A domain knowledge-based interpretable deep learning system for improving clinical breast ultrasound diagnosis.

BACKGROUND: Though deep learning has consistently demonstrated advantages in the automatic interpretation of breast ultrasound images, its black-box nature hinders potential interactions with radiologists, posing obstacles for clinical deployment. METHODS: We proposed a domain knowledge-based interpretable deep learning system for improving breast cancer risk prediction via paired multimodal ultrasound images. The deep learning system was developed on 4320 multimodal breast ultrasound images of 1440 biopsy-confirmed lesions from 1348 prospectively enrolled patients across two hospitals between August 2019 and December 2022. The lesions were allocated to 70% training cohort, 10% validation cohort, and 20% test cohort based on case recruitment date. RESULTS: Here, we show that the interpretable deep learning system can predict breast cancer risk as accurately as experienced radiologists, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval = 0.882 - 0.921), sensitivity of 75.2%, and specificity of 91.8% on the test cohort. With the aid of the deep learning system, particularly its inherent explainable features, junior radiologists tend to achieve better clinical outcomes, while senior radiologists experience increased confidence levels. Multimodal ultrasound images augmented with domain knowledge-based reasoning cues enable an effective human-machine collaboration at a high level of prediction performance. CONCLUSIONS: Such a clinically applicable deep learning system may be incorporated into future breast cancer screening and support assisted or second-read workflows.

Breast cancer is one of the most common cancers, and finding it early can greatly improve patients' chances of survival and recovery. We create a tool based on artificial intelligence (AI)­whereby computer software learns to perform tasks that normally require human thinking­called MUP-Net. MUP-Net can analyze medical images to predict a patient's risk of having breast cancer. To make this AI tool usable in clinical practice, we enabled doctors to see the reasoning behind the AI's predictions by visualizing the key image features it analyzed. We showed that our AI tool not only makes doctors more confident in their diagnosis but also helps them make better decisions, especially for less experienced doctors. With further testing, our AI tool may help clinicians to diagnose breast cancer more accurately and quickly, potentially improving patient outcomes.

Association between metabolic reprogramming and immune regulation in digestive tract tumors.

BACKGROUND: The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer (GC) and Esophageal cancer (ESCA), are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. SUMMARY: Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing-equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. KEY MESSAGES: In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence antitumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anticancer immunotherapy.

Diagnosis and management of intraspinal tuberculoma with osseous involvement: a case report.

Introduction and importance: Intraspinal tuberculoma is rare and challenging situation, which results in serious neurological dysfunctions. Case presentation: This case report shows an intraspinal tuberculoma with osseous involvement in a 31-year-old male patient with subacute progressing neurologic deficit. His medical history included tuberculosis of pulmonary and intestinal 8 years previously, at which time he had been treated with intestinal obstruction operation and antituberculosis treatment. A quadruple antituberculosis treatment was carried out after admission; however, his neurological condition was steadily worsening. He underwent debulking of mass for decompression and pathological analysis revealed intraspinal tuberculoma. The patient was prescribed a 12-month course of antituberculosis therapy, and a good clinical outcome was obtained subsequently. Clinical discussion: This case was treated by microsurgical resection and antituberculosis therapy, and the outcome was favourable. Conclusion: Intraspinal tuberculoma should be considered when an intraspinal mass is found with a history of tuberculosis, it can be effectively diagnosed by MRI and treated by the combination of medical and surgical treatments.

Inhibition of autophagy-related protein 7 enhances anti-tumor immune response and improves efficacy of immune checkpoint blockade in microsatellite instability colorectal cancer.

