Effective neoadjuvant immunotherapy and chemotherapy in stage IIIA adenosquamous carcinoma of the lung with a complete response and surgical success: A case report.

There has been rapid advancement in the development of neoadjuvant therapy for non-small cell lung cancer (NSCLC), which holds great promise as an effective treatment strategy. Some clinical trials have confirmed that immunotherapy in combination with chemotherapy can be a recommended first-line regimen for neoadjuvant treatment of NSCLC. The present study describes the case of a male patient aged 65 years who was diagnosed with stage IIIA (cT2N2M0) adenosquamous carcinoma of the lung. After the administration of two cycles of neoadjuvant immunotherapy (sintilimab) in combination with chemotherapy, stable disease was observed in the primary tumor, whereas partial remission was detected in the mediastinal lymph nodes based on imaging assessment. The patient underwent an immediate upper lobectomy of the left lung. Pathological analysis revealed a complete response in the primary lesion, with only minimal presence of tumor cells observed in the lymph nodes surrounding the mediastinum and bronchi. This indicated that the present neoadjuvant therapy could be used in the treatment of stage III adenosquamous lung carcinoma; however, to conclusively determine its efficacy, further studies targeting this specific cancer type are essential.

Association of preoperative coronavirus disease 2019 with mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery: An observational cohort study.

STUDY OBJECTIVE: To assess the impact of preoperative infection with the contemporary strain of severe acute respiratory coronavirus 2 (SARS-CoV-2) on postoperative mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery. DESIGN: An ambidirectional observational cohort study. SETTING: A tertiary and teaching hospital in Shanghai, China. PATIENTS: All adult patients (≥ 18 years of age) who underwent elective, noncardiac surgery under general anesthesia at Huashan Hospital of Fudan University from January until March 2023 were screened for eligibility. A total of 2907 patients were included. EXPOSURE: Preoperative coronavirus disease 2019 (COVID-19) positivity. MEASUREMENTS: The primary outcome was 30-day postoperative mortality. The secondary outcomes included postoperative pulmonary complications (PPCs), myocardial injury after noncardiac surgery (MINS), acute kidney injury (AKI), postoperative delirium (POD) and postoperative sleep quality. Multivariable logistic regression was used to assess the risk of postoperative mortality and morbidity imposed by preoperative COVID-19. MAIN RESULTS: The risk of 30-day postoperative mortality was not associated with preoperative COVID-19 [adjusted odds ratio (aOR), 95% confidence interval (CI): 0.40, 0.13-1.28, P = 0.123] or operation timing relative to diagnosis. Preoperative COVID-19 did not increase the risk of PPCs (aOR, 95% CI: 0.99, 0.71-1.38, P = 0.944), MINS (aOR, 95% CI: 0.54, 0.22-1.30; P = 0.168), or AKI (aOR, 95% CI: 0.34, 0.10-1.09; P = 0.070) or affect postoperative sleep quality. Patients who underwent surgery within 7 weeks after COVID-19 had increased odds of developing delirium (aOR, 95% CI: 2.26, 1.05-4.86, P = 0.036). CONCLUSIONS: Preoperative COVID-19 or timing of surgery relative to diagnosis did not confer any added risk of 30-day postoperative mortality, PPCs, MINS or AKI. However, recent COVID-19 increased the risk of POD. Perioperative brain health should be considered during preoperative risk assessment for COVID-19 survivors.

DNA Methylation-Based Diagnosis and Treatment of Breast Cancer.

DNA methylation is a key epigenetic modifier involved in tumor formation, invasion, and metastasis. The development of breast cancer is a complex process, and many studies have now confirmed the involvement of DNA methylation in breast cancer. Moreover, the number of genes identified as aberrantly methylated in breast cancer is rapidly increasing, and the accumulation of epigenetic alterations becomes a chronic factor in the development of breast cancer. The combined effects of external environmental factors and the internal tumor microenvironment promote epigenetic alterations that drive tumorigenesis. This article focuses on the relevance of DNA methylation to breast cancer, describing the role of detecting DNA methylation in the early diagnosis, prediction, progression, metastasis, treatment, and prognosis of breast cancer, as well as recent advances. The reversibility of DNA methylation is utilized to target specific methylation aberrant promoters as well as related enzymes, from early prevention to late targeted therapy, to understand the journey of DNA methylation in breast cancer with a more comprehensive perspective. Meanwhile, methylation inhibitors in combination with other therapies have a wide range of prospects, providing hope to drug-resistant breast cancer patients.

Tumor Microenvironment Heterogeneity, Potential Therapeutic Avenues, and Emerging Therapies.

