Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions.

Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.

Anatomy and function of the canalis sinuosus and its injury prevention and treatment strategies in implant surgery. / çª¦ç®¡çš„è§£å‰–ä¸ŽåŠŸèƒ½åŠå ¶åœ¨ç§æ¤æœ¯ä¸­æŸä¼¤çš„é˜²æ²»ç­–ç•¥.

The canalis sinuosus, a canal containing the anterior superior alveolar nerve bundle, originates from the infraorbital canal and extends along the maxillary sinus and nasal cavity edges to the anterior maxilla. It was once regarded as an anatomical variation. However, with the widespread application of cone beam computed tomography (CBCT), the detection rate of canalis sinuosus in the population has increased. The canalis sinuosus exhibits diverse courses, branching into multiple accessory canals and terminating at the nasal floor or the anterior tooth region, with the majority traversing the palatal side of the central incisor. The anterior superior alveolar nerve bundle within the canalis sinuosus not only innervates and nourishes the maxillary anterior teeth, their corresponding soft tissues, and the maxillary sinus mucosa, but also relates to the nasal septum, lateral nasal wall, and parts of the palatal mucosa. To minimize surgical complications, implantologists need to investigate strategies for preventing and treating canalis sinuosus injuries. Preoperatively, implantologists should use CBCT to identify the canalis sinuosus and virtually design implant placement at a distance of more than 2 mm from the canalis sinuosus. Intraoperatively, implantologists should assess bleeding and patient comfort, complemented by precision surgical techniques such as the use of implant surgical guide plates. Postoperatively, CBCT can be employed to examine the relationship between the implant and the canalis sinuosus, and treatment of canalis sinuosus injuries can be tailored based on the patient's symptoms. This review summarizes the detection of canalis sinuosus in the population, its anatomical characteristics, and its physiological functions in the anterior maxilla, and discusses strategies for effectively avoiding canalis sinuosus injuries during implant surgery, thereby enhancing implantologists' awareness and providing references for clinical decision-making.

Changes in Corneal Epithelial Thickness in Different Areas After Femtosecond Laser-Assisted LASIK in Patients With High Astigmatism.

PURPOSE: To explore changes in corneal epithelial thickness (CET) after femtosecond laser-assisted laser in situ keratomileusis in patients with high astigmatism. METHODS: CET was measured at every intersection of the concentric circles and specific axes using AngioVue optical coherence tomography (Angio-OCT) preoperatively and 1 month postoperatively. The average thickness of corneal central, paracentral, and peripheral regions was the mean of the points within the central 2, 2 to 5, and 5 to 7 mm areas, respectively. Correlation analysis was performed to investigate the association between CET along different axes and other preoperative and postoperative parameters. RESULTS: Forty-two eyes of 28 patients were included. CET along the astigmatic (K1) and perpendicular (K2) axes in the central and paracentral areas increased (P < .001), whereas that along the K2 axis decreased in the peripheral area 1 month postoperatively (P = .001). The amount of CET change in the peripheral area between the K1 and K2 axes was significantly different (P < .001). In the central area, the change in CET along the K2 axis was positively correlated with ablation depth (r = 0.315, P = .042) and negatively with refractive power after surgery (r = -0.347, P = .024). In the peripheral area, the changes in CET along both K1 and K2 axes were negatively correlated with ablation depth (r = -0.431, P = .004; r = -0.387, P = .011, respectively). CONCLUSIONS: Epithelial modeling differed between the different astigmatism axes after refractive surgery. The compensatory response of the corneal epithelium is more pronounced along the steeper axis. [J Refract Surg. 2024;40(4):e239-e244.].

Predictive Role of Platelet and Inflammation Markers for Severe COVID-19 by Propensity Score Matching.

