anti-HER2 therapy has significantly improved the survival rates of patients with HER2+ breast cancer. However, a subset of these patients eventually experience treatment failure, and the underlying genetic mechanisms remain largely unexplored. This underscores the need to investigate the genomic heterogeneity of HER2+ breast cancer. In this study, we focus on HER2+/HR- breast cancer, as it differs from HER2+/HR+ breast cancer in terms of genetic and biological characteristics. We performed gene-targeted genome sequencing on 45 HER2+/HR- breast cancer samples and identified 650 mutations across 268 cancer-related genes. TP53 (71.1%) and PIK3CA (35.6%) were the most frequently mutated genes in our sample. Additionally, ERBB2 (77.8%), CDK12 (42.2%), and MYC (11.1%) exhibited a high frequency of copy number amplifications (CNAs). Comparative analysis with two other HER2+/HR- breast cancer cohorts revealed that our cohort had higher genetic variation rates in ARID1A, PKHD1, PTPN13, FANCA, SETD2, BRCA2, BLM, STAG2, FAT1, TOP2A, POLE, ATM, KMT2B, FGFR4, and EPAS1. Notably, in our cohort, NF1 and ATM mutations were more prevalent in trastuzumab-resistant patients (NF1, p=0.016; ATM, p=0.006) and were associated with primary trastuzumab resistance (NF1, p=0.042; ATM, p=0.021). Moreover, patients with NF1 mutations (p=0.009) and high histological grades (p=0.028) were more likely to experience early relapse. Ultimately, we identified a unique cancer-related gene mutation profile and a subset of genes associated with primary resistance to trastuzumab and RFS in patients with HER2+/HR- breast cancer in Northwest China. These findings could lay the groundwork for future studies aimed at elucidating the mechanisms of resistance to trastuzumab and improving HER2-targeted treatment strategies.

Modeling and analysis of a human papilloma virus transmission model with impact of media.

The human papillomavirus (HPV) is threatening human health as it spreads globally in varying degrees. On the other hand, the speed and scope of information transmission continues to increase, as well as the significant increase in the number of HPV-related news reports, it has never been more important to explore the role of media news coverage in the spread and control of the virus. Using a decreasing factor that captures the impact of media on the actions of people, this paper develops a model that characterizes the dynamics of HPV transmission with media impact, vaccination and recovery. We obtain global stability of equilibrium points employing geometric method, and further yield effective methods to contain the HPV pandemic by sensitivity analysis. With the center manifold theory, we show that there is a forward bifurcation when R0=1. Our study suggested that, besides controlling contact between infected and susceptible populations and improving effective vaccine coverage, a better intervention would be to strengthen media coverage. In addition, we demonstrated that contact rate and the effect of media coverage result in multiple epidemics of infection when certain conditions are met, implying that interventions need to be tailored to specific situations.

Predicting global geographical distribution and latitudinal suitability gradient for light Brown apple moth.

Epiphyas postvittana, commonly known as the light brown apple moth (LBAM), is native to Australia and has a restricted global distribution. Its polyphagous nature and the recent surge in interceptions have emphasized the need for focused risk assessments to guide effective measures to curb the entry of this pest into new countries. This study aimed to perform a detailed global invasion risk assessment using an optimized MaxEnt model that incorporated 19 bioclimatic variables and elevation. The predictive outcomes underscored the significance of key variables, specifically the minimum temperature of the coldest month (bio6), precipitation of the driest month (bio14), and precipitation of the coldest quarter (bio19), in shaping the potential geographical distribution of LBAM. Regions beyond the existing range, including the southeastern United States, southern Brazil, eastern Argentina, Uruguay, southern Chile, and various Western European countries, were identified as susceptible to invasion and establishment by LBAM. An increase in suitability was observed above 45°N and 40°S under future climate scenario. With respect to climate change, LBAM would expand its potential range in Western Europe and the United States, especially under SSP5-8.5, in the 2050s. An upward trend in the latitudinal suitability gradient for LBAM in mid-high latitude areas implies that amid changing climate conditions, LBAM may find favorable habitats in these regions. For countries and regions with invasion risk, it is imperative to implement corresponding inspections and quarantine measures to thwart the introduction of LBAM, particularly in countries with established trade ties with invaded regions.

Pulmonary tumor thrombotic microangiopathy: Two case reports and literature review.

