Amlodipine inhibits Synaptotagmin-4's oncogenic activity on gastric cancer proliferation by targeting calcium signaling.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies. PURPOSE: This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC. METHODS: We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity. RESULTS: SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca2+ influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine. CONCLUSION: SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca2+-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.

NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion.

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates ß-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of ß-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

Ciliated Muconodular Papillary Tumors of the Lung Harboring STRN::ALK Fusion: Case Report and Review of the Literature.

Ciliated muconodular papillary tumor (CMPT) is a rare pulmonary tumor, typically occurring in middle-aged and elderly individuals. The molecular mutation spectrum of CMPT remains insufficiently explored. Commonly known driver gene alterations include KRAS, BRAF, EGFR, and ALK rearrangement. This report details the clinicopathological features of 2 patients presenting with CMPT as pulmonary nodules during clinical examinations. Microscopic analysis revealed tumors with glandular or papillary structures, consisting of mucinous cells, ciliated columnar cells, and basal cells. Notably, both patients exhibited STRN::ALK fusion, a finding not previously associated with CMPT. STRN::ALK fusion serves as a target for therapy in various tumors, including non-small cell lung cancer, thyroid cancer, and colon cancer. Consequently, we conducted a review of relevant literature, summarizing the clinicopathological and molecular characteristics of CMPT to facilitate further research. Our insights enhance the understanding of this uncommon tumor and contribute to the expansion of its molecular alteration spectrum.

Somatostatin receptor subtype 2A expression and genetics in 184 paragangliomas: a single center retrospective observational study.

PURPOSE: Adrenal and extra-adrenal paragangliomas (PGLs) are a group of neuroendocrine tumors (NETs) with strong heterogeneity, which often express somatostatin receptor subtype 2 A (SSTR2A). However, the association between SSTR2A expression and genetic status of PGLs remains unclear. The purpose of the study was to identify whether various pathogenic variants (PVs) had an impact on SSTR2A expression in PGLs. METHODS: This retrospective study included 184 patients with pathologically confirmed PGLs. The immunohistochemical expression of SSTR2A were studied in 184 tumors and PVs were tested in 159 tumor samples. Clinical and genetic data were compared in SSTR2A positive and negative PGLs. RESULTS: SSTR2A was positive in 63.6% (117/184) of all tumors. PGLs with negative SSTR2A were more likely to be extra-adrenal (37.0% vs 18.0%; P = 0.005) and exhibited a considerably greater proportion of PVs (75.4% vs. 49.0%; P = 0.001) than those with positive SSTR2A. Compared to those without PVs, a higher proportion of PGLs with PVs in cluster 1B (P = 0.004) and cluster 2 (P = 0.004) genes, especially VHL (P = 0.009), FGFR1 (P = 0.010) and HRAS (P = 0.007), were SSTR2A negative. SSTR2A was positive in all tumors (4/4) with SDHx PVs and in 87.5% (7/8) of metastatic PGLs. CONCLUSIONS: SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs.

Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma.

Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

A Transformer-Based microvascular invasion classifier enhances prognostic stratification in HCC following radiofrequency ablation.

BACKGROUND & AIMS: We aimed to develop a Transformer-based deep learning (DL) network for prognostic stratification in hepatocellular carcinoma (HCC) patients undergoing RFA. METHODS: A Swin Transformer DL network was trained to establish associations between magnetic resonance imaging (MRI) datasets and the ground truth of microvascular invasion (MVI) based on 696 surgical resection (SR) patients with solitary HCC ≤3 cm, and was validated in an external cohort (n = 180). The multiphase MRI-based DL risk outputs using an optimal threshold of .5 was employed as a MVI classifier for prognosis stratification in the RFA cohort (n = 180). RESULTS: Over 90% of all enrolled patients exhibited hepatitis B virus infection. Liver cirrhosis was significantly more prevalent in the RFA cohort compared to the SR cohort (72.2% vs. 44.1%, p < .001). The MVI risk outputs exhibited good performance (area under the curve values = .938 and .883) for predicting MVI in the training and validation cohort, respectively. The RFA patients at high risk of MVI classified by the MVI classifier demonstrated significantly lower recurrence-free survival (RFS) and overall survival rates at 1, 3 and 5 years compared to those classified as low risk (p < .001). Multivariate cox regression modelling of a-fetoprotein > 20 ng/mL [hazard ratio (HR) = 1.53; 95% confidence interval (95% CI): 1.02-2.33, p = .047], high risk of MVI (HR = 3.76; 95% CI: 2.40-5.88, p < .001) and unfavourable tumour location (HR = 2.15; 95% CI: 1.40-3.29, p = .001) yielded a c-index of .731 (bootstrapped 95% CI: .667-.778) for evaluating RFS after RFA. Among the three risk factors, MVI was the most powerful predictor for intrahepatic distance recurrence. CONCLUSIONS: The proposed MVI classifier can serve as a valuable imaging biomarker for prognostic stratification in early-stage HCC patients undergoing RFA.

