Synthesis and Flame Retardant Behavior of Phosphorous- and Nitrogen-Containing Copolymer and Its Application in Polypropylene.

In this study, a 4-(hydroxymethyl)-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-oxide (PEPA)-functionalized acrylate monomer, PEPAA, is designed and utilized for the synthesis of macromolecular flame retardants poly(PEPAA-co-AM) with varying PEPAA/AM ratio through copolymerization with acrylamide (AM). The poly(PEPAA-co-AM) is then incorporated into polypropylene (PP) to prepare PP/poly(PEPAA-co-AM) composites. The flame retardant effect of poly(PEPAA-co-AM) on PP is investigated using cone calorimetric test (CCT), and compared with that of PEPAA homopolymer (P-PEPAA), AM homopolymer (PAM), and blends of P-PEPAA/PAM. The results demonstrate that, in comparison with P-PEPAA, PAM, and blends of P-PEPAA/PAM, the incorporation of poly(PEPAA-co-AM) significantly enhances the flame retardancy of PP. Notably, the best flame retardancy is achieved when the ratio of PEPAA/AM copolymerization in poly(PEPAA-co-AM) is 2/8. The morphology and composition of residual chars from combustion are analyzed using SEM-EDS while the residual graphitization degree is examined through Raman spectroscopy. Additionally, TG-FTIR-MS is utilized to investigate the pyrolysis products in gas phase during thermal decomposition of poly(PEPAA-co-AM). Based on these experimental results, a flame retardant mechanism for poly(PEPAA-co-AM) is proposed. The PP/poly(PEPAA-co-AM) composites not only retain the excellent processing properties of pure PP but also exhibit enhanced mechanical properties.

Development of a diagnostic model for biliary atresia based on MMP7 and serological tests using machine learning.

OBJECTIVE: To develop a machine learning diagnostic model based on MMP7 and other serological testing indicators for early and efficient diagnosis of biliary atresia (BA). METHODS: A retrospective analysis was conducted on patient information from those hospitalized for pathological jaundice at Beijing Children's Hospital between January 1, 2019, and December 31, 2023. Patients with serum MMP7, liver stiffness measurements, and other routine serological tests were included in the study. Six machine learning models were constructed, including logistic regression (LR), random forest (RF), decision tree (DET), support vector machine classifier (SVC), neural network (MLP), and extreme gradient boosting (XGBoost), to diagnose BA. The area under the receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the various models. RESULTS: A total of 98 patients were included in the study, comprising 64 BA patients and 34 patients with other cholestatic liver diseases. Among the six machine learning models, the XGBoost algorithm model and RF algorithm model achieved the best predictive performance, with an AUROC of nearly 100% in both the training and validation sets. In the training set, these two algorithm models achieved an accuracy, precision, recall, F1 score, and AUROC of 1. Through model interpretation analysis, serum MMP7 levels, serum GGT levels, and acholic stools were identified as the most important indicators for diagnosing BA. The nomogram constructed based on the XGBoost algorithm model also demonstrated convenient and efficient diagnostic efficacy. CONCLUSION: Machine learning models, especially the XGBoost algorithm and RF algorithm models, constructed based on preoperative serum MMP7 and serological tests can diagnose BA more efficiently and accurately. The most important influencing factors for diagnosis are serum MMP7, serum GGT, and acholic stools.

TrxR1 is involved in the activation of Caspase-11 by regulating the oxidative-reductive status of Trx-1.

Sepsis is a common complication of infections that significantly impacts the survival of critically patients. Currently, effective pharmacological treatment strategies are lacking. Auranofin, known as an inhibitor of Thioredoxin reductase (TrxR), exhibits anti-inflammatory activity, but its role in sepsis is not well understood. Here, we demonstrate the significant inhibitory effect of Auranofin on sepsis in a cecal ligation and puncture (CLP) mouse model. In vitro, Auranofin inhibits pyroptosis triggered by Caspase-11 activation. Further investigations reveal that inhibiting TrxR1 suppresses macrophage pyroptosis induced by E. coli, while TrxR2 does not exhibit this effect. TrxR1, functioning as a reductase, regulates the oxidative-reductive status of Thioredoxin-1 (Trx-1). Mechanistically, the modulation of Trx-1's reductive activity by TrxR1 may be involved in Caspase-11 activation-induced pyroptosis. Additionally, inhibiting TrxR1 maintains Trx-1 in its oxidized state. The oxidized form of Trx-1 interacts with Caveolin-1 (CAV1), regulating outer membrane vesicle (OMV) internalization. In summary, our study suggests that inhibiting TrxR1 suppresses OMV internalization by maintaining the oxidized form of Trx-1, thereby restricting Caspase-11 activation and alleviating sepsis.

GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

Multispectral 3D DNA Machine Combined with Multimodal Machine Learning for Noninvasive Precise Diagnosis of Bladder Cancer.

Extracellular vesicle (EV) molecular phenotyping offers enormous opportunities for cancer diagnostics. However, the majority of the associated studies adopted biomarker-based unimodal analysis to achieve cancer diagnosis, which has high false positives and low precision. Herein, we report a multimodal platform for the high-precision diagnosis of bladder cancer (BCa) through a multispectral 3D DNA machine in combination with a multimodal machine learning (ML) algorithm. The DNA machine was constructed using magnetic microparticles (MNPs) functionalized with aptamers that specifically identify the target of interest, i.e., five protein markers on bladder-cancer-derived urinary EVs (uEVs). The aptamers were hybridized with DNA-stabilized silver nanoclusters (DNA/AgNCs) and a G-quadruplex/hemin complex to form a sensing module. Such a DNA machine ensured multispectral detection of protein markers by fluorescence (FL), inductively coupled plasma mass spectrometry (ICP-MS), and UV-vis absorption (Abs). The obtained data sets then underwent uni- or multimodal ML for BCa diagnosis to compare the analytical performance. In this study, urine samples were obtained from our prospective cohort (n = 45). Our analytical results showed that the 3D DNA machine provided a detection limit of 9.2 × 103 particles mL-1 with a linear range of 4 × 104 to 5 × 107 particles mL-1 for uEVs. Moreover, the multimodal data fusion model exhibited an accuracy of 95.0%, a precision of 93.1%, and a recall rate of 93.2% on average, while those of the three types of unimodal models were no more than 91%. The elevated diagnosis precision by using the present fusion platform offers a perspective approach to diminishing the rate of misdiagnosis and overtreatment of BCa.

Structural basis of odor sensing by insect heteromeric odorant receptors.

Most insects, including human-targeting mosquitoes, detect odors through odorant-activated ion channel complexes consisting of a divergent odorant-binding subunit (OR) and a conserved co-receptor subunit (Orco). As a basis for understanding how odorants activate these heteromeric receptors, we report here cryo-electron microscopy structures of two different heteromeric odorant receptor complexes containing ORs from disease-vector mosquitos Aedes aegypti or Anopheles gambiae. These structures reveal an unexpected stoichiometry of one OR to three Orco subunits. Comparison of structures in odorant-bound and unbound states indicates that odorant binding to the sole OR subunit is sufficient to open the channel pore, suggesting a mechanism of OR activation and a conceptual framework for understanding evolution of insect odorant receptor sensitivity.

Design of novel chiral self-assembling peptides to explore the efficiency and mechanism of mRNA-FIPV vaccine delivery vehicles.

The enhancement of conventional liposome and lipid nanoparticle (LNP) methodologies in the formulation and deployment of messenger RNA (mRNA) vaccines necessitates further refinement to augment both their effectiveness and biosafety profiles. Additionally, researching these innovative delivery carrier materials represents both a prominent focus and a significant challenge in the current scientific landscape. Here we designed new chiral self-assembling peptides as the delivery carrier for RNA vaccines to study the underlying mechanisms in the feline infectious peritonitis virus (FIPV) model system. Firstly, we successfully transcribed mature enhanced green fluorescent protein (EGFP) mRNA and feline infectious peritonitis virus nucleocapsid (FIPV N) mRNA in vitro from optimized vectors. Subsequently, we developed chiral self-assembling peptide-1 (CSP-1) and chiral self-assembling peptide-2 (CSP-2) peptides, taking into account the physical and chemical characteristics of nucleic acid molecules as well as the principles of self-assembling peptides, with the aim of improving the delivery efficiency of mRNA molecule complexes. We determined the optimal coating ratio between CSP and mRNA by electrophoretic mobility shift assay. We found that the peptides and mRNA complexes can protect the mRNA from RNase A enzyme and efficiently deliver mRNA into cells for target antigen proteins expression. Animal experiments confirmed that CSP-1/mRNA complex can effectively trigger immune response mechanisms involving IFN-γ and T cell activation. It can also stimulate CD4+ and CD8+ T cell proliferation and induce serum antibody titers up to 10,000 times higher. And no pathological changes were observed by immunohistochemistry in liver, spleen, and kidney, indicating that CSP-1 may be a safe and promising delivery system for mRNA vaccines. Methodologically, this research represents a novel endeavor in the utilization of chiral self-assembling peptides within the realm of mRNA vaccines. This approach not only introduces fresh prospects for employing such nanomaterials in various mRNA vaccines but also expands the potential for developing small molecules, proteins, and antibodies. Furthermore, it paves the way for new clinical applications of existing pharmaceuticals.

