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Introduction: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC)., Method: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI., Results: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC., Conclusions: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types 1 . PTEN is the major negative regulator of PI3K signalling. The PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3Kβ led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Clinical manifestations, imaging findings, pathologic features, and genetic mutations of Chinese adult patients with cerebrotendinous xanthomatosis (CTX) were analyzed in order to achieve a greater understanding of CTX that can improve early detection, diagnosis, and treatment. Methods: Clinical data including medical history, neurologic and auxiliary examinations, imaging findings, and genetic profile were collected for an adult patient with CTX admitted to the Sixth Medical Center of Chinese People's Liberation Army General Hospital in August 2020. Additionally, a systematic review of genetically diagnosed Chinese adult CTX cases reported in major databases in China and other countries was performed and age of onset, first symptoms, common signs and symptoms, pathologic findings, imaging changes, and gene mutations were analyzed. Results: The proband was a 39-year-old female with extensive, early-onset nervous system manifestations including cognitive dysfunction and ataxia. Systemic lesions included juvenile cataract and a tendon mass. Cranial magnetic resonance imaging revealed cerebral atrophy, symmetric white matter changes predominantly in the pyramidal tract, and lesions in the cerebellar dentate nucleus. A novel homozygous mutation in the sterol-27-hydroxylase (CYP27A1) gene (c.1477-2A>C) was identified. There were no family members with similar clinical presentation although some were carriers of the c.1477-2A>C mutation. The patient showed a good response to deoxycholic acid treatment. Totally there were 56 cases of adult CTX patients in China, mostly in East China (31/56, 55.4%), at a male-to-female ratio of 1.8 to 1. Multiple organs and tissues including nervous system, tendon, lens, lung, and skeletal muscle were affected in these cases. The most common neurologic manifestations were cognitive dysfunction (44/52, 84.6%) and ataxia (44/51, 86.3%). The cases were characterized by early onset, chronic progressive damage of multiple systems, long disease course, and delayed diagnosis, making the disease difficult to manage clinically and resulting in poor prognosis. The 2 most common genetic mutations in Chinese adult CTX patients were c.1263+1G>A and c.379C>T. Exon 2 of the CYP27A1 gene was identified as a mutation hot spot. Conclusions: Chinese adult patients with CTX have complex clinical characteristics, a long diagnostic cycle, and various CYP27A1 gene mutations. Early diagnosis and intervention can improve the prognosis of these patients.

Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation 1-6 . However, it is not known whether accumulated lactate affects the proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Administration of doses via an extended infusion (EI) is an important strategy to optimize beta-lactams. Available data on the impact of EI on outcomes largely focus on clinical cure or mortality in critically ill patients or those with resistant pathogens. The potential benefits of EI extend beyond these populations and outcomes, and further study is warranted., Methods: This was a retrospective cohort study of adult patients who received cefepime, piperacillin/tazobactam, or meropenem for Gram-negative bacteremia via EI or intermittent infusion. Patients were matched 1:1 based on study drug, sepsis severity, intensive care unit (ICU) status, bacteremia source, and pathogen. Outcomes assessed included time to clinical stabilization, rates of treatment failure, mortality, recurrence, and length of stay (LOS)., Results: Two hundred sixty-eight patients were included. Baseline characteristics were similar between groups. Forty-two percent of patients were in the ICU at infection onset and the most common pathogen was Escherichia coli (41%). After adjusting for residual differences between groups, receipt of EI was independently associated with shorter time to clinical stability (adjusted odds ratio, 0.32; 95% confidence interval, .22-.47), time to defervescence, and time to white blood cell count normalization. Furthermore, EI was associated with a lower incidence of treatment failure, decreased recurrence of bacteremia, and shorter LOS. There was no difference in mortality. These findings were consistent regardless of patient location (ICU vs ward), baseline renal function, source of bacteremia, or study drug received., Conclusions: These findings suggest that EI beta-lactams are an important stewardship strategy to improve clinical outcomes in patients with Gram-negative bacteremia., Competing Interests: Potential conflicts of interest. The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To explore the mechanism of electroacupuncture (EA) at "Zusanli" (ST36) on improving glucose metabolism disorder in chronic restraint induced depressed rats., Methods: A total of 30 male SD rats were randomly divided into control, model and EA groups, with 10 rats in each group. The depression model was established by chronic restraint 2.5 h each day for 4 weeks. For rats in the EA group, EA stimulation (1 mA, 2 Hz, 30 min) was applied to bilateral ST36 during the modeling period, once a day for 4 weeks. The body weight of the rats was recorded before and after modeling. The behavior of rats was observed by sugar-water preference and forced swimming after modeling. The contents of glucose and glycosylated albumin in serum were determined by biochemical method. The histopathological morphology and liver glycogen content were observed by HE and PAS staining. The expression levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K (p-PI3K), protein kinase B (Akt), p-Akt, glycogen synthase kinase-3β (GSK3β) and p-GSK3β proteins in liver were determined by Western blot., Results: Compared with the control group, the weight increment and sugar-water preference index decreased ( P <0.01), the immobile swimming time was prolonged ( P <0.01), the glucose and glycosylated albumin contents in serum increased ( P <0.05), the expression of p-Akt protein and the ratio of p-Akt/Akt in liver tissues decreased ( P <0.001), the expression of p-GSK3β protein and the ratio of p-GSK3β/GSK3β in liver tissues increased ( P <0.01, P <0.001) in the model group. Compared with the model group, the weight increment and sugar-water preference index increased ( P <0.05), the immobile swimming time was shortened ( P <0.05), the glucose and glycosylated albumin contents in serum decreased ( P <0.05), the expressions of p-PI3K and p-Akt proteins and the ratio of p-PI3K/PI3K and p-Akt/Akt in liver tissues increased ( P <0.05), the expression of p-GSK3β protein and the ratio of p-GSK3β/GSK3β in liver tissues decreased ( P <0.01) in the EA group. HE staining showed that the structure of the hepatic lobule was intact, no obvious inflammatory cell infiltration or fibrosis was observed in the lobule and interstitium, and no abnormalities were observed in the small bile duct, portal vein and artery in the portal area. PAS staining showed that the intensity of staining from the center of the hepatic lobule to the periphery of the hepatic lobule was gradually enhanced in the blank group, that is, the glycogen-rich granules in the hepatic cells were gradually increased; most of the hepatocytes were light colored and glycogen was lost significantly in the model group; while the intensity of hepatocyte staining increased, the staining intensity of the perilobular zone was weaker than that in the blank group, and the glycogen particles partially recovered in the EA group., Conclusion: EA intervention can regulate glucose metabolism disorder in chronic restraint induced depressed rats through PI3K/Akt/GSK3β signaling pathway.

Purpose: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities., Methods: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation., Results: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023])., Conclusion: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population., (© 2022. The Author(s).)