BACKGROUND: This study aims to ascertain the predictive value of platelet and inflammation markers in severe cases of COVID-19. METHODS: A retrospective real-world cohort study was conducted using propensity score matching (PSM). Patients were classified into severe and non-severe COVID-19 groups based on the severity of the disease, and the correlation between severe COVID-19 and laboratory parameters at admission was analyzed. RESULTS: The study included 397 adult patients, comprising 212 (53%) males and 185 (47%) females. Among these, 309 were non-severe and 88 were severe cases. The severe group had a higher median age than the non-severe group (60 vs. 42 years, p < 0.001). Independent risk factors for severe COVID-19 included age, diabetes comorbidity, fever, respiratory symptoms, platelet count, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and the ratio of arterial oxygen partial pressure (PaO2) to the fraction of inspired oxygen (FiO2) (P/F ratio). After one-to-one PSM, adjusted for age, diabetes comorbidities, fever, and respiratory symptoms, significant differences in laboratory parameters at admission were observed. Compared to the non-severe group (n = 71), in the severe group (n = 71), elevated levels of hsCRP (median: 27.1 mg/L vs. 14.6 mg/L, p = 0.005) and IL-6 (median: 16.2 pg/mL vs. 15.3 pg/mL, p = 0.005) were observed, while platelet count (164 ± 36 × 109 vs. 180 ± 50 × 109, p = 0.02) and P/F ratio (median: 351 vs. 397, p = 0.001) were reduced. CONCLUSIONS: Elevated levels of hsCRP and IL-6, along with reduced platelet count and P/F ratio at admission, were significantly associated with severe COVID-19 and may serve as predictive indicators.

Spatiotemporal distribution of mediastinal neoplasms: A comprehensive multi-center study.

OBJECTIVES: Mediastinal neoplasms are typical but uncommon thoracic diseases with increasing incidence and unfavorable prognoses. A comprehensive understanding of their spatiotemporal distribution is essential for accurate diagnosis and timely treatment. However, previous studies are limited in scale and data coverage. Therefore, this study aims to elucidate the distribution of mediastinal lesions, offering valuable insights into this disease. MATERIALS AND METHODS: This multi-center, hospital-based observational study included 20 nationwide institutions. A retrospective search of electronic medical records from January 1st, 2009, to December 31st, 2020, was conducted, collecting sociodemographic data, computed tomography images, and pathologic diagnoses. Analysis focused on age, sex, time, location, and geographical region. Comparative assessments were made with global data from a multi-center database. RESULTS: Among 7,765 cases, thymomas (30.7%), benign mediastinal cysts (23.4%), and neurogenic tumors (10.0%) were predominant. Distribution varied across mediastinal compartments, with thymomas (39.6%), benign cysts (28.1%), and neurogenic tumors (51.9%) most prevalent in the prevascular, visceral, and paravertebral mediastinum, respectively. Age-specific variations were notable, with germ cell tumors prominent in patients under 18 and aged 18-29, while thymomas were more common in patients over 30. The composition of mediastinal lesions across different regions of China remained relatively consistent, but it differs from that of the global population. CONCLUSION: This study revealed significant heterogeneity in the spatiotemporal distribution of mediastinal neoplasms. These findings provide useful demographic data when considering the differential diagnosis of mediastinal lesions, and would be beneficial for tailoring disease prevention and control strategies.

Impact of operative time on textbook outcome after minimally invasive esophagectomy, a risk-adjusted analysis from a high-volume center.

