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 cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy3-5 (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 metabolism6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.

Spleen regeneration after subcutaneous heterotopic autotransplantation in a mouse model.

BACKGROUND: Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the spleen. Splenic autografts rapidly restore the regular splenic microanatomy in model animals. However, the functional competence of such regenerated autografts in terms of lympho- and hematopoietic capacity remains uncertain. Therefore, this study aimed to monitor the dynamics of B and T lymphocyte populations, the monocyte-macrophage system, and megakaryocytopoiesis in murine splenic autografts. METHODS: The model of subcutaneous splenic engraftment was implemented in C57Bl male mice. Cell sources of functional recovery were studied using heterotopic transplantations from B10-GFP donors to C57Bl recipients. The cellular composition dynamics were studied by immunohistochemistry and flow cytometry. Expression of regulatory genes at mRNA and protein levels was assessed by real-time PCR and Western blot, respectively. RESULTS: Characteristic splenic architecture is restored within 30 days post-transplantation, consistent with other studies. The monocyte-macrophage system, megakaryocytes, and B lymphocytes show the highest rates, whereas the functional recovery of T cells takes longer. Cross-strain splenic engraftments using B10-GFP donors indicate the recipient-derived cell sources of the recovery. Transplantations of scaffolds populated with splenic stromal cells or without them afforded no restoration of the characteristic splenic architecture. CONCLUSIONS: Allogeneic subcutaneous transplantation of splenic fragments in a mouse model leads to their structural recovery within 30 days, with full reconstitution of the monocyte-macrophage, megakaryocyte and B lymphocyte populations. The circulating hematopoietic cells provide the likely source for the cell composition recovery.

Comparison of the accumulation and metabolite of fluoxetine in zebrafish larva under different environmental conditions with or without carbon nanotubes.

Few studies have focused on the influence of environmental conditions on the bioavailability of pollutants interacted with nanomaterials in organisms. In this study, we primarily compared the influence of multiwalled carbon nanotubes (MWCNTs) on the bioavailability of fluoxetine in zebrafish (Danio rerio) larva under different environmental conditions: natural organic matter (NOM) and salinity. The results showed that fluoxetine accumulated in the larvae and then transformed into the metabolite norfluoxetine, with the metabolic rates from 2.8 to 3.5. Following co-exposure to MWCNTs, the accumulation of fluoxetine and norfluoxetine were further enhanced, suggesting a superior carrier of MWCNTs for fluoxetine, especially the functional MWCNTs. The consistent increase in the fluoxetine and norfluoxetine accumulation highlights the bioavailability of absorbed fluoxetine on MWCNTs in zebrafish larvae. The presence of NOM promoted the accumulation of fluoxetine and norfluoxetine in zebrafish, but alleviated the carrier effects of MWCNTs, acting as a natural antidote. Salinity negatively influenced the bioavailability of fluoxetine in the larvae, and further reversed the enhancements caused by MWCNTs. These findings provide a new insight into the influence of environmental conditions on the interactions between nanomaterials and pollutants in organisms.

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 µg (the acute cohort) and 0, 0.05, 0.1, 0.35 µg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 µg (5/10 rats) and 0.35 µg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 µg, and the no-observed-adverse-effect-level was 0.05 µg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

Role of Protease-Activated Receptor-1 in Glioma Growth.

Activation of a thrombin receptor, protease-activated receptor-1 (PAR-1), induces angiogenesis, cell proliferation, and invasion in tumors. The present study examined the effect of host PAR-1 gene deletion on glioma growth in a mouse model. F98 glioma cells were implanted into the right caudate of either wild type (WT) or PAR-1 knockout (KO) mice. Mice underwent magnetic resonance imaging (MRI) and the brains were used for measurements of brain water content and tumor mass. Levels of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were also measured by ELISA (enzyme-linked immunosorbent assay). We found brain water content in the ipsilateral hemisphere and the tumor mass were significantly lower in PAR-1 KO than WT mice at day 12 after implantation of F98 cells (p < 0.05). HIF-1α protein levels in the ipsilateral hemisphere were higher in the WT mice (373 ± 25 pg/g brain tissue vs 333 ± 35 pg/g brain tissue in PAR-1 KO mice, p < 0.05) 7 days after F98 cell implantation. VEGF protein levels were also higher in the ipsilateral hemisphere of WT mice (219 ± 21 vs 166 ± 22 pg/g brain tissue in PAR-1 KO mice, p < 0.01). In conclusion, PAR-1 has a role in glioma growth and could be a new therapeutic target for gliomas.

[Biological Effect of Microplastics with Different Functional Groups on the Bacterial Communities and Metabolic Functions of Zebrafish (Danio rerio) Embryos].

