Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models.

The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA.

Case report: Bronchoscopic intervention for rare benign airway tumors: a report of 4 cases and literature review.

Due to their unique location, airway tumors have a significant impact on patient quality of life and survival. Current research has focused extensively on malignant airway tumors; however, benign airway tumors, especially rare ones, are less understood due to their low incidence. These tumors are often misdiagnosed and mistreated due to diagnostic challenges. Therefore, there is still a lack of consensus on the treatment of some rare benign airway tumors. Our center summarizes the diagnosis and treatment of four rare cases of benign airway stenosis in recent years, highlighting the bronchoscopic manifestations and therapeutic approaches to improve the understanding of these diseases.

Impact of vaginal microecological differences on pregnancy outcomes and endometrial microbiota in frozen embryo transfer cycles.

PURPOSE: This prospective study investigates the correlation between vaginal microecology and pregnancy outcomes and explores their impact on endometrial microbiota composition during frozen embryo transfer (FET) cycles. Additionally, the impact of transvaginal Lactobacillus supplementation on reproductive outcomes in patients with previous failed cycles was assessed. METHODS: A total of 379 patients undergoing FET at a reproductive medicine center were categorized into clinical pregnancy (CP), miscarriage (MISC), and non-pregnant (NP) groups. Vaginal specimens were collected for microecological evaluation prior to embryo transfer. Endometrial microbiota samples were obtained during embryo transfer for 16S rRNA gene sequencing analysis to assess endometrial microbiota composition. Vaginal microecological indicators, including pH, Lactobacillus dominance, and leukocyte esterase activity, were measured. Transvaginal Lactobacillus supplementation was investigated in 60 patients with previous failed cycles. RESULTS: Vaginal microecology significantly correlated with pregnancy outcomes, with normal microecology associated with a higher clinical pregnancy rate. Vaginal pH and leukocyte esterase activity were significantly associated with clinical pregnancy. Furthermore, vaginal microecological differences significantly impacted endometrial microbiota composition. However, no significant differences were observed in endometrial microbiota composition among the CP, MISC, and NP groups. Notably, transvaginal Lactobacillus supplementation increased the clinical pregnancy rate without affecting the miscarriage rate. CONCLUSION: This study highlights that normal vaginal microecology, characterized by lower pH and leukocyte esterase negativity, is associated with a higher likelihood of clinical pregnancy following FET. Importantly, vaginal microecological differences influence endometrial microbiota composition. Moreover, transvaginal Lactobacillus supplementation appears promising in improving clinical pregnancy rates in patients with previous failed cycles. These findings contribute to a better understanding of the interplay between vaginal and endometrial microbiota and offer potential interventions to enhance reproductive success in assisted reproductive technologies.

Development and clinical validation of a microfluidic-based platform for CTC enrichment and downstream molecular analysis.

Background: Although many CTC isolation and detection methods can provide information on cancer cell counts, downstream gene and protein analysis remain incomplete. Therefore, it is crucial to develop a technology that can provide comprehensive information on both the number and profile of CTC. Methods: In this study, we developed a novel microfluidics-based CTC separation and enrichment platform that provided detailed information about CTC. Results: This platform exhibits exceptional functionality, achieving high rates of CTC recovery (87.1%) and purification (∼4 log depletion of WBCs), as well as accurate detection (95.10%), providing intact and viable CTCs for downstream analysis. This platform enables successful separation and enrichment of CTCs from a 4 mL whole-blood sample within 15 minutes. Additionally, CTC subtypes, selected protein expression levels on the CTC surface, and target mutations in selected genes can be directly analyzed for clinical utility using immunofluorescence and real-time polymerase chain reaction, and the detected PD-L1 expression in CTCs is consistent with immunohistochemical assay results. Conclusion: The microfluidic-based CTC enrichment platform and downstream molecular analysis together provide a possible alternative to tissue biopsy for precision cancer management, especially for patients whose tissue biopsies are unavailable.