Hypertrophic scar (HS) affects the function and beauty of patients, and brings a heavy psychological burden to patients. However, the specific pathogenesis mechanism of HS in molecular biology level is not yet clear, and this disease is still one of the clinical diseases difficult to prevent and cure. MicroRNA (miR) is a family of single-stranded endogenous noncoding RNAs that can regulate gene expression. The abnormal transcription of miR in hypertrophic scar fibroblasts can affect the transduction and expression of downstream signal pathway or protein, and the exploration of miR and its downstream signal pathway and protein helps deeply understand the occurrence and development mechanism of scar hyperplasia. This article summarized and analyzed how miR and multiple signal pathways involve in the formation and development of HS in recent years, and further outlined the interaction between miR and target genes in HS.

Introduction: Despite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic. The mechanisms underlying osimertinib resistance are heterogenous. While genetic mutations within EGFR or other cancer driver pathways mediated mechanisms are well-documented, the role of tumor cell and tumor immune microenvironment in mediating the response to osimertinib remains elusive., Methods and Results: Here, using a syngeneic mouse model of EGFR-mutant lung cancer, we show that tumor regression elicited by osimertinib requires activation of CD8+ T cells. However, tumor-associated macrophages (TAMs) accumulated in advanced tumors inhibit CD8+ T cell activation and diminish the response to osimertinib. These results are corroborated by analyses of clinical data. Notably, reprogramming TAMs with a systemic STING agonist MSA-2 reinvigorates antitumor immunity and leads to durable tumor regression in mice when combined with osimertinib., Discussion: Our results reveal a new mechanism of EGFR-TKI resistance and suggest a new therapeutic strategy for the treatment of EGFR-mutant tumors., Competing Interests: QW and JZ are co-inventors of the patent: Cancer vaccine compositions and methods for using same to treat cancer DFCI 2409.001; DFS-203.60. QW and JZ are co-inventors of the patent: Methods of treating cancers using STING agonists DFCI 2947.P01US; DFS-310.60. Q.W. is a scientific consultant for Crimson Biopharm Inc. JZ is co-founder and director of Crimson Biopharm Inc. and Geode Therapeutics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Lin, Wang, Jiang, Wang and Zhao.)

Atmospheric fine particulate matter (PM 2.5 ) mainly contributes to Pb accumulation in the edible leaves of Chinese cabbage in North China. It was found that a low-Pb-accumulation (LPA) genotype of Chinese cabbage contained less Pb in leaves than high-Pb-accumulation (HPA) genotype exposed to PM 2.5 -Pb. However, there are no data on the transcriptional regulatory mechanisms of foliar PM 2.5 -Pb uptake by Chinese cabbage. The present study investigated the retention of PM 2.5 -Pb in foliar apoplast and symplasm and the underlying molecular mechanisms of reduced Pb in LPA leaves. It appeared more Pb in apoplast and less Pb in symplasm of LPA leaves, whereas the pattern was opposite in HPA. There were 2646 and 3095 differentially expressed genes (DEGs) in LPA and HPA leaves under PM 2.5 -Pb stress with clearly genotype-specific function, respectively. Furthermore, mRNA levels of XTH16 regulating cell wall thickening, PME2 and PME6 involved in cell wall remodification were significantly expressed in LPA, but not in HPA. Meanwhile, foliar PM 2.5 -Pb stress downregulated expression of ZIP1, YSL1, and CNGC3 responsible for Pb influx to cell, and upregulated expression of ABCG36 regulated Pb efflux from symplasm in LPA leaves. These results improve our understanding to the mechanisms underlying foliar Pb uptake from PM 2.5 -Pb at transcriptomic level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The prevalence of thyroid diseases in China continues to increase, especially for hypothyroidism. This article focuses on the existing problems in the diagnosis and treatment of hypothyroidism in special groups, including obese patients, the elderly, children and pregnant women. The pathogenesis and intervention measures of obesity-induced hypothyroidism have been the hot research frontiers. The prevalence of subclinical hypothyroidism in the elderly is the highest, while its diagnostic criteria and treatment strategies are still controversial. The hazard and treatment of subclinical hypothyroidism and hypothyroxinemia during pregnancy have now become an international concern. And there also exist some problems in the screening, diagnosis and treatment of congenital hypothyroidism in children. So it is urgent to carry out high-quality clinical research to provide theoretical basis for clinical diagnosis and treatment, and carry out in-depth research on related mechanisms to establish a foundation for the construction of a scientific prevention and treatment system for hypothyroidism.

Importance: Immune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced esophageal squamous cell carcinoma in both first- and second-line settings. However, the benefit of ICIs in patients with low programmed death ligand 1 (PD-L1) expression remains unclear., Objective: To derive survival data for patient subgroups with low PD-L1 expression from clinical trials comparing ICIs with chemotherapy in esophageal squamous cell carcinoma and to perform a pooled analysis., Data Sources: Kaplan-Meier curves from the randomized clinical trials were extracted after a systematic search of Scopus, Embase, PubMed, and Web of Science from inception until October 1, 2021., Study Selection: Randomized clinical trials that investigated the effectiveness of anti-PD-1-based regimens for advanced esophageal squamous cell carcinoma and that reported overall survival (OS), progression-free survival, or duration of response were included in this meta-analysis., Data Extraction and Synthesis: Kaplan-Meier curves of all-comer populations, subgroups with high PD-L1, and those with low PD-L1 (when available) were extracted from published articles. A graphic reconstructive algorithm was used to calculate time-to-event outcomes from these curves. In studies with unreported curves for subgroups with low PD-L1 expression, KMSubtraction was used to impute survival data. KMSubtraction is a workflow to derive unreported subgroup survival data with from subgroups. An individual patient data pooled analysis including previously reported and newly imputed subgroups was conducted for trials with the same treatment line and PD-L1 scoring system. Data analysis was conducted from January 1, 2022, to June 30, 2022., Main Outcomes and Measures: Primary outcomes included Kaplan-Meier curves and hazard ratios (HRs) for OS for subgroups with low PD-L1 expression. Secondary outcomes included progression-free survival and duration of response., Results: The randomized clinical trials CheckMate-648, ESCORT-1st, KEYNOTE-590, ORIENT-15, KEYNOTE-181, ESCORT, RATIONALE-302, ATTRACTION-3, and ORIENT-2 were included, totaling 4752 patients. In the pooled analysis of first-line trials that evaluated a tumor proportion score (CheckMate-648 and ESCORT-1st), no significant benefit in OS was observed with immunochemotherapy compared with chemotherapy in the subgroup of patients who had a tumor proportion score lower than 1% (HR, 0.91; 95% CI, 0.74-1.12; P = .38) compared with chemotherapy. In the pooled analysis of first-line trials that evaluated combined positive score (KEYNOTE-590 and ORIENT-15), there was a significant but modest OS benefit for immunochemotherapy compared with chemotherapy in the subgroup with a combined positive score lower than 10 (HR, 0.77; 95% CI, 0.62-0.94; P = .01)., Conclusions and Relevance: Findings suggest a lack of survival benefit of ICI-based regimens in the first-line setting compared with chemotherapy alone in the subgroup with a tumor proportion score lower than 1%.

