ABO and Rhesus blood groups and multiple health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous studies have been conducted to investigate the relationship between ABO and Rhesus (Rh) blood groups and various health outcomes. However, a comprehensive evaluation of the robustness of these associations is still lacking. METHODS: We searched PubMed, Web of Science, Embase, Scopus, Cochrane, and several regional databases from their inception until Feb 16, 2024, with the aim of identifying systematic reviews with meta-analyses of observational studies exploring associations between ABO and Rh blood groups and diverse health outcomes. For each association, we calculated the summary effect sizes, corresponding 95% confidence intervals, 95% prediction interval, heterogeneity, small-study effect, and evaluation of excess significance bias. The evidence was evaluated on a grading scale that ranged from convincing (Class I) to weak (Class IV). We assessed the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation criteria (GRADE). We also evaluated the methodological quality of included studies using the A Measurement Tool to Assess Systematic Reviews (AMSTAR). AMSTAR contains 11 items, which were scored as high (8-11), moderate (4-7), and low (0-3) quality. We have gotten the registration for protocol on the PROSPERO database (CRD42023409547). RESULTS: The current umbrella review included 51 systematic reviews with meta-analysis articles with 270 associations. We re-calculated each association and found only one convincing evidence (Class I) for an association between blood group B and type 2 diabetes mellitus risk compared with the non-B blood group. It had a summary odds ratio of 1.28 (95% confidence interval: 1.17, 1.40), was supported by 6870 cases with small heterogeneity (I2 = 13%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10, but the largest study effect was not more conservative than the summary effect size) or excess of significance (P < 0.10, but the value of observed less than expected). And the article was demonstrated with high methodological quality using AMSTAR (score = 9). According to AMSTAR, 18, 32, and 11 studies were categorized as high, moderate, and low quality, respectively. Nine statistically significant associations reached moderate quality based on GRADE. CONCLUSIONS: Our findings suggest a potential relationship between ABO and Rh blood groups and adverse health outcomes. Particularly the association between blood group B and type 2 diabetes mellitus risk.

Brain-Controlled Hand Exoskeleton Based on Augmented Reality-Fused Stimulus Paradigm.

Advancements in brain-machine interfaces (BMIs) have led to the development of novel rehabilitation training methods for people with impaired hand function. However, contemporary hand exoskeleton systems predominantly adopt passive control methods, leading to low system performance. In this work, an active brain-controlled hand exoskeleton system is proposed that uses a novel augmented reality-fused stimulus (AR-FS) paradigm as a human-machine interface, which enables users to actively control their fingers to move. Considering that the proposed AR-FS paradigm generates movement artifacts during hand movements, an enhanced decoding algorithm is designed to improve the decoding accuracy and robustness of the system. In online experiments, participants performed online control tasks using the proposed system, with an average task time cost of 16.27 s, an average output latency of 1.54 s, and an average correlation instantaneous rate (CIR) of 0.0321. The proposed system shows 35.37% better efficiency, 8.03% reduced system delay, and 35.28% better stability than the traditional system. This study not only provides an efficient rehabilitation solution for people with impaired hand function but also expands the application prospects of brain-control technology in areas such as human augmentation, patient monitoring, and remote robotic interaction. The video in Graphical Abstract Video demonstrates the user's process of operating the proposed brain-controlled hand exoskeleton system.

Human papillomavirus infection and the risk of cancer at specific sites other than anogenital tract and oropharyngeal region: an umbrella review.

BACKGROUND: Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070). FINDINGS: The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR = 7.03, 95% CI = 3.87-12.76), oesophageal cancer (OR = 3.32, 95% CI = 2.54-4.34), oesophageal squamous cell carcinoma (OR = 2.69, 95% CI = 2.05-3.54), lung cancer (OR = 3.60, 95% CI = 2.59-5.01), and breast cancer (OR = 6.26, 95% CI = 4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer. INTERPRETATION: The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease. FUNDING: National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.

Single-cell RNA sequencing reveals the process of CA19-9 production and dynamics of the immune microenvironment between CA19-9 (+) and CA19-9 (-) PDAC.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated. METHODS: We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (three each from CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9. RESULTS: Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment. CONCLUSIONS: Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.

Intermittent fasting and health outcomes: an umbrella review of systematic reviews and meta-analyses of randomised controlled trials.