Impact of time-to-treatment initiation on survival in single primary non-small cell lung Cancer: A population-based study.

Background: Understanding the effects of a delayed time-to-treatment initiation(TTI) for non-small cell lung cancer (NSCLC) is vital. Methods: We analyzed NSCLC data from the Surveillance, Epidemiology, and End Results database, focusing on lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). TTI was studied as both continuous and dichotomous variables. Restricted cubic splines were employed to identify potential nonlinear dependency between the hazard ratio (HR) and TTI. Propensity score matching was used to ensure a balanced patient allocation, and then survival differences between groups were assessed using Kaplan-Meier analysis and competing risk models. We used overall survival (OS) as the primary outcome and cancer-specific cumulative mortality (CSCM) as a complementary indicator. Finally, sensitivity analyses were performed on censored data. Results: A total of 80,020 with NSCLC were analyzed. TTI was assessed as a continuous variable, showing a noticeable increase in the HR for stage I to II NSCLC with TTI >1 month. Conversely, the trend for stage III to IV NSCLC was the opposite. In stage I LUAD, the 'early' group demonstrated a higher OS compared to the 'delayed' group (Log-rank P = 0.002), while there was no significant difference in CSCM (Fine-gray P = 0.321). In stage I LUSC, there was no significant difference in OS(Log-rank P = 0.260), but the 'early' group had a lower CSCM (Fine-gray P = 0.018). For stage II-IV NSCLC, the 'delayed' group did not exhibit a negative impact on OS or CSCM. The sensitivity analysis further supported the results of the main analysis. Conclusion: Prolongation of TTI ≥31 days has a negative impact on OS or CSCM in stage I NSCLC only. Further exploration and validation are needed to determine whether these results can be used as evidence for a 'safe' TTI threshold setting for future NSCLC.

Stage-mediated priority effects and season lengths shape long-term competition dynamics.

The relative arrival time of species can affect their interactions and thus determine which species persist in a community. Although this phenomenon, called priority effect, is widespread in natural communities, it is unclear how it depends on the length of growing season. Using a seasonal stage-structured model, we show that differences in stages of interacting species could generate priority effects by altering the strength of stabilizing and equalizing coexistence mechanisms, changing outcomes between exclusion, coexistence and positive frequency dependence. However, these priority effects are strongest in systems with just one or a few generations per season and diminish in systems where many overlapping generations per season dilute the importance of stage-specific interactions. Our model reveals a novel link between the number of generations in a season and the consequences of priority effects, suggesting that consequences of phenological shifts driven by climate change should depend on specific life histories of organisms.

Erratum: miR-199a-3p/5p regulate tumorgenesis via targeting Rheb in non-small cell lung cancer: Erratum.

[This corrects the article DOI: 10.7150/ijbs.70312.].

Bridging theory and experiments of priority effects.

Priority effects play a key role in structuring natural communities, but considerable confusion remains about how they affect different ecological systems. Synthesizing previous studies, we show that this confusion arises because the mechanisms driving priority and the temporal scale at which they operate differ among studies, leading to divergent outcomes in species interactions and biodiversity patterns. We suggest grouping priority effects into two functional categories based on their mechanisms: frequency-dependent priority effects that arise from positive frequency dependence, and trait-dependent priority effects that arise from time-dependent changes in interacting traits. Through easy quantification of these categories from experiments, we can construct community models representing diverse biological mechanisms and interactions with priority effects, therefore better predicting their consequences across ecosystems.

Prognosis prediction and comparison between pancreatic signet ring cell carcinoma and pancreatic duct adenocarcinoma: a retrospective observational study.