A Rapid Self-Assembling Peptide Hydrogel for Delivery of TFF3 to Promote Gastric Mucosal Injury Repair.

Self-assembled peptide-based nanobiomaterials exhibit promising prospects for drug delivery applications owing to their commendable biocompatibility and biodegradability, facile tissue uptake and utilization, and minimal or negligible unexpected toxicity. TFF3 is an active peptide autonomously secreted by gastric mucosal cells, possessing multiple biological functions. It acts on the surface of the gastric mucosa, facilitating the repair process of gastric mucosal damage. However, when used as a drug, TFF3 faces significant challenges, including short retention time in the gastric mucosal cavity and deactivation due to degradation by stomach acid. In response to this challenge, we developed a self-assembled short peptide hydrogel, Rqdl10, designed as a delivery vehicle for TFF3. Our investigation encompasses an assessment of its properties, biocompatibility, controlled release of TFF3, and the mechanism underlying the promotion of gastric mucosal injury repair. Congo red/aniline blue staining revealed that Rqdl10 promptly self-assembled in PBS, forming hydrogels. Circular dichroism spectra indicated the presence of a stable ß-sheet secondary structure in the Rqdl10 hydrogel. Cryo-scanning electron microscopy and atomic force microscopy observations demonstrated that the Rqdl10 formed vesicle-like structures in the PBS, which were interconnected to construct a three-dimensional nanostructure. Moreover, the Rqdl10 hydrogel exhibited outstanding biocompatibility and could sustainably and slowly release TFF3. The utilization of the Rqdl10 hydrogel as a carrier for TFF3 substantially augmented its proliferative and migratory capabilities, while concurrently bolstering its anti-inflammatory and anti-apoptotic attributes following gastric mucosal injury. Our findings underscore the immense potential of the self-assembled peptide hydrogel Rqdl10 for biomedical applications, promising significant contributions to healthcare science.

Discovery of a new bimetallic borate with strong optical anisotropy activated by π-conjugated [B2O5] units.

Birefringent materials with high optical anisotropy have been identified as a research hotspot owing to their significant scientific and technological significance in modern optoelectronics for manipulating light polarization. Researchers studying borate systems have discovered that adding π-conjugated units placed in parallel can significantly increase the birefringence of crystalline solids; some examples include [BO3] units, [B2O5] units, and [B3O6] units. However, there are not many borates with strictly parallel configurations of π-conjugated [B2O5] units. In this study, a new bimetallic borate Sr2Cd4(B2O5)3 with near-parallel arrangement of π-conjugated [B2O5] units was discovered. Sr2Cd4(B2O5)3 possesses the maximum number density of [B2O5] units, shortest dihedral angle of [B2O5] units (between the two [BO3]), and largest degree of [CdO6] octahedral distortion among all the currently known Sr-Cd-B-O tetragonal system borates, making it demonstrate a large birefringence of 0.102 at 532 nm. Theoretical analysis proves that π-conjugated [B2O5] anions are the primary source of the large birefringence of Sr2Cd4(B2O5)3.

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor.

The µ-opioid receptor (µOR) is an important target for pain management1 and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of ß-arrestin-1 with the µOR core binding site appears less specific and occurs with much lower affinity than binding of Gi.

The formation of unsaturated IrOx in SrIrO3 by cobalt-doping for acidic oxygen evolution reaction.

Electrocatalytic water splitting is a promising route for sustainable hydrogen production. However, the high overpotential of the anodic oxygen evolution reaction poses significant challenge. SrIrO3-based perovskite-type catalysts have shown great potential for acidic oxygen evolution reaction, but the origins of their high activity are still unclear. Herein, we develop a Co-doped SrIrO3 system to enhance oxygen evolution reaction activity and elucidate the origin of catalytic activity. In situ experiments reveal Co activates surface lattice oxygen, rapidly exposing IrOx active sites, while bulk Co doping optimizes the adsorbate binding energy of IrOx. The Co-doped SrIrO3 demonstrates high oxygen evolution reaction electrocatalytic activity, markedly surpassing the commercial IrO2 catalysts in both conventional electrolyzer and proton exchange membrane water electrolyzer.

Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier.

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment, significantly curtailing the efficacy of these treatments and, in some cases, resulting in fatal consequences. Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis, the paucity of effective treatments for such damage is evident. In our study, we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells, thereby fortifying the integrity of the intestinal mucus barrier. This enhanced barrier function serves to resist microbial invasion and subsequently reduces the inflammatory response. Importantly, this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs. Mechanistically, E. copr up-regulates the expression of AUF1, leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells. An especially significant finding is that E. copr activates the AhR pathway, thereby promoting the expression of AUF1. In summary, our results strongly indicate that E. copr enhances the intestinal mucus barrier, effectively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway, consequently enhancing Muc2 mRNA stability.

Optoelectronic Tweezers Micro-Well System for Highly Efficient Single-Cell Trapping, Dynamic Sorting, and Retrieval.

Single-cell arrays have emerged as a versatile method for executing single-cell manipulations across an array of biological applications. In this paper, an innovative microfluidic platform is unveiled that utilizes optoelectronic tweezers (OETs) to array and sort individual cells at a flow rate of 20 µL min-1. This platform is also adept at executing dielectrophoresis (DEP)-based, light-guided single-cell retrievals from designated micro-wells. This presents a compelling non-contact method for the rapid and straightforward sorting of cells that are hard to distinguish. Within this system, cells are individually confined to micro-wells, achieving an impressive high single-cell capture rate exceeding 91.9%. The roles of illuminating patterns, flow velocities, and applied electrical voltages are delved into in enhancing the single-cell capture rate. By integrating the OET system with the micro-well arrays, the device showcases adaptability and a plethora of functions. It can concurrently trap and segregate specific cells, guided by their dielectric signatures. Experimental results, derived from a mixed sample of HepG2 and L-O2 cells, reveal a sorting accuracy for L-O2 cells surpassing 91%. Fluorescence markers allow for the identification of sequestered, fluorescence-tagged HepG2 cells, which can subsequently be selectively released within the chip. This platform's rapidity in capturing and releasing individual cells augments its potential for future biological research and applications.

Neoadjuvant Chemotherapy Alone or Combined with EGFR-Directed Targeted Therapy or Anti-PD-1 Immunotherapy for Locally Advanced Lacrimal Sac and Nasolacrimal Duct Carcinomas.

BACKGROUND/AIMS: We describe our findings in patients with locally advanced lacrimal sac and nasolacrimal duct (NLD) carcinoma who received neoadjuvant systemic therapy. METHODS: We identified patients with locally advanced primary lacrimal sac/NLD carcinoma treated with neoadjuvant systemic intravenous therapy at our institution during 2017-2019. RESULTS: The study included seven patients, four men and three women; the mean age was 60.4 years (range: 43-76). All patients had locally advanced disease with significant orbital soft tissue invasion with or without skull base invasion making eye-sparing surgery not feasible as an initial step. Three patients had poorly differentiated squamous cell carcinoma; two, invasive carcinoma with basaloid and squamous features; one, high-grade carcinoma with features suggestive of sebaceous differentiation; and one, undifferentiated carcinoma. The neoadjuvant regimens were cisplatin and docetaxel (n = 1); carboplatin and docetaxel (n = 1); paclitaxel and cetuximab (n = 1); carboplatin, paclitaxel, and cetuximab (EGFR inhibitor) (n = 2); cisplatin, docetaxel, and pembrolizumab (anti-PD-1 immunotherapy) (n = 1); and carboplatin, paclitaxel, and pembrolizumab (n = 1). All patients had radiologic disease regression, and one patient had radiologic near-complete response. After neoadjuvant therapy, all patients underwent wide local excision and adjuvant concurrent chemoradiation. Two patients had a complete pathologic response. At a median follow-up period of 13 months after chemoradiation (range, 8-54 months), all patients were alive without evidence of disease. One patient had nodal metastasis treated with lymph node dissection and adjuvant chemoradiation. CONCLUSIONS: Neoadjuvant systemic therapy can shrink tumors in patients with locally advanced primary lacrimal sac/NLD carcinoma with orbital or skull base invasion.

In Situ Fenestration and Carotid-Subclavian Bypass for Left Subclavian Artery Revascularization During Thoracic Endovascular Aortic Repair.

