Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP1R) agonists have been approved by Food and Drug Administration for management of obesity. However, the causal relationship of GLP1R agonists (GLP1RA) with cancers still unclear. METHODS: The available cis-eQTLs for drugs target genes (GLP1R) were used as proxies for exposure to GLP1RA. Mendelian randomizations (MR) were performed to reveal the association of genetically-proxied GLP1RA with 14 common types cancer from large-scale consortia. Type 2 diabetes was used as positive control, and the GWASs data including 80 154 cases and 853 816 controls. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, all the related randomized controlled trails (RCTs) on GLP1RA were systematically searched from PubMed, Embase, and the Cochrane Library to comprehensively synthesize the evidence to validate any possible association with cancers. RESULT: A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instrument. The association of genetically-proxied GLP1RA with significantly decreased type 2 diabetes risk [OR (95%)=0.82 (0.79-0.86), P<0.001], which ensuring the effectiveness of identified genetic instruments. The authors found favorable evidence to support the association of GLP1RA with reduced breast cancer and basal cell carcinoma risk [0.92 (0.88-0.96), P<0.001, 0.92 (0.85-0.99), P=0.029, respectively], and with increased colorectal cancer risk [1.12 (1.07-1.18), P<0.001]. In addition, there was no suggestive evidence to support the association of GLP1RA with ovarian cancer [0.99 (0.90-1.09), P=0.827], lung cancer [1.01 (0.93-1.10), P=0760], and thyroid cancer [0.83 (0.63-1.10), P=0.187]. Our findings were consistent with the meta-analysis. Finally, 80 RCTs were included in the systematic review, with a low incidence of different kinds of cancer. CONCLUSIONS: Our study suggests that GLP1RA may decrease the risk of breast cancer and basal cell carcinoma, but increase the risk of colorectal cancer. However, according to the systematic review of RCTs, the incidence of cancer in patients treated with GLP1RA is low. Larger sample sizes of RCTs with long-term follow-up are necessary to establish the incidence of cancers and evaluate the risk-benefit ratios.

Self-evolutionary recycling of flame-retardant polyurethane foam enabled by controllable catalytic cleavage.

Polyurethane (PU) foams, pivotal in modern life, face challenges suh as fire hazards and environmental waste burdens. The current reliance of PU on potentially ecotoxic halogen-/phosphorus-based flame retardants impedes large-scale material recycling. Here, our demonstrated controllable catalytic cracking strategy, using cesium salts, enables self-evolving recycling of flame-retardant PU. The incorporation of cesium citrates facilitates efficient urethane bond cleavage at low temperatures (160 °C), promoting effective recycling, while encouraging pyrolytic rearrangement of isocyanates into char at high temperatures (300 °C) for enhanced PU fire safety. Even in the absence of halogen/phosphorus components, this foam exhibits a substantial increase in ignition time (+258.8%) and a significant reduction in total smoke release (-79%). This flame-retardant foam can be easily recycled into high-quality polyol under mild conditions, 60 °C lower than that for the pure foam. Notably, the trace amounts of cesium gathered in recycled polyols stimulate the regenerated PU to undergo self-evolution, improving both flame-retardancy and mechanical properties. Our controllable catalytic cracking strategy paves the way for the self-evolutionary recycling of high-performance firefighting materials.

Biomimetic Nanoporous Transparent Universal Fire-Resistant Coatings.

The inherent flammability of most polymeric materials poses a significant fire hazard, leading to substantial property damage and loss of life. A universal flame-retardant protective coating is considered as a promising strategy to mitigate such risks; however, simultaneously achieving high transparency of the coatings remains a great challenge. Here, inspired by the moth eye effect, we designed a nanoporous structure into a protective coating that leverages a hydrophilic-hydrophobic interactive assembly facilitated by phosphoric acid protonated amino siloxane. The coating demonstrates robust adhesion to a diverse range of substrates, including but not limited to fabrics, foams, paper, and wood. As expected, its moth-eye-inspired nanoporous structure conferred a high visible light transparency of >97% and water vapor transmittance of 96%. The synergistic effect among phosphorus (P), nitrogen (N), and silicon (Si) largely enhanced the char-forming ability and restricted the decomposition of the coated substrates, which successfully endowed the coating with high fire-fighting performance. More importantly, for both flexible and rigid substrates, the coated samples all possessed great mechanical properties. This work provides a new insight for the design of protective coatings, particularly focusing on achieving high transparency.