OBJECTIVE: This review describes the comprehensive portrait of tumor microenvironment (TME). Additionally, we provided a panoramic perspective on the transformation and functions of the diverse constituents in TME, and the underlying mechanisms of drug resistance, beginning with the immune cells and metabolic dynamics within TME. Lastly, we summarized the most auspicious potential therapeutic strategies. RESULTS: TME is a unique realm crafted by malignant cells to withstand the onslaught of endogenous and exogenous therapies. Recent research has revealed many small-molecule immunotherapies exhibiting auspicious outcomes in preclinical investigations. Furthermore, some pro-immune mechanisms have emerged as a potential avenue. With the advent of nanosystems and precision targeting, targeted therapy has now transcended the "comfort zone" erected by cancer cells within TME. CONCLUSION: The ceaseless metamorphosis of TME fosters the intransigent resilience and proliferation of tumors. However, existing therapies have yet to surmount the formidable obstacles posed by TME. Therefore, scientists should investigate potential avenues for therapeutic intervention and design innovative pharmacological and clinical technologies.

Frailty and prognosis in lung cancer: systematic review and meta-analysis.

Lung cancer is one of the most common malignant tumours. Patients are frequently at risk of frailty as lung cancer progresses. The meta-analysis aims to explore the impact of frailty on the long-term prognosis and the incidence of short-term chemotherapy toxicity in patients with lung cancer. This study was designed adhered to the criteria of Cochrane Handbook for Systematic Reviews. Systematic searches were performed on PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies until December 2022. The outcome measures were overall survival, progression-free survival, chemotherapy toxicity and all-cause mortality. We then performed sensitivity analyses, subgroup analyses and evidence quality. This meta-analysis was performed using Review Manager V.5.4 software. Of the included studies, six were retrospective and five were prospective. There was a statistically significant difference between the frail and non-frail groups in overall survival (HR 2.27, 95% CI 1.24 to 4.15, p=0.008), all-cause mortality (HR 1.63, 95% CI 1.00 to 2.65, p=0.05) and chemotherapy toxicity (OR 3.73, 95% CI 1.99 to 7.00, p<0.0001). We conducted a sensitivity analysis, and the result was stable. The study revealed frail group had shorter survival and experienced more severe adverse effects than the non-frail group. Frailty affects the long-term prognosis and the incidence of short-term chemotherapy toxicity of patients with lung cancer. Consequently, medical professionals should focus on frailty screening in patients with lung cancer and implement active intervention measures. PROSPERO registration number is CRD42023398606.

A porphyrin-MOF-based integrated nanozyme system for catalytic cascades and light-enhanced synergistic amplification of cellular oxidative stress.

Peroxidase (POD)-like nanozymes have been found to act as nanoreactors for the generation of reactive oxygen species (ROS) to resolve drug resistance in the tumor microenvironment (TME). Amplifying cellular oxidative stress is considered to be a drug-free strategy to efficiently induce apoptosis in tumor cells. However, the limited content of intracellular hydrogen peroxide (H2O2) extremely restricts the performance of POD-like nanozymes to amplify cellular oxidative stress. Moreover, additional operational processes combined with exogenous reagents to achieve oxidative stress lead to a dilemma of extra cytotoxicity. Here, an integrated iron-porphyrin-MOF-based nanozyme composite named HA@GOx@PCN-224(Fe) (HGPF) was precisely designed and constructed. Generally, the POD-like nanozyme PCN-224(Fe) was used as a platform to immobilize glucose oxidase (GOx), and further embedded with hyaluronic acid (HA) to enable the targeting ability of tumor cells. When endocytosed by tumor cells, intracellular glucose was oxidized to H2O2 and gluconic acid catalyzed by immobilized GOx of HGPF. Afterwards, inspired by heme analogs, H2O2 was catalyzed by iron-porphyrin active sites of the HGPF nanozyme to generate hydroxyl radicals (˙OH). Under light irradiation, the iron-porphyrin of HGPF acted as a photosensitizer to facilely produce singlet oxygen (1O2). Such a synergistic generation of ROS strikingly amplified oxidative stress and induced severe apoptosis in tumor cells. HGPF was expected to integrate intracellular oxygen sources and overcome the dilemma of limited intracellular H2O2 content. Consequently, HGPF was constructed as an integrated nanoreactor to simultaneously achieve light-enhanced catalytic oxidation cascades, providing a promising strategy for a synergistic amplification of cellular oxidative stress.

Flame-retardant effect of tannic acid-based intumescent fire-retardant applied on flammable natural rubber.

