Comprehensive analysis of clinicopathological characteristics in oral squamous cell carcinoma arising from oral submucous fibrosis: a retrospective study.

BACKGROUND: Oral squamous cell carcinoma arising from oral submucous fibrosis is recognized as a clinicopathologically distinct disease. This study aims to summarize and compare the population and clinicopathologic characteristics of OSCC-OSF with other OSCC in Hunan Province, China. The objective is to formulate treatment strategies more in line with regional characteristics. METHODS: A retrospective review of OSCC cases recruited from the Second Xiangya Hospital from 2010 to 2020 was conducted. A total of 1,413 OSCC patients were selected, including 481 patients with OSCC-OSF and 932 were other OSCC. Population characteristics, risk factors and clinicopathological manifestations were explored in OSCC-OSF and other OSCC, as well as thinprep cytologic test and DNA quantification. RESULTS: We found that OSCC-OSF patients were younger than those with other OSCC. Both types of disease were predominantly observed in males compared to females. Tumor biopsy analysis indicated that tumor cells within OSCC-OSF patients were more likely to be well differentiated and showed a higher frequency of lymph node metastases. Clinicopathological factors, such as the chewing betel nuts habit and smoking, were more prevalent in OSCC-OSF patients in contrast to other OSCC. DNA quantification revealed that the number of DNA aneuploid cells was higher in OSCC-OSF compared to other OSCCs. CONCLUSION: In this study, OSCC-OSF is considered a clinicopathologically distinct disease. Compared with other OSCC, OSCC-OSF patients have a higher incidence of nodal metastases, an early clinical TNM stage, and a lower three-year survival rate. Therefore, early diagnosis and treatment are crucial to improving the prognosis of OSCC-OSF.

Dual-Mode Semiconductor Device Enabling Optoelectronic Detection and Neuromorphic Processing with Extended Spectral Responsivity.

High-performance semiconductor devices capable of multiple functions are pivotal in meeting the challenges of miniaturization and integration in advanced technologies. Despite the inherent difficulties of incorporating dual functionality within a single device, a high-performance, dual-mode device is reported. This device integrates an ultra-thin Al2O3 passivation layer with a PbS/Si hybrid heterojunction, which can simultaneously enable optoelectronic detection and neuromorphic operation. In mode 1, the device efficiently separates photo-generated electron-hole pairs, exhibiting an ultra-wide spectral response from ultraviolet (265 nm) to near-infrared (1650 nm) wavelengths. It also reproduces high-quality images of 256 × 256 pixels, achieving a Q-value as low as 0.00437 µW cm- 2 at a light intensity of 8.58 µW cm- 2. Meanwhile, when in mode 2, the as-assembled device with typical persistent photoconductivity (PPC) behavior can act as a neuromorphic device, which can achieve 96.5% accuracy in classifying standard digits underscoring its efficacy in temporal information processing. It is believed that the present dual-function devices potentially advance the multifunctionality and miniaturization of chips for intelligence applications.

MRI-measured periprostatic to subcutaneous adipose tissue thickness ratio as an independent risk factor in prostate cancer patients undergoing radical prostatectomy.

The purpose of this study is to evaluate whether the periprostatic adipose tissue thickness (PPATT) is an independent prognostic factor for prostate cancer patients after laparoscopic radical prostatectomy (LRP). This retrospective cohort study included consecutive prostate cancer patients who underwent LRP treatment at Wuhan Union Hospital from June 2, 2016, to September 7, 2023. PPATT was defined as the thickness of periprostatic fat and was obtained by measuring the shortest vertical distance from the pubic symphysis to the prostate on the midsagittal T2-weighted MR images. Subcutaneous adipose tissue thickness (SATT) was obtained by measuring the shortest vertical distance from the pubic symphysis to the skin at the same slice with PPATT. The primary outcome of the study was biochemical recurrence (BCR), and the secondary outcome was overall survival (OS). Multivariable Cox regression analysis was used to identify independent prognostic factors for prostate cancer survival and prognosis. Based on the optimal cutoff value, 162 patients were divided into a low PPATT/SATT group (n = 82) and a high PPATT/SATT group (n = 80). During the entire follow-up period (median 23.5 months), 26 patients in the high PPATT/SATT group experienced BCR (32.5%), compared to 18 in the low PPATT/SATT group (22.0%). Kaplan-Meier curve analysis indicated that the interval to BCR was significantly shorter in the high PPATT/SATT group (P = 0.037). Multivariable Cox regression analysis revealed that an increase in the PPATT/SATT ratio was associated with BCR (hazard ratio: 1.90, 95% CI, 1.03-3.51; P = 0.040). The PPATT/SATT ratio is a significant independent risk factor for BCR after LRP for prostate cancer patients.

