A novel technique of percutaneous transhepatic treatment of biliary-enteric anastomotic occlusive strictures with compliant balloon-occluded distal cholangiography and large-bore catheter: a retrospective case series.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary balloon dilatation (PTBD) is a challenge in resolving biliary-enteric anastomotic occlusive strictures (BEAOS) and/or coexisting stones. The biliary-enteric anastomosis (BEA) often cannot be seen because of the surgically altered gastrointestinal anatomy. Here, a technique that combined percutaneous compliant-occluded distal cholangiography and the maintenance of a large-bore catheter is described to resolve this issue. Methods: A retrospective review of 10 patients who presented with BEAOS with/without coexisting stones who were treated with percutaneous compliant balloon-occluded distal cholangiography, bile duct stone removal, and the maintenance of a large-bore catheter between February 2017 and January 2021 was performed. Treatment response, laboratory examinations, including hepatic function tests, routine blood tests, and blood electrolytes, complications, and imaging data were evaluated. Paired t-tests were used to investigate the difference of laboratory examinations before and after the procedure. Results: All 10 cases were technically successful. A total of 9 stones in 6 patients were successfully removed by the compliant balloon. All catheters were removed after the patency of the stricture was confirmed by percutaneous transhepatic cholangiography (PTHC) 6 months later. No severe adverse events occurred during the perioperative period. There were 2 patients who experienced episodes of cholangitis during the follow-up period (mean, 17 months; range, 4-24 months), and neither BEAOS nor bile duct stones recurred within 2 years after the procedure. White blood cells (WBC), total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were (6.0±1.4)×109/L and (6.0±1.6)×109/L (P=0.91), 31.4±15.7 and 29.6±10.3 µmol/L (P=0.74), 50.8±20.0 and 85.8±67.0 U/L (P=0.16), and 42.6±15.2 and 71.8±44.9 U/L (P=0.09) pre and postintervention, respectively. Conclusions: Percutaneous transhepatic compliant balloon-occluded distal cholangiography and the maintenance of a large-bore catheter probably provide an effective and safe alternative method for resolving BEAOS and/or coexisting stones.

Efficacy and safety of pyrotinib combined with albumin-bound paclitaxel as first-line treatment for HER2-positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single-arm, phase 2 prospective clinical trial.

OBJECTIVE: It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. METHODS: Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. RESULTS: From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. CONCLUSIONS: This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. RESULTS: In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3-61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8+/CD4+ ratio on day 14 indicated a longer OS (p = 0.010). CONCLUSIONS: Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. TRIAL REGISTRATION: NCT04766320, Jan 04, 2021.

Hypomethylation-enhanced CRTC2 expression drives malignant phenotypes and primary resistance to immunotherapy in hepatocellular carcinoma.

The cyclic AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a crucial regulator of hepatic lipid metabolism and gluconeogenesis and correlates with tumorigenesis. However, the mechanism through which CRTC2 regulates hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that increased CRTC2 expression predicted advanced tumor grade and stage, as well as worse prognosis in patients with HCC. DNA promoter hypomethylation led to higher CRTC2 expression in HCC. Functionally, CRTC2 contributed to HCC malignant phenotypes through the activated Wnt/ß-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939. Moreover, Crtc2 facilitated tumor growth while concurrently downregulating the PD-L1/PD-1 axis, resulting in primary resistance to immunotherapy. In immunocompetent mice models of HCC, targeting Crtc2 in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting CRTC2 might be a promising therapeutic strategy to sensitize immunotherapy in HCC.

Cisplatin-activated and hemoglobin-mediated injectable hydrogel system for antitumor chemodynamic and chemotherapy.

Low specificity and hypoxia-induced drug resistance are significant challenges in traditional cancer treatment. To enhance the anticancer efficacy, an injectable hydrogel system is developed through the formation of dynamic covalent bonds in hyaluronic acid, allowing for localized controlled release of drugs. This system also utilizes double-stranded DNA sequences for the intercalation delivery of the chemotherapeutic drug, enabling a multifaceted approach to therapy. Cisplatin not only serves as a chemotherapy drug but also acts as a catalyst for chemodynamic therapy (CDT) to initiate CDT cascades by creating hydrogen peroxide for the Fenton reaction. Hemoglobin, enclosed in PLGA nanoparticles, provides ferrous ions that react with hydrogen peroxide in an acidic environment, yielding hydroxyl radicals that induce cancer cell death. Additionally, oxygen released from hemoglobin mitigates hypoxia-induced chemoresistance, bolstering overall anticancer efficacy. Results demonstrate the shear-thinning properties and injectability of the hydrogel. Cisplatin elevates intracellular hydrogen peroxide levels in tumor cells, while hemoglobin efficiently releases ferrous ions and generates reactive oxygen species (ROS) in the presence of hydrogen peroxide. In in vitro and in vivo study, the combinational use of chemo- and chemodynamic therapies achieves a synergistic anticancer effect on combating glioblastoma. In summary, our CDT-based hydrogel, activated by endogenous cues and mediated by chemo drugs, spontaneously produces ROS and ameliorates the adverse tumor microenvironment with rational and selective antitumor strategies.