Proteomic Characterization Identifies Clinically Relevant Subgroups of Gastrointestinal Stromal Tumors.

BACKGROUND & AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities. METHODS: Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models. RESULTS: Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis. CONCLUSIONS: Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.

Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses.

Acral melanoma (AM) is a rare subtype of melanoma characterized by a high incidence of lymph node (LN) metastasis, a critical factor in tumor dissemination and therapeutic decision-making. Here, we employ single-cell and spatial transcriptomic analyses to investigate the dynamic evolution of early AM dissemination. Our findings reveal substantial inter- and intra-tumor heterogeneity in AM, alongside a highly immunosuppressive tumor microenvironment and complex intercellular communication networks, particularly in patients with LN metastasis. Notably, we identify a strong association between MYC+ Melanoma (MYC+MEL) and FGFBP2+NKT cells with LN metastasis. Furthermore, we demonstrate that LN metastasis requires a metabolic shift towards fatty acid oxidation (FAO) induced by MITF in MYC+MEL cells. Etomoxir, a clinically approved FAO inhibitor, can effectively suppress MITF-mediated LN metastasis. This comprehensive dataset enhances our understanding of LN metastasis in AM, and provides insights into the potential therapeutic targeting for the management of early AM dissemination.

Comparison of two pathological processing methods for large endoscopic submucosal dissection (ESD) specimens.

AIMS: Accurate histopathological evaluation of the endoscopic submucosal dissection (ESD) specimens is essential for clinicians to guide further triage and management. This study aimed to report a novel processing technique for large ESD (≥4 cm) specimens. METHODS: 92 patients with colorectal neoplasms who had undergone ESD were included. 46 ESD specimens were treated with conventional handling process, while the rest 46 cases were given the optimised method. Macrobiocassettes and L-shaped embedding moulds were applied in the optimised method. We evaluated the efficacy of this improved procedure in terms of the number of paraffin blocks, storage space and time consumption of pathological assessment. RESULTS: The average diameter of ESD specimens was 4.5±0.4 cm and 4.7±0.5 cm in the control and test group (p=0.023), respectively. In control group, 398 paraffin blocks of 46 cases were obtained. With the same cases number and larger lesion size, only 276 blocks were achieved in test group (p<0.001). As for the storage space, the total volume of paraffin blocks and slides (4554.0 cm3 and 1207.5 cm3) of optimised method was significantly reduced compared with the control group (6208.8 cm3 and 1741.3 cm3) (p=0.001, p<0.001). In addition, the optimised method was superior to the conventional one in shortening time consumption of pathological assessment (164.5 min and 269.0 min, p<0.001). CONCLUSIONS: The optimised technique not only reduced the workload and storage space, but also facilitated accurate pathological assessment.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Contrast-Enhanced Imaging Features and Clinicopathological Investigation of Steatohepatitic Hepatocellular Carcinoma.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinctive histologic variant of HCC for the presence of steatohepatitis. This study intended to evaluate the contrast-enhanced imaging features and clinicopathological characteristics of 26 SH-HCCs in comparison with 26 age-and-sex-matched non-SH-HCCs. The frequency of obesity (34.6%, p = 0.048) and type 2 diabetes mellitus (23.1%, p = 0.042) were significantly higher in SH-HCC patients. As seen via B-mode ultrasound (BMUS), SH-HCCs were predominantly hyperechoic (65.4%, p = 0.002) lesions, while non-SH-HCCs were mainly hypo-echoic. As seen via contrast-enhanced ultrasound (CEUS), 96.2% of SH-HCCs exhibited hyperenhancement in the arterial phase. During the portal venous and late phase, 88.5% of SH-HCCs showed late and mild washout. Consequently, most SH-HCCs and all non-SH-HCCs were categorized as LR-4 or LR-5. As seen via magnetic resonance imaging (MRI), a signal drop in the T1WI opposed-phase was observed in 84.6% of SH-HCCs (p = 0.000). Notably, diffuse fat in mass was detected in 57.7% (15/26) SH-HCCs (p < 0.001). As seen via contrast-enhanced MRI (CEMRI), most of the SH-HCCs and non-SH-HCCs exhibited heterogeneous hyperenhancement in the arterial phase (80.8% versus 69.2%, p = 0.337). During the delayed phase, 76.9% SH-HCCs and 88.5% non-SH-HCCs exhibited hypo-enhancement. Histopathologically, the rate of microvascular invasion (MVI) was significantly lower in SH-HCCs than non-SH-HCCs (42.3% versus 73.1%, p = 0.025). The frequency of hepatic steatosis >5% in non-tumoral liver parenchyma of SH-HCCs was significantly higher than in non-SH-HCCs (88.5% versus 26.9%, p = 0.000). Additionally, the fibrotic stages of S0, S1 and S2 in SH-HCCs were significantly higher than in non-SH-HCCs (p = 0.044). During follow-up, although the PFS of SH-HCC patients was significantly longer than non-SH-HCC patients (p = 0.046), for the overall survival rate of SH-HCC and non-SH-HCC patients there was no significant difference (p = 0.162). In conclusion, the frequency of metabolism-related diseases in SH-HCC patients was significantly higher than in non-SH-HCC patients. The imaging features of SH-HCCs combined the fatty change and typical enhancement performance of standard HCC as seen via CEUS/CEMRI.