The gut microbiome modulate response to immunotherapy in cancer.

Gut microbiota have been reported to play an important role in the occurrence and development of malignant tumors. Currently, clinical studies have identified specific gut microbiota and its metabolites associated with efficacy of immunotherapy in multiple types of cancers. Preclinical investigations have elucidated that gut microbiota modulate the antitumor immunity and affect the efficacy of cancer immunotherapy. Certain microbiota and its metabolites may favorably remodel the tumor microenvironment by engaging innate and/or adaptive immune cells. Understanding how the gut microbiome interacts with cancer immunotherapy opens new avenues for improving treatment strategies. Fecal microbial transplants, probiotics, dietary interventions, and other strategies targeting the microbiota have shown promise in preclinical studies to enhance the immunotherapy. Ongoing clinical trials are evaluating these approaches. This review presents the recent advancements in understanding the dynamic interplay among the host immunity, the microbiome, and cancer immunotherapy, as well as strategies for modulating the microbiome, with a view to translating into clinical applications.

MitoAMPK inhibits the Warburg effect by MZF1-SIRT6 with glycosis related genes in NSCLC.

MitoAMPK was proved to inhibit the Warburg effect, but the specific mechanisms on non-small-cell lung cancer remain unclear. Here, we selected SIRT6 and MZF1 to clarify the mechanism. By western blotting, quantitative polymerase chain reaction, the CCK-8 assay, and immunohistochemistry assays, we found SIRT6 expression was lower in NSCLC tissues and cell lines than normal tissues and cells. Moreover, SIRT6 could inhibit the Warburg effect by regulating glycolysis-related genes of SLC2A2, SLC2A4 and PKM2. Finally, we demonstrated the interaction between SIRT6 and MZF1 using ChIP-qPCR. In conclusion, mitoAMPK inhibits the Warburg effect by regulating the expression of the MZF1-SIRT6 complex.

Association between thymus density loss and efficacy in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

Background: Although the thymus undergoes degeneration with the advancement of age, recent studies have continuously revealed that the thymus possesses the potential for regeneration and may reverse this aging trend. Furthermore, an increasing number of studies indicate an association between thymus function and immunotherapy. Considering that lung cancer patients typically undergo chest computed tomography (CT) scans during treatment, this provides convenient conditions for us to observe thymic remodeling through imaging data. Therefore, exploring the changes in the thymus on CT images is of great significance for understanding its relationship with the efficacy of immunotherapy in non-small cell lung cancer (NSCLC) patients. This study investigated the CT imaging characteristics of thymic density changes in patients with advanced NSCLC after immunotherapy. The primary objective was to determine whether changes in thymic density are predictors of response to immunotherapy in patients with NSCLC. Methods: A total of 412 patients with advanced NSCLC who underwent immunotherapy were included. Thymic density measurements were taken initially and after immunotherapy, with the annualized change calculated. Comprehensive analysis, including disease progression, survival, and subgroup assessments, was conducted. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Results: The annual change in density of the thymic region ranged from -108 to 108 HU after the initiation of ICIs. Patients were categorized into "loss" or "non-loss" groups (210 vs. 202) based on thymic density changes. Analysis of short-term progression of solid tumors revealed no statistically significant differences in ORR (P=0.55) and DCR (P=0.67) between the two groups. Throughout the entire follow-up period, 41 patients (19.5%) in the "loss" group and 64 patients (31.7%) in the "non-loss" group died. Thymic density reduction was not associated with PFS (P=0.08), but it was positively associated with increased OS (P=0.003). The results were consistent across subgroups. Conclusions: Thymic density changes were observed in nearly all NSCLC patients undergoing immunotherapy, with decreased density associated with longer OS. These findings suggest a potential association between thymic density changes and immune efficacy in NSCLC immunotherapy.