Data-dependent acquisition (DDA) mode in ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) can provide massive amounts of MS 1 and MS/MS information of compounds in untargeted metabolomics and can thus facilitate compound identification greatly. In this work, we developed a new platform called AntDAS-DDA for the automatic processing of UHPLC-HRMS data sets acquired under the DDA mode. Several algorithms, including extracted ion chromatogram extraction, feature extraction, MS/MS spectrum construction, fragment ion identification, and MS 1 spectrum construction, were developed within the platform. The performance of AntDAS-DDA was investigated comprehensively with a mixture of standard and complex plant data sets. Results suggested that features in complex sample matrices can be extracted effectively, and the constructed MS 1 and MS/MS spectra can benefit in compound identification greatly. The efficiency of compound identification can be improved by about 20%. AntDAS-DDA can take full advantage of MS/MS information in multiple sample analyses and provide more MS/MS spectra than single sample analysis. A comparison with advanced data analysis tools indicated that AntDAS-DDA may be used as an alternative for routine UHPLC-HRMS-based untargeted metabolomics. AntDAS-DDA is freely available at http://www.pmdb.org.cn/antdasdda.

Importance: Despite the adoption of the optimized Enhanced Recovery After Surgery (ERAS) protocol, postoperative ileus (POI) severely impairs recovery after colorectal resection and increases the burden on the health care system., Objective: To assess the efficacy of electroacupuncture (EA) in reducing the duration of POI with the ERAS protocol., Design, Setting, and Participants: This multicenter, randomized, sham-controlled trial was conducted in China from October 12, 2020, through October 17, 2021. There was a 1:1 allocation using the dynamic block random method, and analyses were by intention to treat. Patients 18 years or older undergoing laparoscopic resection of colorectal cancer for the first time were randomly assigned to treatment group by a central system., Interventions: Patients were randomly assigned to 4 sessions of EA or sham electroacupuncture (SA) after surgery. All patients were treated within the ERAS protocol., Main Outcomes and Measures: The primary outcome was the time to first defecation. Secondary outcomes included other patient-reported outcome measures, length of postoperative hospital stay, readmission rate within 30 days, and incidence of postoperative complications and adverse events., Results: A total of 249 patients were randomly assigned to treatment groups. After the exclusion of 1 patient because of a diagnosis of intestinal tuberculosis, 248 patients (mean [SD] age, 60.2 [11.4] years; 153 men [61.7%]) were included in the analyses. The median (IQR) time to first defecation was 76.4 (67.6-96.8) hours in the EA group and 90.0 (73.6-100.3) hours in the SA group (mean difference, -8.76; 95% CI, -15.80 to -1.73; P = .003). In the EA group compared with the SA group, the time to first flatus (median [IQR], 44.3 [37.0-58.2] hours vs 58.9 [48.2-67.4] hours; P < .001) and the tolerability of semiliquid diet (median [IQR], 105.8 [87.0-120.3] hours vs 116.5 [92.0-137.0] hours; P = .01) and solid food (median [IQR], 181.8 [149.5-211.4] hours vs 190.3 [165.0-228.5] hours; P = .01) were significantly decreased. Prolonged POI occurred in 13 of 125 patients (10%) in the EA group vs 25 of 123 patients (20%) in the SA group (risk ratio [RR], 0.51; 95% CI, 0.27-0.95; P = .03). Other secondary outcomes were not different between groups. There were no severe adverse events., Conclusions and Relevance: Results of this randomized clinical trial demonstrated that in patients undergoing laparoscopic surgery for colorectal cancer with the ERAS protocol, EA shortened the duration of POI and decreased the risk for prolonged POI compared with SA. EA may be considered as an adjunct to the ERAS protocol to promote gastrointestinal function recovery and prevent prolonged POI after surgery., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000038444.

Background: Tertiary lymphoid structures (TLSs), as ectopic lymphoid-like tissues, are highly similar to secondary lymphoid organs and are not only involved in chronic inflammation and autoimmune responses but are also closely associated with tumor immunotherapy and prognosis. The complex composition of the urological tumor microenvironment not only varies greatly in response to immunotherapy, but the prognostic value of TLSs in different urological tumors remains controversial., Summary: We searched PubMed, Web of Science, and other full-text database systems. TLSs, kidney cancer, uroepithelial cancer, bladder cancer, and prostate cancer as keywords, relevant literature was searched from the time the library was built to 2023. Systematically explore the role and mechanism of TLSs in urological tumors. It includes the characteristics of TLSs, the role and mechanism of TLSs in urological tumors, and the clinical significance of TLSs in urological tumors., Key Messages: The prognostic role of TLSs in different urological tumors was significantly different. It is not only related to its enrichment in the tumor but also highly correlated with the location of the tumor. In addition, autoimmune toxicity may be a potential barrier to its role in the formation of TLSs through induction. Therefore, studying the mechanisms of TLSs in autoimmune diseases may help in the development of antitumor target drugs., (© 2023 S. Karger AG, Basel.)

Background: Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic., Methods: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer., Results: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade., Conclusions: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer., Competing Interests: Competing interests: LD, QW and JJZ are co-inventors of the patent related to this study (US application 63/148426). QW is a scientific consultant for Crimson Biopharm. PAK is a scientific consultant for Alkermes, AstraZeneca, Bayer, GSK, Merck, Pfizer, Tesaro, Mersana, Repare, Kadmon and served as the principal investigator (PI) of institutional support clinical trial for AstraZeneca, Bayer, GSK, Merck, Lilly, and BMS. TMR is cofounder of Crimson Biopharm and Geode Therapeutics, and a SAB member for Shiftbio and K2B Therapeutics. GJF has patents/pending royalties on the PD-L1/PD-1 pathway from Roche, Merck MSD, Bristol Myers Squibb, Merck KGA, Boehringer Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, Eli Lilly, and Novartis. GJF has served on advisory boards for Roche, Bristol Myers Squibb, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Trillium, GV20, IOME, and Geode. GJF has equity in Nextpoint, Triursus, Xios, iTeos, IgM, Trillium, Invaria, GV20, and Geode. JFL has served as a scientific consultant for Genentech/Roche and Bristol Myers Squibb, and has been on advisory boards for Clovis Oncology, Genentech/Roche, GlaxoSmithKline, Regeneron, AstraZeneca, and Eisai. JFL has served as the institutional PI (support to the institution) of clinical trials by Genentech/Roche, AstraZeneca, Boston Biomedical, Acetylon Pharmaceuticals, Bristol Myers Squibb, Agenus, CytomX Therapeutics, Regeneron, Tesaro/GSK, Clovis Oncology, Surface Oncology, 2X Oncology, Vigeo Therapeutics, Aravive, Arch Oncology and Zentalis Pharmaceuticals. UM has served on the advisory boards of 2X Oncology, Fujifilm, Immunogen, Mersana, Geneos, and Merck. JJZ is cofounder and director of Crimson Biopharm and Geode Therapeutics. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In this study we aimed to assess the clinicopathological characteristics and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) having distinct steatosis distribution patterns., Methods: Clinicopathological data of 238 individuals with biopsy-confirmed NAFLD were collected. Nonalcoholic steatohepatitis-clinical research network (NASH-CRN) and steatosis, activity and fibrosis (SAF)/fatty liver inhibition of progression (FLIP) algorithm were used. Cumulative incidence of liver-related events (LREs) was compared by Kaplan-Meier analysis. Univariate and multivariate logistic regression analyses were used to identify independent predictors for steatosis distribution., Results: Eligible patients were categorized into three groups based on their steatosis distribution, including azonal steatosis (AS) (62 [26.1%]), perivenular steatosis (PVS) (147 [61.8%]), and the pan-acinar steatosis (PAS) groups (29 [12.1%]). There were significantly higher ballooning grade and disease activity (P < 0.05), more severe fibrosis (P < 0.001), and a higher cumulative incidence of LREs (hazard ratio [HR] 8.0, 95% confidence interval [CI] 2.34-27.35, P < 0.0001) in the AS group than in the PVS and PAS groups after a median of 3.6-year follow-up. Multivariate logistic regression analysis revealed age (odds ratio [OR] 1.11, 95% CI 1.06-1.16, P < 0.001) might be independently associated with AS distribution, and PNPLA3 rs738409 CG/GG genotype (OR 3.36, 95% CI 0.98-11.47, P = 0.053) might also play a role., Conclusions: AS is associated with more severe disease activity and fibrosis stage in NAFLD, and predisposes toward poor prognosis. Age might be an independent predictor for AS in NAFLD, while PNPLA3 rs738409 CG/GG genotype might also play a role., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Zika virus (ZIKV) causes microcephaly and congenital eye disease. The cellular and molecular basis of congenital ZIKV infection are not well understood. Here, we utilized a biologically relevant cell-based system of human fetal retinal pigment epithelial cells (FRPEs), hiPSC-derived retinal stem cells (iRSCs), and retinal organoids to investigate ZIKV-mediated ocular cell injury processes. Our data show that FRPEs were highly susceptible to ZIKV infection exhibiting increased apoptosis, whereas iRSCs showed reduced susceptibility. Detailed transcriptomics and proteomics analyses of infected FRPEs were performed. Nucleoside analogue drug treatment inhibited ZIKV replication. Retinal organoids were susceptible to ZIKV infection. The Asian genotype ZIKV exhibited higher infectivity, induced profound inflammatory response, and dysregulated transcription factors involved in retinal organoid differentiation. Collectively, our study shows that ZIKV affects ocular cells at different developmental stages resulting in cellular injury and death, further providing molecular insight into the pathogenesis of congenital eye disease.