Contrast-enhanced Imaging in Peripheral Pulmonary Lesions: The Role in US-guided Biopsies.

Purpose To compare the tissue adequacy and diagnostic accuracy of US-guided biopsies of peripheral pulmonary lesions (PPLs) with and without contrast agents. Materials and Methods A retrospective study was conducted at four medical centers in patients with PPLs who underwent US-guided percutaneous transthoracic needle biopsy (PTNB) between January 2017 and October 2022. The patients were divided into contrast-enhanced US (CEUS) and US groups based on whether prebiopsy CEUS evaluation was performed. Tissue adequacy and the diagnostic accuracy of PTNB, stratified by lesion size, were analyzed and compared between groups. A propensity score matching (PSM) analysis was conducted using the nearest-neighbor matching method. Results A total of 1027 lesions were analyzed, with 634 patients (mean age, 59.4 years ± 13.0 [SD]; 413 male) in the US group and 393 patients (mean age, 61.2 years ± 12.5; 270 male) in the CEUS group. The CEUS group produced more acceptable samples than the US group (98.2% vs 95.7%; P = .03) and achieved higher diagnostic accuracy (96.9% vs 94.2%; P = .04), with no evidence of a difference in sensitivity (96.7% vs 94.0%; P = .06). PSM and stratified analyses (n = 358 per group) indicated higher tissue adequacy (99.0% vs 95.7%; P = .04) and diagnostic accuracy (98.5% vs 92.9%; P = .006) in the CEUS group compared with the US group for 2-7-cm PPLs but not for lesions larger than 7 cm. Conclusion PTNB with prebiopsy CEUS evaluation demonstrated significantly better tissue adequacy and diagnostic accuracy compared with US guidance alone for PPLs ranging from 2 to 7 cm, with similar biopsy performance achieved between groups for lesions larger than 7 cm. Keywords: Contrast Material, Thoracic Diseases, Ultrasonography, Image-Guided Biopsy © RSNA, 2024.

(±)-hypermonanones A-G, seven pairs of monoterpenoid polyprenylated acylphloroglucinol enantiomers from Hypericum monanthemum.

Seven pairs of undescribed monoterpenoid polyprenylated acylphloroglucinol enantiomers [(±)-hypermonanones A-G (1-7)], together with three known analogues, were identified from the whole plant of Hypericum monanthemum Hook. The structures of these compounds were determined by analyses of their UV, HRESIMS, 1D/2D NMR spectroscopic data, and NMR calculations. The absolute configurations of these compounds were assigned by ECD calculations after chiral HPLC separation. Diverse monoterpene moieties were fused at C-3/C-4 of the dearomatized acylphloroglucinol core, which led to 3,4-dihydro-2H-pyran-integrated angular or linear type 6/6/6 tricyclic skeletons in 1-7. Compounds (-)-2 and (+)-2 exhibited significant NO inhibitory activity against LPS induced RAW264.7 cells with the IC50 values of 7.07 ± 1.02 µM and 11.39 ± 0.24 µM, respectively.

Crosstalk between cancer cells and macrophages promotes OSCC cell migration and invasion through a CXCL1/EGF positive feedback loop.