Radiomic feature reliability of amide proton transfer-weighted MR images acquired with compressed sensing at 3T.

Compressed sensing (CS) is a novel technique for MRI acceleration. The purpose of this paper was to assess the effects of CS on the radiomic features extracted from amide proton transfer-weighted (APTw) images. Brain tumor MRI data of 40 scans were studied. Standard images using sensitivity encoding (SENSE) with an acceleration factor (AF) of 2 were used as the gold standard, and APTw images using SENSE with CS (CS-SENSE) with an AF of 4 were assessed. Regions of interest (ROIs), including normal tissue, edema, liquefactive necrosis, and tumor, were manually drawn, and the effects of CS-SENSE on radiomics were assessed for each ROI category. An intraclass correlation coefficient (ICC) was first calculated for each feature extracted from APTw images with SENSE and CS-SENSE for all ROIs. Different filters were applied to the original images, and the effects of these filters on the ICCs were further compared between APTw images with SENSE and CS-SENSE. Feature deviations were also provided for a more comprehensive evaluation of the effects of CS-SENSE on radiomic features. The ROI-based comparison showed that most radiomic features extracted from CS-SENSE-APTw images and SENSE-APTw images had moderate or greater reliabilities (ICC ≥ 0.5) for all four ROIs and all eight image sets with different filters. Tumor showed significantly higher ICCs than normal tissue, edema, and liquefactive necrosis. Compared to the original images, filters (such as Exponential or Square) may improve the reliability of radiomic features extracted from CS-SENSE-APTw and SENSE-APTw images.

Reducing Oxidative Stress Levels and Inhibiting Aging by l-Cysteine-Derived Carbon Dots with Highly Efficient Broad-Spectrum UV Absorption.

Ultraviolet (UV) exposure causes damage to human skin and mucous membranes, resulting in oxidative stress, and can also lead to inflammation of human skin, skin aging, and even diseases such as squamous cell carcinoma and melanoma of the skin. The main means of protection against UV radiation is physical shielding and the use of sunscreen products. Carbon dots as a novel nanomaterial provide a new option for UV protection. In this article, we introduced sulfhydryl groups to synthesize l-cysteine-derived carbon dots (GLCDs) with UV resistance. GLCDs exhibit high-efficiency and excellent UV absorption, achieving 200-400 nm UV absorption (99% UVC, 97% UVB, and 86% UVA) at a low concentration of 0.5 mg/mL. Meanwhile, GLCDs can reduce apoptosis and UVB-induced oxidative damage, increase collagen type I gene expression, and inhibit skin aging in zebrafish. It also inhibits senescence caused by the senescence inducer 2,2'-azobis(2-methylpropionamidine) dihydrochloride and reduces oxidative damage. The above studies show that GLCDs possess efficient broad-spectrum UV absorption, antiphotoaging, and antiaging capabilities, which will have a broad application prospect in UV protection.

The microbiota-dependent tryptophan metabolite alleviates high-fat diet-induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis.

Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.

The adhesin RadD enhances Fusobacterium nucleatum tumour colonization and colorectal carcinogenesis.

Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.

Application and research progress of magnetic resonance proton density fat fraction in metabolic dysfunction-associated steatotic liver disease: a comprehensive review.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD), is a chronic liver disorder associated with disturbances in lipid metabolism. The disease is prevalent worldwide, particularly closely linked with metabolic syndromes such as obesity and diabetes. Magnetic Resonance Proton Density Fat Fraction (MRI-PDFF), serving as a non-invasive and highly quantitative imaging assessment tool, holds promising applications in the diagnosis and research of MASLD. This paper aims to comprehensively review and summarize the applications and research progress of MRI-PDFF technology in MASLD, analyze its strengths and challenges, and anticipate its future developments in clinical practice.

Association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with immune checkpoint inhibitors: an updated meta-analysis.

