Causal relationship between immune cells and prostate cancer: a Mendelian randomization study.

Introduction: Despite the abundance of research indicating the participation of immune cells in prostate cancer development, establishing a definitive cause-and-effect relationship has proven to be a difficult undertaking. Methods: This study employs Mendelian randomization (MR), leveraging genetic variables related to immune cells from publicly available genome-wide association studies (GWAS), to investigate this association. The primary analytical method used in this study is inverse variance weighting (IVW) analysis. Comprehensive sensitivity analyses were conducted to assess the heterogeneity and horizontal pleiotropy of the results. Results: The study identifies four immune cell traits as causally contributing to prostate cancer risk, including CD127- CD8+ T cell %CD8+ T cell (OR = 1.0042, 95%CI:1.0011-1.0073, p = 0.0077), CD45RA on CD39+ resting CD4 regulatory T cell (OR = 1.0029, 95%CI:1.0008-1.0050, p = 0.0065), CD62L- Dendritic Cell Absolute Count (OR = 1.0016; 95%CI:1.0005-1.0026; p = 0.0039), CX3CR1 on CD14+ CD16- monocyte (OR = 1.0024, 95%CI:1.0007-1.0040, p = 0.0060). Additionally, two immune cell traits are identified as causally protective factors: CD4 on monocyte (OR = 0.9975, 95%CI:0.9958-0.9992, p = 0.0047), FSC-A on plasmacytoid Dendritic Cell (OR = 0.9983, 95%CI:0.9970-0.9995, p = 0.0070). Sensitivity analyses indicated no horizontal pleiotropy. Discussion: Our MR study provide evidence for a causal relationship between immune cells and prostate cancer, holding implications for clinical diagnosis and treatment.

Tracking the carbon flows in municipal waste management in China.

Municipal solid waste (MSW), a carbon-intensive waste stream, may create both instant and indirect impacts onto environmental and climate management. Despite multiple studies made for greenhouse gases (GHGs) emissions of municipal waste, this research aims to achieve a comprehensive assessment for the carbon cycle by exploring evolution of waste composition and temporal-spatial disparities in waste management. Carbon flows embodied in MSW have been estimated across 31 provinces in Mainland China in the period 2000-2018. This improved estimation could be 15-40% smaller than the conventional estimation employing a constant waste composition. Aggregately some 578 ± 117 megatonnes carbon (MtC) were contained in MSW, including 239 ± 60 Mt of fossil carbon and 339 ± 58 Mt of degradable organic carbon. After treatment, 299 ± 66 MtC were possibly deposited in landfills and dumps. 279 ± 51 MtC were released to the atmosphere, creating net GHGs emissions equivalent to1870 ± 334 megatonnes of CO2 (MtCO2e). MSW generation in China nearly doubled during the period, net GHGs emissions increased by 1.8×, whereas fossil carbon grew by a factor of 3.5, mainly propelled by an increasing content of waste plastic in MSW. More rapid growth was witnessed in provinces in southern China than in northern. Distinct spatial-temporal evolution of waste and carbon metabolism was driven by increment, composition, and management effects. In the long run, the increment and composition effects may drop off. Enhanced practices of waste management integrating the circular economy are needed to fully recycle carbon flows, minimize emissions, and manage carbon deposits in aging landfills and dumps.

Enhanced heavy metal stabilization and phosphorus retention during the hydrothermal carbonization of swine manure by in-situ formation of MgFe2O4.

Hydrothermal carbonization is an efficient technique for the disposal of livestock manure, enabling its harmless treatment, quantity reduction, and resourceful utilization. Co-hydrothermal of modified materials facilitates the production of more valuable carbonaceous materials. However, further exploration is needed to understand their potential impact on the environmental risks associated with livestock manure disposal and the application of products derived from it. Therefore, the carbonization degree, heavy metals stabilization, and phosphorus retention during the hydrothermal treatment of swine manure were systematically investigated in this study under the influence of in-situ formed MgFe2O4. The results revealed that the in-situ formation of MgFe2O4 improved the dehydration and decarboxylation of organic components in swine manure, thereby improving its carbonization degree. Furthermore, both hydrothermal carbonization and MgFe2O4 modified hydrothermal carbonization resulted in an enhanced stabilization of heavy metals, leading to a significant reduction in their soluble/exchangeable fraction and reducible fraction. Phosphorus was predominantly retained in the hydrochars, with the highest retention rate reaching 88%, attributed to the significant decrease in soluble and exchangeable phosphorus fractions facilitated by the in-situ formation of MgFe2O4. Moreover, MgFe2O4 modified hydrochars exhibited remarkable adsorption capacity for Pb(II) and Cu(II) without any leaching of heavy metals. Overall, the findings indicated that the in-situ formation of MgFe2O4 positively influenced the hydrothermal of swine manure, improving certain economic benefits in its practical application.