BACKGROUND: C-X-C motif chemokine ligand 1 (CXCL1) and epithelial growth factor (EGF) are highly secreted by oral squamous cell carcinoma (OSCC) cells and tumor-associated macrophages, respectively. Recent studies have shown that there is intricate "cross-talk" between OSCC cells and macrophages. However, the underlying mechanisms are still poorly elucidated. METHODS: The expression of CXCL1 was detected by immunohistochemistry in OSCC clinical samples. CXCL1 levels were evaluated by RT‒PCR and ELISA in an OSCC cell line and a normal epithelial cell line. The expression of EGF was determined by RT‒PCR and ELISA. The effect of EGF on the proliferation of OSCC cells was evaluated by CCK-8 and colony formation assays. The effect of EGF on the migration and invasion ability and epithelial-mesenchymal transition (EMT) of OSCC cells was determined by wound healing, Transwell, RT‒PCR, Western blot and immunofluorescence assays. The polarization of macrophages was evaluated by RT‒PCR and flow cytometry. Western blotting was used to study the molecular mechanism in OSCC. RESULTS: The expression of C-X-C motif chemokine ligand 1 (CXCL1) was higher in the OSCC cell line (Cal27) than in immortalized human keratinocytes (Hacat cells). CXCL1 derived from Cal27 cells upregulates the expression of epithelial growth factor (EGF) in macrophages. Paracrine stimulation mediated by EGF further facilitates the epithelial-mesenchymal transition (EMT) of Cal27 cells and initiates the upregulation of CXCL1 in a positive feedback-manner. Mechanistically, EGF signaling-induced OSCC cell invasion and migration can be ascribed to the activation of NF-κB signaling mediated by the epithelial growth factor receptor (EGFR), as determined by western blotting. CONCLUSIONS: OSCC cell-derived CXCL1 can stimulate the M2 polarization of macrophages and the secretion of EGF. Moreover, EGF significantly activates NF-κB signaling and promotes the migration and invasion of OSCC cells in a paracrine manner. A positive feedback loop between OSCC cells and macrophages was formed, contributing to the promotion of OSCC progression.

Biomimetic hydrogels with mesoscale collagen architecture for patient-derived tumor organoids culture.

Patient-derived tumor organoids (PDTOs) shows great potential as a preclinical model. However, the current methods for establishing PDTOs primarily focus on modulating local properties, such as sub-micrometer topographies. Nevertheless, they neglect to capture the global millimeter or intermediate mesoscale architecture that have been demonstrated to influence tumor response to therapeutic treatment and tumor progression. In this study, we present a rapid technique for generating collagen bundles with an average length of 90 ± 27 µm and a mean diameter of 5 ± 1.5 µm from tumor tissue debris that underwent mechanical agitation following enzymatic digestion. The collagen bundles were subsequently utilized for the fabrication of biomimetic hydrogels, incorporating microbial transglutaminase (mTG) crosslinked gelatin. These biomimetic hydrogels, referred to as MC-gel, were specifically designed for patient-derived tumor organoids. The lung cancer organoids cultured in MC-gel exhibited larger diameters and higher cell viability compared to those cultured in gels lacking the mesoscale collagen bundle; moreover, their irregular morphology more closely resembled that observed in vivo. The MC-gel-based lung cancer organoids effectively replicated the histology and mutational landscapes observed in the original donor patient's tumor tissue. Additionally, these lung cancer organoids showed a remarkable similarity in their gene expression and drug response across different matrices. This recently developed model holds great potential for investigating the occurrence, progression, metastasis, and management of tumors, thereby offering opportunities for personalized medicine and customized treatment options.

NCOA4-mediated ferritinophagy participates in cadmium-triggered ferroptosis in spermatogonia.

Cadmium (Cd) is a common pollutant with reproductive toxicity. Our previous study revealed that Cd triggered spermatogonia ferroptosis. However, the underlying mechanisms remain unclear. Nuclear receptor coactivator 4 (NCOA4) mediates ferritinophagy and specific degradation of ferritin through lysosomes, resulting in the release of ferrous ions. Excessive autophagy can lead to ferroptosis. This study investigated the role of autophagy in Cd-triggered ferroptosis using GC-1 spermatogonial (spg) cells which exposed to CdCl2 (5µM, 10µM, or 20µM) for 24 without/with CQ. The cells which transfected with Ncoa4-siRNA were used to explore the role of NCOA4-mediated ferritinophagy in Cd-triggered ferroptosis. The results revealed that Cd caused mitochondrial swelling, rupture of cristae, and vacuolar-like changes. The Cd-treated cells exhibited more autophagosomes. Simultaneously, Cd increased intracellular iron, reactive oxygen species, and malondialdehyde concentrations while decreasing glutathione content and Superoxide Dismutase-2 activity. Moreover, Cd upregulated mRNA levels of ferritinophagy-associated genes (Ncoa4, Lc3b and Fth1), as well as enhanced protein expression of NCOA4, LC3B, and FTH1. While Cd decreased the mRNA and protein expression of p62/SQSTM1. These results showed that Cd caused ferritinophagy and ferroptosis. The use of chloroquine to inhibit autophagy ameliorated Cd-induced iron overload and ferroptosis. Moreover, Ncoa4 knockdown in spermatogonia significantly reduced intracellular iron concentration and alleviated Cd-triggered ferroptosis. In conclusion, our findings demonstrate that Cd activates the ferritinophagy pathway mediated by NCOA4, resulting in iron accumulation through ferritin degradation. This causes oxidative stress, ultimately initiating ferroptosis in spermatogonia. Our results may provide new perspectives and potential strategies for preventing and treating Cd-induced reproductive toxicity.