Background: Benefits of Intermittent fasting (IF) on health-related outcomes have been found in a range of randomised controlled trials (RCTs). Our umbrella review aimed to systematically analyze and synthesize the available causal evidence on IF and its impact on specific health-related outcomes while evaluating its evidence quality. Methods: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane databases (from inception up to 8 January 2024) to identify related systematic reviews and meta-analyses of RCTs investigating the association between IF and human health outcomes. We recalculated the effect sizes for each meta-analysis as mean difference (MD) or standardized mean difference (SMD) with corresponding 95% confidence intervals (CIs). Subgroup analyses were performed for populations based on three specific status: diabetes, overweight or obesity, and metabolic syndrome. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. This study is registered with PROSPERO (CRD42023382004). Findings: A total of 351 associations from 23 meta-analyses with 34 health outcomes were included in the study. A wide range of outcomes were investigated, including anthropometric measures (n = 155), lipid profiles (n = 83), glycemic profiles (n = 57), circulatory system index (n = 41), appetite (n = 9), and others (n = 6). Twenty-one (91%) meta-analyses with 346 associations were rated as high confidence according to the AMSTAR criteria. The summary effects estimates were significant at p < 0.05 in 103 associations, of which 10 (10%) were supported by high certainty of evidence according to GRADE. Specifically, compared with non-intervention diet in adults with overweight or obesity, IF reduced waist circumference (WC) (MD = -1.02 cm; 95% CI: -1.99 to -0.06; p = 0.038), fat mass (MD = -0.72 kg; 95% CI: -1.32 to -0.12; p = 0.019), fasting insulin (SMD = -0.21; 95% CI: -0.40 to -0.02; p = 0.030), low-density lipoprotein cholesterol (LDL-C) (SMD = -0.20; 95% CI: -0.38 to -0.02; p = 0.027), total cholesterol (TC) (SMD = -0.29; 95% CI: -0.48 to -0.10; p = 0.003), and triacylglycerols (TG) (SMD = -0.23; 95% CI: -0.39 to -0.06; p = 0.007), but increased fat free mass (FFM) (MD = 0.98 kg; 95% CI: 0.18-1.78; p = 0.016). Of note, compared with the non-intervention diet, modified alternate-day fasting (MADF) reduced fat mass (MD = -0.70 kg; 95% CI: -1.38 to -0.02; p = 0.044). In people with overweight or obesity, and type 2 diabetes, IF increases high-density lipoprotein cholesterol (HDL-C) levels compared to continuous energy restriction (CER) (MD = 0.03 mmol/L; 95% CI: 0.01-0.05; p = 0.010). However, IF was less effective at reducing systolic blood pressure (SBP) than a CER diet in adults with overweight or obesity (SMD = 0.21; 95% CI: 0.05-0.36; p = 0.008). Interpretation: Our findings suggest that IF may have beneficial effects on a range of health outcomes for adults with overweight or obesity, compared to CER or non-intervention diet. Specifically, IF may decreased WC, fat mass, LDL-C, TG, TC, fasting insulin, and SBP, while increasing HDL-C and FFM. Notably, it is worth noting that the SBP lowering effect of IF appears to be weaker than that of CER. Funding: This work was supported by the National Key Research and Development Program of China (Q-JW), the Natural Science Foundation of China (Q-JW and T-TG), Outstanding Scientific Fund of Shengjing Hospital of China Medical University (Q-JW), and 345 Talent Project of Shengjing Hospital of China Medical University (T-TG).

Microplastics are detected in human gallstones and have the ability to form large cholesterol-microplastic heteroaggregates.

Ubiquitous pollution due to microplastics through the food chain is a major cause of various deleterious effects on the human health. The aim of this study was to determine the existence of microplastics and the internal mechanism of microplastics as accelerators of cholelithiasis. Gallstones were collected from 16 patients after cholecystectomy, and microplastics in the gallstones were detected through laser direct infrared and pyrolysis gas chromatographymass spectrometry examinations. Mice model of gallstone were constructed with or without different diameters of microplastic (0.5, 5 and 50 µm). The affinity between microplastic and cholesterol or bilirubin was tested by co-culturing and qualified using molecular dynamics simulations. Finally, altered gut microbiota among the groups were identified using 16 s rRNA sequencing. The presence of microplastics in the gallstones of all the patients were confirmed. Microplastic content was significantly higher in younger chololithiasis patients (age<50 years). Mice fed a high-cholesterol diet with microplastic drinks showed more severe chololithiasis. In terms of the mechanism, microplastics showed a higher affinity for cholesterol than for bilirubin. Significant alterations in the gut microbiota have also been identified after microplastic intake in mice. Our study revealed the presence of microplastics in human gallstones, showcasing their potential to aggravate chololithiasis by forming large cholesterol-microplastic heteroaggregates and altering the gut microbiota.