BACKGROUND: We aimed to study the impact of operative time on textbook outcome (TO), especially postoperative complications and length of postoperative stay in minimally invasive esophagectomy. METHODS: Patients undergoing esophagectomy for curative intent within a prospectively maintained database from 2016 to 2022 were retrieved. Relationships between operative time and outcomes were quantified using multivariable mixed-effects models with medical teams random effects. A restricted cubic spline (RCS) plotting was used to characterize correlation between operative time and the odds for achieving TO. RESULTS: Data of 2210 patients were examined. Median operative time was 270 mins (interquartile range, 233-313) for all cases. Overall, 902 patients (40.8%) achieved TO. Among non-TO patients, 226 patients (10.2%) had a major complication (grade ≥ III), 433 patients (19.6%) stayed postoperatively longer than 14 days. Multivariable analysis revealed operative time was associated with higher odds of major complications (odds ratio 1.005, P < 0.001) and prolonged postoperative stay (≥ 14 days) (odds ratio 1.003, P = 0.006). The relationship between operative time and TO exhibited an inverse-U shape, with 298 mins identified as the tipping point for the highest odds of achieving TO. CONCLUSIONS: Longer operative time displayed an adverse influence on postoperative morbidity and increased lengths of postoperative stay. In the present study, the TO displayed an inverse U-shaped correlation with operative time, with a significant peak at 298 mins. Potential factors contributing to prolonged operative time may potentiate targets for quality metrics and risk-adjustment process.

Perioperative immune checkpoint blockades improve prognosis of resectable non-small cell lung cancer.

OBJECTIVES: Immune checkpoint blockades (ICB) have been proven to improve prognosis of non-small cell lung cancer in the neoadjuvant setting, while whether its perioperative use could bring extra benefit remained unidentified. We aimed to demonstrate the prognostic benefit of perioperative ICB over preoperative-only use and investigate who could benefit from this 'sandwich ICB therapy'. METHODS: Patients undergoing neoadjuvant therapy followed by surgery from 2018 to 2022 were retrospectively reviewed, and were divided into 4 groups based on the perioperative regimens: pre-ICB + post-computed tomography (CT), pre-ICB-only, pre-CT + post-ICB and pre-CT-only. Treatment-related adverse events, surgical outcomes, therapeutic response, recurrence-free survival and overall survival were compared. RESULTS: Of 214 enrolled patients with preoperative therapy, 108 underwent immunochemotherapy and 106 underwent platinum-based chemotherapy. Compared with preoperative chemotherapy, preoperative immunochemotherapy was demonstrated with significantly higher major pathologic response (57/108 vs 12/106) and pathologic complete response (35/108 vs 4/106) rates with comparable adverse events. Regarding survival, perioperative ICB significantly improved the recurrence-free survival [versus pre-CT-only hazard ratio (HR) 0.15; 95% CI 0.09-0.27; versus pre-ICB-only HR 0.36; 95% CI 0.15-0.88] and overall survival (versus pre-CT-only HR 0.24; 95% CI 0.08-0.68). In patients without major pathologic response, perioperative ICB was observed to decrease the risk of recurrence (HR 0.31; 95% CI 0.11-0.83) compared with preoperative ICB, and was an independent prognostic factor (P < 0.05) for recurrence-free survival. CONCLUSIONS: Perioperative ICB showed promising efficacy in improving pathological response and survival outcomes of resectable non-small cell lung cancer. For patients without major pathologic response after resection followed by preoperative ICB, sequential ICB treatment could be considered.

Pre- and intra-operative risk factors predict postoperative respiratory failure after minimally invasive oesophagectomy.

OBJECTIVES: Severe pulmonary complications such as postoperative respiratory failure can occur after minimally invasive oesophagectomy. However, the risk factors have not been well identified. The goal of this study was to develop a predictive model for the occurrence of postoperative respiratory failure with a large sample. METHODS: We collected data from patients with oesophageal cancer who had a minimally invasive oesophagectomy at Shanghai Chest Hospital from 2019 to 2022. Univariable and backward stepwise logistic regression analysis of 19 pre- and intra-operative factors was used before model fitting, and its performance was evaluated with the receiver operating characteristic curve. Internal validation was assessed with a calibration plot, decision curve analysis and area under the curve with 95% confidence intervals, obtained from 1000 resamples set by the bootstrap method. RESULTS: This study enrolled 2,386 patients, 57 (2.4%) of whom developed postoperative respiratory failure. Backward stepwise logistic regression analysis revealed that age, body mass index, cardiovascular disease, diabetes, diffusion capacity of the lungs for carbon monoxide, tumour location and duration of chest surgery ≥101.5 min were predictive factors. A predictive model was constructed and showed acceptable performance (area under the curve: 0.755). The internal validation with the bootstrap method proves the good agreement for prediction and reality. CONCLUSIONS: Obesity, severe diffusion dysfunction and upper segment oesophageal cancer were strong predictive factors. The established predictive model has acceptable predictive validity for postoperative respiratory failure after minimally invasive oesophagectomy, which may improve the identification of high-risk patients and enable health-care professionals to perform risk assessment for postoperative respiratory failure at the initial consultation.