Discovery of N-(phenylsulfonyl)thiazole-2-carboxamides as potent α-glucosidase inhibitors.

In a search for novel nonsugar α-glucosidase inhibitors for diabetes treatment, a series of N-(phenylsulfonyl)thiazole-2-carboxamide derivatives were designed and synthesized, the α-glucosidase inhibitory activities were then evaluated. Several compounds with promising α-glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α-glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 µM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 µM). W24 was identified as a promising candidate in the development of α-glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α-glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol.

Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) is well-known to cause biofilm-associated drug resistance and infections that often lead to treatment failure. Herein, we reported a dual-acting antibiofilm strategy by inhibiting both the bacterial quorum sensing system and the iron uptake system. A series of coumarin derivatives were synthesized and evaluated, and compound 4t was identified as the most effective biofilm inhibitor (IC50 = 3.6 µM). Further mechanistic studies have confirmed that 4t not only inhibits the QS systems but also competes strongly with pyoverdine as an iron chelator, causing an iron deficiency in P. aeruginosa. Additionally, 4t significantly improved the synergistic antibacterial effects of ciprofloxacin and tobramycin by more than 200-1000-fold compared to the single-dose antibiotic treatments. Therefore, our study has shown that 4t is a potentially novel antibacterial synergist candidate to treat bacterial infections.

circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis.

Background and aim: As non-coding RNAs, circular RNAs (circRNAs) contribute to the progression of malignancies by regulating various biological processes. In prostate cancer, however, there is still a lack of understanding regarding the potential molecular pathways and roles of circRNAs. Methods: Loss-off function experiments were performed to investigate the potential biological function of circRNA in the progression of prostate cancer. Western blot, qRT-PCR, and IHC assay were used to examine the expression level of different genes or circRNAs. Further molecular biology experiments were conducted to uncover the molecular mechanism underlying circRNA in prostate cancer using dual luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: A novel circRNA (hsa_circ_0124696, named circROBO1) was identified as a significantly upregulated circRNA in both prostate cancer cells and tissues. Suppression of circROBO1 significantly attenuated the proliferation of prostate cancer cells. In addition, we found that the knockdown of circROBO1 remarkably increased the sensitivity of prostate cancer to enzalutamide treatment. A deceleration in glycolysis rate was observed after inhibition of circROBO1, which could suppress prostate cancer growth and overcome resistance to enzalutamide. Our results revealed that circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis. Conclusion: Our study identified the biological role of the circROBO1-miR-556-5p-PGK1 axis in the growth and enzalutamide resistance of prostate cancer, which is the potential therapeutic target of prostate cancer.

Carbon dioxide reduction to high-value chemicals in microbial electrosynthesis system: Biological conversion and regulation strategies.

Large emissions of atmospheric carbon dioxide (CO2) are causing climatic and environmental problems. It is crucial to capture and utilize the excess CO2 through diverse methods, among which the microbial electrosynthesis (MES) system has become an attractive and promising technology to mitigate greenhouse effects while reducing CO2 to high-value chemicals. However, the biological conversion and metabolic pathways through microbial catalysis have not been clearly elucidated. This review first introduces the main acetogenic bacteria for CO2 reduction and extracellular electron transfer mechanisms in MES. It then intensively analyzes the CO2 bioconversion pathways and carbon chain elongation processes in MES, together with energy supply and utilization. The factors affecting MES performance, including physical, chemical, and biological aspects, are summarized, and the strategies to promote and regulate bioconversion in MES are explored. Finally, challenges and perspectives concerning microbial electrochemical carbon sequestration are proposed, and suggestions for future research are also provided. This review provides theoretical foundation and technical support for further development and industrial application of MES for CO2 reduction.