Unusual triterpenoids and steroids from Cipadessa baccifera and their biological activities.

Five undescribed triterpenoids and steroids (1-5), as well as ten known compounds, were purified from the branches and leaves of Cipadessa baccifera. Notably, 1 and 2 are rare cipadesin-type limonoids with an unusual 8,30-epoxide ring and 1,8-ether linkage, respectively. Compound 5 possessed pregnane steroid skeleton with an uncommon 5/6/6/6/5-fused ring system. Their structures were constructed by extensive spectroscopic analysis (NMR, IR, UV, and HRESIMS), and their absolute configurations were confirmed by ECD calculations and quantum chemical calculations. All the isolates were in vitro assayed for their antimicrobial potentials against 6 pathogenic microorganisms and antiproliferation activities against five human cancer cell lines. As a result, compounds 5, 12, 13, and 14 exhibited moderate antibacterial activities (MIC: 25-50 µg/mL). Moreover, 5 showed cytotoxicity against five cancer cell lines with IC50 values ranging from 8.0 to 19.9 µM.

Rapidly growing extensive polypoid endometriosis after gonadotropin-releasing hormone agonist discontinuation: A case report.

BACKGROUND: Polypoid endometriosis (PEM) is a rare and unique type of endometriosis. To date, no article has provided a systematic report of this disease. The current article provides a complete report on rare PEM based on ultrasound, magnetic resonance imaging, intraoperative findings and postoperative pathology data. CASE SUMMARY: A 38-year-old female patient was admitted to our hospital after complaining of "vague pain in the right lower quadrant with an aggravated menstrual period for 8 mo". The patient underwent laparoscopic exploratory surgery on January 7, 2022. The postoperative pathology revealed extensive PEM. CONCLUSION: PEM is a type of endometriosis that is a benign disease but has biological properties similar to malignant tumours.

NtMYB12 requires for competition between flavonol and (pro)anthocyanin biosynthesis in Narcissus tazetta tepals.

The color of flowers is one of the main characteristics adopted for plants to attract pollinators to ensure the reproductive success of the plant, they are also important in their ornamental appeal in Narcissus plant. In this study, we identified a NtMYB12 locus encoding an R2R3-MYB transcription factor. Comparative transcriptome analysis of loss- and gain- of NtMYB12 tissue relative to wild-type narcissus showed NtMYB12 was mainly involved in flavonol and phenylpropanoid metabolic pathways. Biochemical evidences of dual-luciferase activity and chromatin immunoprecipitation assay supported that MYB12 directly bound to promoters of NtFLS, NtLAR, and NtDFR that were cloned by genome walking assay, and activated NtFLS and NtLAR expression but repressed NtDFR expression. More interestingly, NtMYB12 can interact with NtbHLH1 and NtWD40-1 proteins via R3 domain that were selected by transcriptome-based WGCNA and confirmed by yeast two hybrid, bimolecular fluorescence complementation and coimmunoprecipitation assay. Interaction of NtMYB12 with NtbHLH1 and NtWD40-1 forming MYB-bHLH-WD40 triplex specially activated NtDFR and NtANS expression and promoted (pro)anthocyanin accumulation, while NtMYB12 alone activated NtFLS and NtLAR expression and accumulated flavonols, but repressed NtDFR expression. These results indicated that NtMYB12 alone or NtMYB12-bHLH1-WD40-1 triplex requires for competition of metabolism fluxes between flavonol and (pro)anthocyanin biosynthesis. NtMYB12 dually functions on flavonol and proanthocyanin biogenesis via physically binding to NtFLS and NtLAR promoter activating their expression and on (pro)anthocyanin biosynthesis via NtMYB12-NtWD40-NtbHLH (MBW) triplex activating NtDFR and NtANS expression. Requirement of NtMYB12 alone or MBW complex for the competition between flavonol and anthocyanin biosynthesis results in narcissus colorized petal traits.