Morphological entropy encodes cellular migration strategies on multiple length scales.

Cell migration is crucial for numerous physiological and pathological processes. A cell adapts its morphology, including the overall and nuclear morphology, in response to various cues in complex microenvironments, such as topotaxis and chemotaxis during migration. Thus, the dynamics of cellular morphology can encode migration strategies, from which diverse migration mechanisms can be inferred. However, deciphering the mechanisms behind cell migration encoded in morphology dynamics remains a challenging problem. Here, we present a powerful universal metric, the Cell Morphological Entropy (CME), developed by combining parametric morphological analysis with Shannon entropy. The utility of CME, which accurately quantifies the complex cellular morphology at multiple length scales through the deviation from a perfectly circular shape, is illustrated using a variety of normal and tumor cell lines in different in vitro microenvironments. Our results show how geometric constraints affect the MDA-MB-231 cell nucleus, the emerging interactions of MCF-10A cells migrating on collagen gel, and the critical transition from proliferation to invasion in tumor spheroids. The analysis demonstrates that the CME-based approach provides an effective and physically interpretable tool to measure morphology in real-time across multiple length scales. It provides deeper insight into cell migration and contributes to the understanding of different behavioral modes and collective cell motility in more complex microenvironments.

The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability.

R-loops are three-stranded structures that can pose threats to genome stability. RNase H1 precisely recognizes R-loops to drive their resolution within the genome, but the underlying mechanism is unclear. Here, we report that ARID1A recognizes R-loops with high affinity in an ATM-dependent manner. ARID1A recruits METTL3 and METTL14 to the R-loop, leading to the m6A methylation of R-loop RNA. This m6A modification facilitates the recruitment of RNase H1 to the R-loop, driving its resolution and promoting DNA end resection at DSBs, thereby ensuring genome stability. Depletion of ARID1A, METTL3, or METTL14 leads to R-loop accumulation and reduced cell survival upon exposure to cytotoxic agents. Therefore, ARID1A, METTL3, and METTL14 function in a coordinated, temporal order at DSB sites to recruit RNase H1 and to ensure efficient R-loop resolution. Given the association of high ARID1A levels with resistance to genotoxic therapies in patients, these findings open avenues for exploring potential therapeutic strategies for cancers with ARID1A abnormalities.

A cancer cell nanotherapy method based on GHz film bulk acoustic resonator and nanoscale CaO2.

Sonodynamic therapy (SDT) is an emerging cancer treatment method in recent years. However, the ultrasound signal utilized for SDT is usually located at a low-frequency spectrum (<2 MHz), and in the field of SDT research, few studies have focused on the exploration and development of ultrasound frequency. Studies have shown that the GHz-level ultrasound can increase cell membrane permeability and have a negligible effect on cell vitality. Herein, we reported the study of a GHz thin film bulk acoustic resonator as an ultrasound source for synergistic treatment with nanoscale calcium peroxide (CaO2). It was discovered that this ultrasound source ultimately achieved an efficient therapeutic outcome on mouse breast cancer cell line 4T1. Such GHz-level ultrasound application in SDT is of high significance to broaden the cognition and application scope of SDT.

Upconversion 3D Bioprinting for Noninvasive In Vivo Molding.