PURPOSE: To evaluate the safety and feasibility of left subclavian artery (LSA) revascularization techniques during thoracic endovascular aortic repair (TEVAR)-the in situ needle fenestration (ISNF) technique and the carotid-subclavian bypass (CS-Bp)-for complicated aortic pathologies. METHODS: A retrospective single-center observational study was conducted to identify all patients with thoracic aortic pathologies who underwent TEVAR with LSA revascularization using either CS-Bp or ISNFs from January 2014 to December 2020. RESULTS: One hundred and twelve consecutive patients who received TEVAR with LSA revascularization were included. Among them, 69 received CS-Bp and 43 received ISNF (29 using the Futhrough adjustable puncture needles, 14 using the binding stent-graft puncture systems). Technical success, defined as achieving aortic arch pathology exclusion and LSA preservation, was attained in 99.1% patients. Early mortality was 0.9%. Major adverse events within 30 days, including one cerebral hemorrhage, one cervical incision hemorrhage, one stroke and two paraplegia, were exclusively observed in the CS-Bp group. Immediate type I, II and III endoleaks occurred in 0%, 4.7% and 2.3% in the ISNF group, respectively, compared to 0%, 2.9% and 0% in the CS-Bp group.One hundred and eight (97.2%) patients were available for follow-up at a median 50 (maiximum of 103) months, revealing a LSA patency rates of 99.1%. Six patients died during follow-ups-five in the CS-Bp group and one in the ISNF group. Cause of death include one aortic-related stent-graft infection, three non-related and two with unknow causes. The survival exhibited no significantly different between the ISNF (97.7%) and CS-Bp (89.9%) groups (p = 0.22). CONCLUSIONS: Both CS-Bp and ISNF are feasible techniques for LSA reconstruction in TEVAR. ISNF, whether using Futhrough or BPS, seems to be competitive with CS-Bp.

Etiology and Characteristics of Patients Presenting with Eyelid Lacerations at a Level 1 Trauma Center.

Purpose: To investigate the etiology and demographic associations of patients presenting with eyelid lacerations to a US level 1 trauma center emergency department (ED). Patient and Methods: A retrospective chart review of all patients with eyelid lacerations presenting to the ED at a single level 1 trauma center was performed. Eyelid lacerations were categorized as simple eyelid lacerations, eyelid lacerations with eyelid margin involvement, and eyelid lacerations with nasolacrimal system involvement. Data on demographics and clinical characteristics were analyzed. Results: A total of 303 eyelid laceration cases were identified, 56% were simple eyelid lacerations, followed by 24% with nasolacrimal involvement and 20% involving the eyelid margin. Sixty percent of animal bites/scratches resulted in a nasolacrimal system involving laceration, most commonly affecting children. Falls were the most common etiology in children and patients over the age of 60. Black patients, patients presenting with concomitant ophthalmic injuries, and those with Medicaid insurance were more likely to have an assault etiology (p < 0.05 for all). Conclusion: Falls were the most common etiology for eyelid lacerations in children and the elderly, while assault was the most common in adults. Identifying the most common etiology by demographic factors can help raise awareness regarding targeted prevention strategies for high-risk populations.

Terrestrial algae: pioneer organisms of carbonate rock solutional weathering in South China karst.

The formation of soil in karst ecosystem has always been a scientific problem of great concern to human beings. Algae can grow on the exposed and non-nutrition carbonate surface, inducing and accelerating weathering of rock substrates, thus promoting soil formation. Yet the actual contribution of algae to solutional weathering intensity remains unclear. In this study, we performed weathering simulation experiment on two algae species (Klebsormidium dissectum (F.Gay) H.Ettl & G.Gärtner and Chlorella vulgaris Beijerinck), which were screened from carbonated rock surfaces from a typical karst region in South China. The results showed: (1) both algae have solutional weathering effect on carbonate rock, (2) there is no difference of solutional intensity observed, yet the solutional modes are different, suggesting different ecological adaptative strategies, (3) algae on carbonate rocks have higher carbonic anhydrase activity (CAA) and secrete more extracellular polysaccharide (EPS), accelerating rock weathering. (4) The absolute dissolution amount of carbonate rock with algae participation is 3 times of that of without algae. These results indicate the significant impact of terrestrial algae on carbonate rock solutional weathering and provides quantitative evidence that terrestrial algae are pioneer species. It also contributes to our further understanding of soil formation in karst ecosystems in South China.

SM22α deficiency: promoting vascular fibrosis via SRF-SMAD3-mediated activation of Col1a2 transcription following arterial injury.