CRISPR/Cas9 screen reveals that targeting TRIM34 enhances ferroptosis sensitivity and augments immunotherapy efficacy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by complex heterogeneity and drug resistance. Resistance to ferroptosis is closely related to the progression of HCC. While HCC tumors vary in their sensitivity to ferroptosis, the precise factors underlying this heterogeneity remain unclear. In this study, we sought to elucidate the mechanisms that contribute to ferroptosis resistance in HCC. Whole-genome CRISPR/Cas9 screen using a subtoxic concentration (IC20) of ferroptosis inducer erastin in the HCC cell line Huh7 revealed TRIM34 as a critical driver of ferroptosis resistance in HCC. Further investigation revealed that TRIM34 suppresses ferroptosis in HCC cells, promoting their proliferation, migration, and invasion both in vitro and in vivo. Furthermore, TRIM34 expression is elevated in HCC tumor tissues, correlating with a poor prognosis. Mechanistically, TRIM34 directly interacts with Up-frameshift 1 (UPF1), a core component of the nonsense-mediated mRNA decay (NMD) pathway, to promote its ubiquitination and degradation. This interaction suppresses GPX4 transcript degradation, thus promoting the protein levels of this critical ferroptosis suppressor in HCC. In light of the close crosstalk between ferroptosis and the adaptive immune response in cancer, HCC cells with targeting knockdown of TRIM34 exhibited an improved response to anti-PD-1 treatment. Taken together, the TRIM34/UPF1/GPX4 axis mediates ferroptosis resistance in HCC, thereby promoting malignant phenotypes. Targeting TRIM34 may thus represent a promising new strategy for HCC treatment.

Construction of exosome-related genes risk model in kidney cell carcinoma predicts prognosis and immune therapy response.

Renal cell carcinoma (RCC) is one of the most prevalent types of urological cancer. Exosomes are vesicles derived from cells and have been found to promote the development of RCC, but the potential biomarker and molecular mechanism of exosomes on RCC remain ambiguous. Here, we first screened differentially expressed exosome-related genes (ERGs) by analyzing The Cancer Genome Atlas (TCGA) database and exoRBase 2.0 database. We then determined prognosis-related ERGs (PRERGs) by univariate Cox regression analysis. Gene Dependency Score (gDS), target development level, and pathway correlation analysis were utilized to examine the importance of PRERGs. Machine learning and lasso-cox regression were utilized to screen and construct a 5-gene risk model. The risk model showed high predictive accuracy for the prognosis of patients and proved to be an independent prognostic factor in three RCC datasets, including TCGA-KIRC, E-MTAB-1980, and TCGA-KIRP datasets. Patients with high-risk scores showed worse outcomes in different clinical subgroups, revealing that the risk score is robust. In addition, we found that immune-related pathways are highly enriched in the high-risk group. Activities of immune cells were distinct in high-/low-risk groups. In independent immune therapeutic cohorts, high-risk patients show worse immune therapy responses. In summary, we identified several exosome-derived genes that might play essential roles in RCC and constructed a 5-gene risk signature to predict the prognosis of RCC and immune therapy response.

Nanogalvanic Cells Release Highly Reactive Electrons in Tumors to Effectively Eliminate Tumors.