Background Aims: As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated., Approach Results: We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, up-regulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus, or adeno-associated virus-mediated Trim31 gene therapy restrain NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7 and conjugates K48-linked ubiquitination chains to promote MAP3K7 degradation, thus blocking MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes., Conclusions: TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders., (Copyright © 2022 American Association for the Study of Liver Diseases.)

Objective: Thrombectomy greatly improves the clinical prognosis of patients with acute ischemic stroke (AIS). The aim of this study is to develop a nomogram model that can predict the prognosis of patients with acute ischemic stroke undergoing thrombectomy., Methods: We retrospectively collected information of patients with acute ischemic stroke who were admitted to the stroke Green Channel of the First Affiliated Hospital of Soochow University from September 2018 to May 2022. The main outcome was defined as a three-month unfavorable outcome (modified Rankin Scale 3-6). Based on the results of multivariate regression analysis, a nomogram was established. We tested the accuracy and discrimination of our nomogram by calculating the consistency index (C-index) and plotting the calibration curve., Results: National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.418; 95% CI, 1.177-1.707; P ＜0.001), low density lipoprotein cholesterol (LDL-C) (OR, 2.705; 95% CI, 1.203-6.080; P = 0.016), Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (OR, 0.633; 95% CI, 0.421-0.952; P = 0.028), infarct core volume (OR, 1.115; 95% CI, 1.043-1.192; P = 0.001) and ischemic penumbra volume (OR, 1.028; 95% CI, 1.006-1.050; P = 0.012) were independent risk factors for poor clinical prognosis of AIS patients treated with thrombectomy. The C-index of our nomogram was 0.967 and the calibration plot revealed a generally fit in predicting three-month unfavorable outcomes. Based on this nomogram, we stratified the risk of thrombectomy population. We found that low-risk population is less than or equal to 65 points, and patients of more than 65 points tend to have a poor clinical prognosis., Conclusion: The nomogram, composed of NIHSS, LDL-C, ASPECTS, infarct core volume and ischemic penumbra volume, may predict the clinical prognosis of cerebral infarction patients treated with thrombectomy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Despite promising trials, catheter ablation is still regarded as an adjunct to antiarrhythmic drugs (AADs) in the treatment of paroxysmal atrial fibrillation (PAF). This study aimed to compare the effectiveness of various ablation therapies and AADs., Method: Randomised controlled trials or propensity score-matched studies comparing atrial tachyarrhythmia recurrence among any combination of ablation modalities or AAD were retrieved. Kaplan-Meier curves and risk tables for this outcome were graphically reconstructed to extract patient-level data. Frequentist network meta-analysis (NMA) using derived hazard ratios (HRs), as well as 2 restricted mean survival time (RMST) NMAs, were conducted. Treatment strategies were ranked using P-scores., Results: Across 24 studies comparing 6 ablation therapies (5,132 patients), Frequentist NMA-derived HRs of atrial fibrillation recurrence compared to AAD were 0.35 (95% confidence interval [CI]=0.25-0.48) for cryoballoon ablation (CBA), 0.34 (95% CI=0.25-0.47) for radiofrequency ablation (RFA), 0.14 (95% CI=0.07-0.30) for combined CBA and RFA, 0.20 (95% CI=0.10-0.41) for hot-balloon ablation, 0.43 (95% CI=0.15-1.26) for laser-balloon ablation (LBA), and 0.33 (95% CI=0.18-0.62) for pulmonary vein ablation catheter. RMST-based NMAs similarly showed significant benefit of all ablation therapies over AAD. The combination of CBA + RFA showed promising long-term superiority over CBA and RFA, while LBA showed favourable short-term efficacy., Conclusion: The advantage of ablation therapies over AAD in preventing atrial tachyarrhythmia recurrence suggests that ablation should be considered as the first-line treatment for PAF in patients fit for the procedure. The promising nature of several specific therapies warrants further trials to elicit their long-term efficacy and perform a cost-benefit analysis.

Low-density lipoprotein cholesterol (LDL-C) has been considered as the primary target for the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, there are still residual cardiovascular risks in some patients even if LDL-C achieves the target level. Emerging evidence suggestes that elevated triglyceride (TG) level or triglyceride-rich lipoprotein (TRL) cholesterol (TRL-C) is one of the important components of the residual cardiovascular risks. Omega-3 fatty acids have been shown to be one of the effective drugs for reducing TG. However, its efficacy in reducing the risk of ASCVD is inconsistent in large randomized clinical trials. There is lack of consensus among Experts regarding the application of omega-3 fatty acids in cardiovascular diseases including heart failure, arrhythmia, cardiomyopathy, hypertension, and sudden death. Hence, the current consensus will comprehensively and scientifically present the detailed knowledge about the omega-3 fatty acids from a variety of aspects to provide a reference for its management of omega-3 fatty acids application in the Chinese population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Dou, Zhou, Zhao, Ye, Zhao and Guo.)