Cytosine-phosphate-guanine oligodeoxynucleotides alleviate radiation-induced kidney injury in cervical cancer by inhibiting DNA damage and oxidative stress through blockade of PARP1/XRCC1 axis.

BACKGROUND: Radiotherapy can cause kidney injury in patients with cervical cancer. This study aims to investigate the possible molecular mechanisms by which CpG-ODNs (Cytosine phosphate guanine-oligodeoxynucleotides) regulate the PARP1 (poly (ADP-ribose) polymerase 1)/XRCC1 (X-ray repair cross-complementing 1) signaling axis and its impact on radiation kidney injury (RKI) in cervical cancer radiotherapy. METHODS: The GSE90627 dataset related to cervical cancer RKI was obtained from the Gene Expression Omnibus (GEO) database. Bioinformatics databases and R software packages were used to analyze the target genes regulated by CpG-ODNs. A mouse model of RKI was established by subjecting C57BL/6JNifdc mice to X-ray irradiation. Serum blood urea nitrogen (BUN) and creatinine levels were measured using an automated biochemical analyzer. Renal tissue morphology was observed through HE staining, while TUNEL staining was performed to detect apoptosis in renal tubular cells. ELISA was conducted to measure levels of oxidative stress-related factors in mouse serum and cell supernatant. An in vitro cell model of RKI was established using X-ray irradiation on HK-2 cells for mechanism validation. RT-qPCR was performed to determine the relative expression of PARP1 mRNA. Cell proliferation activity was assessed using the CCK-8 assay, and Caspase 3 activity was measured in HK-2 cells. Immunofluorescence was used to determine γH2AX expression. RESULTS: Bioinformatics analysis revealed that the downstream targets regulated by CpG-ODNs in cervical cancer RKI were primarily PARP1 and XRCC1. CpG-ODNs may alleviate RKI by inhibiting DNA damage and oxidative stress levels. This resulted in significantly decreased levels of BUN and creatinine in RKI mice, as well as reduced renal tubular and glomerular damage, lower apoptosis rate, decreased DNA damage index (8-OHdG), and increased levels of antioxidant factors associated with oxidative stress (SOD, CAT, GSH, GPx). Among the CpG-ODNs, CpG-ODN2006 had a more pronounced effect. CpG-ODNs mediated the inhibition of PARP1, thereby suppressing DNA damage and oxidative stress response in vitro in HK-2 cells. Additionally, PARP1 promoted the formation of the PARP1 and XRCC1 complex by recruiting XRCC1, which in turn facilitated DNA damage and oxidative stress response in renal tubular cells. Overexpression of either PARP1 or XRCC1 reversed the inhibitory effects of CpG-ODN2006 on DNA damage and oxidative stress in the HK-2 cell model and RKI mouse model. CONCLUSION: CpG-ODNs may mitigate cervical cancer RKI by blocking the activation of the PARP1/XRCC1 signaling axis, inhibiting DNA damage and oxidative stress response in renal tubule epithelial cells.

A new method for treating chronic pancreatitis and preventing fibrosis using bioactive calcium silicate ion solution.

Chronic pancreatitis (CP) is a multifactorial fibroinflammatory syndrome. At present, there is no effective way to treat it clinically. In this study, we proposed a new approach by application of a highly active calcium silicate ion solution derived from calcium silicate (CS) bioceramics, which effectively inhibited the development of CP. This bioceramic derived bioactive ionic solution mainly regulated pancreatic acinar cells (PACs), macrophages and pancreatic stellate cells (PSCs) by SiO32- ions to inhibit inflammation and fibrosis and promote acinar regeneration. The possible mechanism of the therapeutic effect of CS ion solution mainly includes the inhibition of PAC apoptosis by down-regulating the c-caspase3 signal pathway and promotion of the regeneration of PACs by up-regulating the WNT/ß-catenin signaling pathway. In addition, the CS ion solution also effectively down-regulated the NF-κB signaling pathway to reduce macrophage infiltration and PAC inflammatory factor secretion, thereby reducing PSC mediated pancreatic fibrosis. This bioceramics-based ion solution provides a new idea for disease treatment using biomaterials, which may have the potential for the development of new therapy for CP.

