Trehalose enhanced cold atmospheric plasma-mediated cancer treatment.

Cold atmospheric plasma (CAP) is a unique form of physical plasma that has shown great potential for cancer therapy. CAP uses ionized gas to induce lethal oxidative stress on cancer cells; however, the efficacy of CAP therapy continues to be improved. Here, we report an injectable hydrogel-mediated approach to enhance the anti-tumor efficacy of CAP by regulating the phosphorylation of eIF2α. We discovered that reactive oxygen and nitrogen species (ROS/RNS), two main anti-tumor components in CAP, can lead to lethal oxidative stress on tumor cells. Elevated oxidative stress subsequently induces eIF2α phosphorylation, a pathognomonic marker of immunogenic cell death (ICD). Trehalose, a natural disaccharide sugar, can further enhance CAP-induced ICD by elevating the phosphorylation of eIF2α. Moreover, injectable hydrogel-mediated delivery of CAP/trehalose treatment promoted dendritic cell (DC) maturation, initiating tumor-specific T-cell mediated anti-tumor immune responses. The combination therapy also supported the polarization of tumor-associated macrophages to an M1-like phenotype, reversing the immunosuppressive tumor microenvironment and promoting tumor antigen presentation to T cells. In combination with immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1 antibody, aPD1), CAP/trehalose therapy further inhibited tumor growth. Importantly, our findings also indicated that this hydrogel-mediated local combination therapy engaged the host systemic innate and adaptive immune systems to impair the growth of distant tumors.

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

Background: The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. Methods: We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Results: Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Conclusions: Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism.

Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimer of p110α catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine kinases. Although p85α recruits p110α to activated receptors on membranes, p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. p110α localizes to microtubules via microtubule-associated protein 4 (MAP4), facilitating its interaction with activated receptor kinases on endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85α knockdown, the residual p110α, coupled predominantly to p85ß, exhibits enhanced recruitment with receptor tyrosine kinases to endosomes. Moreover, the p110α C2 domain binds PI3-phosphate, and this interaction is also required to recruit p110α to endosomes and for PI3K/Akt signaling. Stable knockdown of p85α, which mimics the reduced p85α levels observed in cancer, enhances cell growth and tumorsphere formation, and these effects are abrogated by MAP4 or p85ß knockdown, underscoring their role in the tumor-promoting activity of p85α loss.

Unraveling the molecular mechanisms of lymph node metastasis in ovarian cancer: focus on MEOX1.

BACKGROUND: Lymph node metastasis (LNM) is a major factor contributing to the high mortality rate of ovarian cancer, making the treatment of this disease challenging. However, the molecular mechanism underlying LNM in ovarian cancer is still not well understood, posing a significant obstacle to overcome. RESULTS: Through data mining from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we have identified MEOX1 as a specific gene associated with LNM in ovarian cancer. The expression of MEOX1 was found to be relatively high in serous ovarian adenocarcinoma, and its higher expression were associated with increased tumor grade and poorer clinical prognosis for ovarian cancer patients. Bioinformatics analysis revealed that MEOX1 exhibited the highest mRNA levels among all cancer types in ovarian cancer tissues and cell lines. Furthermore, gene set enrichment analysis (GSEA) and pathway analysis demonstrated that MEOX1 was involved in various LNM-related biological activities, such as lymphangiogenesis, lymphatic vessel formation during metastasis, epithelial-mesenchymal transition (EMT), G2/M checkpoint, degradation of extracellular matrix, and collagen formation. Additionally, the expression of MEOX1 was positively correlated with the expression of numerous prolymphangiogenic factors in ovarian cancer. To validate our findings, we conducted experiments using clinical tissue specimens and cell lines, which confirmed that MEOX1 was highly expressed in high-grade serous ovarian cancer (HGSOC) tissues and various ovarian cancer cell lines (A2780, SKOV3, HO8910, and OVCAR5) compared to normal ovarian tissues and normal ovarian epithelial cell line IOSE-80, respectively. Notably, we observed a higher protein level of MEOX1 in tumor tissues of LNM-positive HGSOC compared to LNM-negative HGSOC. Moreover, our fundamental experiments demonstrated that suppression of MEOX1 led to inhibitory effects on ovarian cancer cell proliferation and EMT, while overexpression of MEOX1 enhanced the proliferation and EMT capacities of ovarian cancer cells. CONCLUSIONS: The results of our study indicate that MEOX1 plays a role in the lymph node metastasis of ovarian cancer by regulating multiple biological activities, including the proliferation and EMT of ovarian cancer, lymphangiogenesis, and ECM remodeling. Our findings suggest that MEOX1 could serve as a potential biomarker for the diagnosis and treatment of ovarian cancer with LNM.