BACKGROUND: The efficacy of anti-PD-1 therapy is primarily hindered by the limited T-cell immune response rate and immune evasion capacity of tumor cells. Autophagy-related protein 7 (ATG7) plays an important role in autophagy and it has been linked to cancer. However, the role of ATG7 in the effect of immune checkpoint blockade (ICB) treatment on high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) CRC is still poorly understood. METHODS: In this study, patients from the cancer genome altas (TCGA) COAD/READ cohorts were used to investigate the biological mechanism driving ATG7 development. Several assays were conducted including the colony formation, cell viability, qRT-PCR, western blot, immunofluorescence, flow cytometry, ELISA, immunohistochemistry staining and in vivo tumorigenicity tests. RESULTS: We found that ATG7 plays a crucial role in MSI-H CRC. Its knockdown decreased tumor growth and caused an infiltration of CD8+ T effector cells in vivo. ATG7 inhibition restored surface major histocompatibility complex I (MHC-I) levels, causing improved antigen presentation and anti-tumor T cell response by activating reactive oxygen species (ROS)/NF-κB pathway. Meanwhile, ATG7 inhibition also suppressed cholesterol accumulation and augmentation of anti-tumor immune responses. Combining ATG7 inhibition and statins improved the therapeutic benefit of anti-PD-1 in MSI-H CRC. Importantly, CRC patients with high expression of both ATG7 and recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) experienced worse prognosis compared to those with low ATG7 and HMGCR expression. CONCLUSIONS: Inhibition of ATG7 leads to upregulation of MHC-I expression, augments immune response and suppresses cholesterol accumulation. These findings demonstrate that ATG7 inhibition has therapeutic potential and application of statins can increase the sensitivity to immune checkpoint inhibitors.

Case Report: Gas in the esophagus, stomach wall and portal vein with congenital hypertrophic pyloric stenosis.

Background: CHPS dramatically affects infant growth and development and can even cause aspiration resulting from esophageal reflux. There is potential danger. CHPS is common, while CHPS with gas in the stomach wall and portal vein is rare. Gas in the stomach wall and portal vein are often the key features of more serious disease. It can be easily mistaken as a serious disease when patients with CHPS have gas in the stomach wall and portal vein. Case presentation: A 56-day-old baby was hospitalized for aspiration pneumonia after vomiting without bile for 20 days. Compared with vomiting, which is the most common symptom, pneumonia tends to attract more attention. Because of pneumonia, a chest CT scan was performed and revealed massive gas accumulation in the walls of the esophagus, stomach, and portal vein. Therefore, NEC was considered first and was treated conservatively for one week. However, the vomiting continued, and CHPS was confirmed by ultrasound. The delay in CHPS diagnosis was due to insufficient recognition of the signs of gas accumulation. Because of inexperience and lack of knowledge about CHPS with gastrointestinal pneumatosis, physicians failed to make an early accurate diagnosis. Case 2 was a 29-day-old male who was admitted to the hospital with vomiting without bile. He was examined by ultrasound, which revealed gas in the stomach wall and portal vein after admission to the hospital. No peritonitis was found after a detailed and comprehensive physical examination. Emergency life-threatening diseases such as NEC were quickly ruled out. He received surgery as soon as possible and had an uneventful recovery with no complications. Conclusion: CHPS may present with gas in the gastric or esophageal wall and portal vein, which is not a contraindication to surgery.

CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer.

As the world's fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.

Clinical outcomes and medical resource utilization of toripalimab combination therapy versus bevacizumab plus chemotherapy in advanced non-squamous non-small cell lung cancer.