RATIONALE: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare but serious complication in patients with malignancy; its main manifestation includes acute pulmonary hypertension with severe respiratory distress. More than 200 cases have been reported since it was first identified in 1990. PTTM accounts for approximately 0.9% to 3.3% of deaths due to malignancy, but only a minority of patients are diagnosed ante-mortem, with most patients having a definitive diagnosis after autopsy. PATIENT CONCERNS: Two middle-aged women both died within a short period of time due to progressive dyspnea and severe pulmonary hypertension. DIAGNOSES: One patient was definitively confirmed as a gastrointestinal malignant tumor by liver puncture biopsy pathology. Ultimately, the clinical diagnosis was pulmonary tumor thrombotic microangiopathy. INTERVENTIONS: The patient was treated symptomatically with oxygen, diuresis, and anticoagulation, while a liver puncture was perfected to clarify the cause. OUTCOMES: Two cases of middle-aged female patients with rapidly progressive pulmonary hypertension and respiratory failure resulted in death with malignant neoplasm. LESSONS: PTTM has a rapid onset and a high morbidity and mortality rate. Our clinicians need to be more aware of the need for timely diagnosis through a targeted clinical approach, leading to more targeted treatment and a better prognosis.

Facial tightening using a novel vacuum-assisted microneedle fractional radiofrequency system: A prospective, randomized, split-face study.

BACKGROUND: The microneedle fractional radiofrequency system (MFRS) is able to rejuvenate facial appearance by heating and coagulating certain depth of skin tissue. OBJECTIVE: To evaluate the safety and efficacy of a novel vacuum-assisted MFRS for facial contour tightening. METHODS: This prospective, randomized, split-face study included 21 patients who underwent three treatments with a vacuum-assisted MFRS at 1-month intervals. Half of the face was treated with the MFRS; the other half was untreated (control). Facial volume changes and wrinkles were objectively measured using a three-dimensional imaging system and VISIA-CR. RESULTS: Volume changes of the treated midface were -0.24 ± 0.75, -0.59 ± 0.92, and -0.55 ± 0.65 mL at 1, 3, 6 months follow-up; however, measurements of the control side were 0.08 ± 0.70, -0.08 ± 0.53, and - 0.10 ± 0.86 mL, indicating significant reductions (p < 0.05). The number of facial wrinkles on the treated side was significantly reduced to 12.44 ± 4.85 at 3 months and sustained at 6 months (11.11 ± 4.100) compared to the control side (14.89 ± 5.26 and 13.22 ± 4.44, respectively; p < 0.05). No long-term side effects occurred. CONCLUSION: The vacuum-assisted MFRS is safe and effective and is recommended for improving facial tightening and reducing wrinkles. This technology is sufficient to ensure the insertion depth, thus helping to improve the treatment accuracy and safety. The MFRS provides sustained effects for at least 6 months.

CLEC4D as a Novel Prognostic Marker Boosts the Proliferation and Migration of Gastric Cancer via the NF-κB/AKT Signaling Pathway.

Purpose: The functions of C-type lectin domain family 4 member D (CLEC4D), one member of the C-type lectin/C-type lectin-like domain superfamily, in immunity have been well described, but its roles in cancer biology remain largely unknown. Patients and Methods: This study aims to explore the role of CLEC4D in gastric cancer (GC). Bioinformatics preliminarily analyzed the expression of CLEC4D in gastric cancer. Immunohistochemical staining was used to detect the expression level and clinical pathological characteristics of CLEC4D in gastric cancer. The biological function of CLEC4D in gastric cancer cell lines was verified through in vitro and in vivo experiments. Results: In this study, CLEC4D expression was found to be markedly increased in gastric cancer (GC) tissues compared with matched normal gastric tissues, and high CLEC4D expression independently predicted unfavorable overall survival in patients with GC. Knockdown of CLEC4D markedly inhibited GC cell proliferation and migration. Mechanistically, CLEC4D knockdown deactivated the Akt and NF-κB signaling pathways in GC cells. Conclusion: Together, these results demonstrate that aberrantly increased CLEC4D expression promotes cancer phenotypes via the Akt and NF-κB signaling pathways in GC cells.

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.

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Droplet Energy Harvesting System Based on Total-Current Nanogenerator.

