BackgroundOvarian and endometrial cancers together account for nearly 10% of all female cancer-related deaths worldwide, with ovarian cancer being the deadliest gynecologic malignancy. We aimed to evaluate the diagnostic performance of genetic mutations and DNA methylation markers detected from cervicovaginal swabs for identifying ovarian and endometrial cancers.MethodsWe conducted a retrospective multicenter cohort study including 238 women (127 ovarian/endometrial cancers; 111 benign controls) from three tertiary hospitals between 2018 and 2023. Targeted sequencing was performed for TP53, PTEN, BRCA1, and BRCA2; DNA methylation profiling was analyzed using quantitative methylation-specific PCR (qMSP). Logistic regression and ROC analyses assessed diagnostic accuracy. Survival was evaluated by Kaplan–Meier methods and Cox regression.ResultsTP53 and PTEN mutations were identified in 68% and 47% of cancer samples, respectively, versus <5% among controls. The combined molecular panel (mutations + methylation markers) achieved an AUC of 0.91 (95% CI 0.87–0.95), with sensitivity = 86.5% and specificity = 90.1%. Stratified analysis showed AUC 0.93 in premenopausal and 0.89 in postmenopausal women. TP53 mutation independently predicted 1-year mortality (HR 1.78, 95% CI 1.14–2.64; p = 0.008). The addition of methylation markers improved overall model performance (ΔAUC +0.05, p = 0.02).ConclusionsGenetic and epigenetic alterations detectable in cervicovaginal swabs can accurately identify ovarian and endometrial cancers, demonstrating feasibility for non-invasive molecular triage. Incorporation of TP53 and PTEN sequencing with methylation profiling warrants further prospective investigation as a potential adjunct to upper-tract oncologic surveillance.

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of cancer-related deaths. Its progression is driven by genetic and epigenetic alterations, with increasing evidence emphasizing the role of the transcriptome, particularly post-transcriptional modifications. Human antigen R (HuR), an RNA-binding protein (RBP), plays a crucial role in post-transcriptional regulation of gene expression. In the context of tumor progression, HuR affects a range of cellular processes, including cell proliferation, survival, and metabolic reprogramming, via regulating target mRNA stability and translation. Additionally, HuR influences the tumor microenvironment (TME) through modulating target mRNAs involved in inflammation, immune responses, extracellular matrix remodeling and angiogenesis. Despite these insights, the precise mechanisms by which HuR regulates post-transcriptional process in CRC remain unclear. This review first provides an overview of HuR’s roles and the underlying mechanisms involved in CRC progression, including its regulation of mRNA expression, control of the cell cycle, and modulation of the TME. We also discussed the potential of HuR as a therapeutic target, exploring how targeting HuR could slow down CRC progression and metastasis, ultimately leading to more effective and personalized treatment strategies.

Biased allosteric modulators (BAMs) offer a promising avenue for developing safer and more selective therapeutics for G protein-coupled receptors (GPCRs). However, their molecular mechanisms remain unclear due to the complex combination of biased and allosteric characteristics. Motivated by the challenge, we proposed a machine learning navigated allosteric network strategy to address the issue. It consists of molecular dynamics simulation, a residue-level interpretable deep learning model, and allosteric network analysis, named as RMLNA. RMLNA first obtains biased conformation states through MD simulation and a density map. Then, an interpretable CNN-based classification model is utilized to identify important residues deciding the biased conformation. Navigated with these important residues, allosteric network analysis uncovers their regulation effects. With RMLNA, we revealed the biased allosteric modulation mechanism of a β-arrestin-biased modulator (SBI-553) for the clinically important target NTSR1. SBI-553 stabilizes a unique β-arrestin-biased state with an expanded intracellular binding site and the orthosteric ligand binding mode related to the β-arrestin-biased signaling. The interpretable deep learning model suggests that the middle and the lower parts of TM5 and TM6 are key determinants for the G protein/β-arrestin bias, while SBI-553 modulates the β-arrestin signaling mainly by H8 and the intracellular end of TM6 and TM7. Under the guidance of these results, the community network analysis underlines that the communication between TM5/6 and TM1/7 or TM2/4 is important for the β-arrestin-biased signaling, where SBI-553 redirects the communication between TM5/6 and TM1/7 via F8.50 of H8, inducing enhanced β-arrestin-biased signaling. NTS-NTSR1-β-arrestin complexes with and without binding of SBI-553 are constructed and simulated to further reveal the biased allosteric modulation mechanism to the β-arrestin and validate the reliability of the workflow. Collectively, this work provides molecular insights into the biased allosteric modulation of SBI-553 on NTSR1. More importantly, the novel computational workflow can be extended to other GPCRs.