Tissue engineered bracket materials provide essential support for the physiological protection and therapeutics of patients. Unfortunately, the implantation process of such devices poses the risk of surgical complications and infection. In this study, an upconversion nanoparticles (UCNPs)-assisted 3D bioprinting approach is developed to realize in vivo molding that is free from invasive surgery. Reasonably designed UCNPs, which convert near-infrared (NIR) photons that penetrate skin tissues into blue-violet emission (300-500 nm), induce a monomer polymerization curing procedure in vivo. Using a fused deposition modeling coordination framework, a precisely predetermined trajectory of the NIR laser enables the manufacture of implantable medical devices with tailored shapes. A proof of the 3D bioprinting of a noninvasive fracture fixation scaffold is achieved successfully, thus demonstrating an entirely new method of in vivo molding for biomedical treatment.

Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study.

OBJECTIVE: This study aims to report the 2-year outcomes of patients with clinical stage N2-3 esophageal squamous cell carcinoma who received neoadjuvant chemotherapy and immunotherapy followed by surgery from a phase 2 NICE trial. METHODS: Eligible patients with clinical stage N2-3 esophageal squamous cell carcinoma were screened and enrolled, then treated with regimen of nab-paclitaxel (100 mg/m2, days 1, 8, 15), carboplatin (area under the curve = 5, day 1), camrelizumab (200 mg, day 1) of two 21-day cycles and esophagectomy 4 to 6 weeks after the last chemotherapy. Oncologic outcomes, recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) were explored. RESULTS: From November 20, 2019, to December 22, 2020, 60 patients were recruited. After a median follow-up of 27.4 months, disease recurrence was observed in 19 (37.3%) patients, with 5 (9.8%) locoregional recurrence, 9 (17.6%) distant metastasis, and 5 (9.8%) combined recurrence. Lung was the most commonly involved metastatic site. The median time to recurrence was 10.8 months (interquartile range, 7.5-12.7 months). The 2-year OS and RFS rates were 78.1% and 67.9%, respectively. Patients who achieved major pathologic response (MPR) had a significantly greater 2-year OS rate (91.4% vs 47.7%; P < .001) and RFS rate (77.1% vs 45.9%; P = .003). On multivariable analysis, MPR was indicated as an independent prognostic factor for disease recurrence (hazard ratio, 0.39; 95% confidence interval, 0.21-0.82; P = .029). CONCLUSIONS: In patients receiving neoadjuvant chemotherapy and immunotherapy, distant metastasis remains the predominant recurrence pattern. MPR is associated with lower recurrence and better survival. Long-term results derived from randomized controlled trials are further required. TRIAL REGISTRATION NUMBER: ChiCTR1900026240.

Ga-Doped Ultrahigh-Nickel Oxide Microspheres with Radially Aligned Primary Grains as a Cathode for Stable Cycling Li-Ion Batteries.

Owing to the high energy density, ultrahigh-nickel (Ni > 0.9) layered oxides are used as promising cathode materials for next-generation Li-ion batteries. Unfortunately, the serious pulverization and rapid capacity fading during cycling limit the commercial viability of an ultrahigh-nickel oxide cathode. Herein, the introduction of Ga into LiNi0.96Co0.04O2 brings a radially aligned microstructural change of oxide microspheres during the lithiation of the Ni0.96Co0.04(OH)2 precursor. As expected, such radially aligned needle-like primary grains on microspheres have a positive influence to reduce the anisotropic volume change and suppress the formation of microcracks of Ga-induced Li(Ni0.96Co0.04)0.99Ga0.01O2 during cycling. Specifically, compared with irregular primary grains of LiNi0.96Co0.04O2, Ga-induced oxide presents a high initial discharge capacity of 227.9 mA h g-1 at 0.1C rate between 2.8 and 4.3 V. Especially, Ga-induced oxide delivers higher initial discharge capacities of 233.9 and 240.3 mA h g-1 with higher cutoff charge voltages of 4.4 and 4.5 V at 0.1C, respectively. Furthermore, a good capacity retention of 74.1% at 1 C rate is obtained after 300 cycles, which is almost 85% higher than that of the pristine sample, mainly due to the generation of microcracks of oxide microspheres during the long-term cycle. Therefore, the introduction of Ga into LiNi0.96Co0.04O2 is a feasible approach for improving the microstructure and cycling stability of the ultrahigh-Ni layered oxides.