The droplet-based nanogenerator (DNG) is a highly promising technology for harvesting high-entropy water energy in the era of the Internet of Things. Yet, despite the exciting progress made in recent years, challenges have emerged unexpectedly for the AC-type DNG-based energy system as it transitions from laboratory demonstrations to real-world applications. In this work, we propose a high-performance DNG system based on the total-current nanogenerator concept to address these challenges. This system utilizes the water-charge-shuttle architecture for easy scale-up, employs the field effect to boost charge density of the triboelectric layer, adopts an on-solar-panel design to improve compatibility with solar energy, and is equipped with a novel DC-DC buck converter as power management circuit. These features allow the proposed system to overcome the existing bottlenecks of DNG and empower the system with superior performances compared with previous ones. Notably, with the core architecture measuring only 15 cm × 12.5 cm × 0.3 cm in physical dimensions, this system reaches a record-high open-circuit voltage of 4200 V, capable of illuminating 1440 LEDs, and can charge a 4.7 mF capacitor to 4.5 V in less than 24 min. In addition, the practical potential of the proposed DNG system is further demonstrated through a self-powered, smart greenhouse application scenario. These demonstrations include the continuous operation of a thermohygrometer, the operation of a Bluetooth plant monitor, and the all-weather energy harvesting capability. This work will provide valuable inspiration and guidance for the systematic design of next-generation DNG to unlock the sustainable potential of distributed water energy for real-world applications.

The c-Abl-RACK1-FAK signaling axis promotes renal fibrosis in mice through regulating fibroblast-myofibroblast transition.

BACKGROUND: Renal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood. METHODS: To investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts. RESULTS: In this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis. CONCLUSIONS: Our findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.

ACAT2 suppresses the ubiquitination of YAP1 to enhance the proliferation and metastasis ability of gastric cancer via the upregulation of SETD7.

The contributions of aberrantly expressed metabolic enzymes to gastric cancer (GC) initiation and progression have been widely appreciated in recent years. Acetyl-CoA acetyltransferase 2 (ACAT2) is one member of the acetyl- CoA thiolase family. Previous studies demonstrated that ACAT2 either promotes or suppresses tumor progression in different conditions. However, the function and mechanisms of ACAT2 in GC remain unknown. We found that the expression of this enzyme was significantly increased in GC tissues compared with normal counterparts, which prompted us to further investigate the roles of this protein in GC biology. In vitro functional studies showed that ACAT2 knockdown markedly halted the proliferation and the motility of GC cells; these functions favoring malignant phenotypes of GC cells were further validated in animal experiments. Mechanistically, ACAT2 depletion significantly reduced the transcription of SETD7, which is a histone methyltransferase and plays critical roles in GC cells. We found that the pro-tumoral functions of ACAT2 were largely dependent on SETD7. Moreover, SETD7 decreased the ubiquitination level of Yes-associated protein 1 (YAP1), thereby protecting YAP1 from proteasome degradation. Increased YAP1 protein expression remarkably activated the YAP1/TAZ-TEAD1 signaling pathway, which further boosted the malignant phenotypes in GC cells. In conclusion, these findings highlight the pro-tumoral functions and molecular underpinnings of ACAT2 in GC cells, and suggest that ACAT2 could be a promising target in GC treatment.

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.

Extracellular vesicles from Fusobacterium nucleatum: roles in the malignant phenotypes of gastric cancer.

The increase of the Fusobacterium nucleatum level has been previously identified in various cancers including gastric cancer (GC), but how the F. nucleatum exerts its carcinogenic role in GC remains unclear. Several studies revealed that F. nucleatum contributes to cancer progression via its secretion of extracellular vehicles (EVs). Hence, it's designed to reveal the influence of F. nucleatum-derived EVs (Fn-EVs) in GC progression. The tumor and adjacent tissues were collected from 30 GC patients, and the abundance of F. nucleatum was found to be highly expressed in tumor samples. The ultracentrifugation was employed to isolate EVs from F. nucleatum and Escherischia coli (E. coli), which were labeled Fn-EVs and E. coli-EVs, respectively. After treating GC cells with Fn-EVs and E. coli-EVs, cell counting kit 8, colony formation, wound healing as well as transwell assay were performed, which revealed that Fn-EVs effectively enhanced oxaliplatin resistance, and facilitated cell proliferation, migration, invasion, and stemness in GC cells while E. coli-EVs exert no significant effect on GC cells. Besides, the stemness and DNA repair of GC cells were also enhanced by Fn-EVs, as revealed by the sphere-forming assay and the detection of stemness- and DNA repair-associated proteins by western blotting. In vivo analyses demonstrated that Fn-EVs administration not only promoted GC tumor growth and liver metastasis but also conferred GC tumor resistance to oxaliplatin resistance. This study first revealed the contributive role of F. nucleatum in GC development via Fn-EVs, which provided a better perspective for manipulating F. nucleatum in treating GC patients with malignant phenotypes.