External stimuli triggering chemical reactions in cancer cells to generate highly reactive chemical species are very appealing for cancer therapy, in which external irradiation activating sensitizers to transfer energy or electrons to surrounding oxygen or other molecules is critical for generating cytotoxic reactive species. However, poor light penetration into tissue, low activity of sensitizers, and reliance on oxygen supply restrict the generation of cytotoxic chemical species in hypoxic tumors, which lowers the therapeutic efficacy. Here, this work presents galvanic cell nanomaterials that can directly release highly reactive electrons in tumors without external irradiation or photosensitizers. The released reactive electrons directly react with surrounding biomolecules such as proteins and DNA within tumors to destroy them or react with other surrounding (bio)molecules to yield cytotoxic chemical species to eliminate tumors independent of oxygen. Administering these nanogalvanic cells to mice results in almost complete remission of subcutaneous solid tumors and deep metastatic tumors. The results demonstrate that this strategy can further arouse an immune response even in a hypoxic environment. This method offers a promising approach to effectively eliminate tumors, similar to photodynamic therapy, but does not require oxygen or irradiation to activate photosensitizers.

Simultaneous integrated boost intensity-modulated radiotherapy post breast-conserving surgery: clinical efficacy, adverse effects, and cosmetic outcomes in breast cancer patients.

BACKGROUND: Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) is an innovative technique delivering a higher dose to the tumor bed while irradiating the entire breast. This study aims to assess the clinical outcomes, adverse effects, and cosmetic results of SIB-IMRT following breast-conserving surgery in breast cancer patients. METHODS: We conducted a retrospective analysis of 308 patients with stage 0-III breast cancer who underwent breast-conserving surgery and SIB-IMRT from January 2016 to December 2020. The prescribed doses included 1.85 Gy/27 fractions to the whole breast and 2.22 Gy/27 fractions or 2.20 Gy/27 fractions to the tumor bed. Primary endpoints included overall survival (OS), local-regional control (LRC), distant metastasis-free survival (DMFS), acute and late toxicities, and cosmetic outcomes. RESULTS: The median follow-up time was 36 months. The 3-year OS, LRC, and DMFS rates were 100%, 99.6%, and 99.2%, respectively. Five patients (1.8%) experienced local recurrence or distant metastasis, and one patient succumbed to distant metastasis. The most common acute toxicity was grade 1-2 skin reactions (91.6%). The most common late toxicity was grade 0-1 skin and subcutaneous tissue reactions (96.7%). Five patients (1.8%) developed grade 1-2 upper limb lymphedema, and three patients (1.1%) had grade 1 radiation pneumonitis. Among the 262 patients evaluated for cosmetic outcomes at least 2 years post-radiotherapy, 96.9% achieved excellent or good results, while 3.1% had fair or poor outcomes. CONCLUSIONS: SIB-IMRT after breast-conserving surgery in breast cancer patients demonstrated excellent clinical efficacy, mild acute and late toxicities, and satisfactory cosmetic outcomes in our study. SIB-IMRT appears to be a feasible and effective option for breast cancer patients suitable for breast-conserving surgery.

Genomic landscape and distinct molecular subtypes of primary testicular lymphoma.

Primary testicular lymphoma (PTL) is a rare lymphoma predominantly occurring in the elderly male population. It is characterized by a limited response to treatment and a heightened tendency towards relapse. Histologically, approximately 90% of PTL cases are classified as diffuse large B-cell lymphomas (DLBCL). Genetic features of PTL were delineated in a limited scope within several independent studies. Some of the articles which analyzed the genetic characterization of DLBCL have incorporated PTL samples, but these have been constrained by small sample sizes. In addition, there have been an absence of independent molecular typing studies of PTL. This report summarizes the common mutational features, copy number variations (CNVs) and molecular typing of PTL patients, based on whole-exome sequencing (WES) conducted on a cohort of 25 PTL patients. Among them, HLA, CDKN2A and MYD88 had a high mutation frequency. In addition, we found two core mutational characteristics in PTL including mutation in genes linked to genomic instability (TP53 and CDKN2A) and mutation in immune-related genes (HLA, MYD88, CD79B). We performed molecular typing of 25 PTL patients into C1 subtype with predominantly TP53 mutations and C2 subtype with predominantly HLA mutations. Notably, mutations in the TP53 gene predicted a poor outcome in most types of lymphomas. However, the C1 subtype, dominated by TP53 mutations, had a better prognosis compared to the C2 subtype in PTL. C2 subtype exhibited a worse prognosis, aligning with our finding that the mechanism of immune escape in PTL was primarily the deletions of HLA rather than PD-L1/PD-L2 alterations, a contrast to other DLBCLs. Moreover, we calculated the tumor mutation burden (TMB) and identified that TMB can predict prognosis and recurrence rate in PTL. Our study underscores the significance of molecular typing in PTL based on mutational characteristics, which plays a crucial role in prognostication and guiding therapeutic strategies for patients.