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT 1 R) could be involved in depression. Herein we hypothesize that CysLT 1 R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT 1 R in the astrocytes that participate in occurrence of depression. We found that CysLT 1 R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT 1 R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT 1 R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT 1 R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT 1 R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT 1 R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by β-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT 1 R of DG. Our study demonstrated that astrocyte CysLT 1 R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT 1 R could be a potential target for developing novel drugs of anti-depression., Competing Interests: Declaration of Competing Interest The manuscript has not been published previously, and is not under consideration for publication elsewhere. All authors declare that there are no competing financial interests in this study., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To report a case of combined oxidative phosphorylation deficiency 28 (COXPD28) in China, identified the pathogenic mutation and explored the pathogenic mechanism preliminarily. Methods: The clinical characteristics of a patient with COXPD28 were retrospectively analyzed and the pathogenic mutations were identified by mitochondrial gene sequencing and whole exome sequencing. The wild-type and mutant plasmids of pathogenic genes were constructed, and effect of mutation on protein expression by quantitative real-time PCR (qPCR) and Western blot were evaluated. Statistical methods mainly used one-way ANOVA and LSD test. Results: A 21 year old female patient presented with lactic acid poisoning due to repeated chest distress and wheezing since childhood. The sequencing of the whole exon group gene found that solute carrier family 25 member 26 (SLC25A26) gene had a compound heterozygous mutation (c.34G>C, p.A12P; c.197C>A, p.A66E), which was the first report in China. In vitro function test showed that the expression levels of SLC25A26 mRNA and S-adenosylmethionine carrier (SAMC) protein in cells transfected with SLC25A26 mutant plasmid were significantly lower than those transfected with wild type plasmid. The p.A66E mutant plasmid reduced the expression level of SLC25A26 mRNA and SAMC protein to 6% and 26% of wild type plasmids respectively (both P <0.001), while p.A12P mutant plasmid decreased to 62% and 82% of wild type plasmids respectively ( P <0.001, P =0.044). When the double mutant (p.A66E+p.A12P) plasmids were co-transfected, the expression levels of SLC25A26 mRNA and SAMC protein decreased to 47% and 57% of the wild type plasmids, respectively ( P <0.001, P =0.001). Conclusion: The pathogenic mutation gene of this patient with COXPD28 is SLC25A26 gene mutation (p.A66E, p.A12P), which causes the decrease of SLC25A26 expression level, mitochondrial oxidative phosphorylation dysfunction, and induces COXPD28.

The coronavirus SARS-CoV-2 has caused a health care crisis all over the world since the end of 2019. Although vaccines and neutralizing antibodies have been developed, rapidly emerging variants usually display stronger immune escape ability and can better surpass vaccine protection. Therefore, it is still vital to find proper treatment strategies. To date, antiviral drugs against SARS-CoV-2 have mainly focused on proteases or polymerases. Notably, noncanonical nucleic acid structures called G-quadruplexes (G4s) have been identified in many viruses in recent years, and numerous G4 ligands have been developed. During this pandemic, literature on SARS-CoV-2 G4s is rapidly accumulating. Here, we first summarize the recent progress in the identification of SARS-CoV-2 G4s and their intervention by ligands. We then introduce the potential interacting proteins of SARS-CoV-2 G4s from both the virus and the host that may regulate G4 functions. The innovative strategy to use G4s as a diagnostic tool in SARS-CoV-2 detection is also reviewed. Finally, we discuss some key questions to be addressed in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Classical swine fever (CSF), African swine fever (ASF), and atypical porcine pestivirus (APPV) are acute, virulent, and contagious viral diseases currently hampering the pig industry in China, which result in mummification or stillbirths in piglets and mortality in pigs. Diagnostic assays for the differentiation of infection and vaccination of CSFV, in addition to the detection of ASFV and APPV, are urgently required for better prevention, control, and elimination of these viral diseases in China., Methods: A quadruple PCR-based gene microarray assay was developed in this study to simultaneously detect wild-type and vaccine CSFV strains, ASFV and APPV according to their conserved regions. Forty-two laboratory-confirmed samples, including positive samples of 10 other swine viral diseases, were tested using this assay to confirm its high specificity., Results: This assay's limit of detections (LODs) for the wild-type and vaccine CSFV were 6.98 and 6.92 copies/µL. LODs for ASFV and APPV were 2.56 × 10 and 1.80 × 10 copies/µL, respectively. When compared with standard RT-PCR or qPCR for CSFV (GB/T 26875-2018), ASFV (MARR issue No.172), or APPV (CN108611442A) using 219 clinical samples, the coincidence was 100%. The results showed that this assay with high sensitivity could specifically distinguish ASFV, APPV, and CSFV, including CSFV infection and immunization., Conclusion: This assay provides a practical, simple, economic, and reliable test for the rapid detection and accurate diagnosis of the three viruses and may have good prospects for application in an epidemiological investigation, prevention, and control and elimination of these three diseases., (© 2022. The Author(s).)

The soil's rhizosphere is a highly active place where the exchange of substances and information occurs among plants, soils, and microorganisms. The microorganisms involved are crucial to the activities of plant growth and development, metabolism, and reproduction. Fritillaria L. medicinal plants are unique Chinese medicinal ingredients, but the continuous cropping obstacles formed in the artificial planting process is severely harmful to the growth and development of these medicinal plants. In this review, we summarized the current species and distribution of Fritillaria L. in China, and analyzed the changes in microbial diversity (mainly among bacteria and fungi) in the rhizosphere of these plants under long-term continuous cropping. The fungi showed an increasing trend in the soil rhizosphere, resulting in the transition of the soil from the high-fertility "bacterial type" to the low-fertility "fungal type" as planting years increased. Furthermore, the interaction between Fritillaria L. medicinal plants and the rhizosphere microorganisms was reviewed, and promising applications for the rhizosphere microbiome in the cultivation of Fritillaria L. medicinal plants were suggested. It is expected that this review will facilitate the in-depth understanding of rhizosphere microorganisms in the growth, accumulation of active ingredients, and disease control of Fritillaria L., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Mei, Zhu, Zhao, Ma and Li.)