Background: Pancreatic signet ring cell carcinoma (PSRCC) is a rare and aggressive cancer that has been reported primarily as case reports. Due to limited large-scale epidemiological and prognostic analyses, the outcomes of PSRCC patients varies greatly in the absence of recognized first-line treatment strategies. This study aimed to compare the clinical features, treatment, and prognosis of PSRCC and pancreatic ductal cell carcinoma (PDAC), the most common subtype of pancreatic cancer, and to establish predictive models for these subtypes. Methods: The data on PSRCC and PDAC patients from 1998 to 2018 was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Thereafter, the clinical, demographic, and treatment characteristics of the two groups and the differences and influencing factors of the two groups were evaluated by propensity score matching (PSM), Kaplan-Meier survival curves, Cox risk regression analyses, and least absolute shrinkage and selection operator (LASSO) analysis. Next, prognosis models were constructed and validated by KM and ROC analysis. Finally, a nomogram was constructed, based on the results of these analyses, to predict survival outcomes of PSRCC and PDAC patients. Results: A total of 84,789 patients (432 PSRCC and 84357 PDAC patients) were included in this study. The results of the study revealed that, compared to the PDAC patients, PSRCC patients were more likely to be male, aged between 58-72 years, have larger tumor masses, and less likely to undergo chemotherapy. Before PSM, the overall survival and cancer-specific survival of the PSRCC group were significantly lower than those PDAC group, but there was no difference in the prognosis of the two groups after PSM. Additionally, lymph node ratio (LNR), log odds of positive lymph node (LODDS), tumor size, age, T-stage, marital status, and summary stage were found to be independent prognostic factors for PSRCC. Lastly, the prediction model and nomogram based on these prognostic factors could accurately predict the survival rate of the patients in SEER datasets and external validation datasets. Conclusion: The prognosis of PSRCC and PDAC patients is similar under the same conditions; however, PSRCC patients may have more difficulty in receiving better treatment, thus resulting in their poor prognosis.

Priority Effects Determine How Dispersal Affects Biodiversity in Seasonal Metacommunities.

AbstractThe arrival order of species frequently determines the outcome of their interactions. This phenomenon, called the priority effect, is ubiquitous in nature and determines local community structure, but we know surprisingly little about how it influences biodiversity across different spatial scales. Here, we use a seasonal metacommunity model to show that biodiversity patterns and the homogenizing effect of high dispersal depend on the specific mechanisms underlying priority effects. When priority effects are driven only by positive frequency dependence, dispersal-diversity relationships are sensitive to initial conditions but generally show a hump-shaped relationship: biodiversity declines when dispersal rates become high and allow the dominant competitor to exclude other species across patches. When spatiotemporal variation in phenological differences alters species' interaction strengths (trait-dependent priority effects), local, regional, and temporal diversity are surprisingly insensitive to variation in dispersal, regardless of the initial numeric advantage. Thus, trait-dependent priority effects can strongly reduce the effect of dispersal on biodiversity, preventing the homogenization of metacommunities. Our results suggest an alternative mechanism that maintains local and regional diversity without environmental heterogeneity, highlighting that accounting for the mechanisms underlying priority effects is fundamental to understanding patterns of biodiversity.

Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.

BACKGROUND AND AIMS: A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR). METHODS: The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package). RESULTS: Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%. CONCLUSIONS: A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR.

Cortisol dysregulation in anxiety infertile women and the influence on IVF treatment outcome.

