Construction of exosome-related genes risk model in kidney cell carcinoma predicts prognosis and immune therapy response.

Renal cell carcinoma (RCC) is one of the most prevalent types of urological cancer. Exosomes are vesicles derived from cells and have been found to promote the development of RCC, but the potential biomarker and molecular mechanism of exosomes on RCC remain ambiguous. Here, we first screened differentially expressed exosome-related genes (ERGs) by analyzing The Cancer Genome Atlas (TCGA) database and exoRBase 2.0 database. We then determined prognosis-related ERGs (PRERGs) by univariate Cox regression analysis. Gene Dependency Score (gDS), target development level, and pathway correlation analysis were utilized to examine the importance of PRERGs. Machine learning and lasso-cox regression were utilized to screen and construct a 5-gene risk model. The risk model showed high predictive accuracy for the prognosis of patients and proved to be an independent prognostic factor in three RCC datasets, including TCGA-KIRC, E-MTAB-1980, and TCGA-KIRP datasets. Patients with high-risk scores showed worse outcomes in different clinical subgroups, revealing that the risk score is robust. In addition, we found that immune-related pathways are highly enriched in the high-risk group. Activities of immune cells were distinct in high-/low-risk groups. In independent immune therapeutic cohorts, high-risk patients show worse immune therapy responses. In summary, we identified several exosome-derived genes that might play essential roles in RCC and constructed a 5-gene risk signature to predict the prognosis of RCC and immune therapy response.

Evaluation of Molecular Residual Disease by a Fixed Panel in Resectable Colorectal Cancer.

Purpose: Molecular residual disease (MRD) is a promising biomarker in colorectal cancer (CRC) for prognosis and guiding treatment, while the whole-exome sequencing (WES) based tumor-informed assay is standard for evaluating MRD based on circulating tumor DNA (ctDNA). In this study, we assessed the feasibility of a fixed-panel for evaluating MRD in CRC. Materials and Methods: 75 patients with resectable stage I-III CRC were enrolled. Tumor tissues obtained by surgery, and pre-operative and post-operative day 7 blood samples were collected. The ctDNA was evaluated using the tumor-agnostic and tumor-informed fixed assays, as well as the WES-based and panel-based personalized assays in randomly selected patients. Results: The tumor-informed fixed assay had a higher pre-operative positive rate than the tumor-agnostic assay (73.3% vs 57.3%). The pre-op ctDNA status failed to predict disease-free survival (DFS) in either of the fixed assays, while the tumor-informed fixed assay-determined post-op ctDNA positivity was significantly associated with worse DFS (HR, 20.74, 95%CI 7.19-59.83; p<0.001), which was an independent predictor by multivariable analysis (HR, 28.57, 95%CI 7.10-114.9; p<0.001). Sub-cohort analysis indicated the WES-based personalized assay had the highest pre-operative positive rate (95.1%). The two personalized assays and the tumor-informed fixed assay demonstrated same results in post-op landmark (HR, 26.34, 95%CI, 6.01-115.57; p<0.001), outperforming the tumor-agnostic fixed panel (HR, 3.04, 95%CI, 0.94-9.89; p=0.052). Conclusion: Our study confirmed the prognostic value of the ctDNA positivity at post-op day 7 by the tumor-informed fixed panel. The tumor-informed fixed panel may be a cost-effective method to evaluate MRD, which warrants further studies in future.

Advancing Evidence Generation for Circulating Tumor DNA: Lessons Learned from A Multi-Assay Study of Baseline Circulating Tumor DNA Levels across Cancer Types and Stages.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

ESCO2's oncogenic role in human tumors: a pan-cancer analysis and experimental validation.