Global analysis of HLA-A2 restricted MAGE-A3 tumor antigen epitopes and corresponding TCRs in non-small cell lung cancer.

Background: Advanced non-small cell lung cancer (NSCLC) is the most common type of lung cancer with poor prognosis. Adoptive cell therapy using engineered T-cell receptors (TCRs) targeting cancer-testis antigens, such as Melanoma-associated antigen 3 (MAGE-A3), is a potential approach for the treatment of NSCLC. However, systematic analysis of T cell immune responses to MAGE-A3 antigen and corresponding antigen-specific TCR is still lacking. Methods: In this study, we comprehensively screened HLA-A2 restricted MAGE-A3 tumor epitopes and characterized the corresponding TCRs using in vitro artificial antigen presentation cells (APC) system, single-cell transcriptome and TCR V(D)J sequencing, and machine-learning. Furthermore, the tumor-reactive TCRs with killing potency was screened and verified. Results: We identified the HLA-A2 restricted T cell epitopes from MAGE-A3 that could effectively induce the activation and cytotoxicity of CD8+ T cells using artificial APC in vitro. A cohort of HLA-A2+ NSCLC donors demonstrated that the number of epitope specific CD8+ T cells increased in NSCLC than healthy controls when measured with tetramer derived from the candidate MAGE-A3 epitopes, especially epitope Mp4 (MAGE-A3: 160-169, LVFGIELMEV). Statistical and machine-learning based analyses demonstrated that the MAGE-A3-Mp4 epitope-specific CD8+ T cell clones were mostly in effector and proliferating state. Importantly, T cells artificially expressing the MAGE-A3-Mp4 specific TCRs exhibited strong MAGE-A3+ tumor cell recognition and killing effect. Cross-reactivity risk analysis of the candidates TCRs showed high binding stability to MAGE-A3-Mp4 epitope and low risk of cross-reaction. Conclusions: This work identified candidate TCRs potentially suitable for TCR-T design targeting HLA-A2 restricted MAGE-A3 tumor antigen.

Design, synthesis and biological evaluation of novel 3-hydroxypyridin-4(1H)-ones based hybrids as Pseudomonas aeruginosa biofilm inhibitors.

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative pathogenic bacterium, often causative drug-resistance related human infections, given its great capacity to form bioflm. It uses three major quorum sensing (QS) systems, las, rhl, and pqs, to regulate the expression of genes related to virulence and biofilm formation. Consequently, strategies for inhibiting QS have garnered considerable attention as antimicrobial therapies. In this study, we designed and synthesized several 3-hydroxypyridin-4(1H)-one hybrids and assessed their potential as the inhibitors of P. aeruginosa biofilm formation. The most active compound identified was 12h; it exhibited satisfactory biofilm inhibitory activity (IC50: 10.59 ± 1.17 µM). Mechanistic studies revealed that 12h significantly inhibited the fluorescence of the PAO1-lasB-gfp and PAO1-pqsA-gfp fluorescent reporter strains and the production of Las-regulated (elastase) and Pqs-regulated (pyocyanin) virulence factors. These findings indicate that 12h inhibited biofilm formation by suppressing the expression of lasB and pqsA, thereby inactivating the las and pqs pathways. Furthermore, 12h improved the antibiotic susceptibility of P. aeruginosa and reduced the acute virulence of this bacterium in the African green monkey kidney cell line Vero. In conclusion, 3-hydroxypyridin-4(1H)-one hybrids, such as 12h, represent a promising class of antibacterial agents against P. aeruginosa.

Legacy persistent organic pollutants (POPs) in eggs of night herons and poultries from the upper Yangtze Basin, Southwest China.