OBJECTIVE: This study aimed to evaluate the real-world clinical efficacy and safety, economic burdens and medical resource utilization (MRU) of toripalimab treatment patterns compared with bevacizumab plus chemotherapy (BCP) for patients with advanced non-squamous NSCLC in China. METHODS: Progression-free survival (PFS), adverse drug reactions (ADR) and the costs of drugs, laboratory testing, imageology examinations (including CT, B ultrasound, MRI), medical service, nursing, treatment, genetic test and medical disposable material were compared between two groups. A retrospective observational study was conducted with electronic medical records from Fudan University Huashan hospital. Data was obtained from established electronic medical records (EMRs) and patient surveys. Survival time from the study enrollment to disease progression or death plus from 1st progression disease (PD) in the maintenance phase to 2nd PD (PFS II), adverse events (AE), direct medical costs, MRU and AE-related costs were collected and compared between toripalimab group and BCP group. A total of 246 patients were enrolled. RESULTS: Toripalimab combination therapy has significantly prolonged PFS comparing with BCP (13.8 months vs. 6.2 months, p < .001). A statistically significant improvement in PFS was observed favoring all toripalimab regimen subgroups compared with the bevacizumab group. Patients in toripalimab group occupied more overall resource consumption, more direct medical costs ($47,056.9 vs. $29,951.0, p < .0001) and AE-related costs ($4,500.2 vs. $784.4, p < .0001) than BCP group. Although patients in the toripalimab group used more drugs to prevent AEs ($4,500.2 vs. $784.4, p < .0001), they still experienced more AEs than patients in BCP group (51.4% vs. 41.4%). CONCLUSION: Toripalimab combination therapy could significantly prolonged PFS for patients with advanced non-squamous NSCLC compared with BCP, but at the expense of more MRU, costs and AEs.

Pulmonary RNA interference against acute lung injury mediated by mucus- and cell-penetrating nanocomplexes.

Trans-mucosal delivery of anti-inflammatory siRNA into alveolar macrophages represents a promising modality for the treatment of acute lung injury (ALI). However, its therapeutic efficacy is often hurdled by the lack of effective carriers that can simultaneously overcome the mucosal barrier and cell membrane barrier. Herein, we developed mucus/cell membrane dual-penetrating, macrophage-targeting polyplexes which enabled efficient intratracheal delivery of TNF-α siRNA (siTNF-α) to attenuate pulmonary inflammation against lipopolysaccharide (LPS)-induced ALI. P-G@Zn, a cationic helical polypeptide bearing both guanidine and zinc dipicolylamine (Zn-DPA) side charged groups, was designed to condense siTNF-α and promote macrophage internalization due to its helicity-dependent membrane activity. Coating of the polyplexes with charge-neutralizing carboxylated mannan (Man-COOH) greatly enhanced the mucus penetration potency due to shielding of the electrostatic adhesive interactions with the mucus, and it cooperatively enabled active targeting to alveolar macrophages to potentiate the intracellular delivery efficiency of siTNF-α. As such, intratracheally administered Man-COOH/P-G@Zn/siTNF-α polyplexes provoked notable TNF-α silencing by ∼75 % in inflamed lung tissues at 500 µg siRNA/kg, and demonstrated potent anti-inflammatory performance to treat ALI. This study provides an effective tool for the synchronized trans-mucosal delivery of siRNA into macrophages, and the unique properties of the polyplexes render remarkable potentials for anti-inflammatory therapy against ALI. STATEMENT OF SIGNIFICANCE: siRNA-mediated anti-inflammatory management of acute lung injury (ALI) is greatly challenged by the insufficient delivery across the mucus layer and cell membrane. To address such critical issue, mucus/cell membrane dual-penetrating, macrophage-targeting polyplexes are herein developed, which are comprised of an outer shell of carboxylated mannan (Man-COOH) and an inner nanocore formed by TNF-α siRNA (siTNF-α) and a cationic helical polypeptide P-G@Zn. Man-COOH coating endowed the polyplexes with high mucus-penetrating capability and macrophage-targeting ability, while P-G@Zn bearing both guanidine and zinc dipicolylamine afforded potent siTNF-α condensation capacity and high intracellular delivery efficiency with reduced cytotoxicity. Intratracheally administered polyplexes solicit pronounced TNF-α silencing and anti-inflammatory efficiencies in ALI mice. This study renders an effective example for overcoming the multiple barriers against trans-mucosal delivery of siRNA into macrophages, and holds profound potentials for gene therapy against ALI.

STAT3 and STAT6 polymorphisms predict the severity of adverse reactions in Chinese NSCLC patients receiving EGFR-TKIs therapy.