PURPOSE: Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the mitotic S-phase adhesins acetylation and is responsible for bridging two sister chromatids. However, present ESCO2 cancer research is limited to a few cancers. No systematic pan-cancer analysis has been conducted to investigate its role in diagnosis, prognosis, and effector function. METHODS: We thoroughly examined the ESCO2 carcinogenesis in pan-cancer by combining public databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), UALCAN and Tumor Immune Single-cell Hub (TISCH). The analysis includes differential expression analysis, survival analysis, cellular effector function, gene mutation, single cell analysis, and tumor immune cell infiltration. Furthermore, we confirmed ESCO2's impacts on clear cell renal cell carcinoma (ccRCC) cells' proliferative and invasive capacities in vitro. RESULTS: In our study, 30 of 33 cancer types exhibited considerably greater levels of ESCO2 expression in tumor tissue using TCGA and GTEx databases, whereas acute myeloid leukemia (LAML) exhibited significantly lower levels. Kaplan-Meier survival analyses in adrenocortical carcinoma (ACC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), mesothelioma (MESO), and pancreatic adenocarcinoma (PAAD) demonstrated that tumor patients with high ESCO2 expression have short survival periods. However, in thymoma (THYM), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), ESCO2 was a favorable prognostic factor. Moreover, ESCO2 expression positively correlates with tumor stage and tumor size in several cancers, including LIHC, KIRC, KIRP and LUAD. Function analysis revealed that ESCO2 participates in mitosis, cell cycle, DNA damage repair, and other processes. CDK1 was identified as a downstream gene regulated by ESCO2. Furthermore, ESCO2 might also be implicated in immune cell infiltration. Finally, ESCO2'S knockdown significantly inhibited the A498 and T24 cells' proliferation, invasion, and migration. CONCLUSIONS: In conclusion, ESCO2 is a possible pan-cancer biomarker and oncogene that can reliably predict the prognosis of cancer patients. ESCO2 was also implicated in the cell cycle and proliferation regulation. In a nutshell, ESCO2 is a therapeutically viable and dependable target.

Tumor Supplying Artery Injection of Liposome@Sunitinib Could Effectively Inhibit the Progression of Kidney Tumor.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system and is not sensitive to chemotherapy or radiotherapy in its advanced stages. Sunitinib is recommended as a first-line target drug for unresectable and metastatic RCC by targeting tyrosine kinase-related signaling pathways, but its therapeutic effect is unsatisfactory. Recently, nanomaterials have shown great prospects in the medical field because of their unique physicochemical properties. Particularly, liposomes are considered as ideal drug delivery systems due to their biodegradability, biocompatibility, and ideal drug-loading efficiency. Considering that tumor supplying artery injection can directly distribute drugs into tumor tissues, in this study, liposomes were employed to encapsulate water-insoluble sunitinib to construct the liposome@sunitinib (Lipo@Suni) complex, so that the drug could directly target and distribute into tumor tissue, and effectively trapped in tumor tissues after tumor supplying artery injection for the advantage of the physicochemical properties of liposomes, thereby achieving a better therapeutic effect on advanced RCC. Here, we found that compared with the peripheral intravenous administration, trans-renal arterial administration increases the content and prolongs the retention time of liposomes in tumor tissues; accordingly, more sunitinib is dispersed and retained in tumor tissues. Ultimately, trans-renal arterial administration of Lipo@Suni exerts a better suppressive effect on RCC progression than peripheral intravenous administration, even better than the conventional oral administration of sunitinib.

UFObow: A single-wavelength excitable Brainbow for simultaneous multicolor ex-vivo and in-vivo imaging of mammalian cells.

Brainbow is a genetic cell-labeling technique that allows random colorization of multiple cells and real-time visualization of cell fate within a tissue, providing valuable insights into understanding complex biological processes. However, fluorescent proteins (FPs) in Brainbow have distinct excitation spectra with peak difference greater than 35 nm, which requires sequential imaging under multiple excitations and thus leads to long acquisition times. In addition, they are not easily used together with other fluorophores due to severe spectral bleed-through. Here, we report the development of a single-wavelength excitable Brainbow, UFObow, incorporating three newly developed blue-excitable FPs. We have demonstrated that UFObow enables not only tracking the growth dynamics of tumor cells in vivo but also mapping spatial distribution of immune cells within a sub-cubic centimeter tissue, revealing cell heterogeneity. This provides a powerful means to explore complex biology in a simultaneous imaging manner at a single-cell resolution in organs or in vivo.

Distinct fibroblast subpopulations associated with bone, brain or intrapulmonary metastasis in advanced non-small-cell lung cancer.