Black-crowned night heron (Nycticorax nycticorax) eggs have been identified as useful indicators for biomonitoring the environmental pollution in China. In this study, we investigated thirty eggs of black-crowned night heron collected from the upper Yangtze River (Changjiang) Basin, Southwest China, for the occurrence of legacy persistent organic pollutants (POPs), including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Our results showed a general presence of POPs in night heron eggs with OCPs being the dominant contaminants, having a geometric mean concentration of 22.2 ng g-1 wet weight (ww), followed by PCBs (1.36 ng g-1 ww), PBDEs (0.215 ng g-1 ww), and PCDD/Fs (23.0 pg g-1 ww). The concentration levels were found to be significantly higher in night heron eggs than in poultry eggs by one or two magnitude orders. Among OCP congeners, p,p'-DDE was found to be predominant in night heron eggs, with a geometric mean concentration of 15.1 ng g-1 ww. Furthermore, species-specific congener patterns in eggs suggested similar or different sources for different POPs, possibly associated with contaminated soil and parental dietary sources. Additionally, estimated daily intakes (EDIs) were used to evaluate non-carcinogenic and carcinogenic risk associated with consumption of bird eggs. Our results revealed non-negligible non-cancer and cancer risk for humans who consume wild bird eggs as a regular diet instead of poultry eggs.

Antibiotic removal by microalgae-bacteria consortium: Metabolic pathways and microbial responses.

The proliferation of antibiotic-resistance genes is a result of the rise in the discharge of residual antibiotics into waterbodies from a variety of sources. Antibiotic removal by microalgae-bacteria consortium has been shown to be effective, therefore, there is a need to understand the involved microbial processes. This review summarizes the microbiological removal mechanisms of antibiotics by the microalgae-bacteria consortium, such as biosorption, bioaccumulation, and biodegradation. Factors that influence antibiotic removal are discussed. Co-metabolism of nutrients and antibiotics in the microalgae-bacteria consortium and the metabolic pathways revealed by omics technologies are also highlighted. Furthermore, the responses of microalgae and bacteria to antibiotic stress are elaborated, including reactive oxidizing species (ROS) generation and its effects on photosynthesis machinery, antibiotic stress tolerance, microbial community shift, and the emergence of antibiotic resistance genes (ARGs). Finally, we offer a prospective solutions for the optimization and applications of microalgae-bacteria symbiotic systems for antibiotic removal.

Zoledronic acid and thymosin α1 elicit antitumor immunity against prostate cancer by enhancing tumor inflammation and cytotoxic T cells.

BACKGROUND: Advanced or metastatic prostate cancer (PCa) is still an incurable malignancy with high lethality and a poor prognosis. Despite the remarkable success of immunotherapy against many types of cancer, most patients with PCa receive minimal benefit from current immunotherapeutic strategies, because PCa is an immune cold tumor with scarce T-cell infiltration in the tumor microenvironment. The aim of this study was to develop an effective immunotherapeutic approach for immune cold PCa tumors. METHODS: The therapeutic efficacy of androgen deprivation therapy (ADT) and zoledronic acid (ZA) plus thymosin α1 (Tα1) therapy was analyzed retrospectively in patients with advanced or metastatic PCa. The effects and mechanisms by which ZA and Tα1 regulated the immune functions of PCa cells and immune cells were evaluated by a PCa allograft mouse model, flow cytometric analysis, immunohistochemical and immunofluorescence staining assays, and PCR, ELISA, and Western blot analyses. RESULTS: In this study, clinical retrospective analysis revealed that ADT combined with ZA plus Tα1 improved the therapeutic outcomes of patients with PCa, which might be associated with an enhanced frequency of T cells. ZA and Tα1 treatment synergistically inhibited the growth of androgen-independent PCa allograft tumors, with increased infiltration of tumor-specific cytotoxic CD8+ T cells and enhanced tumor inflammation. Functionally, ZA and Tα1 treatment relieved immunosuppression in PCa cells, stimulated pro-inflammatory macrophages, and enhanced the cytotoxic function of T cells. Mechanistically, ZA plus Tα1 therapy blocked the MyD88/NF-κB pathway in PCa cells but activated this signaling in macrophages and T cells, altering the tumor immune landscape to suppress PCa progression. CONCLUSIONS: These findings uncover a previously undefined role for ZA and Tα1 in inhibiting the disease progression of immune cold PCa tumors by enhancing antitumor immunity and pave the way for the application of ZA plus Tα1 therapy as an immunotherapeutic strategy for treating patients with immunologically unresponsive PCa.