A total of 162 non-small cell lung cancer (NSCLC) patients were divided into discovery (N = 68) and validation (N = 94) groups. Nine Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway-related single nucleotide polymorphisms were selected to explore the potential associations between genetic polymorphisms and adverse drug reactions (ADRs). The TT genotype of STAT6 rs324011 was significantly associated with severe ADRs in the recessive genetic model (TT vs. CC + CT, OR = 13.5, 95% CI = 2.12-86.09, p = 0.006 in the discovery group; OR = 8.41, 95% CI = 1.95-36.19, p = 0.004 in the validation group). The T allele was associated with a higher incidence of severe ADRs than was the C allele of rs324011 (OR = 3.67, 95% CI = 1.46-9.19, p = 0.006 in the discovery group; OR = 3.17, 95% CI = 1.44-6.99, p = 0.004 in the validation group). Patients with the CC genotype in STAT3 rs1053023 (and rs1053005) or the TT genotype of STAT6 rs324011 were likely to experience severe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) related ADRs.

Physiological and Pathological Roles of NTSR2 in Several Organs and Diseases (Review).

Neurotensin (NTS) and its receptors (NTSRs) have long been the subject of study and have shown to have a vital function in a variety of systems. They are specifically implicated in the development of tumors and have both oncogenic and anti-apoptotic effects. Neurotensin receptor 2 (NTSR2), like NTSR1, belongs to the G protein-coupled receptor family and has been linked to analgesia, mental disorders, and hematological cancers. However, several research reports have revealed that it exists in numerous different systems. As a result, it seems to be an extremely promising therapeutic target for a variety of diseases. As NTSR2 is particularly prevalent in the brain and has different distribution and developmental characteristics from NTSR1, it may play a specific role in the nervous system. The present review summarizes the expression and function of NTSR2 in different systems, to highlight its potential as a diagnostic tool or therapeutic target.

Carfilzomib suppressed LDHA-mediated metabolic reprogramming by targeting ATF3 in esophageal squamous cell carcinoma.

Carfilzomib, a second-generation proteasome inhibitor, has been approved as a treatment for relapsed and/or refractory multiple myeloma. Nevertheless, the molecular mechanism by which Carfilzomib inhibits esophageal squamous cell carcinoma (ESCC) progression largely remains to be determined. In the present study, we found that Carfilzomib demonstrated potent anti-tumor activity against esophageal squamous cell carcinoma both in vitro and in vivo. Mechanistically, carfilzomib triggers mitochondrial apoptosis and reprograms cellular metabolism in ESCC cells. Moreover, it has been identified that activating transcription factor 3 (ATF3) plays a crucial cellular target role in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively antagonized the effects of carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, the ATF3 protein is specifically bound to lactate dehydrogenase A (LDHA) to effectively suppress LDHA-mediated metabolic reprogramming in response to carfilzomib treatment. Research conducted in xenograft models demonstrates that ATF3 mediates the anti-tumor activity of Carfilzomib. The examination of human esophageal squamous cell carcinoma indicated that ATF3 and LDHA have the potential to function as innovative targets for therapeutic intervention in the treatment of ESCC. Our findings demonstrate the novel function of Carfilzomib in modulating ESCC metabolism and progression, highlighting the potential of Carfilzomib as a promising therapeutic agent for the treatment of ESCC.

TS-2021, a third-generation oncolytic adenovirus that carried Ki67 promoter, TGF-ß2 5'UTR, and IL-15 against experimental glioblastoma.

Oncolytic virotherapy is a promising therapeutic approach for glioblastoma (GBM) treatment, although the outcomes are partially satisfactory. Hence, more effective strategies are needed urgently to modify therapeutic viruses to enhance their efficiency and safety in killing tumor cells and improve the survival rate of GBM patients. This study generated a new-generation oncolytic adenovirus Ad5 KT-E1A-IL-15 (TS-2021) and evaluated its antitumor efficacy. Ex vivo analyses revealed Ki67 and TGF-ß2 co-localized in GBM cells. In addition, TS-2021 selectively replicated in GBM cells, which was dependent on the expression of Ki67 and TGF-ß2. The immunocompetent mice model of GBM demonstrated the in vivo efficacy of TS-2021 by inhibiting tumor growth and improving survival proficiently. Notably, TS-2021 effectively reduced MMP3 expression by inactivating the MKK4/JNK pathway, thereby reducing tumor invasiveness. Altogether, the findings of the present study highlight that TS-2021 can effectively target GBM cells expressing high levels of Ki67 and TGF-ß2, exerting potent antitumor effects. Additionally, it can improve efficacy and suppress tumor invasiveness by inhibiting the MKK4/JNK/MMP3 pathway. Thus our study demonstrates the efficiency of the novel TS-2021 in the mouse model and provides a potential therapeutic option for patients with GBM.