Angiogenesis is a defining feature of a pre-metastatic niche and is essential for primary colorectal cancer (CRC) tumor metastasis. Epithelial-mesenchymal transition (EMT) also serves as a critical driver of CRC tumor metastatic progression. Here, we hypothesized that exosomes from CRC cells promoted liver metastasis by remodeling tumor microenvironment. To verify this hypothesis, exosomes from CRC cells were isolated and identified, and the effects of these exosomes on human umbilical vein endothelial cells (HUVECs) were investigated. Exosomes from CRC cells promoted vascularization, permeability and migration of HUVECs. Mechanistically, exosomes derived from CRC cells delivered Fibrinogen gamma (FGG) to exert their effects on HUVECs. Furthermore, FGG downregulated the levels of VE-cadherin and E-cadherin in CRC cells, while upregulating N-cadherin and vimentin levels, thereby enhancing endothelial permeability and promoting EMT. In vivo experiments demonstrated that FGG downregulated VE-cadherin in CRC tissues and upregulated CD31 in liver tissues, ultimately leading to an increased number of metastatic liver nodules in a mouse model of CRC liver metastasis. In conclusion, FGG facilitates CRC liver metastasis by regulating key angiogenic, adhesion and mesenchymal markers via exosome-mediated mechanisms, resulting enhanced angiogenesis, vascular permeability, and EMT induction. These findings offer new insights into the mechanisms and treatment strategies of CRC liver metastasis.

ObjectiveExtranodal natural killer/T-cell lymphoma (ENKTL) is recognized for its aggressive nature and variable clinical presentation, often leading to a poor prognosis. While the combined assessment of baseline serum lactate dehydrogenase (LDH) and albumin (ALB) levels has demonstrated prognostic value across various malignancies, its specific application and evidence in ENKTL are unstudied.PurposeThis study aimed to investigate the impact of the lactate dehydrogenase/albumin ratio (LAR) in ENKTL, offering nutritional and immunological insights to enhance risk stratification.ResultsWe conducted a retrospective analysis of 484 ENKTL patients treated with asparaginase-based regimens. The optimal thresholds for serum LDH and ALB levels were identified as 230 u/L and 40 g/L, respectively, and 5.4 for LAR. With a median follow-up of 70 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were determined to be 58.7% and 52.0%, respectively. Patients with higher LAR values exhibited more unfavorable clinical features and poorer 5-year OS and PFS rates compared to those with lower LAR values. Utilizing the LAR-associated prognostic score, patients were categorized into distinct risk groups, revealing significant differences in 5-year OS and PFS among these groups. By integrating the LAR and LAR-associated prognostic score into the prognostic index for natural killer lymphoma (PINK) and PINK with Epstein-Barr virus (PINK-E) models, we found that these measures provided additional prognostic information.ConclusionElevated LDH and decreased ALB levels at the time of initial diagnosis are indicative of a poor prognosis in ENKTL patients. The LAR and LAR-associated prognostic score may serve as independent prognostic indicators for ENKTL, potentially aiding in risk stratification and informing clinical decision-making.

BACKGROUND:Increasing evidence connects gallstone disease (GSD) to all types of cancer incidence; however, the results were inconsistent. The present study aimed to evaluate whether and to what extent these associations exist comprehensively. METHODS:We systematically searched published longitudinal studies indexed in PubMed and Embase database from dates of inception to March 31, 2020. We pooled the effect of GSD on all-cause cancer incidence. Moreover, we further employed stratified analysis concerning sex, geographic background, surgery status, and follow-up period. Trial sequential analysis (TSA) was applied to decide whether the included sample size was sufficient for evaluating these associations. RESULTS:Fifty-one studies incorporating over 13 million participants were eligible for analysis in this study. GSD pose an increased risk of all-cause cancer risk (pooled RR = 1.43; 95% CI: 1.33-1.54) compared with the healthy controls, especially hematologic malignancy (pooled RR = 1.14; 95% CI: 1.05-1.25), gastrointestinal cancers (pooled RR = 1.28; 95% CI: 1.15-1.41), liver, pancreas, and biliary tract cancer (pooled RR = 1.84; 95% CI: 1.62-2.10), and kidney cancer (pooled RR = 1.19; 95% CI: 1.03-1.37). These associations are not markedly changed after stratification by different subgroups. Moreover, the TSA confirmed the sample size was sufficient to draw these conclusive conclusions. CONCLUSIONS:The present meta-analysis with sufficient evidence indicates GSD increases the risk for all causes of cancer incidence. The evidence may warrant GSD patients to perform screening and prophylactic treatment for the prevention of these complications. The indication for cholecystectomy should be determined through a comprehensive evaluation of the patient's clinical presentation, with a thorough assessment of the potential therapeutic benefits and surgical risks.