Microcage flame retardants with complete recyclability and durability via reversible interfacial locking engineering.

Flame retardants are effective in protecting materials from fire but pose environmental challenges due to limited recyclability. Urgently needed for circular material economy are new flame retardants that are chemically recyclable and durable. Here, we report a new facile and scalable strategy for engineering reversible microcages with infinite chemical recyclability to starting monomers, exceptional durability, and versatile flame retardancy. This is achieved through a highly synergistic hierarchical assembly of easily obtainable phosphoric acid and Cu2+ monomers. By leveraging dynamic reversible assembly networks, microcages can be circularly and infinitely dissociated into starting monomers via eco-friendly pH adjustment. Remarkable recovery rates of 92% for phosphoric acid and 96.2% for Cu2+ monomers are achieved, while the separated virgin matrix undergoes conventional chemical recycling, facilitating reformulation and seamless reintroduction into new supply chains as needed. Notably, when integrated with matrix-like surfaces, microcage clasp matrices tightly engage through in situ formed interfacial locking structures, showcasing outstanding flame-retardant efficiency, prolonged durability in hydrothermal aging, and extensive applicability across diverse polymeric materials such as polyurethane, epoxy resin, and polycarbonate. This study emphasizes a novel, straightforward, and scalable chemical platform, utilizing reversible interfacial locking engineering, for the development of flame retardants that are not only infinitely recyclable but also durable and broadly applicable.

Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies.

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation of iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in the biological processes of tumors. Intriguingly, mesenchymal and dedifferentiated cancer cells, which are usually resistant to apoptosis and traditional therapies, are exquisitely vulnerable to ferroptosis, further underscoring its potential as a treatment approach for cancers, especially for refractory cancers. However, the impact of ferroptosis on cancer extends beyond its direct cytotoxic effect on tumor cells. Ferroptosis induction not only inhibits cancer but also promotes cancer development due to its potential negative impact on anticancer immunity. Thus, a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from the laboratory to clinical applications. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms, biological functions, regulatory pathways, and interactions with the tumor microenvironment. We also summarize the potential applications of ferroptosis induction in immunotherapy, radiotherapy, and systemic therapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis markers, the current challenges and future directions of ferroptosis in the treatment of cancer.

Electrocatalytic Coenhancement of Bimetallic Polyphthalocyanine-Anchored Ru Nanoclusters Enabling Efficient Overall Water Splitting at Ampere-Level Current Densities.

Efficient electrocatalysts capable of operating continuously at industrial ampere-level current densities are crucial for large-scale applications of electrocatalytic water decomposition for hydrogen production. However, long-term industrial overall water splitting using a single electrocatalyst remains a major challenge. Here, bimetallic polyphthalocyanine (FeCoPPc)-anchored Ru nanoclusters, an innovative electrocatalyst comprising the hydrogen evolution reaction (HER) active Ru and the oxygen evolution reaction (OER) active FeCoPPc, engineered for efficient overall water splitting are demonstrated. By density functional theory calculations and systematic experiments, the electrocatalytic coenhancement effect resulting from unique charge redistribution, which synergistically boosts the HER activity of Ru and the OER activity of FeCoPPc by optimizing the adsorption energy of intermediates, is unveiled. As a result, even at a large current density of 2.0 A cm-2 , the catalyst exhibits low overpotentials of 220 and 308 mV, respectively, for HER and OER. It exhibits excellent stability, requiring only 1.88 V of cell voltage to achieve a current density of 2.0 A cm-2 in a 6.0 m KOH electrolyte at 70 °C, with a remarkable operational stability of over 100 h. This work provides a new electrocatalytic coenhancement strategy for the design and synthesis of electrocatalyst, paving the way for industrial-scale overall water splitting applications.

Controllable proton-reservoir ordered gel towards reversible switching and reliable electromagnetic interference shielding.