Morusin suppresses the stemness characteristics of gastric cancer cells induced by hypoxic microenvironment through inhibition of HIF-1α accumulation.

Gastric cancer (GC) is a common, life-threatening malignancy that contributes to the global burden of cancer-related mortality, as conventional therapeutic modalities show limited effects on GC. Hence, it is critical to develop novel agents for GC therapy. Morusin, a typical prenylated flavonoid, possesses antitumor effects against various cancers. The present study aimed to demonstrate the inhibitory effect and mechanism of morusin on the stemness characteristics of human GC in vitro under hypoxia and to explore the potential molecular mechanisms. The effects of morusin on cell proliferation and cancer stem cell-like properties of the human GC cell lines SNU-1 and AGS were assessed by MTT assay, colony formation test, qRT-PCR, flow cytometry analysis, and sphere formation test under hypoxia or normoxia condition through in vitro assays. The potential molecular mechanisms underlying the effects of morusin on the stem-cell-like properties of human GC cells in vitro were investigated by qRT-PCR, western blotting assay, and immunofluorescence assay by evaluating the nuclear translocation and expression level of hypoxia-inducible factor-1α (HIF-1α). The results showed that morusin exerted growth inhibitory effects on SNU-1 and AGS cells under hypoxia in vitro. Moreover, the proportions of CD44+/CD24- cells and the sphere formation ability of SNU-1 and AGS reduced in a dose-dependent manner following morusin treatment. The expression levels of stem cell-related genes, namely Nanog, OCT4, SOX2, and HIF-1α, gradually decreased, and the nuclear translocation of the HIF-1α protein was apparently attenuated. HIF-1α overexpression partially reversed the abovementioned effects of morusin. Taken together, morusin could restrain stemness characteristics of GC cells by inhibiting HIF-1α accumulation and nuclear translocation and could serve as a promising compound for GC treatment.

Engineered platelet-based immune engager for tumor post-surgery treatment.

Tumor metastasis and recurrence are principal reasons for the high mortality and poor prognosis of cancers. Inefficient engagement between T cell and tumor cell, as well as the universal existence of immune checkpoints, are important factors to the limited immunological surveillance of the immune systems to tumor cells. Herein, an immune engager based on engineered platelets with CD3 antibody modification (P-aCD3) was constructed to facilitate the contact between T cell and tumor cell via providing the anchoring sites of above two cells. Combined with the immune checkpoint blockade strategy, P-aCD3 effectively enhanced T cell mediated cytotoxicity and inhibited tumor recurrence and metastasis in mice melanoma postoperative model and breast cancer model, resulting in significantly prolonged survival of mice.

Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis.

Background: Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene-positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC and concluded the efficacy of altered subtypes. Methods: A literature search was performed using PubMed, Web of Science, and Cochrane databases. The primary endpoints included the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients with oncogene-driven NSCLC. Results: In all, 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORRs in clinical trials treated with monoimmunotherapy of EGFR, ALK, and KRAS alteration were 6%, 0%, and 23%, respectively. In retrospective studies, the pooled ORRs of EGFR, ALK, KRAS, BRAF, MET, HER2, RET, and ROS1 alteration were 8%, 3%, 28%, 24%, 23%, 14%, 7%, and 8%, respectively. Among them, the pooled ORRs of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping, and MET-amplification were 33% 40%, 20%, 34%, 17%, and 60%, respectively. In addition, the pooled mPFS rates of EGFR, KRAS, MET, HER2, and RET alteration were 2.77, 3.24, 2.48, 2.31, and 2.68 months, while the pooled mOS rates of EGFR and KRAS alteration were 9.98 and 12.29 months, respectively. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. Conclusions: EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.