Background: An updated systematic review and meta-analysis was conducted to compare radiofrequency ablation (RFA) versus repeat hepatectomy (RH) for patients with recurrent hepatocellular carcinoma (rHCC) after a previous liver resection., Methods: PubMed, EMBASE, and Cochrane databases were searched from inception to October 2021 for randomized controlled trials and propensity-score matched studies. Individual participant survival data of disease-free survival (DFS) and overall survival (OS) were extracted and reconstructed followed by one-stage and two-stage meta-analysis. Secondary outcomes were major complications and length of hospital stay (LOHS)., Results: A total of seven studies (1317 patients) were analysed. In both one-stage and two-stage meta-analysis, there was no significant difference in OS between the RFA and RH cohorts (Hazard Ratio (HR) 1.15, 95% CI 0.98-1.36, P = 0.094 and HR 1.12, 95% CI 0.77-1.64, P = 0.474 respectively), while the RFA group had a higher hazard rate of disease recurrence compared to the RH group (HR 1.30, 95% CI 1.13-1.50, P &lt; 0.001 and HR 1.31, 95% CI 1.09-1.57, P = 0.013, respectively). RFA was associated with fewer major complications and shorter LOHS versus RH (Odds Ratio 0.34, 95% CI 0.15-0.76, P = 0.009 and Weighted Mean Difference - 4.78, 95% CI - 6.30 to - 3.26, P &lt; 0.001, respectively)., Conclusions: RH may be associated with superior DFS for rHCC, at the expense of higher morbidity rate and longer LOHS. However, OS is comparable between both modalities. As such, these techniques may be utilized as complementary strategies depending on individual patient and disease factors. Large-scale, randomized, prospective studies are required to corroborate these findings., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting., Method: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed., Results: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis., Conclusion: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Forty-six patients were treated with eravacycline (ERV) for Acinetobacter baumannii infections, where 69.5% of isolates were carbapenem resistant (CRAB). Infections were primarily pulmonary (58.3%), and most patients received combination therapy (84.4%). The median (IQR) ERV duration was 6.9 days (5.1 to 11.1). Thirty-day mortality was 23.9% in the cohort and 21.9% in CRAB patients. One patient experienced an ERV-possible adverse event. IMPORTANCE Acinetobacter baumannii, particularly when carbapenem resistant (CRAB), is one of the most challenging pathogens in the health care setting. This is complicated by the fact that there is no consensus guideline regarding management of A. baumannii infections. However, the recent Infectious Diseases Society of America guidelines for treatment of resistant Gram-negative infections provided expert recommendations for CRAB management. The panel suggest using minocycline among tetracycline derivatives rather than eravacycline (ERV) until sufficient clinical data are available. Therefore, we present the largest multicenter real-world cohort in patients treated with ERV for A. baumannii, where the majority of isolates were CRAB (69.5%). Our analysis demonstrate that patients treated with ERV-based regimens achieved a 30-day mortality of 23.9% and had a low incidence of ERV-possible adverse events (2.1%). This study is important as it fills the gap in the literature regarding the use of a novel tetracycline (i.e., ERV) in the treatment of this challenging health care infection.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8)) is an auxiliary AMPA receptor (AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD, whereby adolescent TARP γ-8 knockout (KO) mice exhibited ADHD-like behaviors, including hyperactivity, impulsivity, anxiety, impaired cognition, and memory deficits. Human single-nucleotide polymorphism (SNP) analysis also revealed strong associations between intronic alleles in CACNG8 genes and ADHD susceptibility. In addition, synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice. Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice. Methylphenidate (MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans. This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8 deficiency, which has great potential for the development of new therapies.

Aim: To investigate the histological characteristics and ultrastructure of recurrent Chinese R124L mutated corneal dystrophy after keratoplasty., Methods: The subjects were enrolled from a Chinese family of corneal dystrophy with R124L heterozygous gene mutation and with a history of consanguineous marriage. Normal corneal samples were used as controls., Results: In this family, 2 patients (3 eyes) underwent penetrating keratoplasty (PKP) and 2 patients (4 eyes) underwent lamellar keratoplasty (LKP). They had recurrence at 33.5±3.0 (range 30-36)mo after keratoplasty. Among them, 1 patient (1 eye) underwent PKP again and 1 patient (2 eyes) underwent LKP again. In the R124L mutated recurrent corneal dystrophy, the corneal turbidity was mainly distributed from the upper corneal cortex to the anterior stroma; the corneal epithelium surface was rougher and more uneven; and, the corneal erosions were larger. Hematoxylin-eosin staining showed that the thickness of the corneal epithelium was uneven; the arrangement of the epithelial cells was disordered; and, some corneal epithelial cells were swollen. The results of Congo red staining, Masson's trichrome staining and Periodic acid-Schiff staining were positive, while that of Alcian blue staining was negative. Under a transmission electron microscope, deposition of high electron density substances between epithelial and basal cells, and, apoptosis of basal cells were observed. Many high electron density depositions were observed in the sub-epithelial and anterior corneal matrix., Conclusion: In the Chinese family of recurrent corneal dystrophy with R124L gene mutation, the corneal epithelia of the recurrent cases are rougher, and the corneal depositions are extracellular amyloid fibrin., (International Journal of Ophthalmology Press.)

Objectives: To investigate the current status of antibiotic use in very low birth weight/extremely low birth weight infants in Jiangsu Province of China, and to provide a clinical basis for the quality and improvement of antibiotic management in the neonatal intensive care unit (NICU)., Methods: A retrospective analysis was performed on the data on general conditions and antibiotic use in the very low birth weight/extremely low birth weight infants who were admitted to 15 hospitals of Jiangsu Province from January 1, 2019 to December 31, 2020. A questionnaire containing 10 measures to reduce antibiotic use was designed to investigate the implementation of these intervention measures., Results: A total of 1 920 very low birth weight/extremely low birth weight infants were enrolled, among whom 1 846 (96.15%) were treated with antibiotic, and the median antibiotic use rate (AUR) was 50/100 patient-days. The AUR ranged from 24/100 to 100/100 patient-days in the 15 hospitals. After adjustment for the confounding factors including gestational age, birth weight, and neonatal critical score, the Poisson regression analysis showed that there was a significant difference in the adjusted AUR (aAUR) among the hospitals ( P< 0.01). The investigation results showed that among the 10 measures to reduce antibiotic use, 8 measures were implemented in less than 50% of these hospitals, and the number of intervention measures implemented was negatively correlated with aAUR ( r s =-0.564, P =0.029)., Conclusions: There is a high AUR among the very low birth weight/extremely low birth weight infants in the 15 hospitals of Jiangsu Province, with a significant difference among hospitals. The hospitals implementing a relatively few measures to reduce antibiotic use tend to have a high AUR. It is expected to reduce AUR in very low birth weight/extremely low birth weight infants by promoting the quality improvement of antibiotic use management in the NICU.

From November 1,2018 to January 31,2019 (OP 2018-2019 ) and from November 1,2019 to January 20, 2020 (OP 2019-2020 ), PM 1 measurement was conducted daily for two consecutive years. The concentration of trace elements in the atmospheric PM 1 in Qingdao in autumn and winter was analyzed. The observation period was divided into four air quality levels (Level Ⅰ, Level Ⅱ, Level Ⅲ, and Level Ⅳ), and the characteristics and sources of the concentration of trace elements in PM 1 were analyzed. The non-carcinogenic risks (Zn, Pb, Mn, Cu, and V) and carcinogenic risks (As, Cr, Ni, Cd, and Co) of different people with different air quality levels were evaluated. The results showed that the changes in total metal element concentrations were associated with changes in Ca, K, and Al concentrations at different air quality classes during OP 2019-2020 compared to those during OP 2018-2019 and were more influenced by dust and biomass combustion sources. Compared with that during OP 2018-2019 , the V concentration in different air quality levels (Level Ⅰ, Level Ⅱ, Level Ⅲ, and Level Ⅳ) during OP 2019-2020 decreased by 19.0%, 60.5%, 82.7%, and 77.5%, respectively. This was presumed to be related to the implementation of the Domestic Emission Control Area (DECA) policy for ships, which led to the significant reduction in V concentration due to the change in fuel quality of ships in the waters around Qingdao. The results of the enrichment factor, the ratio method, and the backward trajectory of airflow further indicated that the changes in V concentrations were mainly influenced by the DECA policy. However, after the implementation of the DECA, the V/Ni value as a limit for judging the influence of ship sources in the area required further exploration. The health risk assessment results showed that the risk factor of Mn ranged from 0.07 to 1.22 during OP 2018-2019 and OP 2019-2020 . It was recommended to strengthen the management and control of Mn-containing pollution sources. The lifetime carcinogenic risk (ILCR) value of As and Cd under different air qualities during OP 2018-2019 and OP 2019-2020 was lower than 10 -4 but higher than 10 -6 , indicating that there was a carcinogenic probability, although it was still at an acceptable level. During OP 2018-2019 , when the air quality was Ⅳ, the ILCR value of Cr was higher than 10 -4 , and there was a risk of cancer.