Zwitterionic modified and freeze-thaw reinforced foldable hydrogel as intraocular lens for posterior capsule opacification prevention.

Posterior capsule opacification (PCO) is a predominant postoperative complication, often leading to visual impairment due to the aberrant proliferation and adhesion of lens epithelial cells (LECs) and protein precipitates subsequent to intraocular lens (IOL) implantation. To address this clinical issue, a foldable and antifouling sharp-edged IOL implant based on naturally-derived cellulose hydrogel is synthesized. The mechanical strength and transparency of the hydrogel is enhanced via repeated freeze-thaw (FT) cycles. The incorporated zwitterionic modifications can remarkably prevent the incidence of PCO by exhibiting proteins repulsion and cell anti-adhesion properties. The graft of dopamine onto both the haptic and the periphery of the posterior surface ensures the adhesion of the hydrogel to the posterior capsule and impedes the migration of LECs without compromising transparency. In in vivo study, the zwitterionic modified foldable hydrogel exhibits uveal and capsular biocompatibility synchronously with no signs of inflammatory response and prevent PCO formation, better than that of commercialized and PEG-modified IOL. With foldability, endurability, antifouling effect, and adhesive to posterior capsule, the reported hydrogel featuring heterogeneous surface design displays great potential to eradicate PCO and attain post-operative efficacy after cataract surgery.

TRPV3 regulates Breast Cancer Cell Proliferation and Apoptosis by EGFR/AKT pathway.

Breast cancer (BC) is one of the most common cancer types worldwide and the first cause of cancer-related deaths in women. Transient receptor potential vanillin 3 (TRPV3) has been preliminarily discovered to play an important role in various cancers, including BC. Here, we explored the effect of TRPV3 on breast cancer cells and its potential mechanism. TRPV3 level was measured in BC tissue and adjacent noncancerous breast tissue using real-time RT-PCR and Western blot. Wound healing was used to detect cell migration. MTT and EDU were detected cell proliferation. TUNEL and Caspase-3 activity were used to detect cell apoptosis. We found that TRPV3 expression significantly increased in both human BC tissues and breast cells line. TRPV3 siRNA (TRPV3 inhibition) dramatically suppressed cell migration and proliferation, promoted the apoptosis, and decreased [Ca2+]i; whereas Carvacrol (TRPV3 agonist) has opposite effect in MCF-7 cells. We validated EGFR (Epidermal growth factor receptor) is a direct target protein of TRPV3. Mechanism studies have shown that Carvacrol increased phosphorylation levels of EGFR and AKT, and were decreased by suppression of TRPV3. Moreover, Erlotinib (EGFR inhibitor) and LY294002 (PI3K inhibitor) diminished Carvacrol induced cell migration and proliferation, promoted cell apoptosis, and increased [Ca2+]i in Carvacrol group. Our results collectively suggest that TRPV3 siRNA inhibits migration and proliferation, and promoted apoptosis in breast cancer cells by EGFR/AKT pathway. These findings indicate that TRPV3 may represent a novel therapeutic strategy for breast cancer.

Single-cell and bulk RNA-sequence identified fibroblasts signature and CD8+ T-cell - fibroblast subtype predicting prognosis and immune therapeutic response of bladder cancer, based on machine-learning bioinformatics retrospective study.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are found in primary and advanced tumours. They are primarily involved in tumour progression through complex mechanisms with other types of cells in the tumour microenvironment. However, essential fibroblasts-related genes (FRG) in bladder cancer still need to be explored, and there is a shortage of an ideal predictive model or molecular subtype for the progression and immune therapeutic assessment for bladder cancer, especially muscular-invasive bladder cancer based on the FRG. MATERIALS AND METHODS: CAF-related genes of bladder cancer were identified by analyzing single-cell RNA sequence datasets, and bulk transcriptome datasets and gene signatures were used to characterize them. Then, ten types of machine learning algorithms were utilized to determine the hallmark FRG and construct the FRG index (FRGI) and subtypes. Further molecular subtypes combined with CD8+ T-cells were established to predict the prognosis and immune therapy response. RESULTS: 54 BLCA-related FRG were screened by large-scale scRNA-sequence datasets. The machine learning algorithm established a 3-genes FRG index (FRGI). High FRGI represented a worse outcome. Then, FRGI combined clinical variables to construct a nomogram, which shows high predictive performance for the prognosis of bladder cancer. Furthermore, the BLCA datasets were separated into two subtypes - fibroblast hot and cold types. In five independent BLCA cohorts, the fibroblast hot type showed worse outcomes than the cold type. Multiple cancer-related hallmark pathways are distinctively enriched in these two types. In addition, high FRGI or fibroblast hot type shows a worse immune therapeutic response. Then, four subtypes called CD8-FRG subtypes were established under the combination of FRG signature and activity of CD8+ T-cells, which turned out to be effective in predicting the prognosis and immune therapeutic response of bladder cancer in multiple independent datasets. Pathway enrichment analysis, multiple gene signatures, and epigenetic alteration characterize the CD8-FRG subtypes and provide a potential combination strategy method against bladder cancer. CONCLUSIONS: In summary, we established a novel FRGI and CD8-FRG subtype by large-scale datasets and organized analyses, which could accurately predict clinical outcomes and immune therapeutic response of BLCA after surgery.