Multiplex immune profiling reveals the role of serum immune proteomics in predicting response to preoperative chemotherapy of gastric cancer.

Responses toward preoperative chemotherapy are heterogeneous in patients with gastric adenocarcinoma. Existing studies in the field focus heavily on the tumor microenvironment (TME), whereas little is known about the relationship between systemic immunity and chemotherapy response. In this study, we collect serum samples from patients with gastric adenocarcinoma before, on, and after preoperative chemotherapy and study their immune proteomics using an antibody-based proteomics panel. We also collect surgically resected tumor samples and incorporate multiple methods to assess their TME. We find that both local and systemic immune features are associated with treatment response. Preoperative chemotherapy induces a sophisticated systemic immune response indicated by dynamic serum immune proteomics. A pretreatment serum protein scoring system is established for response prediction. Together, these findings highlight the fundamental but largely underestimated role of systemic immunity in the treatment of gastric cancer, suggesting a patient stratification strategy based on pretreatment serum immune proteomics.

Region-resolved multi-omics of the mouse eye.

The eye is a complex organ consisting of multiple compartments with unique and specialized properties, and small disturbances in one eye region can result in impaired vision and blindness. Although there have been advancements in ocular research, the hierarchical molecular network in region-wide resolution, indicating the division of labor and crosstalk among different eye regions, is not yet comprehensively illuminated. Here, we present an atlas of region-resolved proteome and lipidome of mouse eye. Multiphoton microscopy-guided laser microdissection combined with in-depth label-free proteomics identifies 13,536 proteins across various mouse eye regions. Further integrative analysis of spectral imaging, label-free proteome, and imaging mass spectrometry of the lipidome and phosphoproteome reveals distinctive molecular features, including proteins and lipids of various anatomical mouse eye regions. These deposited datasets and our open proteome server integrating all information provide a valuable resource for future functional and mechanistic studies of mouse eye and ocular disease.

Iodide Excess Inhibits Thyroid Hormone Synthesis Pathway Involving XBP1-Mediated Regulation.

Iodine is an essential micronutrient for producing thyroid hormone (TH); however, iodide excess can lead to adverse thyroidal effects. Unfortunately, the lack of a proper in vitro model system hampered the studies of the effect of iodide excess on thyroid physiology and pathology. Here, we demonstrated that excessive iodide intake downregulated the genes related to TH synthesis in the thyroids of mice. Since sodium iodide has no effect on these genes in cultured cell lines, we developed a three-dimensional (3D) culture system to enable the murine thyrocytes to form organoids in vitro with thyroid follicle-like structures and function and found that the in vivo effect of iodide excess could be mimicked in these thyroid organoids. Our data indicate that iodide excess mainly activated the XBP1-mediated unfolded protein response in both murine thyroid and thyroid organoids, while activation of XBP1 was able to mimic the sodium iodide effect on genes for the synthesis of TH in murine thyroid organoids. Lastly, our results suggest that XBP1 might transcriptionally repress the genes involved in the synthesis of TH. Based on these findings, we propose that iodide excess inhibits the transcription of genes related to TH synthesis through a mechanism involving XBP1-mediated action.

Intrahepatic splenosis: Contrast enhanced ultrasound and magnetic resonance imaging findings.

OBJECTIVE: To evaluate the contrast enhanced ultrasound (CEUS) and contrast enhanced magnetic resonance imaging (CEMRI) features of intrahepatic splenosis (IHS). METHODS & MATERIALS: Five patients (three males and two females, median age, 44 years; range,32-73 years) with seven IHSs were retrieved from the database of our hospital from March 2012 to October 2021. All IHSs were confirmed histologically by surgery. The CEUS and CEMRI characteristics of individual lesion were fully analyzed. RESULTS: All IHS patients were asymptomatic and four out of five patients had history of splenectomy. On CEUS, all IHSs were hyperenhancement in arterial phase. 71.4% (5/7) of IHSs manifested overall filling within few seconds, the other two lesions showed centripetal filling. Subcapsular vascular hyperenhancement and feeding artery was seen in 28.6% (2/7) and 42.9% (3/7) of IHSs, respectively. During portal venous phase, IHSs presented hyperenhancement (2/7) or isoenhancement (5/7). Moreover, rim-like hypoenhanced area was uniquely observed surrounding 85.7% (6/7) of IHSs. In late phase, seven IHSs remained continuous hyper- or isoenhancement. On CEMRI, five IHSs showed mosaic hyperintense in early arterial phase, the other two lesions showed homogeneous hyperintense. In portal venous phase, all IHSs revealed continuous hyper- (71.4%, 5/7) or iso-intense (28.6%, 2/7). During late phase, one IHS (14.3%, 1/7) became hypointense, the other lesions remained hyper- or isointense. CONCLUSION: Diagnosis of IHS can be based on typical CEUS and CEMRI features in patients with history of splenectomy.

