Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation.

VHL loss enhances antitumor immunity by activating the anti-viral DNA-sensing pathway.

von Hippel-Lindau (), known as a tumor suppressor gene, is frequently mutated in clear cell renal cell carcinoma (ccRCC). However, mutation is not sufficient to promote tumor formation. In most cases other than ccRCC, loss alters cellular homeostasis and causes cell stress and metabolic changes by stabilizing hypoxia-inducible factor (HIF) levels, resulting in a fitness disadvantage.

Caspase-3 promotes oncogene-induced malignant transformation via EndoG-dependent Src-STAT3 phosphorylation.

Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer.

Disclosing phototransformation mechanisms of decabromodiphenyl ether (BDE-209) in different media by simulated sunlight: Implication by compound-specific stable isotope analysis.

As one of the typical brominated flame retardants, decabromodiphenyl ether (BDE-209) has been widely detected in environment. However, scarce information was available on BDE-209 phototransformation mechanisms in various media. In this study, compound-specific stable isotope analysis was first applied to investigate BDE-209 phototransformation in n-hexane, MeOH:HO (v:v, 8:2), and simulated seawater by simulated sunlight.

VHL loss enables immune checkpoint blockade therapy by boosting type I interferon response.

Despite a moderate mutation burden, clear cell renal cell carcinoma (ccRCC) responds well to immune checkpoint blockade (ICB) therapy. Here we report that loss-of-function mutations in the von Hippel-Lindau (VHL) gene, the most frequent in ccRCC, underlies its responsiveness to ICB therapy. We demonstrate that genetic knockout of the gene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner.

Novel Insights into Uptake, Translocation, and Transformation Mechanisms of 2,2',4,4'-Tetra Brominated Diphenyl Ether (BDE-47) in Wheat ( L.): Implication by Compound-Specific Stable Isotope and Transcriptome Analysis.

The uptake, translocation, and transformation of 2,2',4,4'-tetra brominated diphenyl ether (BDE-47) in wheat ( L.) were comprehensively investigated by hydroponic experiments using compound-specific stable isotope analysis (CSIA) and transcriptome analysis. The results indicated that BDE-47 was quickly adsorbed on epidermis of wheat roots and then absorbed in roots via water and anion channels as well as an active process dependent on energy.

Mechanistic characterization of anaerobic microbial degradation of BTBPE in coastal wetland soils: Implication by compound-specific stable isotope analysis.

As a novel brominate flame retardants, 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) has been extensively used in various consumer products, and frequently detected in various environmental matrices. However, the microbial degradation of BTBPE remains unclear in the environment. This study comprehensively investigated the anaerobic microbial degradation of BTBPE and therein stable carbon isotope effect in the wetland soils.

Near-Death Cells Cause Chemotherapy-Induced Metastasis via ATF4-Mediated NF-κB Signaling Activation.

Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear.

Systematic characterization of sediment microbial community structure and function associated with anaerobic microbial degradation of PBDEs in coastal wetland.

As the widely used flame retardant, polybrominated diphenyl ethers (PBDEs) have been ubiquitously detected in wetland sediments. Microbial degradation is the importantly natural attenuation process for PBDEs in sediments. In this study, the microbial degradation of PBDEs and inherent alternation of microbial communities were explored in anaerobic sediments from coastal wetland, North China.

Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor.

Repopulation of residual tumor cells impedes curative radiotherapy, yet the mechanism is not fully understood. It is recently appreciated that cancer cells adopt a transient persistence to survive the stress of chemo- or targeted therapy and facilitate eventual relapse. Here, it is shown that cancer cells likewise enter a "radiation-tolerant persister" (RTP) state to evade radiation pressure in vitro and in vivo.

Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy.

Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy.

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

Unlabelled: The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression.

Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft--Host Disease While Preserving Graft-Versus-Leukemia Effect.

Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors.

A pleiotropic ATM variant (rs1800057 C>G) is associated with risk of multiple cancers.

ATM (ataxia-telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect on cancer development.

miR-29b-3p Increases Radiosensitivity in Stemness Cancer Cells Modulating Oncogenes Axis.

Radioresistance conferred by cancer stem cells (CSCs) is the principal cause of the failure of cancer radiotherapy. Eradication of CSCs is a prime therapeutic target and a requirement for effective radiotherapy. Three dimensional (3D) cell-cultured model could mimic the morphology of cells and induce CSC properties.

Non-canonical roles of apoptotic and DNA double-strand break repair factors in mediating cellular response to ionizing radiation.

Purpose: To provide an updated summary of recent advances in our understanding of the non-canonical roles of apoptotic and DNA double-strand break repair factors in various biological processes, especially in the cellular response to radiotherapy.

Conclusion: Apoptotic caspases are usually considered as "executioners'' of unwanted or damaged cells or tissues. However, recent studies indicated they play multiple additional, often counterintuitive roles in many biological processes.

A Gene Mutation Signature Predicting Immunotherapy Benefits in Patients With NSCLC.

Introduction: Identification of patients who can benefit from immune checkpoint blockade (ICB) therapy is key for improved clinical outcome. Recently, U.S.

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation.

Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia telangiectasia mutated (ATM) protein plays a central role in sensing DNA double-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy.

Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.

Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions.

JMJD5 couples with CDK9 to release the paused RNA polymerase II.

More than 30% of genes in higher eukaryotes are regulated by RNA polymerase II (Pol II) promoter proximal pausing. Pausing is released by the positive transcription elongation factor complex (P-TEFb). However, the exact mechanism by which this occurs and whether phosphorylation of the carboxyl-terminal domain of Pol II is involved in the process remains unknown.

Limited MOMP, ATM, and their roles in carcinogenesis and cancer treatment.

Limited mitochondria outer membrane permeability (MOMP) is a novel biological process where mammalian cells initiate the intrinsic apoptosis pathway with increased mitochondrial permeability but survive. One of the major consequences of limited MOMP is apoptotic endonuclease-induced DNA double strand breaks. Recent studies indicate that these DNA double stand breaks and ensuing activation of DNA damage response factors such as ATM play important but previously underappreciated roles in carcinogenesis and tumor growth.

Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy.

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation.

ATM Paradoxically Promotes Oncogenic Transformation via Transcriptional Reprogramming.

The role of the ataxia-telangiectasia-mutated (ATM) gene in human malignancies, especially in solid tumors, remains poorly understood. In the present study, we explored the involvement of ATM in transforming primary human cells into cancer stem cells. We show that ATM plays an unexpected role in facilitating oncogene-induced malignant transformation through transcriptional reprogramming.

JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes.

More than 30% of genes in higher eukaryotes are regulated by promoter-proximal pausing of RNA polymerase II (Pol II). Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. The exact mechanism on how the sequestered P-TEFb is released from the 7SK snRNP complex and recruited to Pol II CTD remains unknown.