To investigate the influences of functional groups on the biological effects caused by microplastics, the accumulation of three polystyrene microplastics (PS, PS-NH2, and PS-COOH) in zebrafish (Danio rerio) embryos were analyzed, and then the responses of metabolic functions and microbial communities in zebrafish larvae were revealed using the combination of the microbiome and metabolome methods. The results showed that all microplastics could accumulate in zebrafish with concentrations ranging from 143 to 175 µg·g-1, and there were no significant differences in the accumulation potentials among different PS treatments. Exposure to plain PS significantly affected the metabolic capacity of aminoglycosides in zebrafish larvae, whereas the metabolic processes of amino acids were affected by PS-NH2. In the PS-COOH treatment, the metabolic pathways of the tricarboxylic acid cycle, amino acids, and glycolysis in zebrafish were markedly altered. The metabolic functions of zebrafish larvae were changed by all PS microplastics, resulting in toxic effects on zebrafish, and the functional group modification of microplastics may have further enhanced these toxicities. Compared to that in the control, exposure to PS-NH2 significantly reduced the diversity of microbial communities in zebrafish larvae and increased the proportion of Proteobacteria in the composition, leading to an imbalance of the bacterial community in zebrafish and thus disrupting the metabolic functions in the fish. Therefore, the functional modifications of microplastics may significantly alter the related stresses on aquatic organisms, leading to unpredictable ecological risks.

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

Integrative bioinformatics approach for identifying key genes and potential therapeutic targets in the concurrent manifestation of hypertrophic cardiomyopathy and pulmonary hypertension.

Background: Hypertrophic cardiomyopathy (HCM), identified as a primary cause of sudden cardiac death (SCD), intertwines with pulmonary hypertension (PH) to amplify cardiovascular morbidity. This complex synergy poses significant therapeutic challenges due to the absence of drugs specifically targeting their concurrent manifestation. This study seeks to unravel the molecular intricacies linking HCM and PH, aiming to lay the groundwork for targeted therapeutic interventions. Methods: Through the analysis of gene expression profiles from datasets GSE36961 (HCM) and GSE113439 (PH) within the public data repository of Gene Expression Omnibus (GEO), this research systematically identified differentially expressed genes (DEGs), conducted extensive functional annotations, and constructed detailed protein-protein interaction (PPI) networks to uncover crucial hub genes. Further, co-expression analyses, alongside drug prediction and molecular docking simulations, were employed to pinpoint potential therapeutic agents that could ameliorate the combined pathology of HCM and PH. Results: Our comprehensive analysis unearthed 79 DEGs shared between HCM and PH, highlighting fourteen as pivotal hub genes. Validation across three additional datasets (GSE35229, GSE32453, and GSE53408) from GEO accentuated secreted phosphoprotein 1 (SPP1) as a key gene of interest. Remarkably, the study identified tacrolimus, ponatinib, bosutinib, dasatinib, doxorubicin, and zanubrutinib as promising drugs for addressing the dual challenge of HCM and PH. Conclusions: The findings of this investigation shed light on the genetic underpinnings of HCM and PH's simultaneous occurrence, emphasizing the central role of SPP1 in their pathogenesis. The identification of six candidate drugs offers a hopeful vista for future therapeutic strategies targeting this complex cardiovascular interplay, marking a significant stride towards mitigating the compounded morbidity of HCM and PH. Future mechanistic and clinical studies are warranted for the investigation of this potential target and therapeutics.

Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors.

Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10(-8) M, 8.0 × 10(-8) M and 3.9 × 10(-10) M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors.

Effects of polystyrene nanoplastics on melanin interference toxicity and transgenerational toxicity of ethylhexyl salicylate based on DNA methylation sequencing.

Organic ultraviolet filters (OUVFs) are new hydrophobic organic pollutants in the aquatic environment. When ingested by aquatic organisms, OUVFs can induce a variety of toxic effects in organisms and be transferred to offspring. However, as the main active ingredient in sunscreens, OUVFs have rarely been investigated for their melanin interference toxicity or transgenerational toxic effects on aquatic organisms and their interactive toxic effects with nanoplastics (NPs). Here, we show the mechanism by which OUVFs interfere with melanogenesis in parental or offspring zebrafish and the effect of polystyrene (PS) NPs on the melanin-interference effect of OUVFs. We found that EHS induced significant enrichment of the melanogenesis pathway, inhibited the expression of the key melanin gene microphthalmia-associated transcription factor a (mitfa) and induced the mitf tyrosinase (tyr)-dopachrome tautomerase (dct)-tyrosinase related protein 1 (tyrp1) signaling cascade in parents, which ultimately induced a decrease in melanin content. After reproduction, transgenerational melanin interference effects of EHS may occur through the maternal inheritance of mitfa. Coexisting PS-NPs may inhibit the melanin interference toxicity or transgenerational toxicity of EHS by reducing ultraviolet irritation to the skin through adsorption of EHS. Our results demonstrate the ecotoxic potential of OUVFs in terms of melanin interference and the interference of PS-NP carrier effects on the toxicity of OUVFs. We anticipate that our assay will contribute to the assessment of the toxic effects of OUVFs and provide a basis for the interactive ecotoxicity assessment of PS-NPs and hydrophobic organic pollutants.