Tiliroside induces ferroptosis to repress the development of triple-negative breast cancer cells.

Ferroptosis is a newly found form of non-apoptotic regulated cell death that is essential for the advancement of cancer. Tiliroside (Til), an effective natural flavonoid glycoside of oriental paperbush flower, has been explored as a potential anticancer agent in a few cancer types. However, it is unclear whether and how Til could promote the death of triple-negative breast cancer (TNBC) cells by inducing ferroptosis. Our study determined that Til induced cell death and attenuated cell proliferation in TNBC cells in vitro and in vivo with less toxicity for the first time. Functional assays showed that ferroptosis was the predominant form that contributed to Til-induced cell death of TNBC. Mechanistically, Til induces ferroptosis of TNBC cells via independent PUFA-PLS pathways but is closely involved in the Nrf2/HO-1 pathway. Silencing of HO-1 substantially abrogated the tumor-inhibiting effects of Til. In conclusion, our findings suggest that the natural product Til exerted its antitumor activity on TNBC by promoting ferroptosis, and the HO-1/SLC7A11 pathway plays an indispensable role in Til-induced ferroptotic cell death.

X-ray sensitive selenium-containing Ru complexes sensitize nasopharyngeal carcinoma cells for radio/chemotherapy.

Radiotherapy has been extensively applied to cancer therapy in clinical trials. However, radiation resistance and dose limitation generally hamper the efficacy of radiotherapy. There is an urgent need for radiosensitizers with high efficiency and safety to enhance the anti-tumor effect of radiotherapy. In this paper, a selenium-containing (Se) ruthenium (Ru) complex (RuSe) was designed as a radiosensitizer to synergistically augment the killing effect of radiotherapy on nasopharyngeal carcinoma cells. In this system, the heavy atomic effect of Ru enhances the photoelectron production triggered by X-rays, thus inducing a burst of reactive oxygen species (ROS). In addition, Se atoms with a strong polarization property were introduced into the ligand of the metal complex to enhance the tumor chemo/radiotherapy effect. Consequently, RuC with a weak atomic polarization effect, as a comparison for RuSe, was also rationally explored to elucidate the role of Se atoms on chemo/radiotherapy sensitization. Indeed, compared with RuC, RuSe at a sub-toxic dose was able to potentiate the lethality of radiotherapy after preconditioning with cancer cells, by inducing ROS over-production, decreasing the mitochondrial membrane potential, and arresting the cell cycle at the sub-G1 phase. Furthermore, upon radiation, RuSe was superior to RuC, by inducing apoptotic cell death by activating caspase-3, -8, and -9. In summary, this study not only demonstrates an effective and safe strategy for the application of RuSe complexes to the cancer-targeted chemo/radiotherapy of human cancers, but also sheds light on the potential mechanisms of such Se-containing drugs as efficient radiotherapy sensitizers.

Occurrence and ecological risk assessment of 16 phthalates in surface water of the mainstream of the Yangtze River, China.

Phthalic acid esters (PAEs), a class of typical endocrine disruptors, have received considerable attention due to their widespread applications and adverse effects on biological health. In this study, 30 water samples, along the mainstream of the Yangtze River (YR), were collected from Chongqing (upper stream) to Shanghai (estuary) from May to June in 2019. The total concentrations of 16 targeted PAEs ranged from 0.437 to 20.5 µg/L, with an average of 1.93 µg/L, where dibutyl phthalate (DBP, 0.222-20.2 µg/L), bis (2-ethylhexyl) phthalate (DEHP, 0.254-7.03 µg/L), and diisobutyl phthalate (DIBP, 0.0645-0.621 µg/L) were the most abundant PAEs. According to the pollution level in the YR to assess the ecological risk posed by PAEs, the results showed medium risk level of PAEs in the YR, among which DBP and DEHP posed a high ecological risk to aquatic organisms. The optimal solution for DBP and DEHP is found in ten fitting curves. The PNECSSD of them is 2.50 µg/L and 0.34 µg/L, respectively.

Hydrothermal Reduction of CO2 to Value-Added Products by In Situ Generated Metal Hydrides.