Introduction: Dysregulation of the stress-regulatory hormone cortisol is associated with anxiety, but its potential impact on infertile women and in vitro fertilization (IVF) treatment remains unclear. This prospective cross-sectional study aimed at evaluating the dysregulation of cortisol and its correlation to anxiety in infertile women. The influence of stress on IVF outcomes was also investigated. Methods: A point-of-care test was used for the measurement of morning serum cortisol in 110 infertile women and 112 age-matching healthy individuals. A Self-Rating Anxiety Scale (SAS) was used for the anxiety assessment of infertile women, and 109 of them underwent IVF treatment starting with the GnRH-antagonist protocol. If clinical pregnancy was not achieved, more IVF cycles were conducted with adjusted protocols until the patients got pregnant or gave up. Results: Higher morning serum cortisol level was identified for infertile patients, especially for the elder. Women with no anxiety showed significant differences in cortisol levels, monthly income, and BMI compared with those with severe anxiety. A strong correlation was found between the morning cortisol level and the SAS score. When the cutoff value is 22.25 µg/dL, cortisol concentration could predict the onset of anxiety with high accuracy (95.45%) among infertile women. After IVF treatments, women with high SAS scores (>50) or cortisol levels (>22.25 µg/dL) demonstrated a lower rate of pregnancy (8.0%-10.3%) and more IVF cycles, although the impact of anxiety was not affirmative. Conclusion: Hypersecretion of cortisol related to anxiety was prevalent among infertile women, but the influence of anxiety on multi-cycle IVF treatment was not affirmative due to the complicated treatment procedures. This study suggested that the assessment of psychological disorders and stress hormone dysregulation should not be overlooked. An anxiety questionnaire and rapid cortisol test might be included in the treatment protocol to provide better medical care.

68Ga-labeled WVP peptide as a novel PET probe for molecular biological diagnosis of unstable thoracic aortic aneurysm and early dissection: an animal study.

Objective: Type IV collagen (Col-IV) is a prospective biomarker for diagnosing and treating of unstable thoracic aortic aneurysm and dissection (TAAD). This study aims to evaluate the feasibility of 68Ga-labeled WVP peptide (68Ga-DOTA-WVP) as a novel Col-IV-targeted probe for TAAD biological diagnosis using PET/CT. Methods: WVP peptide was modified with bifunctional chelator DOTA for 68Ga radiolabeling. Immunohistochemical staining was used to evaluate the expression and location of Col-IV and elastin in aortas treated with 3-aminopropionitrile fumarate (BAPN) at different time points (0, 2, and 4 weeks). The imaging performance of 68Ga-DOTA-WVP was investigated using Micro-PET/CT in a BAPN-induced TAAD mouse model. The relationship between 68Ga-DOTA-WVP uptake in aortic lesions and the serum levels of TAAD-related biomarkers including D-dimer, C-reactive protein (CRP), and serum soluble suppression of tumorigenicity-2 (sST2) was also analyzed. Results: 68Ga-DOTA-WVP was readily prepared with high radiochemical purity and stability in vitro. 68Ga-DOTA-WVP Micro-PET/CT could detect Col-IV exposure of unstable aneurysms and early dissection in BAPN-induced TAAD mice, but little 68Ga-DOTA-WVP uptake was shown in the control group at each imaging time point. The differences of Col-IV expression and distribution of 68Ga-DOTA-WVP both in TAAD and control groups further verified the imaging efficiency of 68Ga-DOTA-WVP PET/CT. Additionally, a higher sST2 level was found in the imaging positive (n = 14) than the negative (n = 8) group (9.60 ± 1.14 vs. 8.44 ± 0.52, P = 0.014). Conclusion: 68Ga-DOTA-WVP could trace the exposure and abnormal deposition of Col-IV in enlarged and early injured aortas, showing a potential for biological diagnosis, whole-body screening, and progression monitoring of TAAD.

Intersection of nanomaterials and organoids technology in biomedicine.

Organoids are stem cell-derived, self-organizing, 3D structures. Compared to the conventional 2D cell culture method, 3D cultured organoids contain a variety of cell types that can form functional "micro-organs" and can be used to simulate the occurrence process and physiological pathological state of organ tissues more effectively. Nanomaterials (NMs) are becoming indispensable in the development of novel organoids. Understanding the application of nanomaterials in organoid construction can, therefore, provide researchers with ideas for the development of novel organoids. Here, we discuss the application status of NMs in various organoid culture systems and the research direction of NMs combined with organoids in the biomedical field.

Chinese expert consensus on interventional diagnosis and management of acquired digestive-respiratory tract fistulas (second edition).