Efficacy of immunotherapy in patients with oncogene-driven non-small cell lung cancer: a systematic review and meta analysis Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced NSCLC. However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC, and concluded the efficacy of altered subtypes. 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORR in clinical trials treated with monoimmunotherapy was of EGFR, ALK and KRAS alteration was 6%, 0%, and 23%, respectively. While in retrospective studies, the pooled ORR of EGFR, ALK, KRAS, BRAF, MET, HER2, RET and ROS1 alteration was 8%, 3%, 28%, 24%, 23%, 14%, 7% and 8%, respectively. Among them, the pooled ORR of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping and MET-amplification was 33% 40%, 20%, 34%, 17% and 60%, respectively. Additionally, the pooled mPFS of EGFR, KRAS, MET, HER2 and RET alteration was 2.77, 3.24, 2.48, 2.31 and 2.68 months, while the pooled mOS of EGFR and KRAS alteration was 9.98 and 12.29 months. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) was reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. EGFR, ALK, HER2, RET and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy, but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation and MET amplification have better response to immunotherapy, and more prospective studies are needed for further research.

Immunomodulation of cuproptosis and ferroptosis in liver cancer.

According to statistics, the incidence of liver cancer is increasing yearly, and effective treatment of liver cancer is imminent. For early liver cancer, resection surgery is currently the most effective treatment. However, resection does not treat the disease in advanced patients, so finding a method with a better prognosis is necessary. In recent years, ferroptosis and cuproptosis have been gradually defined, and related studies have proved that they show excellent results in the therapy of liver cancer. Cuproptosis is a new form of cell death, and the use of cuproptosis combined with ferroptosis to inhibit the production of hepatocellular carcinoma cells has good development prospects and is worthy of in-depth discussion by researchers. In this review, we summarize the research progress on cuproptosis combined with ferroptosis in treating liver cancer, analyze the value of cuproptosis and ferroptosis in the immune of liver cancer, and propose potential pathways in oncotherapy with the combination of cuproptosis and ferroptosis, which can provide background knowledge for subsequent related research.

The effect of Dendrobium officinale extract in inhibiting the senescence of H2O2-induced fibroblasts based on the senescence-associated secretory phenotype.

BACKGROUND: Dendrobium officinale is widely used for a long time in China, with effect of antioxidation, antitumor, enhancing immunity and so on. In recent years, Dendrobium officinale has been gradually used in cosmetics due to its powerful beauty effects. AIMS: Based on senescence-associated secretory phenotype (SASP), we studied the antiaging effect of Dendrobium officinale extract (DOE) on skin. METHODS: The senescent model of human skin fibroblasts was established by the induction of H2O2, and the content of SASP factors was tested after the treatment of DOE, such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-1 (MMP-1). RESULTS: It was found that after the treatment with different concentrations of DOE, the contents of IL-6, MCP-1 and MMP-1 all decreased in different degrees. CONCLUSIONS: It indicated that DOE could inhibit the secretion of SASP factors and was a promising natural antiaging agent.

Comparison of CT and gadoxetic acid-enhanced MRI with liver imaging reporting and data system to assess liver tumors before resection.

BACKGROUND/PURPOSE: Hepatocellular carcinoma (HCC) can be noninvasively diagnosed through dynamic computed tomography (CT) and magnetic resonance imaging (MRI). We compared the diagnostic performance of CT and gadoxetic acid-enhanced MRI (EOB-MRI) in categorizing tumors by using the 2018 version of the Liver Imaging Reporting And Data System (LI-RADS v2018) and assessing liver tumors before resection. METHODS: Data from a prospective cohort from October 2011 to March 2019 on 106 hepatic tumors in 96 patients with suspected malignancy were included in this study. We performed preoperative CT and EOB-MRI, and reviewed these images retrospectively. Ninety-seven tumors from 87 patients were pathologically diagnosed as HCC, and nine tumors were non-HCC. The clinical data, imaging characteristics, diagnostic performance, and outcomes of CT and EOB-MRI were analyzed and compared. RESULTS: EOB-MRI had more favorable diagnostic performance (area under curve: 0.920 vs. 0.868) and significantly higher sensitivity (86.87% vs. 69.70%, p = 0.005) than did CT. However, the specificity of EOB-MRI did not differ from that of CT (88.89% vs. 88.89%, p > 0.999). Fourteen (14.5%) patients with pathologically verified HCC had lesions categorized as LI-RADS 4 through CT and as LI-RADS 5 through EOB-MRI. Patients with EOB-MRI-categorized but not CT-categorized LI-RADS 5 lesions had significantly longer overall survival than did those with LI-RADS 4 lesions (p < 0.001). CONCLUSION: EOB-MRI had higher sensitivity than did CT in diagnosing HCC. Patients with EOB-MRI-categorized LI-RADS 5 lesions had more favorable outcomes than did those with LI-RADS 4 lesions after liver resection.