Expression of PD-L1 through evolution phase from pre-invasive to invasive lung adenocarcinoma.

BACKGROUND: This study evaluated programmed cell death-ligand 1 (PD-L1) expression from pre-invasive adenocarcinoma to invasive lung adenocarcinoma, aimed to investigate the potential association of PD-L1 pathway with lung adenocarcinoma early evolution. METHODS: We evaluated PD-L1 expression in 1123 resected lung specimens of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) of stage IA1-IA3. PD-L1 expression was defined based on the proportion of stained tumor cells using the tumor proportion score: < 1% (negative), ≥ 1% (positive) and ≥ 50% (strongly positive). Correlations between PD-L1 expression and T stage, pathological subtype, adenocarcinoma grade, spread through air space (STAS), vascular invasion, lymphatic invasion and driven genes were analyzed. RESULTS: There was almost no PD-L1 expression in AIS or MIA. However, PD-L1 expression was correlated with invasiveness of lung adenocarcinoma. The percentages of PD-L1 positive in IA1-IA3 were 7.22%, 11.29%, and 14.20%, respectively. The strongly positive rates of PD-L1 were 0.38%, 1.64%, and 3.70% in IA1-IA3, respectively. PD-L1 expression and positive rate were also associated with poor pathological subtype and poor biological behavior, such as adenocarcinoma Grade 3, micropapillary or solid dominant subtype, STAS and vascular invasion. Finally, PD-L1 positive rate seems also corrected with driven gene ALK, ROS-1 and KRAS. CONCLUSIONS: PD-L1 expression was positively correlated with the emergence of invasiveness and poor pathological subtype or biological behavior of early-stage lung adenocarcinoma. PD-L1 pathway may be involved in the early evolution of lung adenocarcinoma from AIS to IAC.

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.

Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.

Identifying HER2 from serum-derived exosomes in advanced gastric cancer as a promising biomarker for assessing tissue HER2 status and predicting the efficacy of trastuzumab-based therapy.

PURPOSE: This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. METHODS: In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab-based first-line therapy. RESULTS: In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum-derived exosome HER2 diagnostic value, including 114 HER2-positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2-positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR] = 0.41, P = 0.017) and OS (HR = 0.30, P < 0.001), respectively. CONCLUSION: Serum exosomal HER2 level might serve as an effective biomarker for assessing tissue HER2 status in AGC and screening the potential patients who might benefit from anti-HER2 therapy.

Sublethal heat treatment enhances lactic acid uptake in macrophages via MCT1, leading to reduced paraspeckle formation and a subsequent decrease in macrophage pyroptosis.

Introduction: Heat ablation is one of the key modalities in treating liver cancer, yet the residual cancer tissues suffering sublethal heat treatment possess a potential for increased malignancy. This study conducts a comprehensive analysis of cellular dynamics, metabolic shifts, and macrophage polarization within the tumor microenvironment following sublethal heat treatment. Methods: We observed significant acidification in tumor cell supernatants, attributed to increased lactic acid production. The study focused on how this pH shift, crucial in tumor progression and resistance, influences macrophage polarization, especially towards the M2 phenotype known for tumor-promoting functions. We also examined the upregulation of MCT1 expression post sublethal heat treatment and its primary role in lactic acid transport. Results: Notably, the study found minimal disparity in MCT1 expression between hepatocellular carcinoma patients and healthy liver tissues, highlighting the complexity of cancer biology. The research further revealed an intricate relationship between lactic acid, MCT1, and the inhibition of macrophage pyroptosis, offering significant insights for therapeutic strategies targeting the tumor immune environment. Post sublethal heat treatment, a reduction in paraspeckle under lactic acid exposure was observed, indicating diverse cellular impacts. Additionally, PKM2 was identified as a key molecule in this context, with decreased levels after sublethal heat treatment in the presence of lactic acid. Discussion: Collectively, these findings illuminate the intertwined mechanisms of sublethal heat treatments, metabolic alterations, and immune modulation in the tumor milieu, providing a deeper understanding of the complex interplay in cancer biology and treatment.