An integrated process by coupling hydrothermal reactions, including CO2 reduction and H2O dissociation with metals, is proposed. The hydrogen could be rapidly produced under hydrothermal conditions, owing to the special characteristics of high temperature water, generating metal hydrides as intermediates. Hydrogen production from the H2O dissociation under hydrothermal conditions is one of the most ideal processes due to its environmentally friendly impact. Recent experimental and theoretical studies on the hydrothermal reduction of CO2 to value-added products by in situ generated metal hydrides are introduced, including the production of formic acid, methanol, methane, and long-chain hydrocarbons. These results indicate that this process holds promise in respect to the conversion of CO2 to useful chemicals and fuels, and for hydrogen storage, which could help alleviate the problems of climate change and energy shortage.

Selenium speciation-dependent cancer radiosensitization by induction of G2/M cell cycle arrest and apoptosis.

Introduction: Radiation therapy has Q6long been a routine and effective treatment for non-small cell lung cancer (NSCLC), but the radioresistance and side effects have limited its application. In recent years, the superiority showed by trace element selenium in tumor radiotherapy sensitization has received wide attention. However, different forms of selenium compounds exhibit different chemical properties and their mechanisms of action on tumors may be different. Methods: Human non-small cell lung cancer SPC-A1 cells were studied. Drug toxicity was detected by MTT assay. The selenium content absorbed in vitro at different time points was detected by ICP-MS. Colony formation were conducted to observe the radiosensitization effect of different selenium compounds on SPC-A1 cells, and to compare the proliferation ability of SPC-A1 cells treated by radiation alone and radiation combined with different selenium compounds. Cell migration was detected by cell scratch assay. The changes of cell cycle and apoptosis were detected by flow cytometry. DCFH-DA fluorescent probe was used to detect the effects of different selenium compounds combined with X-ray on ROS production. Results: In this study, these four representative selenium compounds all have a certain ability to enhance the ability of radiotherapy to inhibit tumor cell proliferation and migration, and the mechanism may be related to blocking cell cycle in G2/M phase, activating the caspase cascade and reducing intracellular ROS levels to induce tumor cell apoptosis. Among them, -2-valent organic selenium has the most obvious effect, mainly inhibits cell migration, and induces early apoptosis by activating a large number of caspase-3, and arrest the cell cycle in S phase and G2/M phase. 0-valent selenium nanoparticles mainly arrest the cell cycle in G2/M phase. +4-valent inorganic selenium exerts its antitumor effects primarily by inhibiting tumor cell migration and inducing early apoptosis of tumor cells. Discussion: In this paper, the antitumor effects of four different forms of selenium compounds combined with X-rays on SPC-A1 cells were investigated, and their inhibitory effects on the proliferation and migration of cancer cells and their mechanisms were examined. We found that the radiosensitizing effect of selenium on NSCLC was closely related to its selenium form through the study of the sensitizing effect of different kinds of selenium compounds on radiotherapy.

Effectiveness and safety of camrelizumab in inoperable or advanced non-small cell lung cancer patients: a multicenter real-world retrospective observational study (CTONG2004-ADV).

Background: Camrelizumab plus chemotherapy have been approved as standards for the treatment of advanced non-small cell lung cancer (NSCLC) patients based on two phase III trials. However, clinical trial results may not be representative of the general population, as clinical trials often have specific inclusion and exclusion criteria. Our research aims to investigate the real-world effectiveness and safety of camrelizumab in inoperable or advanced NSCLC patients. Methods: This multicenter retrospective observational study included inoperable or advanced pathologically confirmed NSCLC patients who received at least one dose of camrelizumab at 22 hospitals. Clinical and follow-up data of camrelizumab were collected retrospectively from the medical records. The primary outcome was the objective response rate (ORR) and secondary outcomes were disease control rate (DCR), 6-month progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Multivariate logistic and Cox regression analyses were applied to identify potential predictive factors of ORR and PFS, respectively. Results: Between July 2019 and March 2021, 336 patients were included. Adenocarcinoma was seen in 58.4% and stage IV disease in 69.3%. Twenty-nine (8.6%) had liver metastasis at baseline. Most patients received camrelizumab in the first-line setting (74.1%) and in combination with chemotherapy (60.7%). The ORR was 40.2% [95% confidence interval (CI): 34.9-45.6%] and DCR was 85.1% (95% CI: 81.3-88.9%), while the 6-month PFS and OS rates were 73.0% (95% CI: 67.1-78.0%) and 93.1% (95% CI: 89.8-95.4%), respectively. In multivariate analyses, liver metastasis [odds ratio (OR), 0.324; 95% CI: 0.115-0.915; P=0.033] and increasing lines of camrelizumab treatment (vs. first line, second line: OR, 0.347; 95% CI: 0.162-0.741; P=0.006; ≥ third line: OR, 0.126; 95% CI: 0.043-0.367; P<0.001) were negatively associated, while a longer duration of camrelizumab treatment was positively associated with ORR and PFS. TRAEs were recorded in 164 (48.8%) patients, without new safety signal. Conclusions: We conducted a comprehensive overview of the effectiveness and safety profile of camrelizumab in a broader NSCLC population in real world NSCLC patients, and subgroup analysis indicated the presence of liver metastasis was associated with worse outcomes.