Tannic acid (TA) is a natural phenolic compound abundant in plants. Its characteristics of low combustion and good absorption make it useful in the flame retardant field. On this basis, a new expansive flame retardant system (ACT) composed of ammonium polyphosphate (APP)/TA functional clay (CT) was used to study the synergistic flame retardancy and smoke suppression of natural rubber (NR). Because of their unique flame retardancy and better mechanical properties compared with the traditional expansive flame retardant system (IFR), new flame retardants have attracted much attention in various fields. The results of the cone calorimeter showed that the ACT system can significantly influence the decomposition behavior of NR and form a highly graphitized and phosphorous carbon layer to protect the composite material, thus a synergistic effect is produced on the flame retardancy and smoke suppression performance of the composite material. In addition, within the effective additive quality range of the ACT system, TC can give the NR composite excellent mechanical properties.

Opposing effects of deubiquitinase OTUD3 in innate immunity against RNA and DNA viruses.

Retinoic acid-inducible-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS) genes encode essential cytosolic receptors mediating antiviral immunity against viruses. Here, we show that OTUD3 has opposing role in response to RNA and DNA virus infection by removing distinct types of RIG-I/MDA5 and cGAS polyubiquitination. OTUD3 binds to RIG-I and MDA5 and removes K63-linked ubiquitination. This serves to reduce the binding of RIG-I and MDA5 to viral RNA and the downstream adaptor MAVS, leading to the suppression of the RNA virus-triggered innate antiviral responses. Meanwhile, OTUD3 associates with cGAS and targets at Lys279 to deubiquitinate K48-linked ubiquitination, resulting in the enhancement of cGAS protein stability and DNA-binding ability. As a result, Otud3-deficient mice and zebrafish are more resistant to RNA virus infection but are more susceptible to DNA virus infection. These findings demonstrate that OTUD3 limits RNA virus-triggered innate immunity but promotes DNA virus-triggered innate immunity.

Contribution of K solubilising bacteria (Burkholderia sp.) promotes tea plant growth (Camellia sinesis) and leaf polyphenols content by improving soil available K level.

K+ availability is important for growth and quality of tea (Camellia sine sis L.). K solubilising bacteria convert insoluble K to available K. This study was conducted to screen K solubilising bacteria isolated from tea rhizosphere soil in Qimen county, Anhui province, China. The maximum K solubilisation colony (the ratio of diameter halo/colony was 2.54) was identified as Burkholderia sp. (storage number: M2021105) by biochemistry and molecular analysis. Pot experiments (Laterite) showed that the inoculation of Burkholderia sp. significantly improved tea plant height (Zhongcha108, 1 year old) and total polyphenols content by 21.14% and 21.58% compared with the control, respectively. Higher polyphenol level promoted the formation of theaflavin in the fermentation experiments. Further experiments showed that tartaric acid and pryuvic acid produced by Burkholderia sp. are important components associated with K solubilisation in vitro . Burkholderia sp. significantly increased soil available K by 15.12%; however, there was no significant difference in available N and P, and Cu, Mg, Zn and Ca compared with the control. K content in inoculated tea roots and leaves was significantly higher (50% and 10%, respectively) than the control. Compared with the control, exogenous supply of 60mgkg-1 K significantly increased levels of polyphenol (53.97%), theaflavin (16.31%), theaflavin-3-gallate (20%), theaflavin 3'-gallic acid ester (32.24%) and theaflavin 3,3'-gallic acid ester (40.95%). Due to its ability to enable higher available soil K, ur study indicated that Burkholderia sp. have potential to increase total polyphenols content be a bio-inoculant for biofortification of tea.

The Study of Enteromorpha-Based Reinforcing-Type Flame Retardant on Flame Retardancy and Smoke Suppression of EPDM.

Enteromorpha, as a waste from marine pollution, brings great pressure to environmental governance every year, especially for China. Under the premise of a shortage of industrial materials, taking appropriate measures can turn waste into wealth, which will benefit us a lot. In this work, a bio-based reinforcing-type flame retardant based on Enteromorpha is designed. The designed Enteromorpha-based flame retardant system (AEG) mainly focuses on the reinforcing and flame retardant effects on ethylene-propylene-diene tripolymer (EPDM). For the AEG system, ammonium polyphosphate (APP) serves as both the acid source and the gas source; the simple hybrid material (GN) produced by loading graphene (GE) and Enteromorpha (EN) using tannic acid (TA) as a regulator serves as an acid source and a carbonizing source. The results show that when 40 phr AEG is added, the LOI of EPDM/AEG40 reaches 32.5% and the UL-94 reaches the V-0 level. The PHRR and THR values of EPDM/AEG40 are 325.9 kW/m2 and 117.6 MJ/m2, respectively, with decrements of 67.3% and 29.7%, respectively, compared with the results of neat EPDM composite. Especially, the TSP and TSR values of EPDM/AEG40 are reduced from 15.2 m2 of neat EPDM to 9.9 m2 with a decrement of 34.9% and reduced from 1715.2 m2/m2 of neat EPDM to 1124.5 m2/m2 with a decrement of 34.4%, indicating that AEG is effective in flame retardancy and smoke suppression. Meanwhile, the tensile strength and tear strength of EPDM/AEG composites are much higher than neat EPDM, therefore, with the future development of innovate reinforcing-type flame-retardant Enteromorpha, the application of Enteromorpha in the polymer flame-retardant field will surely usher in bright development.