Vascular fibrosis, characterized by increased Type I collagen expression, significantly contributes to vascular remodeling. Our previous studies show that disrupting the expression of SM22α (aka SM22, Tagln) induces extensive vascular remodeling following arterial injury, involving oxidative stress, inflammation, and chondrogenesis within the vessel wall. This study aims to investigate the molecular mechanisms underlying the transcription of Col1a2, a key fibrotic extracellular matrix marker. We observed upregulation of COL1A2 in the arterial wall of Sm22-/- mice following carotid injury. Bioinformatics and molecular analyses reveal that Col1a2 transcription depends on a CArG box in the promoter, activated synergistically by SRF and SMAD3. Notably, we detected enhanced nuclear translocation of both SRF and SMAD3 in the smooth muscle cells of the injured carotid artery in Sm22-/- mice. These findings demonstrate that SM22 deficiency regulates vascular fibrosis through the interaction of SRF and the SMAD3-mediated canonical TGF-ß1 signal pathway, suggesting SM22α as a potential therapeutic target for preventing vascular fibrosis.

Multiomics-based classifier to decipher immune landscape of uveal melanoma and predict patient outcomes.

Uveal melanoma (UVM) prognosis and the possibilities for targeted therapy depend on a thorough understanding of immune infiltration features and the analysis of genomic and immune signatures. Leveraging multi-omics data from The Cancer Genome Atlas and GEO datasets, we employed an unsupervised clustering algorithm to categorize UVM into immune-related subgroups. Subsequent multi-omics analysis revealed two distinct UVM subtypes, each characterized by unique genomic mutations and immune microenvironment disparities. The aggressive UMCS2 subtype exhibited higher TNM stage and poorer survival, marked by elevated metabolism and increased immune infiltration. However, UMCS2 displayed heightened tumor mutational burden and immune dysfunction, leading to reduced responsiveness to immunotherapy. Importantly, these subtypes demonstrated differential sensitivity to targeted drugs due to significant variances in metabolic and immune environments, with UMCS2 displaying lower sensitivity. We developed a robust, subtype-specific marker-based risk scoring system. This system's diagnostic accuracy was validated through ROC curves, decision curve analysis, and calibration curves, all yielding satisfactory results. Additionally, cell experiments identified the pivotal function of HTR2B, the most crucial factor in this risk model. Knocking down HTR2B significantly reduced the activity, proliferation, and invasion ability of the UVM cell line. These findings underscored the impact of gene and immune microenvironment alterations in driving distinct molecular subtypes, emphasizing the need for precise treatment strategies. The molecular subtyping-based risk assessment system not only aids in predicting patient prognosis but also guides the identification of populations suitable for combined treatment. Molecules represented by HTR2B in the model may serve as effective therapeutic targets for UVM.Communicated by Ramaswamy H. Sarma.

Diagnose and treatment for Type D congenital esophageal atresia with tracheoesophageal fistula.

Importance: Type D esophageal atresia (EA) with tracheoesophageal fistula (TEF) is characterized by EA with both proximal and distal TEFs. It is a rare congenital anomaly with a very low incidence. Objective: To investigate diagnostic and treatment strategies for this rare condition. Methods: We retrospectively reviewed the clinicopathological features of patients with EA/TEF treated at our institution between January 2007 and September 2021. Results: Among 386 patients with EA/TEF, 14 (3.6%) had type D EA/TEF. Only two patients were diagnosed with proximal TEF preoperatively. Seven patients were diagnosed intraoperatively. Five patients were missed for diagnosis during the initial surgery but was later confirmed by bronchoscopy. During the neonatal period, seven patients underwent a one-stage repair of proximal and distal TEF via thoracoscopy or thoracotomy. Due to missed diagnosis and other reasons, the other 7 patients underwent two-stage surgery for repair of the proximal TEF, including cervical incision and thoracoscopy. Ten of the 14 patients experienced postoperative complications including anastomotic leakage, pneumothorax, esophageal stricture, and recurrence. Patients who underwent one-stage repair of distal and proximal TEF during the neonatal period showed a higher incidence of anastomotic leak (4/7). In contrast, only one of seven patients with two-stage repair of the proximal TEF developed an anastomotic leak. Interpretation: Type D EA/TEF is a rare condition, and proximal TEFs are easily missed. Bronchoscopy may aim to diagnose and determine the correct surgical approach. A cervical approach may be more suitable for repairing the proximal TEF.