Early intervention of precancers is significant for improving cancer outcome. EZH2-mediated epigenetic modification was responsible for the immune escape of cancers; besides, tumor immune evasion is correlated with the impaired MHC-I antigen presentation machinery (APM). Oral potentially malignant disorders (OPMDs), represented by oral leukoplakia (OLK), usually precede head and neck squamous cell carcinoma (HNSCC). EZH2 is correlated with malignant transformation (MT) of OPMDs including OLK, while it remains undetermined that whether EZH2 mediates the initiation of HNSCC by repressing APM. Herein, EZH2 was first reported to negatively correlate with MHC-I and CD8+ GZMB+ T subsets which promote antitumor immunity in OPMDs. In vitro study uncovered that EZH2 triggers H3K27me3 on the promoters of MHC-I associated genes such as HLA-A/B/C, B2M and TAP1. Next, we constructed one hydrogel loaded with GSK126, a specific EZH2 inhibitor, denoted as PPT@GSK126 which is well-tolerated and highly adhesive to mucosa. Preclinical trials demonstrated that topical PPT@GSK126 could significantly prevent the MT of OPMDs and induce robust specific immune killing of dysplastic cells; while individual local αPD-1 therapy was unavailable, PPT@GSK126 synergized with topical αPD-1 therapy to significantly repress the cancerization of OPMDs. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.

3563 Background: This CAPCET randomized phase II trial was designed to assess the efficacy and safety of modified capecitabine and oxaliplatin (mCapOX) plus cetuximab (CET) and modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus cetuximab (CET) for the first-line treatment of left-side unresectable RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC). Methods: CAPCET was an open-label, multicenter, randomized, non-comparative phase II trial. Patients with unresectable RAS/BRAF wt mCRC were randomly assigned (1:1) to receive up to 12 cycles biweekly mCapOX (capecitabine 1000mg/m 2 orally twice daily on Day 1-7 and oxaliplatin 85 mg/m 2 iv on Day 1) plus CET (500mg/m 2 iv on day 1) (arm A) or biweekly mFOLFOX6 (oxaliplatin 85 mg/m 2 iv on day 1, leucovorin 400 mg/m 2 iv on day 1, fluorouracil 400mg/m 2 iv bolus on day 1, then fluorouracil 2400 mg/m 2 continuous infusion over 46-48h) plus CET (500mg/m 2 iv on day 1)(arm B) followed by maintenance(either capecitabine plus CET or capecitabine alone at the discretion of the investigators) or treatment-free intervals until progression on treatment, toxicity, or death. The primary endpoint was progression-free survival (PFS) rate at 9 months from randomization. Results: Between September 2021 and April 2024, 168 patients (84 in arm A and 84 in arm B) were enrolled in 20 China centres. Baseline characteristics were well balanced between arms. After a median follow-up of 21.0 months (IQR,19.5-22.5), the 9 months-PFS rates were 70.9% (95% CI 61.1%-82.3%) in arm A and 66.8% (95% CI 56.7%-78.6%; HR = 1.11, P = 0.558) in arm B, and the primary endpoint was met. The median PFS (arm A/B) was 12.7 months (95% CI 10.8–15.2)/12.0 months (95% CI 9.7–14.1). The overall response rate (ORR) and disease control rate (DCR) in arm A were higher than those in arm B with 69.2% versus 60.3% and 96.2% versus 89.7%, respectively. The 2-year overall survival (OS) rate (arm A/B) was 66.8% (95% CI 54.2%–82.3%)/65.6% (95% CI 52.5%–82.0%), and the median OS not reached. Grade≥3 adverse events (AEs) occurred in 28.8% of safety population set (n = 156), with 7.7% in arm A and 21.2% in arm B. The most commonly Grade≥3 AEs was neutropenia, rash, leukopenia and there were no grade 5 AEs reported. Conclusions: The CAPCET study met its first endpoint of 9-month PFS rate in patients with RAS/BRAF wt mCRC. Biweekly mCapOX plus CET had higher ORR and DCR than mFOLFOX6 plus CET, with signally reduced toxicity. Longer follows-up and a multicenter, open-label, randomized, controlled Phase CAPCET- III study (NCT06616259) will be further validate this innovative regimen. Clinical trial information: NCT05022030 .