BACKGROUND: Bone or brain metastases may develop in 20-40% of individuals with late-stage non-small-cell lung cancer (NSCLC), resulting in a median overall survival of only 4-6 months. However, the primary lung cancer tissue's distinctions between bone, brain and intrapulmonary metastases of NSCLC at the single-cell level have not been underexplored. METHODS: We conducted a comprehensive analysis of 14 tissue biopsy samples obtained from treatment-naïve advanced NSCLC patients with bone (n = 4), brain (n = 6) or intrapulmonary (n = 4) metastasis using single-cell sequencing originating from the lungs. Following quality control and the removal of doublets, a total of 80 084 cells were successfully captured. RESULTS: The most significant inter-group differences were observed in the fraction and function of fibroblasts. We identified three distinct cancer-associated fibroblast (CAF) subpopulations: myofibroblastic CAF (myCAF), inflammatory CAF (iCAF) and antigen-presenting CAF (apCAF). Notably, apCAF was prevalent in NSCLC with bone metastasis, while iCAF dominated in NSCLC with brain metastasis. Intercellular signalling network analysis revealed that apCAF may play a role in bone metastasis by activating signalling pathways associated with cancer stemness, such as SPP1-CD44 and SPP1-PTGER4. Conversely, iCAF was found to promote brain metastasis by activating invasion and metastasis-related molecules, such as MET hepatocyte growth factor. Furthermore, the interaction between CAFs and tumour cells influenced T-cell exhaustion and signalling pathways within the tumour microenvironment. CONCLUSIONS: This study unveils the direct interplay between tumour cells and CAFs in NSCLC with bone or brain metastasis and identifies potential therapeutic targets for inhibiting metastasis by disrupting these critical cell-cell interactions.

Trajectories of physical well-being among adults with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) often undergo physical decline leading to negative outcomes. Identification of distinct trajectories may help guide clinical decision making and supportive care interventions. We built group-based trajectory models (GBTM) to find trajectories of change in the Functional Assessment of Cancer Therapy Physical Well-Being sub scale (FACT-PWB, up to 5 timepoints over 0 to 200 days of follow-up) using data from adults with newly diagnosed AML in four supportive care studies. We also estimated the association of baseline characteristics (age, marital status, education, AML risk, baseline FACT-PWB, depression, anxiety) with group membership. Among 343 patients with ≥ 2 FACT-PWB scores, mean age was 69.6 (SD 12.1) years; most had intermediate risk AML (178, 51.8%), received intensive treatment (244, 71.1%), and died during follow up (199, 58.0%). The GBTM with four distinct trajectories showed the best fit. The largest group (N=153, 45.0%) showed slight improvement, while the smallest experienced early decline with later improvement (N=8, 2.4%). Baseline FACT-PWB was the only characteristic statistically significantly associated with group membership. Adults with AML show distinct trajectories of physical well-being, and many experience some decline. Exploring trajectories of self-reported and objective physical function may inform decision making and interventions. Clinical trial registration: www.clinicaltrials.gov NCT02975869, NCT03310918, NCT03372291.

Nomogram for predicting postoperative ileus after radical cystectomy and urinary diversion: a retrospective single-center study.

OBJECTIVE: To predict the incidence of postoperative ileus in bladder cancer patients after radical cystectomy. METHODS: We retrospectively analyzed the perioperative data of 452 bladder cancer patients who underwent radical cystectomy with urinary diversion at the Second Hospital of Tianjin Medical University between 2016 and 2021. Univariate and multivariate logistic regression were used to identify the risk factors for postoperative ileus. Finally, a nomogram model was established and verified based on the independent risk factors. RESULTS: Our study revealed that 96 patients (21.2%) developed postoperative ileus. Using multivariate logistic regression analysis, we found that the independent risk factors for postoperative ileus after radical cystectomy included age > 65.0 years, high or low body mass index, constipation, hypoalbuminemia, and operative time. We established a nomogram prediction model based on these independent risk factors. Validation by calibration curves, concordance index, and decision curve analysis showed a strong correlation between predicted and actual probabilities of occurrence. CONCLUSION: Our nomogram prediction model provides surgeons with a simple tool to predict the incidence of postoperative ileus in bladder cancer patients undergoing radical cystectomy.

Dual-exposure temporal laser speckle imaging for simultaneously accessing microvascular blood perfusion and angiography.

Laser speckle contrast imaging (LSCI) has gained significant attention in the biomedical field for its ability to map the spatio-temporal dynamics of blood perfusion in vivo. However, LSCI faces difficulties in accurately resolving blood perfusion in microvessels. Although the transmissive detecting geometry can improve the spatial resolution of tissue imaging, ballistic photons directly transmitting forward through tissue without scattering will cause misestimating in the flow speed by LSCI because of the lack of a quantitative theoretical model of transmissvie LSCI. Here, we develop a model of temporal LSCI which accounts for the effect of nonscattered light on estimating decorrelation time. Based on this model, we further propose a dual-exposure temporal laser speckle imaging method (dEtLSCI) to correct the overestimation of background speed when performing traditional transmissive LSCI, and reconstruct microvascular angiography using the scattered component extracted from total transmitted light. Experimental results demonstrated that our new method opens an opportunity for LSCI to simultaneously resolve the blood vessels morphology and blood flow speed at microvascular level in various contexts, ranging from the drug-induced vascular response to angiogenesis and the blood perfusion monitoring during tumor growth.

Efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC): A systematic review and meta-analysis.

BACKGROUND: The optimal management of unresectable hepatocellular carcinoma (uHCC) remains an unresolved challenge. There is ongoing debate regarding the efficacy and safety of drug-eluting bead TACE (DEB-TACE) with tyrosine kinase inhibitors (TKIs). METHODS: We searched PubMed, Embase, Web of Science and the Cochrane Library for eligible studies. The main endpoints under investigation were survival outcomes, including overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Secondary outcomes encompassed tumor response rates and adverse events (AEs). Two researchers conducted the data extraction independently and assessed the quality of the studies. After pooling and analyzing the data, we assessed the heterogeneity and performed both subgroup analysis and sensitivity analysis. Additionally, we evaluated the potential for publication bias. RESULTS: Eight studies with 1513 patients were finally retrieved. Compared to monotherapy, although bigeminal therapy exhibited improved survival benefits (OS: HR: 0.56, 95 % CI 0.41-0.76, p < 0.001; TTP: HR: 0.72, 95 % CI 0.59-0.87, p = 0.001) and tumor response (ORR: RR: 1.59; 95 % CI 1.19-2.13, p = 0.002; DCR: RR: 1.14; 95 % CI 1.03-1.26, p = 0.010), the reliability of results was affected by significant heterogeneity. In the subgroup analysis, compared to DEB-TACE alone, the bigeminal therapy failed to show any statistical differences. Compared to TKIs, it demonstrated significant advantages in both survival (OS: HR: 0.49, 95 % CI 0.40-0.61, p < 0.001; TTP: HR: 0.60, 95 % CI 0.48-0.75, p < 0.001) and tumor response (ORR: RR: 2.40, 95 % CI 1.86-3.09, p < 0.001; DCR: RR: 1.36, 95 % CI 1.20-1.54, p < 0.001) while low heterogeneity was observed. Concerning safety, DEB-TACE provides no more severe AEs while TKIs-related AEs require close monitoring. CONCLUSION: Our findings suggest that DEB-TACE combined with TKIs may be a safe and effective treatment for uHCC, which is more suitable for patients in the advanced stage.

Role of microvascular invasion in early recurrence of hepatocellular carcinoma after liver resection: A literature review.

Hepatectomy is widely considered a potential treatment for hepatocellular carcinoma (HCC). Unfortunately, one-third of HCC patients have tumor recurrence within 2 years after surgery (early recurrence), accounting for more than 60% of all recurrence patients. Early recurrence is associated with a worse prognosis. Previous studies have shown that microvascular invasion (MVI) is one of the key factors for early recurrence and poor prognosis in patients with HCC after surgery. This paper reviews the latest literature and summarizes the predictors of MVI, the correlation between MVI and early recurrence, the identification of suspicious nodules or subclinical lesions, and the treatment strategies for MVI-positive HCC. The aim is to explore the management of patients with MVI-positive HCC.

Transcriptomics analysis revealed that TAZ regulates the proliferation of KIRC cells through mitophagy.

Transcriptional Co-Activator with PDZ-Binding Motif (TAZ, also known as WWTR1) is a downstream effector of the Hippo pathway, involved in the regulation of organ regeneration and cell differentiation in processes such as development and regeneration. TAZ has been shown to play a tumor-promoting role in various cancers. Currently, many studies focus on the role of TAZ in the process of mitophagy. However, the molecular mechanism and biological function of TAZ in renal clear cell carcinoma (KIRC) are still unclear. Therefore, we systematically analyzed the mRNA expression profile and clinical data of KIRC in The Cancer Genome Atlas (TCGA) dataset. We found that TAZ expression was significantly upregulated in KIRC compared with normal kidney tissue and was closely associated with poor prognosis of patients. Combined with the joint analysis of 36 mitophagy genes, it was found that TAZ was significantly negatively correlated with the positive regulators of mitophagy. Finally, our results confirmed that high expression of TAZ in KIRC inhibits mitophagy and promotes KIRC cell proliferation. In conclusion, our findings reveal the important role of TAZ in KIRC and have the potential to be a new target for KIRC therapy.

Comprehensive analysis of disulfidptosis-related genes: a prognosis model construction and tumor microenvironment characterization in clear cell renal cell carcinoma.