[Free posterior interosseous artery perforator flap in the treatment of finger with skin and soft tissue defect].

OBJECTIVE: To explore clinical effects of repairing skin and soft tissue defect of finger with free posterior interosseous artery perforator flap. METHODS: Totally 8 patients with finger skin and soft tissue defect repaired with free posterior interosseous artery perforator flap were treated from May 2021 to November 2022, including 7 males and 1 female aged from 24 to 54 years old, and soft tissue defect area ranged from 3.0 cm×1.5 cm to 5.0 cm×3.0 cm. The time from injury to flap repair ranged from 3 to 83 h. The free posterior interosseous artery perforator flap was applied to repair finger defect, the area of the flap ranged from 3.5 cm×2.0 cm to 5.2 cm×3.5 cm, the donor area of flap was sutured directly. The survival, appearance, texture and donor complications of the flap were observed after operation, and Dargan functional standard was used to evaluate clinical effect of finger function. RESULTS: All flap of 8 patients were survived, and followed up from 3 to 12 months. There was no obvious swelling, soft texture, obvious pigmentation, linear intaglio in donor area only, and without obvious complications were found. Among them, 3 patients'skin flaps were repaired for the defect of palm of the fingers, and sensory recovery was good, two-point discrimination ranged from 5 to 9 mm. According to Dargan functional evaluation, 3 patients excellent, and 5 good. CONCLUSION: Free posterior interosseous artery perforation branch flap could be used to repair the defect of finger. The thickness of flap is moderate, operation is convenient, appearance and texture of the operative flap are good, and the donor site is small without obvious complications, and obtain satisfactory clinical effect.

Gastrointestinal symptoms of long COVID-19 related to the ectopic colonization of specific bacteria that move between the upper and lower alimentary tract and alterations in serum metabolites.

BACKGROUND: Since the coronavirus disease 2019 (COVID-19) outbreak, many COVID-19 variants have emerged, causing several waves of pandemics and many infections. Long COVID-19, or long-term sequelae after recovery from COVID-19, has aroused worldwide concern because it reduces patient quality of life after rehabilitation. We aimed to characterize the functional differential profile of the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. METHODS: We prospectively collected oral, fecal, and serum samples from 983 antibiotic-naïve patients with mild COVID-19 and performed a 3-month follow-up postdischarge. Forty-five fecal and saliva samples, and 25 paired serum samples were collected from patients with gastrointestinal symptoms of long COVID-19 at follow-up and from healthy controls, respectively. Eight fecal and saliva samples were collected without gastrointestinal symptoms of long COVID-19 at follow-up. Shotgun metagenomic sequencing of fecal samples and 2bRAD-M sequencing of saliva samples were performed on these paired samples. Two published COVID-19 gut microbiota cohorts were analyzed for comparison. Paired serum samples were analyzed using widely targeted metabolomics. RESULTS: Mild COVID-19 patients without gastrointestinal symptoms of long COVID-19 showed little difference in the gut and oral microbiota during hospitalization and at follow-up from healthy controls. The baseline and 3-month samples collected from patients with gastrointestinal symptoms associated with long COVID-19 showed significant differences, and ectopic colonization of the oral cavity by gut microbes including 27 common differentially abundant genera in the Proteobacteria phylum, was observed at the 3-month timepoint. Some of these bacteria, including Neisseria, Lautropia, and Agrobacterium, were highly related to differentially expressed serum metabolites with potential toxicity, such as 4-chlorophenylacetic acid, 5-sulfoxymethylfurfural, and estradiol valerate. CONCLUSIONS: Our study characterized the changes in and correlations between the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. Additionally, our findings reveal that ectopically colonized bacteria from the gut to the oral cavity could exist in long COVID-19 patients with gastrointestinal symptoms, with a strong correlation to some potential harmful metabolites in serum.

HPIP is an essential scaffolding protein running through the EGFR-RAS-ERK pathway and drives tumorigenesis.