Chemotherapy‐induced nausea and vomiting (CINV) remains a prevalent treatment complication, often significantly impairing patients' quality of life and reducing adherence to chemotherapy regimens. The standard triplet antiemetic regimen, including either a neurokinin‐1 (NK1) receptor antagonist (RA) or olanzapine, combined with a 5‐hydroxytryptamine type 3 (5‐HT3) RA and dexamethasone (DEX), faces challenges primarily due to DEX‐related adverse effects and its potential to compromise the efficacy of antitumor agents. This study assessed whether omitting DEX (F‐Group: olanzapine + 5‐HT3 RA) is non‐inferior to the standard D‐Group (olanzapine + 5‐HT3 RA + DEX). In this multi‐center, double‐blind, randomized phase III trial, 254 adults with malignant solid tumors (Eastern Cooperative Oncology Group [ECOG] 0–2) scheduled for highly emetogenic chemotherapy (HEC) were randomized 1:1 to the F‐Group or D‐Group. The primary endpoint was the complete response (CR; no emesis/rescue medication) rate over 0–120 h, with a non‐inferiority margin of −15%. Secondary endpoints included CR and complete control (CC; no vomiting/nausea/rescue therapy) rates in acute (0–24 h) and delayed (25–120 h) phases, safety, and quality of life. Overall CR rates were 68.6% (D‐Group) and 69.7% (F‐Group; p = .9658), demonstrating non‐inferiority. Acute phase CR rates were 88.4% versus 86.9% ( p = .8643), and delayed phase CR rates were 69.4% versus 69.7% ( p > .9999). CC rates were comparable across phases, with no new adverse reactions. The combination of a 5‐HT3 RA and olanzapine is as non‐inferior as the standard triplet regimen, providing an alternative option for patients receiving HEC. The trial was registered at ClinicalTrials.gov , number NCT05805800.

Background:Limited evidence and contradictory results exist regarding lymph node metastasis (LNM) and prognosis in early gastric cardia cancer (EGCC) and early gastric non-cardia cancer (EGNCC). This study aims to compare the clinicopathological features, LNM patterns, and survival outcomes between EGCC and EGNCC using a large population-based dataset. Methods:This study utilized data from the Surveillance, Epidemiology, and End Results (SEER) population and employed multivariate analysis, Kaplan-Meier method, propensity score matching (PSM), and nomogram analysis to achieve comprehensive insights. Results:EGCC tended to be younger in age, intestinal type, smaller tumor size, and well-differentiated type (P<0.05). No positive association was found between LNM and tumor location after adjusting for other risk factors [odds ratio (OR): 0.87; 95% confidence interval (CI): 0.60-1.25; P=0.44]. Moreover, patients with EGNCC showed a better prognosis compared with EGCC patients [5-year disease-specific survival (DSS): 87.3% vs. 80.3%, P<0.001 for log-rank test]. Patients with early gastric cancer (EGC) were further divided by invasion depth. When EGC patients were limited to the mucosa, EGCC patients had a similar overall survival (OS) to EGNCC patients (P=0.26). As the depth of infiltration reached the submucosa, EGCC had a significantly worse DSS compared to EGNCC (5-year DSS: 73.9% vs. 85.7%, P<0.001 for log-rank test). PSM further proved that our analysis was credible and reliable. Conclusions:The risk of LNM in EGCC is comparable to that in EGNCC. However, EGCC exhibits poorer survival outcomes compared to EGNCC. This discovery underscores the importance of enhanced monitoring and individualized treatment approaches for patients with EGCC to improve their prognosis and survival.