Smart and dynamic electromagnetic interference (EMI) shielding materials possess a remarkable capacity to modify their EMI shielding abilities, rendering them invaluable in various civil and military applications. However, the present response mechanism of switch-type EMI shielding materials is slightly restricted, as it primarily depends on continuous pressure induction, thereby resulting in concerns regarding their durability and reliability. Herein, for the first time, we demonstrate a novel method for achieving solvent-responsive, reversible switching, and robust EMI shielding capabilities using a controlled proton-reservoir ordered gel. The gel contains polyaniline (PANI) and sodium alginate (SA). Initially, SA acts as a proton reservoir for PANI in an aqueous system, enhancing the doping level of PANI and improving its electrical conductivity. Additionally, PANI and SA chains respond to diverse polar solvents, such as water, acetonitrile, ethanol, n-hexane, and air, inducing distinct conformations that affect the degree of PANI conjugation and electron migration along the chains. This process is reversible and non-destructive to the polymer chain, ensuring the effective and uncompromised performance of the EMI shielding switch. We can achieve precise and reversible tuning (on/off) of EMI shielding with different effectiveness levels by manipulating the solvents within the framework. This work opens a new solvent-stimuli avenue for the development of EMI shielding materials with reliable and intelligent on/off switching capabilities.

Molecular landmarks of tumor disulfidptosis across cancer types to promote disulfidptosis-target therapy.

The mystery about the mechanistic basis of disulfidptosis has recently been unraveled and shows promise as an effective treatment modality for triggering cancer cell death. However, the limited understanding of the role of disulfidptosis in tumor progression and drug sensitivity has hindered the development of disulfidptosis-targeted therapy and combinations with other therapeutic strategies. Here, we established a disulfidptosis signature model to estimate tumor disulfidptosis status in approximately 10,000 tumor samples across 33 cancer types and revealed its prognostic value. Then, we characterized disulfidptosis-associated molecular features and identified various types of molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-tumor drugs. We further showed the vast heterogeneity in disulfidptosis status among 760 cancer cell lines across 25 cancer types. We experimentally validated that disulfidptosis score-high cell lines are more susceptible to glucose starvation-induced disulfidptosis compared to their counterparts with low scores. Finally, we investigated the impact of disulfidptosis status on drug response and revealed that disulfidptosis induction may enhance sensitivity to anti-cancer drugs, but in some cases, it could also lead to drug resistance in cultured cells. Overall, our multi-omics analysis firstly elucidates a comprehensive profile of disulfidptosis-related molecular alterations, prognosis, and potential therapeutic therapies at a pan-cancer level. These findings may uncover opportunities to utilize multiple drug sensitivities induced by disulfidptosis, thereby offering practical implications for clinical cancer therapy.

Corrigendum to 'Oral Azvudine for hospitalised patients with COVID-19 and pre-existing conditions: a retrospective cohort study.' [EClinicalMedicine 59 (2023) 101981].

[This corrects the article DOI: 10.1016/j.eclinm.2023.101981.].

A biomimetic closed-loop recyclable, long-term durable, extreme-condition resistant, flame-retardant nanocoating synthesized by reversible flocculation assembly.

Flame-retardant coatings have attracted increasing attention in mitigating the fire threat of flammable polymer materials. Their durable application inevitably provides high resistance to various complex environments, however, discarded stable materials will turn into another man-made waste disaster. The paradigm shift toward a sustainable future is to combine durability and recyclability of coatings. Herein, we demonstrate a biomimetic coating that reversibly captures active flame-retardant nanomaterials by flocculation assembly using anionic polyacrylamide covering the polyurethane foam surface. Strong hydrogen bonding and microstructural interlocking provide the coating with high durability under complex harsh conditions (underwater, chemical exposure, hydrothermal aging, long-term external extrusion, etc.). Meanwhile, the disassembly/reorganization of the coating can be easily repeated in response to pH stimulation with a recycling rate of 97%. The experiments and theoretical calculations reveal the mechanism of the reversible flocculation assembly. This biomimetic strategy of responsive flocculation assembly opens the way for functional coatings with integrated durability and recyclability.

Serological response following COVID-19 vaccines in patients living with HIV: a dose-response meta-analysis.