Matrix metalloproteinase-2 inducing COL1A1 synthesis via integrin alpha â ¤ promotes invasion and metastasis of cholangiocarcinoma cells.

INTRODUCTION AND OBJECTIVES: Cholangiocarcinoma (CCA) is characterized by early distant invasion and metastasis, whereas the underlying mechanism is still obscure. Increasing evidence shows that collagen type Ι alpha 1 (COL1A1) is a gene associated with the progression of multiple diseases. Here, we attempted to investigate the role of COL1A1 in CCA. MATERIALS AND METHODS: The expression of COL1A1 between tumor tissues and adjacent normal tissues obtained from CCA patients was detected by Western blot and immunofluorescence, followed by analysis of its clinical significance. Then, the biological effects of COL1A1 overexpression or knockdown on CCA cells were evaluated in vitro and in vivo. Finally, molecular mechanism of COL1A1 in regulating the invasion and metastasis of CCA cells was determined by a series of experiments. RESULTS: COL1A1 expression was significantly higher in CCA pathological tissues than in corresponding adjacent normal tissues. Analysis of 83 CCA patients showed that higher expression of COL1A1 was correlated with poorer patient prognosis. Notably, overexpression or knockdown experiments revealed that COL1A1 contributed to the migration and invasion, as well as epithelial-to-mesenchymal transition (EMT), in CCA cells. Further investigations demonstrated that matrix metalloproteinase-2 (MMP2) promoted COL1A1 upregulation via the integrin alpha Ⅴ pathway, therefore affecting ECM remodelling and inducing EMT in CCA cells. Moreover, COL1A1 expression was positively related to PD-1 and PD-L1 in CCA, and COL1A1 increased PD-L1 expression by activating the NF-κB pathway. CONCLUSIONS: COL1A1 plays an important role in regulating CCA progression and may act as a promising biomarker and therapeutic target for CCA.

HDAC1: An Essential and Conserved Member of the Diverse Zn2+-Dependent HDAC Family Driven by Divergent Selection Pressure.

Zn2+-dependent histone deacetylases (HDACs) are enzymes that regulate gene expression by removing acetyl groups from histone proteins. These enzymes are essential in all living systems, playing key roles in cancer treatment and as potential pesticide targets. Previous phylogenetic analyses of HDAC in certain species have been published. However, their classification and evolutionary origins across biological kingdoms remain unclear, which limits our understanding of them. In this study, we collected the HDAC sequences from 1451 organisms and performed analyses. The HDACs are found to diverge into three classes and seven subclasses under divergent selection pressure. Most subclasses show species specificity, indicating that HDACs have evolved with high plasticity and diversification to adapt to different environmental conditions in different species. In contrast, HDAC1 and HDAC3, belonging to the oldest class, are conserved and crucial in major kingdoms of life, especially HDAC1. These findings lay the groundwork for the future application of HDACs.

Cytoreductive surgery is feasible in patients with limited regional platinum-resistant recurrent ovarian cancer.