BACKGROUND: Disulfidptosis, a form of cell death induced by abnormal intracellular accumulation of disulfides, is a newly recognized variety of cell death. Clear cell renal cell carcinoma (ccRCC) is a usual urological tumor that poses serious health risks. There are few studies of disulfidptosis-related genes (DRGs) in ccRCC so far. METHODS: The expression, transcriptional variants, and prognostic role of DRGs were assessed. Based on DRGs, consensus unsupervised clustering analysis was performed to stratify ccRCC patients into various subtypes and constructed a DRG risk scoring model. Patients were stratified into high or low-risk groups by this model. We focused on assessing the discrepancy in prognosis, TME, chemotherapeutic susceptibility, and landscape of immune between the two risk groups. Finally, we validated the expression and explored the biological function of the risk scoring gene FLRT3 through in vitro experiments. RESULTS: The different subtypes had significantly different gene expression, immune, and prognostic landscapes. In the two risk groups, the high-risk group had higher TME scores, more significant immune cell infiltration, and a higher probability of benefiting from immunotherapy, but had a worse prognosis. There were also remarkable differences in chemotherapeutic susceptibility between the two risk groups. In ccRCC cells, the expression of FLRT3 was shown to be lower and its overexpression caused a decrease in cell proliferation and metastatic capacity. CONCLUSIONS: Starting from disulfidptosis, we established a new risk scoring model which can provide new ideas for doctors to forecast patient survival and determine clinical treatment plans.

First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Digital Health Psychosocial Intervention in Adult Patients With Cancer and Their Families: Systematic Review and Meta-Analysis.

BACKGROUND: Patients with cancer and their families often experience significant distress and deterioration in their quality of life. Psychosocial interventions were used to address patients' and families' psychosocial needs. Digital technology is increasingly being used to deliver psychosocial interventions to patients with cancer and their families. OBJECTIVE: A systematic review and meta-analysis were conducted to review the characteristics and effectiveness of digital health interventions on psychosocial outcomes in adult patients with cancer and their family members. METHODS: Databases (PubMed, Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, ProQuest Dissertations and Theses Global, and ClinicalTrials.gov) were searched for randomized controlled trials (RCTs) or quasi-experimental studies that tested the effects of a digital intervention on psychosocial outcomes. The Joanna Briggs Institute's critical appraisal checklists for RCTs and quasi-experimental studies were used to assess quality. Standardized mean differences (ie, Hedges g) were calculated to compare intervention effectiveness. Subgroup analysis was planned to examine the effect of delivery mode, duration of the intervention, type of control, and dosage on outcomes using a random-effects modeling approach. RESULTS: A total of 65 studies involving 10,361 patients (mean 159, SD 166; range 9-803 patients per study) and 1045 caregivers or partners (mean 16, SD 54; range 9-244 caregivers or partners per study) were included in the systematic review. Of these, 32 studies were included in a meta-analysis of the effects of digital health interventions on quality of life, anxiety, depression, distress, and self-efficacy. Overall, the RCT studies' general quality was mixed (applicable scores: mean 0.61, SD 0.12; range 0.38-0.91). Quasi-experimental studies were generally of moderate to high quality (applicable scores: mean 0.75, SD 0.08; range 0.63-0.89). Psychoeducation and cognitive-behavioral strategies were commonly used. More than half (n=38, 59%) did not identify a conceptual or theoretical framework. Most interventions were delivered through the internet (n=40, 62%). The median number of intervention sessions was 6 (range 1-56). The frequency of the intervention was highly variable, with self-paced (n=26, 40%) being the most common. The median duration was 8 weeks. The meta-analysis results showed that digital psychosocial interventions were effective in improving patients' quality of life with a small effect size (Hedges g=0.05, 95% CI -0.01 to 0.10; I2=42.7%; P=.01). The interventions effectively reduced anxiety and depression symptoms in patients, as shown by moderate effect sizes on Hospital Anxiety and Depression Scale total scores (Hedges g=-0.72, 95% CI -1.89 to 0.46; I2=97.6%; P<.001). CONCLUSIONS: This study demonstrated the effectiveness of digital health interventions on quality of life, anxiety, and depression in patients. Future research with a clear description of the methodology to enhance the ability to perform meta-analysis is needed. Moreover, this study provides preliminary evidence to support the integration of existing digital health psychosocial interventions in clinical practice. TRIAL REGISTRATION: PROSPERO CRD42020189698; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=189698.

The association of individual cognition and social environment of smoking with autonomy over tobacco: A survey from rural China.