Meta-analysis of Helicobacter pylori eradication therapy using vonoprazan as an acid suppressor compared with bismuth quadruple therapy.

BACKGROUND: Vonoprazan, a novel acid suppressant, has recently emerged as a regimen for eradicating Helicobacter pylori. However, uncertainties exist about the effectiveness and safety of VPZ-based regimens compared with those of bismuth-based quadruple therapy in eradicating H. pylori. The present meta-analysis was performed to compare the effectiveness and safety of vonoprazan-based regimens with those of bismuth quadruple therapy in eradicating H. pylori. MATERIALS AND METHODS: All randomized controlled trials and non-randomized controlled trials comparing the vonoprazan-based therapy with the bismuth quadruple therapy were included in this meta-analysis. Information was also extracted by two evaluators, and if heterogeneity existed, a random-effects model was used to calculate the combined relative ratio and 95% confidence interval; otherwise, a fixed-effects model was used. And subgroup analyses were performed to explore the sources of heterogeneity. RESULTS: A total of 10 studies, comprising 2587 patients were included in the meta-analysis. The results showed that the combined eradication rate of patients treated with the vonoprazan-based regimen was significantly higher than that of patients treated with bismuth quadruple therapy, in both intention-to-treat and per-protocol analyses, and the differences were statistically significant. Among the intention-to-treat analyses results: (90.28% vs. 83.64% [odds ratio (OR) = 1.85, 95% confidence interval (CI) (1.27, 2.70), p = 0.001]); in the per-protocol analyses: (94.80% vs. 89.88%, [OR = 2.25, 95% CI (1.37, 3.69), p = 0.001]). The occurrence of adverse events was significantly lower in patients treated with vonoprazan-based regimens than in those treated with bismuth quadruple therapy, (14.50% vs. 25.89%, [OR = 0.49, 95% CI (0.32, 0.75), p = 0.001]). CONCLUSIONS: For eradicating H. pylori, vonoprazan-based regimens are remarkably advantageous over bismuth quadruple therapy. Furthermore, vonoprazan-based regimens exhibit a lower rate of adverse events than bismuth quadruple therapy.

Unravelling the non-classical nucleation mechanism of an amyloid nanosheet through atomic force microscopy and an infrared probe technique.

Understanding the amyloid nucleation mechanism is fundamentally important for the development of diagnostics and therapeutics of amyloid-related diseases and for the design and application of amyloid-based materials. To this end, we here explore the use of atomic force microscopy (AFM) and a side-chain-based infrared (IR) probe technique to investigate the amyloid nanosheet formation mechanism of an Aß16-22 variant, KLVFXAK, where X is p-cyanophenylalanine with its side-chain cyano group being an infrared probe. Using AFM, we reveal that the formation of KLVFXAK amyloid nanosheets follows a two-step non-classical nucleation mechanism. The first step is the rapid formation of a metastable fibrillar intermediate and the second step is slow transformation to the final nanosheet. Using the side-chain-based IR probe technique, we obtain spectroscopic evidence for the proposed nucleation mechanism of the amyloid nanosheet as well as the structural details for the intermediate and amyloid nanosheet. By using the structural constraints set by the two techniques, we propose the structural models for both the fibrillar intermediate and the amyloid nanosheet. In addition, we further investigated the amyloid nanosheet formation mechanism of a similar Aß16-22 variant, KLVFXAE, and showed the impact of mutation on the amyloid nucleation mechanism. Our work also provides a nice example of how to use the combined approach of AFM and a side-chain-based IR probe technique to unravel the complex nucleation mechanism of amyloid formation.

Causal associations between gut microbiota and Cholestatic liver diseases: a Mendelian randomization study.