Previous preclinical studies have revealed the biological links between cardiovascular diseases (CVD) and cancer. However, population-based evidence remained inconclusive. We assessed cancer incidence among individuals with and without CVD condition in a prospective cohort from the UK Biobank (UKB). Multivariable Cox regression and competing risk models were fitted to estimate hazard ratios (HR). A systematic literature search was conducted in Medline, Embase and Cochrane Library databases to identify published population-based cohort studies (last updated on 1 October 2023) investigating the associations between CVD status and subsequent cancer risk. Random-effects meta-analysis was employed to pool relative effect estimates reported by eligible cohorts. Subgroup and sensitivity analyses were conducted to evaluate the associations across various CVD and cancer subtypes. For the cohort study in the UKB, after a median follow-up of 11.58 years, a total of 18,471 and 66,891 cancer cases occurred among 94,845 CVD patients and 368,695 non-CVD individuals (Incidence rate: 25.62 vs. 15.41 per 1000 person-years). Individuals with prior CVD exhibited higher overall cancer risk (HR 1.14, 95

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 109/L) and inferior OS (HR: 1.07; 95% CI: 1.04–1.10; p < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (p < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998–1.001; p = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

BACKGROUND:Biological evidence has revealed antitumor effect of vitamin D, but whether it could predict the response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients remains inconclusive. The aim was to investigate the association between pretreatment vitamin D level and response to NAC and subsequent survival outcomes in BC patients. MATERIALS AND METHODS:The authors systematically searched the Medline, Embase, Cochrane Library, and Web of Science databases and clinical trial registries to identify relevant articles from inception to 8 October 2024. Eligible studies investigating the associations between pretreatment plasma vitamin D and response to NAC in BC patients were selected according to the predefined criteria, with the study characteristics extracted by two reviewers. The primary outcome was pathological complete response (pCR), while overall pathological response and event-free survival (EFS) were adopted as secondary outcomes. Summary effect estimates of odds ratios (ORs) or hazard ratios (HRs) with 95% CIs were pooled using a random-effects model. Subgroup and sensitivity analyses were performed based on study characteristics and methodological quality. RESULTS:Six retrospective cohort studies involving 1291 BC patients were included. The authors observed a significant association between pretreatment vitamin D deficiency and 50% increased odds of non-pCR after NAC (OR=1.50, 95% CI: 1.11-2.03, P=0.008) with no heterogeneity (I2=0%). The authors also identified a significant association of vitamin D with the overall pathological response (OR=1.33, 95% CI: 1.01-1.75, P=0.046). A similar association with EFS (HR=1.27, 95% CI: 0.92-1.75, P=0.139) was also noted although the effect estimate was not statistically significant. Sensitivity analyses based on methodological quality showed consistent findings. CONCLUSION:Pretreatment vitamin D deficiency is associated with an inferior response to NAC in BC patients. Our meta-analysis advocates further prospective studies with large sample sizes before vitamin D supplementation could be administered to improve NAC response and subsequent prognosis of BC patients.

Background: In order to reduce the risk of leakage of cytotoxic agents, peripherally inserted central catheters (PICC) are widely used in patients diagnosed with malignancy before chemotherapy. While inflammation has been demonstrated to be associated with deep vein thrombosis (DVT), the connection between systemic immune inflammation indexes and the formation of PICC-DVT remains unclear. Purpose: This study aims to evaluate the association between PICC-DVT and systemic immune inflammation indexes including platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI). Methods: From August 2018 to October 2021, we enrolled consecutive patients diagnosed with malignancy who underwent PICC implantation before chemotherapy. DVT was assessed using color Doppler ultrasonography. Results: Among the 513 patients, 57 patients (11.1%) developed PICC-DVT. The optimal cutoff values for PLR, SII and SIRI were 260.1, 1318.7, and 2.7, respectively. Based on the multiple logistic regression analysis, correlations were found between PICC-DVT and elevated PLR (p = .014), SII (p = .012), and SIRI (p = .022). Patients with malignancy having higher values of PLR, SII or SIRI tended to be more likely to develop PICC-DVT. Conclusions: The systemic immune inflammation indexes increases the risk of PICC-DVT and could be used as auxiliary predictive tests for PICC-DVT.