Background: We aimed to investigate the association between time from admission to appendectomy on perioperative outcomes in order to determine optimal time-to-surgery windows., Methods: We performed a retrospective review of all the appendectomies performed between July 2018 to May 2020. We first compared the perioperative outcomes using preselected time-to-surgery cut-offs, then determined optimal safe windows for surgery, and finally identified subgroups of patients who may require early intervention., Results: Six hundred twenty-one appendectomies were performed in the time period. The patients with a time-to-surgery of ≥12 hours had a significantly longer length of stay (median 2 days [interquartile range 1-3] vs 3 days [interquartile range 2-4], mean difference = 0.74 [95% confidence interval 0.32-1.17, P = .0006]) and higher 30-day readmission risk (odds ratio 2.58, 95% confidence interval 1.12-5.96, P = .0266) versus those with a time-to-surgery of <12 hours. These differences persisted when the time-to-surgery was dichotomized by <24 or ≥24 hours. A time-to-surgery beyond 25 hours was associated with a 3.34-fold increased odds of open conversion (P = .040), longer operation time (mean difference 15.8 mins, 95% confidence interval 3.4-28.3, P = .013) and longer postoperative length of stay (mean difference 10.3 hours, 95% confidence interval 3.4-20.2, P = .042) versus a time-to-surgery of <25 hours. The patients with time-to-surgery beyond 11 hours had a 1.35-fold increased odds of 30-day readmission (95% confidence interval 1.02-5.43, P = .046) compared with those who underwent appendectomy before 11 hours. Older patients, patients with American Society of Anesthesiologist score II to III, and individuals with long duration of preadmission symptoms had higher risk of prolonged operation time, open conversion, increased length of stay, and postoperative morbidity with increasing time-to-surgery., Conclusion: This study identified the safe windows for appendectomy to be 11 to 25 hours from admission for most perioperative outcomes. However, certain patient subgroups may be less tolerant of surgical delays., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome. The underlying pathophysiology is presumed to be closely related with disruption of GABAergic neurotransmission, which is mainly medicated by γ-aminobutyric acid type A receptor (GABA A R). Thus, it is reasonable to assume that rare GABA A R variants might contribute to the pathogenesis of SHE. To test this hypothesis, we performed next-generation sequencing in 58 SHE patients and analyzed the functional effects of the identified variants in both neuronal and non-neuronal cells using a combination of electrophysiology recordings, western blot, flow cytometry, and confocal microscopy. In our study, we detected three rare variants (NM&#95;198904.2: c.269C > T, p.T90M; NM&#95;198904.2: c.950C > A, p.T317N and NM&#95;198903.2: c.649C > T, p.Q217X) in GABRG2 (MIM:137,164, encoding GABA A R γ 2 subunit) in three unrelated patients. Two of the three rare variants were transmitted unaffected maternally (T90M) or unaffected paternally (Q217X), whereas the T317N variant arose de novo. The mother of proband carrying the T90M variant was unaffected and being mosaicism for this variant. Functional analysis showed that T90M and T317N variants decreased GABA-evoked current amplitudes by diverse mechanisms including impaired surface expression, endoplasmic reticulum retention, and channel gating defects. And Q217X variant reduced synaptic clustering and distribution of GABA A R. While a causal role of these variants cannot be established directly from these results, the functional assessment together with the genetic sequencing suggests that these rare GABRG2 variants may constitute genetic risk factors for SHE. Our study further expands the GABRG2 phenotypic spectrum and supports the view that GABAergic neurotransmission participates in the epileptogenesis of SHE., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation., Methods: A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using p scores., Results: Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53-0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66-0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity ( I 2 = 0%) and inconsistency (Cochran's Q = 0.52, p = 0.773) was observed. p scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS., Conclusion: This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies., Competing Interests: Joycelyn Jie Xin Lee has received research funding from Bayer; honoraria for presentations from Ipsen and BMS; and advisory boards with Bayer, Ipsen, Taiho, and Eisai. Stephen Lam Chan has received honoraria from Bayer; has consulting or advisory roles in AstraZeneca/MedImmune, MSD Oncology, and Novartis; speakers' bureau from Amgen, Bayer, and Eisai; and research funding from Novartis and Sirtex Medical. Thomas Yau reports consulting fees from, honoraria from, and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp and Dohme, New B Innovation, Novartis, OrigiMed, Pfizer, Sillajen, Sirtex, and Taiho Pharmaceutical. David Wai Meng Tai has received research funding from Bristol-Myers Squibb, Sirtex, and NMRC Singapore; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen, Eisai, and Bristol-Myers Squibb; and consulting fees from Novartis, Bristol-Myers Squibb, and Merck Sharpe Dohme. Raghav Sundar has received honoraria from Bristol-Myers Squibb, Lilly, Roche, Taiho, Astra Zeneca, DKSH, and MSD; has advisory activity with Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, and AstraZeneca; received research funding from MSD and Paxman Coolers; and has received travel grants from AstraZeneca, Eisai, Roche, and Taiho Pharmaceutical. Chow Wei Too has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and consulting fees from Sirtex., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: For patients who treated with tacrolimus after kidney transplant, therapeutic drug monitoring is essential to improve their prognosis. However, previous detection methods have limitations, such as the overestimation and unacceptable bias in the immunoassays. Precision medicine has been challenged. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is recognized as the gold standard due to its accuracy and specificity, but lack of throughput and complex process limits its clinical application. Therefore, an accurate, simple and high throughput method for tacrolimus monitoring is needed for clinical practice., Methods: A modified LC-MS/MS method was introduced and validated. Whole blood samples were prepared by a one-step protein precipitation method. Chromatographic separation was achieved using a Phenomenex Kinetex 2.6 μm XB-C18 2.1 × 50 mm column with a total run time of 3.5 min to avoid matrix effect. An electrospray ionization source (ESI) was used in positive ion multiple reaction monitoring (MRM) mode for mass spectrometric detection. In order to protect the mass spectrometer, only part of the sample after LC separation was allowed to enter the mass spectrum, through a two HPLC systems coupled one mass spectrometry design. In this way, the instrument throughput is also improved and realizing the detection of 2 samples within 3.5 min and carried out a shorter analyzing time for each sample of 1.75 min. Additionally, we calculated tacrolimus-intrapatient variant (Tac-IPV) based on this modified method and assessed the prognostic value of Tac-IPV in Chinese kidney transplant patients., Results: The LC-MS/MS was modified by streamlining the procedure and increasing the throughput. The method proved to be accurate and reproducible with all performance parameters suitably meeting the clinical requirements over a calibration ranged from 0.37 to 42.90 ng/mL. Parameters such as linearity, limit of quantification (LoQ) and dilution integrity were validated with a clinical reportable range from 0.37 to 343.20 ng/mL, which was particularly useful for high drug concentrations patients (rare but very serious). Both cross-contamination and matrix effects were negligible. Clinical data of 83 patients showed that Tac-IPV was associated with poor kidney transplant outcome in Chinese (Hazard Ratio (HR) = 3.96, 4.75; 95% Cl: 1.10-14.21, 1.23-18.36; P < 0.05)., Conclusions: This modified LC-MS/MS method possessed high throughput and simple sample preparation, allowing it to meet daily clinical needs. At the same time, Tac-IPV based on this modified LC-MS/MS had excellent prognostic value in kidney transplantation. These advantages have great significance for the individualized treatment of Chinese kidney transplant patients and broad application of Tac-IPV., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