Acquired digestive-respiratory tract fistulas occur with abnormal communication between the respiratory tract and digestive tract caused by a variety of benign or malignant diseases, leading to the alimentary canal contents in the respiratory tract. Although various departments have been actively exploring advanced fistula closure techniques, including surgical methods and multimodal therapy, some of which have gotten good clinical effects, there are few large-scale evidence-based medical data to guide clinical diagnosis and treatment. The guidelines update the etiology, classification, pathogenesis, diagnosis, and management of acquired digestive-respiratory tract fistulas. It has been proved that the implantation of the respiratory and digestive stent is the most important and best treatment for acquired digestive-respiratory tract fistulas. The guidelines conduct an in-depth review of the current evidence and introduce in detail the selection of stents, implantation methods, postoperative management and efficacy evaluation.

The effect of growth hormone on the metabolome of follicular fluid in patients with diminished ovarian reserve.

BACKGROUND: Increasing evidence supports that the co-treatment with growth hormone (GH) enhances ovarian response and oocyte quality during controlled ovarian stimulation (COS) in patients with diminished ovarian reserve (DOR). The composition of follicular fluid (FF) plays an essential role in oocyte development and mirrors the communication occurring between the oocyte and follicular microenvironment. However, the effect of GH on the FF metabolome remains unclear. METHODS: This prospective observational study recruited DOR patients undergoing in vitro fertilization (IVF) cycles with minimal stimulation protocol for COS. Each patient receiving GH co-treatment was matched to a patient without GH co-treatment by propensity score matching. The FF was collected after isolating oocytes and assayed by gas chromatograph-mass spectrometry (GC-MS) metabolomics. The Pearson correlation was performed to evaluate the relationship between the number of oocytes retrieved and the levels of differential metabolites. The KEGG database was used to map differential metabolites onto various metabolic pathways. RESULTS: One hundred thirty-four FF metabolites were identified by GC-MS metabolomics. Twenty-four metabolites, including glutathione, itaconic acid and S-adenosylmethionin (SAM) showed significant differences between the GH and control groups (p-value < 0.05 and q-value < 0.1). In addition, the number of oocytes retrieved was significantly higher in the GH group compared to the control group (3 vs 2, p = 0.04) and correlated with the levels of five differential metabolites. Among them, the levels of antioxidant metabolite itaconic acid were upregulated by GH administration, while SAM levels were downregulated. CONCLUSIONS: The co-treatment with GH during COS may improve oocyte development by altering FF metabolite profiles in DOR patients. However, given the downregulation of SAM, a regulator of genomic imprinting, the potential risk of imprinting disturbances should not be neglected.

Dually stimulative single-chain polymeric nano lock with dynamic ligands for sensitive detection of circulating tumor cells.

Circulating tumor cells (CTCs) are important markers for cancer diagnosis and monitoring. However, CTCs detection remains challenging due to their scarcity, where most of the detection methods are compromised by the loss of CTCs in pre-enrichment, and by the lack of universal antibodies for capturing different kinds of cancer cells. Herein, we report a single-chain based nano lock (SCNL) polymer incorporating dually stimulative dynamic ligands that can bind with a broad spectrum of cancer cells and CTCs overexpressing sialic acid (SA) with high sensitivity and selectivity. The high sensitivity is realized by the polymeric single chain structure and the multi-valent functional moieties, which improve the accessibility and binding stability between the target cells and the SCNL. The highly selective targeting of cancer cells is achieved by the dynamic and dually stimulative nano lock structures, which can be unlocked and functionalized upon simultaneous exposure to overexpressed SA and acidic microenvironment. We applied the SCNL to detecting cancer cells and CTCs in clinical samples, where the detection threshold of SCNL reached 4 cells/mL. Besides CTCs enumeration, the SCNL approach could also be extended to metastasis assessment through monitoring the expressing level of surface SA on cancer cells.