The EGFR-RAS-ERK pathway plays a key role in cancer development and progression. However, the integral assembly of EGFR-RAS-ERK signaling complexes from the upstream component EGFR to the downstream component ERK is largely unknown. Here, we show that hematopoietic PBX-interacting protein (HPIP) interacts with all classical components of the EGFR-RAS-ERK pathway and forms at least two complexes with overlapping components. Experiments of HPIP knockout or knockdown and chemical inhibition of HPIP expression showed that HPIP is required for EGFR-RAS-ERK signaling complex formation, EGFR-RAS-ERK signaling activation, and EGFR-RAS-ERK signaling-mediated promotion of aerobic glycolysis as well as cancer cell growth in vitro and in vivo. HPIP expression is correlated with EGFR-RAS-ERK signaling activation and predicts worse clinical outcomes in patients with lung cancer. These results provide insights into EGFR-RAS-ERK signaling complex formation and EGFR-RAS-ERK signaling regulation and suggest that HPIP may be a promising therapeutic target for cancer with dysregulated EGFR-RAS-ERK signaling.

CHMP4A stimulates CD8+ T-lymphocyte infiltration and inhibits breast tumor growth via the LSD1/IFNß axis.

CD8+ T lymphocyte-mediated immunity strategies have represented attractive weapons against breast cancer (BC) recently. However, the mechanisms underlying CD8+ T-lymphocyte infiltration still remain obscure. Here, using bioinformatics analysis, we identified four hub prognostic genes related to CD8+ T-lymphocyte infiltration (CHMP4A, CXCL9, GRHL2, and RPS29), among which CHMP4A was the most significant gene. High CHMP4A mRNA expression was significantly associated with longer overall survival (OS) in BC patients. Functional experiments showed that CHMP4A had the ability to promote CD8+ T-lymphocyte recruitment and infiltration and suppressed BC growth in vitro and in vivo. Mechanistically, CHMP4A stimulates CD8+ T-lymphocyte infiltration by downregulating LSD1 expression, leading to HERV dsRNA accumulation, and promoting IFNß and its downstream chemokine production. Collectively, CHMP4A is not only a novel positive predictor for prognosis in BC but also a stimulator of CD8+ T-lymphocyte infiltration regulated by the LSD1/IFNß pathway. This study suggests that CHMP4A may be a novel target for improving the effectiveness of immunotherapy in patients with BC.

Causal associations between modifiable risk factors and pancreatitis: A comprehensive Mendelian randomization study.

Background: The pathogenesis of pancreatitis involves diverse environmental risk factors, some of which have not yet been clearly elucidated. This study systematically investigated the causal effects of genetically predicted modifiable risk factors on pancreatitis using the Mendelian randomization (MR) approach. Methods: Genetic variants associated with 30 exposure factors were obtained from genome-wide association studies. Summary-level statistical data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were obtained from FinnGen consortia. Univariable and multivariable MR analyses were performed to identify causal risk factors for pancreatitis. Results: Genetic predisposition to smoking (OR = 1.314, P = 0.021), cholelithiasis (OR = 1.365, P = 1.307E-19) and inflammatory bowel disease (IBD) (OR = 1.063, P = 0.008) as well as higher triglycerides (OR = 1.189, P = 0.016), body mass index (BMI) (OR = 1.335, P = 3.077E-04), whole body fat mass (OR = 1.291, P = 0.004) and waist circumference (OR = 1.466, P = 0.011) were associated with increased risk of AP. The effect of obesity traits on AP was attenuated after correcting for cholelithiasis. Genetically-driven smoking (OR = 1.595, P = 0.005), alcohol consumption (OR = 3.142, P = 0.020), cholelithiasis (OR = 1.180, P = 0.001), autoimmune diseases (OR = 1.123, P = 0.008), IBD (OR = 1.066, P = 0.042), type 2 diabetes (OR = 1.121, P = 0.029), and higher serum calcium (OR = 1.933, P = 0.018), triglycerides (OR = 1.222, P = 0.021) and waist-to-hip ratio (OR = 1.632, P = 0.023) increased the risk of CP. Cholelithiasis, triglycerides and the waist-to-hip ratio remained significant predictors in the multivariable MR. Genetically predicted alcohol drinking was associated with increased risk of AAP (OR = 15.045, P = 0.001) and ACP (OR = 6.042, P = 0.014). After adjustment of alcohol drinking, genetic liability to IBD had a similar significant causal effect on AAP (OR = 1.137, P = 0.049), while testosterone (OR = 0.270, P = 0.002) a triglyceride (OR = 1.610, P = 0.001) and hip circumference (OR = 0.648, P = 0.040) were significantly associated with ACP. Genetically predicted higher education and household income levels could lower the risk of pancreatitis. Conclusions: This MR study provides evidence of complex causal associations between modifiable risk factors and pancreatitis. These findings provide new insights into potential therapeutic and prevention strategies.