To quantify the pooled rate and risk ratio of seroconversion following the uncomplete, complete, or booster dose of COVID-19 vaccines in patients living with HIV. PubMed, Embase and Cochrane library were searched for eligible studies to perform a systematic review and meta-analysis based on PRIMSA guidelines. The pooled rate and risk ratio of seroconversion were assessed using the Freeman-Tukey double arcsine method and Mantel-Haenszel approach, respectively. Random-effects model was preferentially used as the primary approach to pool results across studies. A total of 50 studies involving 7160 patients living with HIV were analyzed. We demonstrated that only 75.0% (56.4% to 89.9%) patients living with HIV achieved a seroconversion after uncomplete vaccination, which improved to 89.3% (84.2% to 93.5%) after complete vaccination, and 98.4% (94.8% to 100%) after booster vaccination. The seroconversion rates were significantly lower compared to controls at all the stages, while the risk ratios for uncomplete, complete, and booster vaccination were 0.87 (0.77 to 0.99), 0.95 (0.92 to 0.98), and 0.97 (0.94 to 0.99), respectively. We concluded that vaccine doses were associated with consistently improved rates and risk ratios of seroconversion in patients living with HIV, highlighting the significance of booster vaccination for patients living with HIV.

Oral Azvudine for hospitalised patients with COVID-19 and pre-existing conditions: a retrospective cohort study.

Background: As the COVID-19 pandemic continues to spread, the number of associated deaths continues to increase, especially among those with pre-existing conditions. Azvudine is recommended as a priority treatment for patients with COVID-19, but its efficacy in patients with pre-existing conditions is unknown. Methods: This is a single-centre, retrospective cohort study between December 5, 2022 and January 31, 2023 in Xiangya Hospital of Central South University in China to evaluate the clinical efficacy of Azvudine in hospitalised patients with COVID-19 and pre-existing conditions. Patients with Azvudine and controls were propensity score-matched (1:1) for age, gender, vaccination status, time from symptom onset to treatment exposure, severity at admission, concomitant treatments initiated at admission. The primary outcome was a composite outcome of disease progression, and the secondary outcome was each of these individual disease progression outcomes. The univariate Cox regression model was used to estimate a hazard ratio (HR) with 95% confidence interval (CI) for each result between the groups. Findings: We identified 2118 hospitalised patients with COVID-19 during the study period, with a follow-up of up to 38 days. After exclusions and propensity score matching, we included 245 Azvudine recipients and 245 matched controls. Azvudine recipients had lower crude incidence rate of composite disease progression outcome compared with matched controls (7.125/1000 person-days vs. 16.004/1000 person-days, P = 0.018). There was no significant difference in all-cause death between these two groups (1.934/1000 person-days vs. 4.128/1000 person-days, P = 0.159). Azvudine treatment was associated with significantly lower risks of composite disease progression outcome compared with matched controls (HR: 0.49; 95% CI: 0.27-0.89, P = 0.016). A significant difference in all-cause death was not found (HR: 0.45; 95% CI: 0.15-1.36, P = 0.148). Interpretation: These findings indicate that Azvudine therapy showed substantial clinical benefits in hospitalised patients with COVID-19 and pre-existing conditions, and should be considered for this population of patients. Funding: This work was supported by the National Natural Science Foundation of China (Grant Nos. 82103183 to F. Z., 82102803, 82272849 to G. D.), National Natural Science Foundation of Hunan Province (Grant Nos. 2022JJ40767 to F. Z., 2021JJ40976 to G. D.), Huxiang Youth Talent Program (Grant Nos. 2022RC1014 to M.S.) and Ministry of Industry and Information Technology of China (Grant Nos. TC210804V to M.S.).

Real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir in hospitalized patients with COVID-19: A retrospective cohort study.

Chinese guidelines prioritize the use of Azvudine and nirmatrelvir-ritonavir in COVID-19 patients. Nevertheless, the real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir is still lacking, despite clinical trials showing their effectiveness compared with matched controls. To compare the effectiveness of Azvudine versus nirmatrelvir-ritonavir treatments in real-world clinical practice, we identified 2118 hospitalized COVID-19 patients, with a follow-up of up to 38 days. After exclusions and propensity score matching, we included 281 Azvudine recipients and 281 nirmatrelvir-ritonavir recipients who did not receive oxygen therapy at admission. The lower crude incidence rate of composite disease progression outcome (7.83 vs. 14.83 per 1000 person-days, p = 0.026) and all-cause death (2.05 vs. 5.78 per 1000 person-days, p = 0.052) were observed among Azvudine recipients. Azvudine was associated with lower risks of composite disease progression outcome (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.32-0.94) and all-cause death (HR: 0.40; 95% CI: 0.16-1.04). In subgroup analyses, the results of composite outcome retained significance among patients aged <65 years, those having a history of disease, those with severe COVID-19 at admission, and those receiving antibiotics. These findings suggest that Azvudine treatment showed effectiveness in hospitalized COVID-19 patients compared with nirmatrelvir-ritonavir in terms of composite disease progression outcome.