Feasibility and safety of dual-console telesurgery with the KangDuo Surgical Robot-1500 System using fifth-generation and wired networks: an animal experiment and sea-spanning clinical study.

BACKGROUND: To evaluate the feasibility and safety of dual-console telesurgery with the new KangDuo system in an animal experiment and clinical study. METHODS: Six canine models were performed radical prostatectomy with dual-console KanDuo surgical robot-1500 (KD-SR-1500-RARP). The perioperative outcomes, physical and mental workload of the surgeon were collected. Physical workload was evaluated with surface electromyography. Mental workload was evaluated with NASA-TLX. After conducting animal experiments to verify safety of dual-console KD-SR-1500-RARP, we conducted the clinical trial using 5G and wired networks. RESULTS: In the animal experiment, all surgeries were performed successfully. The operative time was 80.2±32.1 min. The docking time was 2.4±0.5 min. The console time was 49.7±25.3 min. There were no perioperative complications or equipment related adverse events. All dogs can micturate after catheter removal at one week postoperatively. The mental workload was at a low level (a scale ranging from 0 to 60), which scored 15.7±6.9. Among the eight recorded muscles, the fatigue degree of the right radial flexor and left biceps was the highest two (iEMG, resection, 299.8±344 uV, 109.9±16.9 uV; suture, 849.4±1252.5 uV, 423.1±621.3 uV, respectively). In the clinical study, the console time was 136 min. The mean latency time was ≤200 ms. The data pocket loss was <1%. The operation was successfully completed without malfunctions occurring throughout the entire process. CONCLUSIONS: Dual-console telesurgery with the KD-SR-1500 system was shown to be feasible and safe in radical prostatectomy using 5G and wired networks.

12-O-deacetyl-phomoxanthone A inhibits ovarian tumor growth and metastasis by downregulating PDK4.

AIMS: The xanthone dimer 12-O-deacetyl-phomoxanthone A (12-ODPXA) was extracted from the secondary metabolites of the endophytic fungus Diaporthe goulteri. The 12-ODPXA compound exhibited anticancer properties in murine lymphoma; however, the anti-ovarian cancer (OC) mechanism has not yet been explored. Therefore, the present study evaluated whether 12-ODPXA reduces OC cell proliferation, metastasis, and invasion by downregulating pyruvate dehydrogenase kinase (PDK)4 expression. METHODS: Cell counting kit-8, colony formation, flow cytometry, wound healing, and transwell assays were performed to examine the effects of 12-ODPXA on OC cell proliferation, apoptosis, migration, and invasion. Transcriptome analysis was used to predict the changes in gene expression. Protein expression was determined using western blotting. Glucose, lactate, and adenosine triphosphate (ATP) test kits were used to measure glucose consumption and lactate and ATP production, respectively. Zebrafish xenograft models were constructed to elucidate the anti-OC effects of 12-ODPXA. RESULTS: The 12-ODPXA compound inhibited OC cell proliferation, migration, invasion, and glycolysis while inducing cell apoptosis via downregulation of PDK4. In vivo experiments showed that 12-ODPXA suppressed tumor growth and migration in zebrafish. CONCLUSION: Our data demonstrate that 12-ODPXA inhibits ovarian tumor growth and metastasis by downregulating PDK4, revealing the underlying mechanisms of action of 12-ODPXA in OC.