Association between ICW/TBW ratio and cancer prognosis: Subanalysis of a population-based retrospective multicenter study.

BACKGROUND & AIMS: Disease burden is known to alter cellular integrity and water balance. Therefore, the intracellular water/total body water (ICW/TBW) ratio is used as an adjunctive indicator to predict disease severity and prognosis. The ICW/TBW ratio of patients with cancer, who typically present with low muscle mass, poor nutritional status, and high inflammatory response, reportedly differs from that of the healthy population. Herein, we aimed to evaluate the effect of the ICW/TBW ratio on the prognosis of different subgroups of patients with cancer. METHODS: This multicenter cohort study included 2787 patients with malignancies between June 2014 and December 2018. The association between covariates and overall survival (OS) was assessed using restricted cubic spline models. The multivariate Cox regression model included variables demonstrating a statistical significance in the univariate Cox regression analysis (P < 0.05) without multicollinearity. The generated nomogram used the C-index and calibration curves to validate the predictive accuracy of the scoring system. RESULTS: The optimal cut-off value for the ICW/TBW ratio was 0.61. The ICW/TBW ratio was an independent prognostic factor (hazard ratio [HR]: 0.621; 95 % confidence interval [CI]: 0.537-0.719, P < 0.001). Moreover, the ICW/TBW ratio had a greater impact on the prognosis of patients receiving chemoradiotherapy than on those receiving chemotherapy alone (chemoradiotherapy: HR = 0.495, P = 0.005 vs. chemotherapy: HR = 0.646, P < 0.001). Multivariate Cox regression analysis showed that sex, age, tumor stage, body mass index, neutrophil-to-lymphocyte ratio (NLR), and ICW/TBW ratio were associated with OS. Subsequently, a nomogram was developed incorporating these variables and yielded a C-index of 0.743. CONCLUSIONS: The ICW/TBW ratio was associated with muscle mass, nutritional status, and inflammation. A low ICW/TBW ratio is an independent risk factor for poor prognosis in patients with cancer, especially when they are female, have advanced cancer stage, have sarcopenia, and are receiving radiotherapy.

Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis.

Malignant gliomas are an exceptionally lethal form of cancer with limited treatment options. Dihydroartemisinin (DHA), a sesquiterpene lactone antimalarial compound, has demonstrated therapeutic effects in various solid tumors. In our study, we aimed to investigate the mechanisms underlying the anticancer effects of DHA in gliomas. To explore the therapeutic and molecular mechanisms of DHA, we employed various assays, including cell viability, flow cytometry, mitochondrial membrane potential, glucose uptake and glioma xenograft models. Our data demonstrated that DHA significantly inhibited glioma cell proliferation in both temozolomide-resistant cells and glioma stem-like cells. We found that DHA-induced apoptosis occurred via the mitochondria-mediated pathway by initiating mitochondrial dysfunction before promoting apoptosis. Moreover, we discovered that DHA treatment substantially reduced the expression of the mitochondrial biogenesis-related gene, ERRα, in glioma cells. And the ERRα pathway is a critical target in treating glioma with DHA. Our results also demonstrated that the combination of DHA and temozolomide synergistically inhibited the proliferation of glioma cells. In vivo, DHA treatment remarkably extended survival time in mice bearing orthotopic glioblastoma xenografts. Thus, our findings suggest that DHA has a novel role in modulating cancer cell metabolism and suppressing glioma progression by activating the ERRα-regulated mitochondrial apoptosis pathway.

SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation.

Ferroptosis is a non-apoptotic form of regulated cell death. Glutathione (GSH) peroxidase 4 (GPX4) and GSH-independent ferroptosis suppressor protein 1 (FSP1) have been identified as major defenses. Here, we uncover a protective mechanism mediated by GSH S-transferase P1 (GSTP1) by monitoring proteinomic dynamics during ferroptosis. Dramatic downregulation of GSTP1 is caused by SMURF2-mediated GSTP1 ubiquitination and degradation at early stages of ferroptosis. Intriguingly, GSTP1 acts in GPX4- and FSP1-independent manners by catalyzing GSH conjugation of 4-hydroxynonenal and detoxifying lipid hydroperoxides via selenium-independent GSH peroxidase activity. Genetic modulation of the SMURF2/GSTP1 axis or the pharmacological inhibition of GSTP1's catalytic activity sensitized tumor responses to Food and Drug Administration (FDA)-approved ferroptosis-inducing drugs both in vitro and in vivo. GSTP1 expression also confers resistance to immune checkpoint inhibitors by blunting ferroptosis. Collectively, these findings demonstrate a GPX4/FSP1-independent cellular defense mechanism against ferroptosis and suggest that targeting SMURF2/GSTP1 to sensitize cancer cells to ferroptosis has potential as an anticancer therapy.

Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies. / è ºè‹·å¯¹è‚¿ç˜¤èŽ·å¾—æ€§å ç–«çš„æŠ‘åˆ¶ä½œç”¨åŠå¹²é¢„ç­–ç•¥.

Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.

Enhancing the sensitization of neuroblastoma to radiotherapy by the construction of a dual-channel parallel free radicals nanoamplifier.

Radiation therapy (RT) has emerged as one of the most promising anti-tumor strategies for neuroblastoma. Nevertheless, the special tumor microenvironment (TME), including hypoxic and GSH-overexpressed TME, often greatly restricts the RT outcome. In this study, we demonstrated a dual-channel parallel radicals nanoamplifier (ATO@PAE-PEG-AS1411/Fe3+). The nanoamplifier was shaped into a bilayer shell-core structure, in which atovaquone-loaded poly (ß-amino esters)-poly (ethylene glycol) (ATO@PAE-PEG) served as the core while Fe3+-absorbed AS1411 aptamer (AS1411/Fe3+) served as the shell. Taking advantage of the targeting ability of AS1411, ATO@PAE-PEG-AS1411/Fe3+ specifically accumulated in tumor cells, and then released ATO as well as Fe3+ in response to the acidic TME. The released ATO dramatically inhibited the mitochondrial respiration of tumor cells, thus sparing vast amounts of oxygen for the generation of free radicals during RT process, which was the first free radicals-amplifying pathway Meanwhile, the released Fe3+ could consume the tumor-overexpressed GSH through the redox reaction, thus effectively preserving the generated free radicals in RT process, which was the second free radicals-amplifying pathway. Taken together, our study demonstrates a dual-channel parallel free radicals-amplifying RT strategy, and it is expected this work will promote the clinical application prospects of RT treatment against neuroblastoma.

Cigarette Smoking Abstinence Among Pregnant Individuals Using E-Cigarettes or Nicotine Replacement Therapy.