GRADE Use in Evidence Syntheses Published in High-Impact-Factor Gynecology and Obstetrics Journals: A Methodological Survey.

Objective: To identify and describe the certainty of evidence of gynecology and obstetrics systematic reviews (SRs) using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Method: Database searches of SRs using GRADE, published between 1 January 2016 to 31 December 2020, in the 10 "gynecology and obstetrics" journals with the highest impact factor, according to the Journal Citation Report 2019. Selected studies included those SRs using the GRADE approach, used to determine the certainty of evidence. Results: Out of 952 SRs, ninety-six SRs of randomized control trials (RCTs) and/or nonrandomized studies (NRSs) used GRADE. Sixty-seven SRs (7.04%) rated the certainty of evidence for specific outcomes. In total, we identified 946 certainty of evidence outcome ratings (n = 614 RCT ratings), ranging from very-low (42.28%) to low (28.44%), moderate (17.65%), and high (11.63%). High and very low certainty of evidence ratings accounted for 2.16% and 71.60% in the SRs of NRSs, respectively, compared with 16.78% and 26.55% in the SRs of RCTs. In the SRs of RCTs and NRSs, certainty of evidence was mainly downgraded due to imprecision and bias risks. Conclusions: More attention needs to be paid to strengthening GRADE acceptance and building knowledge of GRADE methods in gynecology and obstetrics evidence synthesis.

Complex Emotion Recognition via Facial Expressions with Label Noises Self-Cure Relation Networks.

Current deep learning-based facial expression recognition mainly focused on the six basic human emotions and relied on large-scale and well-annotated data. For complex emotion recognition, such a large amount of data are not easy to obtain, and a high-quality annotation is even more difficult. Therefore, in this paper, we regard complex emotion recognition via facial expressions as a few-shot learning problem and introduce a metric-based few-shot model named self-cure relation networks (SCRNet), which is robust to label noises and is able to classify facial images of new classes of emotions by only few examples from each. Specifically, SCRNet learns a distance metric based on deep features abstracted by convolutional neural networks and predicts a query image's emotion category by computing relation scores between the query image and the few examples of each new class. To tackle the label noise problem, SCRNet gives corrected labels to noise data via class prototype stored in external memory during the meta-training phase. Experimenting on public datasets as well as on synthetic noise datasets demonstrates the effectiveness of our method.

The value of artificial intelligence techniques in predicting pancreatic ductal adenocarcinoma with EUS images: A meta-analysis and systematic review.

Conventional EUS plays an important role in identifying pancreatic cancer. However, the accuracy of EUS is strongly influenced by the operator's experience in performing EUS. Artificial intelligence (AI) is increasingly being used in various clinical diagnoses, especially in terms of image classification. This study aimed to evaluate the diagnostic test accuracy of AI for the prediction of pancreatic cancer using EUS images. We searched the Embase, PubMed, and Cochrane Library databases to identify studies that used endoscopic ultrasound images of pancreatic cancer and AI to predict the diagnostic accuracy of pancreatic cancer. Two reviewers extracted the data independently. The risk of bias of eligible studies was assessed using a Deek funnel plot. The quality of the included studies was measured by the QUDAS-2 tool. Seven studies involving 1110 participants were included: 634 participants with pancreatic cancer and 476 participants with nonpancreatic cancer. The accuracy of the AI for the prediction of pancreatic cancer (area under the curve) was 0.95 (95% confidence interval [CI], 0.93-0.97), with a corresponding pooled sensitivity of 93% (95% CI, 0.90-0.95), specificity of 90% (95% CI, 0.8-0.95), positive likelihood ratio 9.1 (95% CI 4.4-18.6), negative likelihood ratio 0.08 (95% CI 0.06-0.11), and diagnostic odds ratio 114 (95% CI 56-236). The methodological quality in each study was found to be the source of heterogeneity in the meta-regression combined model, which was statistically significant (P = 0.01). There was no evidence of publication bias. The accuracy of AI in diagnosing pancreatic cancer appears to be reliable. Further research and investment in AI could lead to substantial improvements in screening and early diagnosis.