INTRODUCTION: This study explores the association of individual cognition and social environment of smoking with autonomy over tobacco, providing evidence and insights to help smokers effectively prevent and reduce tobacco dependence. METHODS: Data were collected from 1389 participants, aged ≥15 years, by face-to-face interviews from June 2018 to November 2019 in central China. We assessed autonomy over tobacco using the Autonomy Over Smoking Scale (AUTOS), including Withdrawal Symptoms (WS), Psychological Dependence (PD) and Cue-induced Cravings (CC), and examined factors of individual cognition and social environment, as well as covariates, including demographic characteristics, health status, and smoking behavior. RESULTS: AUTOS total score was 16.92 ± 9.05, WS score was the lowest (4.40 ± 3.36) in the three subscales, and CC score was the highest (6.88 ± 3.2). After adjustment, WS score of having a greater awareness of smoking hazards to one's own health was lower than those who had no awareness (ß=0.14; 95% CI: -0.31-0.00), and the total score of AUTOS, the score of PD and CC for those who thought smoking was 'more helpful (high)' to interpersonal communication were higher than 'not helpful (not at all)' (ß=0.14; 95% CI: 0.01-0.28 with ß=0.16; 95% CI: 0.02-0.29; and ß=0.14; 95% CI: 0.00-0.28; respectively). Having a greater difficulty in smoking cessation was associated with higher AUTOS total and subscale scores (p<0.001). Notably, none of the social-environmental factors included had a significant association with AUTOS scores. CONCLUSIONS: Interventions targeting individual cognitive factors of tobacco dependence seem to be more effective in smoking cessation. Future research may explore the influence of family and workplace among social environmental factors, which may reveal the effect of a binding force.

FOXA2 activates HIF2α expression to promote tumor progression and is regulated by the E3 ubiquitin ligase VHL in renal cell carcinoma.

Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system with high mortality and morbidity. However, the molecular mechanisms underlying RCC progression are still largely unknown. In this study, we identified FOXA2, a pioneer transcription factor, as a driver oncogene for RCC. We show that FOXA2 was commonly upregulated in human RCC samples and promoted RCC proliferation, as evidenced by assays of cell viability, colony formation, migratory and invasive capabilities, and stemness properties. Mechanistically, we found that FOXA2 promoted RCC cell proliferation by transcriptionally activating HIF2α expression in vitro and in vivo. Furthermore, we found that FOXA2 could interact with VHL (von Hippel‒Lindau), which ubiquitinated FOXA2 and controlled its protein stability in RCC cells. We showed that mutation of lysine at position 264 to arginine in FOXA2 could mostly abrogate its ubiquitination, augment its activation effect on HIF2α expression, and promote RCC proliferation in vitro and RCC progression in vivo. Importantly, elevated expression of FOXA2 in patients with RCC positively correlated with the expression of HIF2α and was associated with shorter overall and disease-free survival. Together, these findings reveal a novel role of FOXA2 in RCC development and provide insights into the underlying molecular mechanisms of FOXA2-driven pathological processes in RCC.

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial.

INTRODUCTION: Treatment options for treatment-naive patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations are limited. This study evaluated the safety, tolerability, and pharmacokinetics of YK-029A, a third-generation EGFR tyrosine kinase inhibitor, and the preliminary efficacy of YK-029A in treatment-naive patients with EGFR ex20ins mutation. METHODS: This multicenter, dose-escalation, and dose-expansion phase 1 clinical trial enrolled patients with NSCLC harboring EGFR mutations. During the dose-escalation phase, YK-029A was orally administered using the traditional 3+3 principle at 50, 100, 150, 200, and 250 mg/d. In the dose-expansion phase, treatment-naive patients with EGFR ex20ins mutations were enrolled and administered YK-029A 200 mg/d. The primary end point was safety and tolerability. RESULTS: The safety analysis included 108 patients. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common treatment-emergent adverse events were anemia (50.9%), diarrhea (49.1%), and rash (34.3%). There was minimal drug accumulation after multiple doses. A total of 28 treatment-naive patients with EGFR ex20ins mutations were enrolled in the dose-expansion and 26 were included in the efficacy analysis. According to the independent review committee evaluation, the objective response rate was 73.1% (95% confidence interval: 52.21%-88.43%), and the disease control rate was 92.3% (95% confidence interval: 74.87%-99.05%). CONCLUSIONS: YK-029A was found to have manageable safety and be tolerable in patients with NSCLC harboring EGFR mutations and have promising antitumor activity in untreated patients with EGFR ex20ins mutations.