Novel amphiphilic fluorine-containing nanocarriers for oxygen self-sufficiency "AND" GSH depletion sequentially to enhance photodynamic therapy.

In order to maximize the retention of the photodynamic therapy (PDT) efficacy, while avoiding the dilemma of hypoxia and high reducing substances in tumor tissue, fluoropolymers were synthesized in a simple and effective methods. Fluorous effect with good oxygen carrying capacity was endowed by the fluorine-containing section in fluoropolymers and the perfluorodecalin (PFD) together, the reaction site with GSH was provided by the disulfide bond, which enhanced PDT efficiency through the sequential "AND" logic gate design. Two kind of fluorine-containing nanocarriers (M-Ce6 and E-Ce6) were obtained by solvent evaporation or ultrasound emulsification with PFD, respectively. In vitro, both of them showed promising high ROS generation under photoirradiation. Benefiting by cavitation effects, E-Ce6 had a more significant statistical difference in cellular uptake. Furthermore, the cells incubating with E-Ce6 hardly were noticed that the hypoxia signal appeared under hypoxia, while reducing the intracellular GSH content by more than 15%. Through the sequential "AND" logic gate design, ROS production even under hypoxia and GSH conditions of E-Ce6 was also almost 1.5 times that of Ce6 under normoxia. Enhancing effect of E-Ce6 was 13.47 times and 6.85 times, while selectivity ratio reached 5.13 times and 4.81 times compared with Ce6 and M-Ce6. The two-pronged strategy showed a high potential for delivering the Ce6 to deep inside of cancer cells and killing it in the simulated tumor by PDT. These above results demonstrated the potential of E-Ce6, as oxygen self-sufficiency and GSH depletion nanocarriers for combined enhancement of photodynamic therapy.

Arginine monomethylation by PRMT7 controls MAVS-mediated antiviral innate immunity.

Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense.

Zebrafish otud6b Negatively Regulates Antiviral Responses by Suppressing K63-Linked Ubiquitination of irf3 and irf7.

Ovarian tumor domain-containing 6B (OTUD6B) belongs to the OTU deubiquitylating enzyme family. In this study, we report that zebrafish otud6b is induced upon viral infection, and overexpression of otud6b suppresses cellular antiviral response. Disruption of otud6b in zebrafish increases the survival rate upon spring viremia of carp virus and grass carp reovirus exposure. Further assays indicate that otud6b interacts with irf3 and irf7 and diminishes traf6-mediated K63-linked polyubiquitination of irf3 and irf7. In addition, the OTU domain is required for otud6b to repress IFN-1 activation and K63-linked polyubiquitination of irf3 and irf7. Moreover, otud6b also attenuates tbk1 to bind to irf3 and irf7, resulting in the impairment of irf3 and irf7 phosphorylation. This study provides, to our knowledge, novel insights into otud6b function and sheds new lights on the regulation of irf3 and irf7 by deubiquitination in IFN-1 signaling.

Zebrafish Hif3α modulates erythropoiesis via regulation of gata1 to facilitate hypoxia tolerance.

The hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) are master regulators of the cellular response to O2. In addition to HIF1α and HIF2α, HIF3α is another identified member of the HIFα family. Even though the question of whether some HIF3α isoforms have transcriptional activity or repressive activity is still under debate, it is evident that the full length of HIF3α acts as a transcription factor. However, its function in hypoxia signaling is largely unknown. Here, we show that loss of hif3a in zebrafish reduced hypoxia tolerance. Further assays indicated that erythrocyte number was decreased because red blood cell maturation was impeded by hif3a disruption. We found that gata1 expression was downregulated in hif3a null zebrafish, as were several hematopoietic marker genes, including alas2, band3, hbae1, hbae3 and hbbe1 Hif3α recognized the hypoxia response element located in the promoter of gata1 and directly bound to the promoter to transactivate gata1 expression. Our results suggested that hif3a facilities hypoxia tolerance by modulating erythropoiesis via gata1 regulation.