Importance: Smoking cigarettes during pregnancy can impair maternal and child health, and pregnant individuals have increasingly used electronic cigarettes (e-cigarettes) for various reasons, including quitting smoking. Objective: To assess smoking abstinence rates among pregnant individuals who used e-cigarettes compared with those who used nicotine replacement therapy (NRT). Design, Setting, and Participants: This cohort study is a secondary data analysis of phase 8 of the US Pregnancy Risk Assessment Monitoring System, conducted between 2016 and 2020. Eligible participants included pregnant individuals who smoked combustible cigarettes within the 3 months before pregnancy and either used e-cigarettes or NRT during pregnancy. Data analysis was conducted from March 2022 to April 2023. Exposures: Combustible cigarette use within 3 months before pregnancy and use of either e-cigarettes or NRT during pregnancy. Main Outcomes and Measures: The primary outcome was the individual's self-reported smoking abstinence status during the last 3 months of pregnancy. Weighted percentages were reported and weighted multivariable logistic regression models were used to examine the association of e-cigarette use vs NRT with smoking abstinence. A propensity score was used to control for confounding by sociodemographics, pregnancy characteristics, prepregnancy smoking intensity, depression, behavioral support, and hookah use. Results: The cohort included 1329 pregnant individuals (759 ≥25 years [60.2%]; 766 non-Hispanic White individuals [79.8%]) of whom 781 had an education level of high school or lower (61.4%), and 952 had an annual household income of $48 000 or less (81.5%). Of the 1329 individuals, 890 (unweighted percentage, 67.0%) were existing e-cigarette users, 67 (unweighted percentage, 5.0%) were new e-cigarette users, and 372 (unweighted percentage, 28.0%) were NRT users. Compared with individuals who used NRT during pregnancy, individuals who used e-cigarettes had a higher rate of smoking abstinence in late pregnancy (456 individuals [50.8%] vs 67 individuals [19.4%]; propensity score adjusted odds ratio [OR], 2.47; 95% CI, 1.17-5.20; P = .02). In the secondary analysis stratified by the timing of e-cigarette use initiation, existing users of e-cigarettes who initiated before pregnancy had a higher smoking abstinence rate than NRT users (446 users [53.1%] vs 67 users [19.4%]; adjusted OR, 2.61; 95% CI, 1.23-5.51; P = .01). However, new e-cigarette users who initiated use during pregnancy had a similar smoking abstinence rate in late pregnancy when compared with NRT users (10 users [20.6%] vs 67 users [19.4%]; adjusted OR, 1.13; 95% CI, 0.22-5.87; P = .88). Conclusions and Relevance: These findings suggest that individuals who used e-cigarettes during pregnancy had a higher smoking abstinence rate in late pregnancy than individuals who used NRT, especially for those who initiated e-cigarette use before pregnancy, indicating that replacement of cigarettes with e-cigarettes during pregnancy may be a viable strategy for harm reduction.

ESRRG-PKM2 axis reprograms metabolism to suppress esophageal squamous carcinoma progression and enhance anti-PD-1 therapy efficacy.

BACKGROUND: Glycolysis under normoxic conditions, known as the Warburg effect, confers a selective advantage for the survival and proliferation of many tumors. In this study, we investigated the role of estrogen-related receptor gamma (ESRRG) in metabolic reprogramming in esophageal squamous cell carcinoma (ESCC). METHODS: Bioinformatics analysis indicated that ESRRG expression was decreased in ESCC tissue and associated with poor clinical outcomes. We also examined the effects of altered ESRRG expression on the proliferation and metabolic reprogramming of ESCC cells. We explored the impact of ESRRG on Pyruvate kinase M2 (PKM2) expression and malignant behavior in ESCC. RESULTS: Our study revealed the inhibitory effects of ESRRG on the growth, tumorigenesis, and glycolysis activity of ESCC cells, which were mediated by the downregulation of PKM2 expression. We further demonstrated that ESRRG directly interacts with the PKM2 promoter to inhibit its activity in ESCC. Notably, the ESRRG-specific agonist, DY131, inhibited ESCC cell proliferation and glycolysis activity by modulating genes in the glycolysis pathway. Moreover, we verified that DY131 exhibits enhanced activity as an immune checkpoint inhibitor, considering the significance of the ESRRG-PKM2 axis in the lactate regulation of ESCC cells. CONCLUSION: Our findings provide novel insights into the role of ESRRG-PKM2 signaling in regulating ESCC cell metabolism and immune checkpoint regulation. Additionally, we suggest that DY131 holds promise as a promising therapeutic agent for ESCC treatment.