Prognostic Value of Combination of Lymphocyte-to-Monocyte-Ratio and CYFRA 21-1 in Esophageal Squamous Cell Carcinoma.

BACKGROUND: This study aimed to investigate the potential of a combined score based on CYFRA 21-1 level and LMR as a prognostic predictor for patients with ESCC. METHODS: A total of 460 patients who underwent esophagectomy were analyzed, and three groups were established based on the CA-LMR score. OS and RFS were evaluated using the Kaplan-Meier analysis, and associated factors were analyzed by univariate and multivariate Cox analysis. A mpStage system was also established based on the CA-LMR score. RESULTS: The allocation of CA-LMR score of 0, 1, and 2 was 107 (23.3%), 280 (60.9%), and 73 (15.9%). There was a significant association between CA-LMR and male gender (P = 0.001), lower BMI (P = 0.035), longer tumor lesions (P = 0.002), and high pT, pN, pStage (P < 0.001, P = 0.011, P = 0.001). The 5-year OS rates for CA-LMR scores of 0, 1, and 2 were 75.4%, 60.2%, and 32.8%, respectively (P < 0.001). Multivariate analysis showed that CA-LMR score (P = 0.011) was an independent prognostic factor for OS. The proposed mpStage system, based on CA-LMR score, demonstrated superior discriminatory ability, monotonicity, homogeneity, and prognosis prediction ability over AJCC 8th pStage system. CONCLUSIONS: The CA-LMR score, combined with tumor marker and inflammatory index, could use as a potential prognostic indicator; moreover, our modified pStage system exhibited superior stratification and prognostic accuracy for patients with ESCC.

KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer.

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer, but its function and regulatory network in metastasis remain unclear. A comprehensive investigation of key regulators in cancer metastasis is urgently needed. Transcriptome sequencing (RNA-seq) of primary esophageal squamous cell carcinoma (ESCC) and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4 (KCTD4) as a driver of cancer metastasis. KCTD4 expression was found upregulated in metastatic ESCC. High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo. Mechanistically, KCTD4 binds to CLIC1 and disrupts its dimerization, thus increasing intracellular Ca2+ level to enhance NFATc1-dependent fibronectin transcription. KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner, which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback. Furthermore, a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4‒CLIC1 interaction, providing a potential therapeutic strategy. Taken together, our study not only uncovers KCTD4 as a regulator of calcium homeostasis, but also reveals KCTD4/CLIC1-Ca2+-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis. These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.

Progenitor-like exhausted SPRY1+CD8+ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma.

Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8+ T cells expressing SPRY1 (CD8+ Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8+ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8+ T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8+ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8+ T cell effector functions. Overall, our findings unravel progenitor-like CD8+ Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.

DICTrank: The largest reference list of 1318 human drugs ranked by risk of drug-induced cardiotoxicity using FDA labeling.

Drug-induced cardiotoxicity (DICT) is a leading cause of drug trial failure and discontinuation. Current drug annotations for cardiotoxicity largely focus on individual outcomes or mechanisms. Considering the broad spectrum of adverse cardiac events, we developed Drug-Induced Cardiotoxicity Rank (DICTrank) using FDA labeling and comprehensively classified 1318 human drugs into four categories: Most-DICT-Concern (n = 341), Less-DICT-Concern (n = 528), No-DICT-Concern (n = 343), and Ambiguous-DICT-Concern (n = 106). Notably, DICTrank covers diverse therapeutic categories, of which several were enriched with Most-DICT-Concern drugs, such as antineoplastic agents, sex hormones, anti-inflammatory drugs, beta-blockers, and cardiac therapy. DICTrank currently presents the largest drug list of DICT annotation, and it could contribute to the development of new approach methods, including AI models for early identification of DICT risk during drug development and beyond.

The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets.

Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment.