Novel Carbon Quantum Dots Precisely Trigger Ferroptosis in Cancer Cells through Antioxidant Inhibition Synergistic Nanocatalytic Activity.

High levels of glutathione (GSH) are an important characteristic of malignant tumors and a significant cause of ineffective treatment and multidrug resistance. Although reactive oxygen species (ROS) therapy has been shown to induce tumor cell death, the strong clearance effect of GSH on ROS significantly reduces its therapeutic efficacy. Therefore, there is a need to develop new strategies for targeting GSH. In this study, novel carbon quantum dots derived from gentamycin (GM-CQDs) were designed and synthesized. On the basis of the results obtained, GM-CQDs contain sp2 and sp3 carbon atoms as well as nitrogen oxygen groups, which decrease the intracellular levels of GSH by downregulating SLC7A11, thereby disrupting redox balance, mediating lipid peroxidation, and inducing ferroptosis. Transcriptome analysis demonstrated that GM-CQDs downregulated the expression of molecules related to GSH metabolism while significantly increasing the expression of molecules related to ferroptosis. The in vivo results showed that the GM-CQDs exhibited excellent antitumor activity and immune activation ability. Furthermore, because of their ideal biological safety, GM-CQDs are highly promising for application as drugs targeting GSH in the treatment of malignant tumors.

Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma.

BACKGROUND: A substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown. METHODS: Transcriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation. RESULTS: Members of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2. An immunosuppressive microenvironment featured by high infiltrates of Tregs and cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed. CONCLUSIONS: Our study revealed that elevated PHLDA2 expression regulated by DNA hypomethylation was correlated with poor prognosis and immunosuppressive microenvironment, and highlighted the role of PHLDA2 as a robust biomarker for predicting therapeutic efficacy of ICI plus anti-angiogenic agent combination therapy in ccRCC, which expand the dimension of precision medicine.

Genomic and transcriptomic profiling of inflammatory breast cancer reveals distinct molecular characteristics to non-inflammatory breast cancers.

PURPOSE: Inflammatory breast cancer (IBC), a rare and highly aggressive form of breast cancer, accounts for 10% of breast cancer-related deaths. Previous omics studies of IBC have focused solely on one of genomics or transcriptomics and did not discover common differences that could distinguish IBC from non-IBC. METHODS: Seventeen IBC patients and five non-IBC patients as well as additional thirty-three Asian breast cancer samples from TCGA-BRCA were included for the study. We performed whole-exon sequencing (WES) to investigate different somatic genomic alterations, copy number variants, and large structural variants between IBC and non-IBC. Bulk RNA sequencing (RNA-seq) was performed to examine the differentially expressed genes, pathway enrichment, and gene fusions. WES and RNA-seq data were further investigated in combination to discover genes that were dysregulated in both genomics and transcriptomics. RESULTS: Copy number variation analysis identified 10 cytobands that showed higher frequency in IBC. Structural variation analysis showed more frequent deletions in IBC. Pathway enrichment and immune infiltration analysis indicated increased immune activation in IBC samples. Gene fusions including CTSC-RAB38 were found to be more common in IBC. We demonstrated more commonly dysregulated RAS pathway in IBC according to both WES and RNA-seq. Inhibitors targeting RAS signaling and its downstream pathways were predicted to possess promising effects in IBC treatment. CONCLUSION: We discovered differences unique in Asian women that could potentially explain IBC etiology and presented RAS signaling pathway as a potential therapeutic target in IBC treatment.

Osteogenic mechanism of chlorogenic acid and its application in clinical practice.

Natural polyphenols may have a role in counteracting oxidative stress, which is associated with aging and several bone-related diseases. Chlorogenic acid (CGA) is a naturally occurring polyphenolic compound formed by the esterification of caffeic and quininic acids with osteogenic, antioxidant, and anti-inflammatory properties. This review discusses the potential of CGA to enhance osteogenesis by increasing the osteogenic capacity of mesenchymal stem cells (MSCs), osteoblast survival, proliferation, differentiation, and mineralization, as well as its ability to attenuate osteoclastogenesis by enhancing osteoclast apoptosis and impeding osteoclast regeneration. CGA can be involved in bone remodeling by acting directly on pro-osteoclasts/osteoblasts or indirectly on osteoclasts by activating the nuclear factor kB (RANK)/RANK ligand (RANKL)/acting osteoprotegerin (OPG) system. Finally, we provide perspectives for using CGA to treat bone diseases.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

NK-92 cells labeled with Fe3O4-PEG-CD56/Avastin@Ce6 nanoprobes for the targeted treatment and noninvasive therapeutic evaluation of breast cancer.

Adoptive cellular immunotherapy as a promising and alternative cancer therapy platform is critical for future clinical applications. Natural killer (NK) cells have attracted attention as an important type of innate immune regulatory cells that can rapidly kill multiple adjacent cancer cells. However, these cells are significantly less effective in treating solid tumors than in treating hematological tumors. Herein, we report the synthesis of a Fe3O4-PEG-CD56/Avastin@Ce6 nanoprobe labeled with NK-92 cells that can be used for adoptive cellular immunotherapy, photodynamic therapy and dual-modality imaging-based in vivo fate tracking. The labeled NK-92 cells specifically target the tumor cells, which increases the amount of cancer cell apoptosis in vitro. Furthermore, the in vivo results indicate that the labeled NK-92 cells can be used for tumor magnetic resonance imaging and fluorescence imaging, adoptive cellular immunotherapy, and photodynamic therapy after tail vein injection. These data show that the developed multifunctional nanostructure is a promising platform for efficient innate immunotherapy, photodynamic treatment and noninvasive therapeutic evaluation of breast cancer.

Distinct neural activities of the cortical layer 2/3 across isoflurane anesthesia: A large-scale simultaneous observation of neurons.

Anesthesia inhibits neural activity in the brain, causing patients to lose consciousness and sensation during the surgery. Layers 2/3 of the cortex are important structures for the integration of information and consciousness, which are closely related to normal cognitive function. However, the dynamics of the large-scale population of neurons across multiple regions in layer 2/3 during anesthesia and recovery processes remains unclear. We conducted simultaneous observations and analysis of large-scale calcium signaling dynamics across multiple cortical regions within cortical layer 2/3 during isoflurane anesthesia and recovery in vivo by high-resolution wide-field microscopy. Under isoflurane-induced anesthesia, there is an overall decrease in neuronal activity across multiple regions in the cortical layer 2/3. Notably, some neurons display a paradoxical increase in activity during anesthesia. Additionally, the activity among multiple cortical regions under anesthesia was homogeneous. It is only during the recovery phase that variability emerges in the extent of increased neural activity across different cortical regions. Within the same duration of anesthesia, neural activity did not return to preanesthetic levels. To sum up, anesthesia as a dynamic alteration of brain functional networks, encompassing shifts in patterns of neural activity, homogeneousness among cortical neurons and regions, and changes in functional connectivity. Recovery from anesthesia does not entail a reversal of these effects within the same timeframe.

Development and validation of a nomogram to predict postoperative delirium in older patients after major abdominal surgery: a retrospective case-control study.

BACKGROUND: Postoperative delirium is a common complication in older patients, with poor long-term outcomes. This study aimed to investigate risk factors and develop a predictive model for postoperative delirium in older patients after major abdominal surgery. METHODS: This study retrospectively recruited 7577 patients aged ≥ 65 years who underwent major abdominal surgery between January 2014 and December 2018 in a single hospital in Beijing, China. Patients were divided into a training cohort (n = 5303) and a validation cohort (n = 2224) for univariate and multivariate logistic regression analyses and to build a nomogram. Data were collected for 43 perioperative variables, including demographics, medical history, preoperative laboratory results, imaging, and anesthesia information. RESULTS: Age, chronic obstructive pulmonary disease, white blood cell count, glucose, total protein, creatinine, emergency surgery, and anesthesia time were associated with postoperative delirium in multivariate analysis. We developed a nomogram based on the above 8 variables. The nomogram achieved areas under the curve of 0.731 and 0.735 for the training and validation cohorts, respectively. The discriminatory ability of the nomogram was further assessed by dividing the cases into three risk groups (low-risk, nomogram score < 175; medium-risk, nomogram score 175~199; high-risk, nomogram score > 199; P < 0.001). Decision curve analysis revealed that the nomogram provided a good net clinical benefit. CONCLUSIONS: We developed a nomogram that could predict postoperative delirium with high accuracy and stability in older patients after major abdominal surgery.

A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer characterized by rapidly arising diffuse erythema and edema. Genomic studies have not identified consistent alterations and mechanisms that differentiate IBC from non-IBC tumors, suggesting that the microenvironment could be a potential driver of IBC phenotypes. Here, using single-cell RNA sequencing, multiplex staining, and serum analysis in patients with IBC, we identified enrichment of a subgroup of luminal progenitor (LP) cells containing high expression of the neurotropic cytokine pleiotrophin (PTN) in IBC tumors. PTN secreted by the LP cells promoted angiogenesis by directly interacting with the NRP1 receptor on endothelial tip cells located in both IBC tumors and the affected skin. NRP1 activation in tip cells led to recruitment of immature perivascular cells in the affected skin of IBC, which are correlated with increased angiogenesis and IBC metastasis. Together, these findings reveal a role for cross-talk between LPs, endothelial tip cells, and immature perivascular cells via PTN-NRP1 axis in the pathogenesis of IBC, which could lead to improved strategies for treating IBC. SIGNIFICANCE: Nonmalignant luminal progenitor cells expressing pleiotrophin promote angiogenesis by activating NRP1 and induce a prometastatic tumor microenvironment in inflammatory breast cancer, providing potential therapeutic targets for this aggressive breast cancer subtype.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

MR-guided percutaneous microwave coagulation of small breast tumors.

BACKGROUND: To evaluate the technical success and patient safety of magnetic resonance-guided percutaneous microwave coagulation (MR-guided PMC) for breast malignancies. METHODS: From May 2018 to December 2019, 26 patients with breast tumors measuring 2 cm or less were recruited to participate in a prospective, single-institution clinical study. The primary endpoint of this study was the evaluation of treatment efficacy for each patient. Histochemical staining with α-nicotinamide adenine dinucleotide and reduced (NADH)-diaphorase was used to determine cell viability following and efficacy of PMC. The complications and self-reported sensations from all patients during and after ablation were also assessed. The technical success of the PMC procedure was defined when the area of the NADH-diaphorase negative region fully covered the hematoxylin-eosin (H&E) staining region in the tumor. RESULTS: All patients had a complete response to ablation with no residual carcinoma on histopathological specimen. The mean energy, ablation duration, and procedure duration per tumor were 36.0 ± 4.2 kJ, 252.9 ± 30.9 S, and 104.2 ± 13.5 min, respectively. During the ablation, 14 patients underwent prolonged ablation time, and 1 patient required adjusting of the antenna position. Eleven patients had feelings of subtle heat or swelling, and 3 patients experienced slight pain. After ablation, one patient took two painkillers because of moderate pain, and no patients had postoperative oozing or other complications after PMC. Induration around the ablation area appeared in 16 patients. CONCLUSION: MR-guided PMC of small breast tumors is feasible and could be applied in clinical practice in the future. CRITICAL RELEVANCE STATEMENT: MR-guided PMC of small breast tumors is feasible and could be applied in clinical practice in the future. KEY POINTS: • MR-guided PMC of small breast tumors is feasible. • PMC was successfully performed for all patients. • All patients were satisfied with the final cosmetic result.

Familial pulmonary cysts: A clue to diagnose Birt-Hogg-Dubé syndrome: A case report and literature review.

Birt-Hogg-Dubé syndrome (BHD) is an inherited autosomal dominant condition caused by germline mutations in the FLCN gene, mapped to chromosome 17p11.2. Typical manifestations include pulmonary cysts, spontaneous pneumothorax, fibrofolliculomas, and kidney neoplasms. This report details the case of a 56-year-old female non-smoker diagnosed with multiple pulmonary cysts, presenting with a history of recurrent spontaneous pneumothorax. A computed tomography (CT) scan of her daughter revealed similar pulmonary cysts, raising suspicion of BHD. Further abdominal enhanced CT revealed a left renal tumour and cutaneous fibrofolliculomas on her daughter's neck. Consequently, whole-exome sequencing confirmed an FLCN germline mutation in the patient and three relatives, establishing a diagnosis of BHD. This case highlights the importance of familial pulmonary cysts as a clue for diagnosing BHD, providing crucial insights into comparable clinical presentations.

Developing and Validating an Intelligent Mouth-Opening Training Device: A New Solution for Restricted Mouth Opening.

Restricted mouth opening (trismus) is one of the most common complications following head and neck cancer treatment. Early initiation of mouth-opening exercises is crucial for preventing or minimizing trismus. Current methods for these exercises predominantly involve finger exercises and traditional mouth-opening training devices. Our research group successfully designed an intelligent mouth-opening training device (IMOTD) that addresses the limitations of traditional home training methods, including the inability to quantify mouth-opening exercises, a lack of guided training resulting in temporomandibular joint injuries, and poor training continuity leading to poor training effect. For this device, an interactive remote guidance mode is introduced to address these concerns. The device was designed with a focus on the safety and effectiveness of medical devices. The accuracy of the training data was verified through piezoelectric sensor calibration. Through mechanical analysis, the stress points of the structure were identified, and finite element analysis of the connecting rod and the occlusal plate connection structure was conducted to ensure the safety of the device. The findings support the effectiveness of the intelligent device in rehabilitation through preclinical experiments when compared with conventional mouth-opening training methods. This intelligent device facilitates the quantification and visualization of mouth-opening training indicators, ensuring both the comfort and safety of the training process. Additionally, it enables remote supervision and guidance for patient training, thereby enhancing patient compliance and ultimately ensuring the effectiveness of mouth-opening exercises.

Promoting Diabetic Wound Healing through a Hydrogel-Based Cascade Regulation Strategy of Fibroblast-Macrophage.

The management of diabetic wounds (DWs) continues to pose a significant challenge in the field of medicine. DWs are primarily prevented from healing due to damage to macrophage efferocytosis and fibroblast dysfunction. Consequently, a treatment strategy that involves both immunoregulation and the promotion of extracellular matrix (ECM) formation holds promise for healing DWs. Nevertheless, existing treatment methods necessitate complex interventions and are associated with increased costs, for example, the use of cytokines and cell therapy, both of which have limited effectiveness. In this study, a new type of ruthenium (IV) oxide nanoparticles (RNPs)-laden hybrid hydrogel dressing with a double network of Pluronic F127 and F68 has been developed. Notably, the hybrid hydrogel demonstrates remarkable thermosensitivity, injectability, immunoregulatory characteristics, and healing capability. RNPs in hydrogel effectively regulate both fibroblasts and macrophages in a cascade manner, stimulating fibroblast differentiation while synergistically enhancing the efferocytosis of macrophage. The immunoregulatory character of the hydrogel aids in restoring the intrinsic stability of the immune microenvironment in the wound and facilitates essential remodeling of the ECM. This hydrogel therefore offers a novel approach for treating DWs through intercellular communication.

Long noncoding RNA H19: functions and mechanisms in regulating programmed cell death in cancer.

Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs with transcript lengths of >200 nucleotides. Mounting evidence suggests that lncRNAs are closely associated with tumorigenesis. LncRNA H19 (H19) was the first lncRNA to function as an oncogene in many malignant tumors. Apart from the established role of H19 in promoting cell growth, proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and metastasis, it has been recently discovered that H19 also inhibits programmed cell death (PCD) of cancer cells. In this review, we summarize the mechanisms by which H19 regulates PCD in cancer cells through various signaling pathways, molecular mechanisms, and epigenetic modifications. H19 regulates PCD through the Wnt/ß-catenin pathway and the PI3K-Akt-mTOR pathway. It also acts as a competitive endogenous RNA (ceRNA) in PCD regulation. The interaction between H19 and RNA-binding proteins (RBP) regulates apoptosis in cancer. Moreover, epigenetic modifications, including DNA and RNA methylation and histone modifications, are also involved in H19-associated PCD regulation. In conclusion, we summarize the role of H19 signaling via PCD in cancer chemoresistance, highlighting the promising research significance of H19 as a therapeutic target. We hope that our study will contribute to a broader understanding of H19 in cancer development and treatment.

Chrysin alleviates DNA damage to improve disturbed immune homeostasis and pro-angiogenic environment in laser-induced choroidal neovascularization.

Choroidal neovascularization (CNV) is a devastating pathology of numerous ocular diseases, such as wet age-related macular degeneration (wAMD), which causes irreversible vision loss. Although anti-vascular endothelial growth factor (VEGF) therapy has been widely used, poor response or no response still exists in some cases, suggesting that there are other components involved in the angiogenic process. Therefore, the underlying mechanism needs to be clarified and new target of anti-angiogenic therapy is urgently needed. It has been demonstrated that damaged retinal pigment epithelium (RPE) cells can activate inflammasome, driving a degenerative tissue environment and an enhanced pro-angiogenic response, which implies that RPE dysfunction may be a hallmark of the pathogenesis. Previously, we have shown that DNA damage can induce RPE dysfunction, triggering senescence-associated secretory phenotype (SASP) and local inflammation. In this study, we identify that chrysin can reduce DNA damage, especially telomere erosion in vitro, thus compromise the dysfunction of RPE and the decreased expression of SASP factor. Importantly, we find that DNA damage of RPE cells is remarkable in laser-induced CNV lesion, resulting in inflammatory response, which can be ameliorated by chrysin, mainly through IL-17 signaling pathway and its downstream signal transducer and activator of transcription 3 (STAT3) activities. In summary, our results indicate the interplay between DNA damage, perturbed RPE homeostasis, inflammatory response and angiogenesis in laser-induced CNV, and more importantly, chrysin may be an effective therapeutic supplement for CNV.

Differential Effects of Endurance Exercise on Musculoskeletal and Hematopoietic Modulation in Old Mice.

One of the most important strategies for successful aging is exercise. However, the effect of exercise can differ among individuals, even with exercise of the same type and intensity. Therefore, this study aims to confirm whether endurance training (ETR) has the same health-promoting effects on the musculoskeletal and hematopoietic systems regardless of age. Ten weeks of ETR improved endurance exercise capacity, with increased skeletal muscle mitochondrial enzymes in both young and old mice. In addition, age-related deterioration of muscle fiber size and bone microstructure was improved. The expression levels of myostatin, muscle RING-finger protein-1, and muscle atrophy F-box in skeletal muscle and peroxisome proliferator-activated receptor-γ in the femur increased with age but decreased after ETR. ETR differentially modulated hematopoietic stem cells (HSCs) depending on age; ETR induced HSC quiescence in young mice but caused HSC senescence in old mice. ETR has differential effects on modulation of the musculoskeletal and hematopoietic systems in old mice. In other words, endurance exercise is a double-edged sword for successful aging, and great effort is required to establish exercise strategies for healthy aging.

Endoscopic submucosal dissection of endobronchial leiomyoma with a hybrid knife in an adolescent patient: a case report.

Endobronchial leiomyomas are uncommon benign tracheobronchial tumors. Bronchoscopic intervention is a safe and effective strategy for patients with contraindications for surgery or refusal to undergo surgery. Endoscopic submucosal dissection (ESD) is widely used to treat early gastrointestinal tumors. The novel hybrid knife is useful during ESD owing to functions of submucosal injections, lesion dissection and hemostasis, and makes ESD more convenient. Here, we report a case of a benign leiomyoma at the orifice of RB7 in an adolescent boy. The diagnosis was confirmed based on bronchoscopic and pathological findings. The patient was successfully treated with combined electrocautery snare and cryoresection, ESD using a hybrid knife and the wound was managed with argon plasma coagulation. The postoperative course was satisfactory, with a good general condition and no severe respiratory symptoms. This is, to our knowledge, the first reported case of ESD using a hybrid knife to treat an endobronchial leiomyoma in an adolescent patient.

Mannose-doped metal-organic frameworks induce tumor cell pyroptosis via the PERK pathway.

BACKGROUND: The implementation of pyroptosis exhibits significant potential as a tactic to enhance tumor immune microenvironments. Previous applications of pyroptosis inducers have encountered various limitations, such as the development of drug resistance, manifestation of toxic side effects, and a deficiency in targeting capabilities. As a result, there is a growing demand for tumor therapeutic molecules that can overcome these obstacles. Therefore, the objective of this study is to develop a multifunctional nanospheres that addresses these challenges by enabling high-precision targeting of tumor cells and inducing effective pyroptosis. RESULTS: We prepared a mannose-modified MOF called mannose-doped Fe3O4@NH2-MIL-100 (M-FNM). M-FNM could enter CAL27 cells through MR-mediated endocytosis, which caused in a significant increase in the level of intracellular ROS. This increase subsequently triggered ER stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway. CHOP then mediated the downstream cascade of Caspase-1, inducing pyroptosis. In in vivo experiments, M-FNM demonstrated excellent targeting ability and exhibited anti-tumor effects. Additionally, M-FNM reshaped the immune microenvironment by promoting the infiltration of anti-tumor immune cells, primarily T lymphocytes. CONCLUSIONS: M-FNM significantly decreased tumor growth. This novel approach to induce pyroptosis in tumor cells using M-FNM may offer new avenues for the development of effective immunotherapies against cancer.

The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response.

BACKGROUND: The mutational pattern of homologous recombination repair (HRR)-associated gene alterations in Chinese urothelial carcinoma (UC) necessitates comprehensive sequencing efforts, and the clinical implications of HRR gene mutations in UC remain to be elucidated. MATERIALS AND METHODS: We delineated the mutational landscape of 343 Chinese UC patients from West China Hospital and 822 patients from The Cancer Genome Atlas (TCGA) using next-generation sequencing (NGS). Data from 182 metastatic UC patients from MSK-IMPACT cohort were used to assess the association between HRR mutations and immunotherapy efficacy. Comprehensive transcriptomic analysis was performed to explore the impact of HRR mutations on tumor immune microenvironment. RESULTS: Among Chinese UC patients, 34% harbored HRR gene mutations, with BRCA2, ATM, BRCA1, CDK12, and RAD51C being the most prevalently mutated genes. Mutational signatures contributing to UC differed between patients with and without HRR mutations. Signature 22 for exposure to aristolochic acid was only observed in Chinese UC patients. The presence of HRR mutations was correlated with higher tumor mutational burden, neoantigen burden, and PD-L1 expression. Importantly, patients with HRR mutations exhibited significantly improved prognosis following immunotherapy compared to those without HRR mutations. CONCLUSIONS: Our findings provide valuable insights into the genomic landscape of Chinese UC patients and underscore the molecular rationale for utilizing immunotherapy in UC patients with HRR mutations.