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 VHL gene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α and HIF2α induced by VHL gene loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA (mtDNA), which triggered cGAS-STING activation and induced type I interferons. Our study thus provided novel mechanistic insights into the role of VHL gene loss in potentiating ccRCC immunotherapy.

Bacterial-Mediated Tumor Therapy: Old Treatment in a New Context.

Targeted therapy and immunotherapy have brought hopes for precision cancer treatment. However, complex physiological barriers and tumor immunosuppression result in poor efficacy, side effects, and resistance to antitumor therapies. Bacteria-mediated antitumor therapy provides new options to address these challenges. Thanks to their special characteristics, bacteria have excellent ability to destroy tumor cells from the inside and induce innate and adaptive antitumor immune responses. Furthermore, bacterial components, including bacterial vesicles, spores, toxins, metabolites, and other active substances, similarly inherit their unique targeting properties and antitumor capabilities. Bacteria and their accessory products can even be reprogrammed to produce and deliver antitumor agents according to clinical needs. This review first discusses the role of different bacteria in the development of tumorigenesis and the latest advances in bacteria-based delivery platforms and the existing obstacles for application. Moreover, the prospect and challenges of clinical transformation of engineered bacteria are also summarized.

Second malignant neoplasms in childhood malignant brain tumour: a long-term population-based study.

AIM: To provide a profile of second malignant neoplasms (SMN) in patients with childhood primary malignant brain tumour originating from neuroepithelial tissues with latest data in a population-based study. METHODS: Surveillance, Epidemiology, and End Results (SEER) database (1973-2007) was used to identify above-stated patients. SMN patients were further identified, and standardised incidence ratios (SIRs) and excess absolute risks (EARs) for risk-factor-decided subgroups were calculated. Univariate and multivariate analyses of the association between cumulative incidence of SMN and the risk factors were performed in the whole population. RESULTS: A total of 106 patients were identified as having SMNs. EARs peaked at age at primary diagnosis of 10-14. Males had higher SIRs and EARs than females. Both SIRs and EARs increased after 1990. Age was statistically significant in both univariable and multivariable analyses for cumulative incidence of SMN and RT was not significant in both the analyses, in the whole population of 9075 patients. After follow-up recalculation, matched patients in the ≥1990 group had slightly shorter median interval between primary and secondary cancer than those in the <1990 group, but with no significance. CONCLUSION: The risk of SMN in children with primary malignant brain tumours in a more advanced treatment era might have changed. During making further advances in the treatment of these neoplasms, minimising toxicities while maintaining promising prognostic outcomes will keep being our goal.

Targeting purinergic pathway to enhance radiotherapy-induced immunogenic cancer cell death.

Emerging evidence has demonstrated that radiotherapy (RT) can not only cause direct damage to cancer cells but also lead to immunogenic cell death (ICD), which involves the activation of host antitumor immune response in tumor immune microenvironment (TIME). RT-induced ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying cancer cells that result in the activation of tumor-specific immunity to elicit long-term antitumor efficacy in both original and abscopal tumor sites. Adenosine triphosphate (ATP), as an important DAMP released by irradiated cancer cells and an essential factor within purinergic pathway, can be further hydrolyzed to adenosine (ADO) by two key ectonucleotidases, CD39 and CD73, to further modulate the antitumor immunity in TIME through purinergic signaling via the interaction to its specific receptors such as adenosine 2A receptor (A2AR) and A2BR widely expressed on the surface of the components in TIME, including cancer cells and many immune effector cells. In this review, we first introduced key components in purinergic pathway including ATP, ADO, their receptors, and essential ectonucleotidases. Then we reviewed the regulation of ATP and ADO levels and their main mechanisms by which they promote tumor growth and broadly suppress antitumor immunity through inhibiting the pro-inflammatory response of dendritic cells, cytotoxic T lymphocytes, and natural killer cells, while improving the anti-inflammatory response of regulatory T cells, macrophages, and myeloid-derived suppressor cells in TIME, especially after irradiation. Finally, we presented an overview of dozens of promising therapeutics including pharmacological antagonists and specific antibodies targeting ADO receptors and ectonucleotidases CD39 or CD73 investigated in the clinic for cancer treatment, especially focusing on the preclinical studies and clinical trials being explored for blocking the purinergic signaling to enhance RT as a combination antitumor therapeutic strategy, which has a robust potential to be translated to the clinic in the future.

SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

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. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral mimicry to upregulate type I interferons. SETDB1 expression correlated with radiotherapy efficacy in human non-small cell carcinoma and melanoma patients. In a murine tumor model, genetic deletion of Setdb1 significantly enhanced radiotherapy efficacy, and Setdb1-deficient tumors had enhanced intratumoral lymphocyte infiltration, an observation confirmed in human cancer samples. Setdb1 deficiency led to increased basal and radiation-induced endogenous retrovirus (ERV) expression, enhanced MDA5/MAVS signaling, and upregulated type I interferons, which were essential for SETDB1 deficiency-induced radiosensitization. Taken together, these data suggest that inhibition of SETDB1 is a promising approach to enhance cancer radiotherapy efficacy by promoting radiation-induced viral mimicry and antitumor immunity through ERV induction. SIGNIFICANCE: The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.

Microplastic pollution in an urbanized river affected by water diversion: Combining with active biomonitoring.

Microplastics as the most challenging environmental pollutants in ocean have raised increasing concerns, however, the understanding of microplastics in freshwater falls far behind. The main objective of this study is to assess the microplastic pollution in an urbanized river affected by water diversion. The active biomonitoring method with caged native crucian carp (Carassius auratus) was used to evaluate the microplastic risk for riverine fish. It found that microplastic abundance in water and sediment was 1467-20567 items/m³ and 1115-6380 items/kg, respectively. The operational water diversion did not alleviate the microplastic pollution in water. The abundance in sediment was not simply proportional to that in water. However, the main morphological profiles and polymer composition were similar in the water and sediment. Microplastic accumulation in caged fish intestine was higher than that in gill. Intestine seems to be an ideal tissue to reflect the microplastic pollution in water. Shapes may contribute to the accumulation in fish. Based on the pollution load index, all caged fish did not reach to high level risks. These findings not only improve the understanding on the impact of water diversion on microplastic pollution in urban river, but also shed an insight in the related risk for riverine fish.

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. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell-dependent manner. Furthermore, chemical inhibition of ATM potentiated anti-PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.

Factors affecting prognosis of patients with intracranial anaplastic oligodendrogliomas: a single institutional review of 70 patients.

Anaplastic oligodendroglioma (AO) is an uncommon intracranial tumor and prognosis is poor. In this study, we assessed the factors affecting the prognosis of AO patients. Seventy AO patients were recruited from 2001 to 2006 in Shanghai Huashan Hospital of Fudan University; all were treated surgically. Kaplan-Meier survival analysis and Cox regression analysis were used to analyze the prognostic effects of 14 different factors, which were selected from clinical, radiological, pathological, and treatment variables. The results showed that chemotherapy, age, primary or secondary tumors, preoperative Karnofsky Performance Scale (KPS) scores, the presence of epilepsy at initial presentation, radiological contrast infusion, and neurological parameters all correlated with the prognosis of the patients. Furthermore, Cox multivariate analysis also showed that the age (P < 0.048), primary or secondary tumors (P < 0.010), and chemotherapy (P < 0.010) were significantly correlated with the prognosis of the patients. Age and chemotherapy correlated with the prognosis of AO. The patients younger than 50 years old and who received regular chemotherapy were likely to achieve a good outcome. Moreover, individualized treatment after molecular biological typing of AO may improve the prognosis of AO.

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. Furthermore, novel non-canonical roles of DNA repair factors such as ATM in tumor growth and treatment are also emerging. In this review, we try to summarize recent findings on this newly revealed link between DNA double strand break repair and cell death pathways.

A review of the influences of microplastics on toxicity and transgenerational effects of pharmaceutical and personal care products in aquatic environment.

PPCPs (pharmaceutical and personal care products) and microplastics (MPs) are two types of emerging pollutants that are ubiquitous and widely concerned in the environment. Both of them can accumulate in fish or aquatic invertebrates and transfer to offspring, thereby producing toxic effects on both parents and offspring, in which the characteristics of MPs also enable them to adsorb PPCPs thus producing carrier effects. In this study, we have conducted a comprehensive review of MPs and PPCPs and found that MPs can act as a carrier of PPCPs to influence the bioaccumulation of PPCPs. MPs and PPCPs have toxicity and transgenerational effects on both fish and aquatic invertebrates in many aspects, and MPs can also affect the toxicity and transgenerational effects of PPCPs due to their carrier effects. This paper revealed that MPs may have an important impact on the bioavailability of PPCPs and the interaction between MPs and PPCPs is a hot topic in future research. This study also puts forward the shortcomings of the current research and related suggestions, and relevant research should be carried out as soon as possible to provide the basis for the prevention and treatment of fresh water.