INTRODUCTION: To evaluate the efficacy of cytoreductive surgery versus chemotherapy for the treatment of limited regional, platinum-resistant ovarian cancer (PROC). MATERIALS AND METHODS: The clinical records of all patients with PROC treated in our center between March 2015 and March 2022 were retrospectively reviewed. We compared the oncology outcomes of patients who received cytoreduction or chemotherapy alone at relapse and presented information about postoperative adjuvant chemotherapy. RESULTS: Among 52 patients with limited regional recurrence, 40.4% (21/52) underwent cytoreduction because of platinum resistance, and 59.6% (31/52) received chemotherapy alone. No residual disease (R0) was achieved in 20 patients (95.2%). The severe morbidity rate within 30 days after the surgery was 15%. The median follow-up was 70.6 months. Compared with the chemotherapy alone group, the surgery group with R0 had better progression-free survival (PFS) (10.6 vs. 5.1 months; hazard ratio (HR) = 0.421; P = 0.0035) and post-relapse survival (PRS) (32.6 vs. 16.3 months; HR = 0.478; P = 0.047), but there was no difference in overall survival (OS) between the two groups. Laparoscopy is associated with lesser intraoperative blood loss with no differences in survival and postoperative complications compared to the open approach (P = 0.0042). Subgroup survival analysis showed that compared with chemotherapy alone, surgery prolonged PFS in patients regardless of tumor size (greater than or equal to 4 cm or less). Surgery group patients who achieved R0 had an objective response rate (ORR) of 36.8% (7/19), among whom 40% (4/10) received platinum rechallenge chemotherapy and 33.3% (3/9) were administered non-platinum chemotherapy. CONCLUSION: When well-selected PROC patients with limited regional recurrence achieved R0, their outcomes were superior to those of patients who received only chemotherapy with an acceptable morbidity rate. Laparoscope technology could be a reliable alternative surgical approach. The reintroduction of platinum agents may be considered following surgery. Further analyses in a larger population are warranted to elucidate the risks and benefits of this surgery and adjuvant chemotherapy strategy.

Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury.

BACKGROUND: The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. METHODS: A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. RESULTS: In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-ß (IFN-ß) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. CONCLUSIONS: Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-ß-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase g (PIPKIg), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to NRF2. PtdIns(4,5)P 2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIg or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIg and HSP27 as drug targets to destabilize NRF2 in cancer. In brief: Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.

Risk factors for symptomatic malignant pleural effusion recurrence in patients with actionable mutations in advanced lung adenocarcinoma.

Background: Malignant pleural effusion (MPE) comes generally with high mortality and poor prognosis. Recurrence of symptomatic MPE is always accompanied by poor survival quality. In lung adenocarcinoma, researchers speculate whether patients with actionable mutation or without are applicable to different management models for MPE. Under the background of the high mutation probability and the encouraging therapeutic response in Asians, researches on the risk factors of MPE are in need. Methods: This retrospective review included 343 metastatic lung adenocarcinoma patients with MPE. Recurrence was defined as recurrent symptomatic MPE requiring the second thoracentesis to relieve symptoms within 300 days after the first thoracentesis. Univariable and multivariable Cox regression analysis were utilized to investigate independent risk factors for MPE recurrence. Results: Of the 343 patients involved, 139 experienced MPE recurrence within 300 days; 34.3% in 201 patients with actionable mutations and 51.2% in 129 patients without actionable mutations are in the recurrence. The median recurrence-free survival (RFS) of the group without mutations was 161 days. The median RFS of the other group with mutations was 300 days. Patients with actionable mutations showed a significantly lower hazard of MPE recurrence on univariate analysis. The multivariate analysis indicated that receiving targeted therapy after the first thoracentesis within 30 days, lower neutrophil-to-lymphocyte ratio (NLR) level, lower serum lactate dehydrogenase (s-LDH) level, and lower serum carcinoembryonic antigen (s-CEA) level were independent protective factors. In subgroup analysis, risk factors differed. Receiving targeted therapy after the first thoracentesis within 30 days remained an independent factor in the mutated patients. Conclusions: The findings herein indicated the characteristics of specific patients at high risk for MPE recurrence in lung adenocarcinoma. Patients with actionable mutations benefit more in MPE recurrence and could benefit from targeted therapy and active intrapleural management.

Survival outcomes of different neoadjuvant treatment regimens in patients with locally advanced rectal cancer and MRI-detected extramural venous invasion.

