Mining the interpretable prognostic features from pathological image of intrahepatic cholangiocarcinoma using multi-modal deep learning.

BACKGROUND: The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application. METHODS: We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations. RESULTS: The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration. CONCLUSIONS: We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.

Cardioprotection of voluntary exercise against breast cancer-induced cardiac injury via STAT3.

Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

[Pathogenesis of benign prostatic hyperplasia from the perspective of syndrome differentiation of viscera based on the neuro-endocrine-immune network].

According to the theory of traditional Chinese medicine (TCM), benign prostatic hyperplasia (BPH) belongs to the category of "Jing Long". Clinical management of BPH in TCM is root-aimed and kidney-targeted, in combination with the treatment of other viscera based on the syndrome differentiation of zang-fu organs. The neuro-endocrine-immune network of modern medicine is similar to the holistic concept of TCM. Based on the study of the neuro-endocrine-immune network, with kidney deficiency as the root of pathogenesis, and starting from the classification of viscera, this review elucidates the etiologic mechanisms of BHP from the perspective of Chinese and Western medicine and provides some reference for medication.

[Characterization and identification of chemical components from Euodiae Fructus based on UHPLC-Q-TOF-MS].

A sensitive and efficient ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS) approach was established. Based on the self-developed information library, the chemical components from Euodiae Fructus were systematically characterized and identified. The chromatographic separation conditions(e. g., stationary phase,mobile phase, column temperature, and elution gradient) and MS detection conditions(nozzle voltage, capillary voltage, fragmentor,and collision energy) were optimized. Ultimately, an HSS T3 column(2. 1 mm×100 mm, 1. 8 µm) maintained at 35 ℃ was used,and 0. 1% formic acid water-acetonitrile at the flow rate of 0. 4 m L·min~(-1) was used as the mobile phase. Electrospray ionization was adopted to collect the positive and negative ion mass spectrometry data in Auto MS/MS mode. According to the reference compound comparison, fragment ion information interpretation, literature, and retrieval in the self-developed information library, 92 compounds were characterized or derived from the decoction of Euodiae Fructus, including 33 alkaloids, 23 flavonoids, 12 terpenoids, 12phenylpropanoids, and 12 others. Among them, 17 compounds were identified by comparison with the reference compounds, and 11compounds were unreported from Euodiae Fructus. This study realizes the rapid characterization and identification of multi-class chemical components in the decoction of Euodiae Fructus and provides a reference for the studies regarding its effective substances and quality control.

Immune cells: potential carriers or agents for drug delivery to the central nervous system.

Drug delivery systems (DDS) have recently emerged as a promising approach for the unique advantages of drug protection and targeted delivery. However, the access of nanoparticles/drugs to the central nervous system (CNS) remains a challenge mainly due to the obstruction from brain barriers. Immune cells infiltrating the CNS in the pathological state have inspired the development of strategies for CNS foundation drug delivery. Herein, we outline the three major brain barriers in the CNS and the mechanisms by which immune cells migrate across the blood-brain barrier. We subsequently review biomimetic strategies utilizing immune cell-based nanoparticles for the delivery of nanoparticles/drugs to the CNS, as well as recent progress in rationally engineering immune cell-based DDS for CNS diseases. Finally, we discuss the challenges and opportunities of immune cell-based DDS in CNS diseases to promote their clinical development.

Effect of different non-pharmacologic placebo treatments on migraine prevention: a network meta-analysis of randomized controlled trials.

BACKGROUND: Placebo control plays an important role in evaluating the effectiveness of interventions. Specifying differential effects of various placebo controls on migraine prevention would be essential in the explanation of preventive treatment for migraine and the indirect comparison between different prophylactic therapeutics. OBJECTIVES: To access the impact of different non-pharmacologic placebo types on different outcomes in migraine patients. METHODS: We searched PubMed, Cochrane Controlled Register of Trials, Embase, and Web of Science databases from the date of creation to June 19, 2023. Randomized controlled trials of migraine that included sham intervention of acupuncture or cognitive behavioural therapy (CBT) or non-invasive Vagus Nerve Stimulation (nVNS) or repetitive Transcranial Magnetic Stimulation (rTMS) or transcranial Direct Current Stimulation (tDCS) were conducted. The primary outcome was the migraine days, and the secondary outcomes were the number of migraine attacks, headache days, headache frequency, and responder's rate. Placebo effects were assessed using five individual placebos for network meta-analysis, using mean differences to measure the relative effect of pair-wise comparisons between interventions. RESULT: A total of 50 trials with 4880 subjects were included. Twenty-seven trials were evaluated for low risk of bias. The results of indirect comparisons show that sham rTMS and sham tDCS had optimal and similar effects in reducing migraine days; sham acupuncture has the greatest effect on reducing the number of migraine attacks and relieving headache frequency; sham rTMS had a highly significant advantage in reducing headache days compared with the other placebo controls. CONCLUSION: Based on the network meta-analysis results, we found that sham acupuncture had the greatest effect on migraine prophylaxis. The strong placebo effect of sham acupuncture should be considered when assessing the therapeutic effect.

Crystallographic and functional studies of a plant temperature-induced lipocalin.

Arabidopsis thaliana temperature-induced lipocalin (AtTIL) is a prototypical member of plant lipocalins and participates in a variety of cellular processes, particularly stress responses. Bioinformatical and physiological studies have proposed its promiscuous ligand-binding ability, but the molecular basis is yet unclear. Here, we report the 1.9-Šcrystal structure of AtTIL in complex with heme. Spectrophotometric absorbance titration with heme yields a dissociation constant of ∼2 micromolar, indicating the relatively weak interaction between AtTIL and heme, which is confirmed by the AtTIL-heme structure. Although binding to retinal or biliverdin is not detected, such possibility can not be precluded as suggested by comparison with other lipocalin structures. These results show that AtTIL is a structural and functional homolog of the bacterial lipocalin Blc.

Diagnostic and Management Value of Multi-Slice Computed Tomography in Esophageal Jujube Pit Impaction.

Objective: The diagnostic value of multi-slice computed tomography (MSCT) in esophageal jujube pit impaction was explored in this study. Methods: A retrospective analysis was performed on MSCT data obtained from a cohort of 40 patients experiencing esophageal jujube pit impaction. The study period encompassed the interval from December 2018 to November 2019. The analysis involved examining the age distribution of the patients, the location of the jujube pit impaction, its connection to the esophagus, associated complications, and the methods used for treatment. All imaging results were compared with the outcomes of surgical or endoscopic interventions. Results: (1) Out of 40 patients, 30 individuals were 58 years old or above, constituting 75% of the study sample. (2) In 80% of the instances (32 cases), the jujube pit was located in the initial segment of the esophagus, exhibiting a spindle shape with varying levels of central low density. (3) We examined the correlation between the angle of the impacted jujube pit and the esophageal longitudinal axis, categorizing 2 cases as longitudinal impaction, 16 as oblique impaction, and 22 as transverse impaction. Among the 40 cases, 28 displayed only slight thickening of the esophageal wall at the impaction site, while 9 cases exhibited heightened periesophageal fat density, and 3 showed small periesophageal air bubbles. (4) Endoscopic evaluation identified damage to the esophageal mucosa in 35 instances and the formation of esophageal perforation in 5 cases. Among patients with perforation, one or both ends of the jujube pit had penetrated the esophageal wall, accompanied by different levels of surrounding inflammatory encapsulation. Conclusion: MSCT is crucial for pinpointing jujube pit impaction and its relation to the esophageal wall and nearby structures, aiding in preoperative and postoperative complications. It is highly feasible for endoscopic cases but limited in complex ones needing thoracoscopy or open-heart surgery.

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.

Association between pre- and post-diagnosis healthy eating index 2020 and ovarian cancer survival: evidence from a prospective cohort study.

Background: Previous studies on the association between diet quality and ovarian cancer (OC) survival are limited and inconsistent. We evaluated the relationship between pre- and post-diagnosis diet quality based on the Healthy Eating Index-2020 (HEI-2020), as well as their changes and OC survival. Methods: This prospective cohort study involved 1082 patients with OC aged 18-79 years, enrolled between 2015 and 2022. Detailed dietary intake before and after diagnosis was recorded using a validated food frequency questionnaire. Deaths were ascertained until February 16th, 2023 via medical records and active follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: We included 549 OC cases with a median follow-up of 44.9 months, representing 206 total deaths. Higher HEI scores were associated with better OS (pre-diagnosis: HRT3 vs. T1 0.66, 95%CI: 0.46-0.93, HR1-SD 0.84, 95%CI: 0.73-0.96; post-diagnosis: HRT3 vs. T1 0.68, 95%CI: 0.49-0.96, HR1-SD 0.80, 95%CI: 0.69-0.92). Compared to the stable group, the group with decreased HEI scores (>3%) from pre- to post-diagnosis had worse OS (HR 1.93, 95%CI: 1.26-2.97). Conclusion: High pre- and post-diagnosis diet quality was associated with improved OC survival, whereas deterioration in diet quality after diagnosis was associated with decreased OC survival.

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).

Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma.

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+-CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.