Background: The etiological factors of Cholestatic Liver Diseases especially primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are not fully illustrated. It has been reported in previous observational studies that gut microbiota are associated with cholestatic liver diseases. However, there is uncertainty regarding the causality of this association. By using Mendelian randomization, this study aimed to examine the causal impact of gut microbiota on cholestatic liver diseases. Methods: From large-scale genome-wide association studies, genetic instruments for each gut microbiota taxa as well as primary biliary cholangitis and primary sclerosing cholangitis were developed. Subsequently, we conducted a two-sample Mendelian randomization analysis, supplemented by multiple post hoc sensitivity analyses. Additionally, we performed reverse MR analyses to investigate the possibility of the reverse causal association. Result: This two-sample MR study indicated that the order Bacillales, family Peptostreptococcaceae, family Ruminococcaceae, genus Anaerotruncu was associated with a decreased risk of developing PBC, and that order Selenomonadales, family Bifidobacteriaceae may be factors that increase the risk of PBC. On the other hand, we also identified order Selenomonadales, family Rhodospirillaceae, and genus RuminococcaceaeUCG013 were positively associated with PSC. The order Actinomycetales, family Actinomycetaceae, genus Actinomyces, genus Alloprevotella, genus Barnesiella, and genus Peptococcus were found negative associations with the risk of PSC. The reverse MR analysis demonstrated no statistically significant relationship between PBC, PSC and these specific gut microbial taxa. Conclusion: Our findings offered novel evidence that the abundance of particular bacteria contributes to the risk of PBC and PSC, which may contribute to more effective approaches to PBC and PSC therapy and prevention.

EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity.

BACKGROUND: The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3. METHODS: This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3. RESULTS: EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity. CONCLUSIONS: EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.

Blood Pressure Estimation Based on PPG and ECG Signals Using Knowledge Distillation.

OBJECTIVE: Easy access bio-signals are useful for alleviating the shortcomings and difficulties associated with cuff-based and invasive blood pressure (BP) measurement techniques. This study proposes a deep learning model, trained using knowledge distillation, based on photoplethysmographic (PPG) and electrocardiogram (ECG) signals to estimate systolic and diastolic blood pressures. METHODS: The estimation model comprises convolutional layers followed by one bidirectional recurrent layer and attention layers. The training approach involves knowledge distillation, where a smaller model (student model) is trained by leveraging information from a larger model (teacher model). RESULTS: The proposed multistage model was evaluated on 1205 subjects from Medical Information Mart for Intensive Care (MIMIC) III database using the Association for the Advancement of Medical Instrumentation (AAMI) and the standards of the British Hypertension Society (BHS). The results revealed that our model performance achieved grade A in estimating both systolic blood pressure (SBP) and diastolic blood pressure (DBP) and met the requirements of the AAMI standard. After training with knowledge distillation (KD), the model achieved a mean absolute error and standard deviation of 2.94 ± 5.61 mmHg for SBP and 2.02 ± 3.60 mmHg for DBP. CONCLUSION: Our results demonstrate the benefits of the knowledge distillation training method in reducing the number of parameters and improving the predictive accuracy of the blood pressure regression model.

Insulin Use Is Associated With Improved Outcomes in Critically Ill Patients With Acute Pancreatitis: A Retrospective Matched Cohort Study.

BACKGROUND: Severe acute pancreatitis (SAP) has a mortality of 30% with no current targeted therapy. The potential protective effect of insulin on AP has been reported and needs to be confirmed. Thus, we aim to examine the effect of insulin treatment on the outcome of AP patients. METHODS: A retrospective study was performed using data from the Medical Information Mart for Intensive Care (MIMIC) database. Kruskal-Wallis test, t-tests, and Pearson's chi-squared test were used to compare differences between groups. Propensity score matching and further nearest neighbor matching were used to construct a matched cohort. Cox proportional hazards regression analyses, logistic regression analyses, and the doubly robust estimation method were used to assess the relationship between insulin use and mortality. RESULTS: Nine hundred patients were enrolled in the final analysis. Insulin was associated with better outcomes in AP patients admitted to ICU, and could act as an independent predictor for 30-day mortality (HR = 0.36, 95% CI = 0.24-0.55). Subgroup analysis showed that AP patients with heart failure or without kidney disease or respiratory failure may not benefit from insulin treatment. CONCLUSIONS: Insulin treatment is independently associated with lower 30-day mortality in AP patients, except for those with heart failure or without kidney disease or respiratory failure.