PURPOSE: MRI-detected extramural venous invasion (mrEMVI) is associated with poor survival outcomes in patients with locally advanced rectal cancer (LARC). An mrEMVI-positive status is considered a strong indication for neoadjuvant treatment, but the optimal regimen is unknown. PATIENTS AND METHODS: We retrospectively compared pathological and survival outcomes of 584 patients diagnosed with mrEMVI-positive rectal cancer between January 2013 and October 2021, and receiving either neoadjuvant chemotherapy (NCT) alone, neoadjuvant chemoradiotherapy (nCRT) alone, or nCRT plus NCT, prior to total mesorectal excision. Propensity score matching (PSM) was used to balance clinical bias between groups, which were compared using chi-square testing and Kaplan-Meier curves. RESULTS: Median follow-up was 33.9 (range, 10.2-100.4) months. The 3-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS) rates for all patients were 90.4%, 57.5%, 61.1%, and 85.7%, respectively. Of 584 mrEMVI-positive patients at the time of diagnosis, 457 (78.3%) were EMVI-negative on surgical pathology, and they had significantly better 3-year OS, DMFS, DFS, and LRFS rates (all p < 0.001) than patients who remained EMVI-positive. After PSM was applied, patients receiving nCRT alone had significantly better 3-year OS (96.8% vs. 86.5%, p = 0.005) and DMFS (67.1% vs. 53.5%, p = 0.03) rates than those receiving NCT alone. Patients receiving NCT plus nCRT had higher pathological complete response (PCR) (10.8% vs. 2.7%, p = 0.04) and downstaging (33.8% vs. 5.3%, p < 0.001) rates than those receiving nCRT alone, but survival rates did not differ (all p > 0.05). CONCLUSION: Most EMVI-positive patients with LARC converted to EMVI-negative after neoadjuvant treatment, resulting in improved OS and DFS. Patients receiving nCRT had more favorable survival outcomes than those receiving NCT, suggesting the importance of including neoadjuvant radiotherapy. Patients receiving NCT in addition to nCRT had higher rates of PCR and downstaging, but their survival rates were not better.

Potentiating cancer vaccination by adjuvant-loaded cryo-shocked tumor cells.

Cancer vaccine holds vast promise in potentiating tumor immunotherapy. Here, we developed a simple cancer vaccine based on the liquid nitrogen-treated cells (LNT cells) that engineered by one-shot shocking of the live tumor cells in liquid nitrogen. In this vaccine, the obtained LNT cells served as both tumor antigens and delivery vehicles to load the adjuvant imiquimod (R837). This design could achieve efficient co-uptake of antigen/adjuvant by antigen presenting cells (APCs) and prolong in vivo retention of tumor antigens and adjuvants. This adjuvant-loaded LNT cells augmented in vivo antitumor responses and enhanced survival in melanoma-bearing mouse model compared with conventional whole-cell vaccine of the mixture of tumor lysis and adjuvant.

Clinical value of combined serum CA125, NSE and 24-hour urine VMA for the prediction of recurrence in children with neuroblastoma.

BACKGROUND: In this study, we intend to retrospectively analyze the clinical data of postoperative neuroblastoma children, including the results of follow-up examinations and laboratory tests, to explore the clinical value of combined serum Carbohydrate antigen 125 (CA125), neuron-specific enolase (NSE) and 24-hour urine vanillylmandelic acid (VMA) levels at baseline for the prediction of recurrence in children with neuroblastoma. METHODS: 265 children with neuroblastoma were successfully followed up, including 163 cases without recurrence (non-recurrence group) and 102 cases with recurrence (recurrence group). The levels of 24-hour urine VMA were determined using spectrophotometric methods. Additionally, the serum levels of CA125 and NSE were measured using electrochemiluminescence immunoassay. RESULTS: The serum CA125, NSE and 24-hour urine VMA levels were significantly higher in the recurrence group than in the non-recurrence group. It demonstrated a significant positive correlation between the levels of serum CA125, NSE, and 24-hour urine VMA in all children with neuroblastoma. All children in stage IV of neuroblastoma had the highest level of serum CA125, NSE and 24-hour urine VMA and vice versa. The combined CA125, NSE and VMA had significantly better sensitivity and specificity than an individual marker. CONCLUSIONS: Combined serum CA125, NSE and 24-hour urine VMA had the potential to predict neuroblastoma recurrence more effectively.