Safety and efficacy of Pucotenlimab (HX008) - a humanized immunoglobulin G4 monoclonal antibody in patients with locally advanced or metastatic melanoma: a single-arm, multicenter, phase II study.

BACKGROUND: Pucotenlimab is a novel recombinant humanized anti-PD-1 (Programmed death-1) monoclonal antibody, which belongs to the human IgG4/kappa subtype, and can selectively block the binding of PD-1 with its ligands PD-L1 and PD-L2. METHODS: In this phase 2 trial, patients with locally advanced or metastatic melanoma who had failed conventional treatment (chemotherapy, targeted therapy, interferon, IL-2, et al.) were recruited. The patients were administrated with Pucotenlimab of 3 mg/kg every 3 weeks until disease progression, intolerable toxicity, or treatment discontinuation for any other reasons. The primary endpoint was the overall response rate (ORR). The secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: One-hundred and nineteen patients were enrolled and followed up for 19.32 (ranging from 15.901 to 24.608) months by the cutoff date of July 30th, 2021. The ORR was 20.17% (24/119, 95% CI, 13.370%-28.506%) based on both independent review committee (IRC) and the investigator's assessment per RECIST v1.1. The median PFS were 2.89 (95% CI, 2.037-4.074) months and 2.46 (95% CI, 2.004-4.008) months based on IRC and investigator's assessment, respectively, per RECIST v1.1. The median OS was 16.59 (95% CI, 13.963-26.973) months. Treatment-related adverse events (TRAEs) occurred in 77.3% (92/119) of the patients. The incidence of Grade ≥ 3 TRAEs was 15.1% (18/119). In addition, none of the patients died because of TRAEs. As for biomarker analysis, Eotaxin (CCL11) and MCP-1 (CCL2) were related to treatment response, while TNF-α and VEGF were related to treatment failure. CONCLUSIONS: Pucotenlimab as a ≥ 2nd line therapy showed promising efficacy and tolerable toxicity for patients with locally advanced or metastatic melanoma. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04749485 (registered retrospectively on 11/02/2021).

Mechanistic insights into the removal of As(III) and As(V) by iron modified carbon based materials with the aid of machine learning.

The machine learning (ML) technique was used to examine the effects of different microscopic material features on the ability of iron modified carbon-based materials (Fe-CBMs) to remove As(V) and As(III). The findings showed that specific CBMs and Fe-CBMs features (such as surface functionality) from sophisticated microscopic and spectroscopic techniques led to models that were more accurate than those constructed using more basic information, such as bulk elemental composition and surface area (the root-mean-square error fell by 44.7% for As(V) and 56.9% for As(III), respectively). The high non-polar carbon (NPC) content of CBMs and Fe-CBMs had a detrimental influence on As(V) and As(III) removal capability, whereas surface oxygen-containing functional groups (SOFGs) contents on CBMs and Fe-CBMs played an essential role in arsenic removal based on ML approaches. The relative importance of CO was greater by 77.8% and 40.6% than that of C-O on the elimination of As(V) and As(III), respectively. The accurate ML models are helpful for the future design of Fe-CBMs and the relative importance and partial dependence plot analysis can direct the use of Fe-CBMs for arsenic removal in a sensible manner under different application situations.