Background: Although numerous studies have reported the association between tertiary lymphoid structures (TLSs) and clinical outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs), there remains a lack of a newer and more comprehensive meta-analysis. The main objective of this study is to explore prognostic biomarkers in immunotherapy-related patients, through analyzing the associations between tertiary lymphoid structures (TLSs) and clinical outcomes in cancer patients treated with ICIs, so as to investigate their prognostic value in cancer patients treated with ICIs. Methods: A comprehensive search was conducted until February 2024 across PubMed, Embase, Web of Science, and the Cochrane Library databases to identify relevant studies evaluating the association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with ICIs. The clinical outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: Thirteen studies were incorporated in this meta-analysis, among which nine evaluated the prognostic value of TLSs. The results showed the high levels of TLSs predicted a significantly prolonged OS (pooled HR = 0.35, 95% CI: 0.24-0.53, p < 0.001) and PFS (pooled HR = 0.47, 95% CI: 0.31-0.72, p < 0.001), while lower ORR (pooled OR = 3.78, 95% CI: 2.26-6.33, p < 0.001) in cancer patients treated with ICIs. Conclusion: Our results indicated that high levels of TLSs could predict a favorable prognosis for cancer patients treated with ICIs and have the potential to become a prognostic biomarker of immunotherapy-related patients.

Hong Guo Ginseng Guo (HGGG) protects against kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome and regulating intestinal flora.

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious complications of diabetes which leads to end-stage renal failure and approximately one-third of patients need dialysis. There is still a lack of effective and specific treatment for DN. Searching new drugs from natural foods is an alternative approach to treat diabetes and its complications. Hong Guo Ginseng Guo (HGGG), a berry with palatability and nutritional benefits, has exhibited medicinal properties to mitigate the progression of DN. PURPOSE: This study investigates the effects of HGGG on streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats and elucidates the mechanisms underlying its reno-protective and diabetes management benefits. METHODS: The LC-MS spectra method identified the primary ingredients in HGGG. To induce DN, male Sprague-Dawley (SD) rats received a single intraperitoneal injection of 75 mg/kg STZ. Over an eight-week treatment period, we assessed biochemical parameters including blood glucose, urine albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and urine N-acetyl-beta-d-glucosaminidase (NAG). Tissue pathology was examined using Masson's trichrome, Periodic Acid-Schiff (PAS), and Hematoxylin-Eosin (H&E) stains. We analyzed pro-inflammatory mediators and tissue fibrosis extent using Western blotting and immunohistochemistry. Gut microbiota composition was characterized via 16S rDNA sequencing. RESULTS: Seventeen chemical compounds were identified, with lobetyolin, luteolin, and rutin highlighted as the primary active elements. HGGG extract appeared to confer renal protection, demonstrated by improvements in UACR, BUN, and urine NAG levels. The reno protective effects in HGGG-treated DN rats were linked to reduced renal fibrosis and inhibition of the NLRP3 inflammasome. Additionally, HGGG administration improved gut barrier integrity and altered the gut microbiota in DN rats, increasing the relative abundance of beneficial bacteria known for regulating polyamines and producing short-chain fatty acids (SCFAs), including Ruminococcus, Barnesiella_sp, Anaerovoracaceae, and Prevotellaceae_NK3B31. Meanwhile, treatment with HGGG decreasing the presence of Oscillospira, potential pathogens responsible for producing lipopolysaccharide (LPS). CONCLUSION: HGGG has potential as a beneficial fruit for managing diabetes and its associated complications through modulation of the gut microbiota.

Impact of Radiation on Exosomes in Regulating Tumor Immune Microenvironment.

Purpose: Exosomes have been shown to play a role in most, if not all, steps of cancer progression. We still lack a comprehensive understanding of the bidirectional communication of exosomes between tumor cells and immune cells. This article aims to explore how exosomes can influence cancer growth and how they are affected by radiation therapy. Methods and Materials: We searched on PubMed and Web of Science on the impact of radiation on tumor derived exosomes and immune cell derived exosomes in tumor immune microenvironment. We screened all the related articles and summarized their main discoveries and important results. Results: This article reviewed the effects of tumor derived exosomes and immune cell-derived exosomes on TME and tumor progression after radiotherapy, suggesting the dual effects of exosomes which may refer to clinical practice. Moreover, we retrospected the clinical applications based on tumor derived exosomes, including liquid biopsy, radio-resistance and drug delivery, and discussed the challenges and prospects. Conclusions: Exosomes are important in cancer treatment, especially with radiation therapy. Learning more about them could lead to better treatments. However, there are still challenges to overcome. The review points out the need for more research in this area.

Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma.

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.

Predicting Regional Recurrence and Prognosis in Stereotactic Body Radiation Therapy-Treated Clinical Stage I Non-small Cell Lung Cancer Using a Radiomics Model Constructed With Surgical Data.

PURPOSE: Risk stratification of regional recurrence (RR) is clinically important in the design of adjuvant treatment and surveillance strategies in patients with clinical stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). This study aimed to develop a radiomics model predicting occult lymph node metastasis (OLNM) using surgical data and apply it to the prediction of RR in SBRT-treated early-stage NSCLC patients. METHODS AND MATERIALS: Patients with clinical stage I NSCLC who underwent curative surgery with systematic lymph node dissection from January 2013 to December 2018 (the training cohort) and from January 2019 to December 2020 (the validation cohort) were included. A preoperative computed tomography-based radiomics model, a clinical feature model, and a fusion model predicting OLNM were constructed. The performance of the 3 models was quantified and compared in the training and validation cohorts. Subsequently, the radiomics model was used to predict RR in a cohort of consecutive SBRT-treated early-stage NSCLC patients from 2 academic medical centers. RESULTS: A total of 769 patients were included. Eight computed tomography features were identified in the radiomics model, achieving areas under the curves of 0.85 (95% CI, 0.81-0.89) and 0.83 (95% CI, 0.80-0.88) in the training and validation cohorts, respectively. Nevertheless, adding clinical features did not improve the performance of the radiomics model. With a median follow-up of 40.0 (95% CI, 35.2-44.8) months, 32 of the 213 patients in the SBRT cohort developed RR and those in the high-risk group based on the radiomics model had a higher cumulative incidence of RR (P < .001) and shorter regional recurrence-free survival (P = .02), progression-free survival (P = .004) and overall survival (P = .006) than those in the low-risk group. CONCLUSIONS: The radiomics model based on pathologically confirmed data effectively identified patients with OLNM, which may be useful in the risk stratification among SBRT-treated patients with clinical stage I NSCLC.

The first report and biological characterization of Avian Orthoavulavirus 16 in wild migratory waterfowl and domestic poultry in China reveal a potential threat to birds.

RESEARCH HIGHLIGHTS: First confirmation of AOAV-16 in domestic and wild birds in China.AOAV-16 are low virulent viruses for chickens.Co-circulation/co-infection of AOAV-16 and H9N2 subtype AIV enhanced pathogenicity.Different intergenic sequences and recombination events exist within AOAV-16.

Prognostic value of genomic mutation signature associated with immune microenvironment in southern Chinese patients with esophageal squamous cell carcinoma.

The genomic landscape of esophageal squamous cell cancer (ESCC), as well as its impact on the regulation of immune microenvironment, is not well understood. Thus, tumor samples from 92 patients were collected from two centers and subjected to targeted-gene sequencing. We identified frequently mutated genes, including TP53, KMT2C, KMT2D, LRP1B, and FAT1. The most frequent mutation sites were ALOX12B (c.1565C > T), SLX4 (c.2786C > T), LRIG1 (c.746A > G), and SPEN (c.6915_6917del) (6.5%). Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling. A 17-mutated gene-related risk model was constructed using random survival forest analysis and showed significant prognostic value in both our cohort and the validation cohort. Based on the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression (ESTIMATE) algorithm, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm, and the MCPcounter algorithm, we found that the risk score calculated by the risk model was significantly correlated with stimulatory immune checkpoints (TNFSF4, ITGB2, CXCL10, CXCL9, and BTN3A1; p < 0.05). Additionally, it was significantly associated with markers that are important in predicting response to immunotherapy (CD274, IFNG, and TAMM2; p < 0.05). Furthermore, the results of immunofluorescence double staining showed that patients with high risk scores had a significantly higher level of M2 macrophage than those with low risk scores (p < 0.05). In conclusion, our study provides insights into the genomic landscape of ESCC and highlights the prognostic value of a genomic mutation signature associated with the immune microenvironment in southern Chinese patients with ESCC.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy.

OBJECTIVES: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). RESULTS: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001). CONCLUSION: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

Loss of ADAR1 induces ferroptosis of breast cancer cells.

Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.