In recent years, G-quadruplexes (G4s), types of noncanonical four-stranded nucleic acid structures, have been identified in many viruses that threaten human health, such as HIV and Epstein-Barr virus. In this context, G4 ligands were designed to target the G4 structures, among which some have shown promising antiviral effects. In this Perspective, we first summarize the diversified roles of RNA G4s in different viruses. Next, we introduce small-molecule ligands developed as G4 modulators and highlight their applications in antiviral studies. In addition to G4s, we comprehensively review the medical intervention of G4-interacting proteins from both the virus (N protein, viral-encoded helicases, severe acute respiratory syndrome-unique domain, and Epstein-Barr nuclear antigen 1) and the host (heterogeneous nuclear ribonucleoproteins, RNA helicases, zinc-finger cellular nucelic acid-binding protein, and nucleolin) by inhibitors as an alternative way to disturb the normal functions of G4s. Finally, we discuss the challenges and opportunities in G4-based antiviral therapy.

Purpose: MYCN onco-gene amplification in neuroblastoma confers patients to the high-risk disease category for which prognosis is poor and more aggressive multimodal treatment is indicated. This retrospective study leverages machine learning techniques to develop a computed tomography (CT)-based model incorporating semantic and non-semantic features for non-invasive prediction of MYCN amplification status in pediatric neuroblastoma., Methods: From 2009 to 2020, 54 pediatric patients treated for neuroblastoma at a specialized children's hospital with pre-treatment contrast-enhanced CT and MYCN status were identified (training cohort, n = 44; testing cohort, n = 10). Six morphologic features and 107 quantitative gray-level texture radiomics features extracted from manually drawn volume-of-interest were analyzed. Following feature selection and class balancing, the final predictive model was developed with eXtreme Gradient Boosting (XGBoost) algorithm. Accumulated local effects (ALE) plots were used to explore main effects of the predictive features. Tumor texture maps were also generated for visualization of radiomics features., Results: One morphologic and 2 radiomics features were selected for model building. The XGBoost model from the training cohort yielded an area under the receiver operating characteristics curve (AUC-ROC) of 0.930 (95% CI, 0.85-1.00), optimized F1-score of 0.878, and Matthews correlation coefficient (MCC) of 0.773. Evaluation on the testing cohort returned AUC-ROC of 0.880 (95% CI, 0.64-1.00), optimized F1-score of 0.933, and MCC of 0.764. ALE plots and texture maps showed higher "GreyLevelNonUniformity" values, lower "Strength" values, and higher number of image-defined risk factors contribute to higher predicted probability of MYCN amplification., Conclusion: The machine learning model reliably classified MYCN amplification in pediatric neuroblastoma and shows potential as a surrogate imaging biomarker., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To compare peri-operative outcomes of skin closure with octyl cyanoacrylate (OCA) skin adhesive (Dermabond) with or without subcuticular sutures after deep dermal suturing for implantable venous port placement closure., Materials and Methods: Seven hundred and ninety-two single-lumen implantable venous port insertions for chemotherapy were reviewed from September 2019 to March 2021 in a retrospective single-centre study. Propensity-score matching by a 1:1 nearest neighbour algorithm was conducted to control for confounding baseline differences. Distances were determined by logistic regression. Propensity-score matching was performed based on the following variables: age at procedure, gender, race, operator's seniority, use of anchoring polypropylene suture (PROLENE), port model, and volume of intra-operative local analgesia. The primary outcome was wound dehiscence at the first follow-up (∼1 week)., Results: The 792 port insertions were conducted in 302 males (38.1%), median age 63 years (IQR: 54-69). Of the 656 wounds closed with subcuticular sutures and skin adhesive, 136 were matched in a 1:1 fashion against procedures closed without a subcuticular suture. No significant differences were demonstrated in pain scores, bleeding, swelling, bruising, fever, wound dehiscence, and discharge at postoperative day 1 (POD1) and at first follow-up between the groups (all p>0.05). Of note, no significant differences in wound dehiscence at first follow-up was found in both unmatched (p=0.133) and matched cohorts (McNemar-Bowker's χ 2  = 1.167, p=0.761)., Conclusion: These findings suggest that the omission of subcuticular sutures during implantable venous port closure may not compromise peri-operative outcomes when OCA skin adhesives were used., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: Please see research paper for full details of researcher’s COIs. CK is the founder of AbScent, a non-profit patient support group for people with olfactory dysfunction.

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS -driven human cancers and warrant further preclinical and clinical development.

Gliomas are the most aggressive and common type of malignant brain tumor, with limited treatment options and a dismal prognosis. Angiogenesis, a hallmarks of cancer, is one of two critical events in the progression of gliomas. Accumulating evidence has demonstrated that in glioma dysregulated molecules like long noncoding RNAs (lncRNAs), are closely linked to tumorigenesis and prognosis. However, the effects of and mechanisms of action of lncRNAs during tumor angiogenesis are poorly understood. The effect of lncRNA RP11-732M18.3 on angiogenesis was elucidated through an intracranial orthotopic glioma model, immunohistochemistry, and an in vitro angiogenesis assay. Co-culture experiments and cell migration assays were performed to investigate the function of lncRNA RP11-732M18.3 in vitro . lncRNA RP11-732M18.3 increased CD31 + microvessel density, and overexpression of lncRNA RP11-732M18.3 resulted in poor mouse survival. lncRNA RP11-732M18.3 promoted endothelial cell migration and tube formation. Nomogram and Kaplan-Meier survival analyses indicated that higher VEGFA is correlated with a poor prognosis. Mechanistically, lncRNA RP11-732M18.3 promotes angiogenesis by increasing the nuclear level of EP300 and facilitating the transcription and secretion of VEGFA. Our study contributes to the latest understanding of glioma angiogenesis and prognosis. lncRNA RP11-732M18.3 may be a potential treatment target in glioma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kang, Zhao, Yuan, Liao, Yu, Li, Jin, Cao, Chen, Jin, Chen, Ke, Li, Huang, Hu and Huang.)