High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed a distinct S100A9+ tumor cell subtype present in both primary and metastatic sites, strongly associated with poor overall survival. This subtype exhibited high expression of S100A8, S100A9, ADGRF1, CEACAM6, CST6, NDRG2, MUC4, PI3, SDC1, and C15orf48. Individual knockdown of these ten marker genes, validated through in vitro and in vivo models, significantly inhibited ovarian cancer growth and invasion. Around S100A9+ tumor cells, a population of HK2+_CAF was identified, characterized by activated glycolysis metabolism, correlating with shorter overall survival in patients. Notably, similar to CAFs, immunosuppressive tumor-associated macrophage (TAM) subtypes underwent glycolipid metabolism reprogramming via PPARgamma regulation, promoting tumor metastasis. These findings shed light on the mechanisms driving the aggressiveness of HGSC, offering crucial insights for the development of novel therapeutic targets against this formidable cancer.

Biased ligands selectively activating specific downstream signaling pathways (termed as biased activation) exhibit significant therapeutic potential. However, the conformational characteristics revealed are very limited for the biased activation, which is not conducive to biased drug development. Motivated by the issue, we combine extensive accelerated molecular dynamics simulations and an interpretable deep learning model to probe the biased activation features for two complex systems constructed by the inactive mu OR and two different biased agonists (G-protein-biased agonist TRV130 and beta-arrestin-biased agonist endomorphin2). The results indicate that TRV130 binds deeper into the receptor core compared to endomorphin2, located between W2936.48 and D1142.50, and forms hydrogen bonding with D1142.50, while endomorphin2 binds above W2936.48. The G protein-biased agonist induces greater outward movements of the TM6 intracellular end, forming a typical active conformation, while the beta-arrestin-biased agonist leads to a smaller extent of outward movements of TM6. Compared with TRV130, endomorphin2 causes more pronounced inward movements of the TM7 intracellular end and more complex conformational changes of H8 and ICL1. In addition, important residues determining the two different biased activation states were further identified by using an interpretable deep learning classification model, including some common biased activation residues across Class A GPCRs like some key residues on the TM2 extracellular end, ECL2, TM5 intracellular end, TM6 intracellular end, and TM7 intracellular end, and some specific important residues of ICL3 for mu OR. The observations will provide valuable information for understanding the biased activation mechanism for GPCRs. Using aMD simulations with an interpretable deep learning model, the biased activation of mu OR with two distinct biased agonists is revealed.

Fibroepithelial polyps are rare benign tumors originating from the mesoderm and are more commonly found in the renal pelvis and distal ureter and less frequently in the proximal ureter or bladder. This case report presents a fibroepithelial polyp occurring in the bladder of the fetus, showcasing its two-dimensional ultrasound, three-dimensional ultrasound, color Doppler, and spectral Doppler ultrasound findings, providing a reference for the accurate diagnosis of this condition.

Rhabdomyosarcoma (RMS) is a common soft tissue malignant tumor, especially in young patients. Alveolar rhabdomyosarcoma (ARMS) is a subtype of RMS that is prevalent in adolescents. This malignant tumor usually develops in the extremities and can also involve the trunk, perineum, and pelvis. Now, we report a rare case of pelvic lymph node metastatic alveolar RMS in a young patient, which was determined by fine needle aspiration cytology (FNAC). To the best of our knowledge, this is the first case in which the definite diagnosis of ARMS was initially made by FNAC.

Allosteric drugs offer a new avenue for modern drug design. However, the identification of cryptic allosteric sites presents a formidable challenge. Following the allostery nature of residue-driven conformation transition, we propose a state-of-the-art computational pipeline by developing a residue-intuitive hybrid machine learning (RHML) model coupled with molecular dynamics (MD) simulation, through which we can efficiently identify the allosteric site and allosteric modulator as well as reveal their regulation mechanism. For the clinical target beta 2-adrenoceptor (beta 2AR), we discover an additional allosteric site located around residues D792.50, F2826.44, N3187.45 and S3197.46 and one putative allosteric modulator ZINC5042. Using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and protein structure network (PSN), the allosteric potency and regulation mechanism are probed to further improve identification accuracy. Benefiting from sufficient computational evidence, the experimental assays then validate our predicted allosteric site, negative allosteric potency and regulation pathway, showcasing the effectiveness of the identification pipeline in practice. We expect that it will be applicable to other target proteins. The identification of cryptic allosteric sites presents a formidable challenge. Here, the authors develop a residue-intuitive hybrid ML model coupled with MD simulation to successfully identify a novel allosteric site of beta 2AR and a negative allosteric modulator.