A One-Step Self-Flowering Method toward Programmable Ultrathin Porous Carbon-Based Materials for Microwave Absorption and Hydrogen Evolution.

Ultrathin 2D porous carbon-based materials offer numerous fascinating electrical, catalytic, and mechanical properties, which hold great promise in various applications. However, it remains a formidable challenge to fabricate these materials with tunable morphology and composition by a simple synthesis strategy. Here, a facile one-step self-flowering method without purification and harsh conditions is reported for large-scale fabrication of high-quality ultrathin (≈1.5 nm) N-doped porous carbon nanosheets (NPC) and their composites. It is demonstrated that the layered tannic/oxamide (TA/oxamide) hybrid is spontaneously blown, exfoliated, bloomed, in situ pore-formed, and aromatized during pyrolysis to form flower-like aggregated NPC. This universal one-step self-flowering system is compatible with various precursors to construct multiscale NPC-based composites (Ru@NPC, ZnO@NPC, MoS2 @NPC, Co@NPC, rGO@NPC, etc.). Notably, the programmable architecture enables NPC-based materials with excellent multifunctional performances, such as microwave absorption and hydrogen evolution. This work provides a facile, universal, scalable, and eco-friendly avenue to fabricate functional ultrathin porous carbon-based materials with programmability.

Correlation between CD4 T-Cell Counts and Seroconversion among COVID-19 Vaccinated Patients with HIV: A Meta-Analysis.

OBJECTIVE: To evaluate the potential factors for predicting seroconversion due to the coronavirus disease 2019 (COVID-19) vaccine in people living with HIV (PLWH). METHOD: We searched the PubMed, Embase and Cochrane databases for eligible studies published from inception to 13th September 2022 on the predictors of serologic response to the COVID-19 vaccine among PLWH. This meta-analysis was registered with PROSPERO (CRD42022359603). RESULTS: A total of 23 studies comprising 4428 PLWH were included in the meta-analysis. Pooled data demonstrated that seroconversion was about 4.6 times in patients with high CD4 T-cell counts (odds ratio (OR) = 4.64, 95% CI 2.63 to 8.19) compared with those with low CD4 T-cell counts. Seroconversion was about 17.5 times in patients receiving mRNA COVID-19 vaccines (OR = 17.48, 95% CI 6.16 to 49.55) compared with those receiving other types of COVID-19 vaccines. There were no differences in seroconversion among patients with different ages, gender, HIV viral load, comorbidities, days after complete vaccination, and mRNA type. Subgroup analyses further validated our findings about the predictive value of CD4 T-cell counts for seroconversion due to COVID-19 vaccines in PLWH (OR range, 2.30 to 9.59). CONCLUSIONS: The CD4 T-cell counts were associated with seroconversion in COVID-19 vaccinated PLWH. Precautions should be emphasized in these patients with low CD4 T-cell counts, even after a complete course of vaccination.

Inhibiting SCD expression by IGF1R during lorlatinib therapy sensitizes melanoma to ferroptosis.

Induction of ferroptosis is an emerging strategy to suppress melanoma progression. Strategies to enhance the sensitivity to ferroptosis induction would be a major advance in melanoma therapy. Here, we used a drug synergy screen that combined a ferroptosis inducer, RSL3, with 240 anti-tumor drugs from the FDA-approved drug library and identified lorlatinib to synergize with RSL3 in melanoma cells. We further demonstrated that lorlatinib sensitized melanoma to ferroptosis through inhibiting PI3K/AKT/mTOR signaling axis and its downstream SCD expression. Moreover, we found that lorlatinib's target IGF1R, but not ALK or ROS1, was the major mediator of lorlatinib-mediated sensitivity to ferroptosis through targeting PI3K/AKT/mTOR signaling axis. Finally, lorlatinib treatment sensitized melanoma to GPX4 inhibition in preclinical animal models, and melanoma patients with low GPX4 and IGF1R expression in their tumors survived for longer period. Altogether, lorlatinib sensitizes melanoma to ferroptosis by targeting IGF1R-mediated PI3K/AKT/mTOR signaling axis, suggesting that combination with lorlatinib could greatly expand the utility of GPX4 inhibition to melanoma patients with IGF1R-proficient expression.