A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma.

BACKGROUND: NRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide. METHODS: We conducted a multicenter, single-arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety. FINDINGS: Between November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All (n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment-related deaths occurred. INTERPRETATION: Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

Gut microbiome of mealworms (Tenebrio molitor Larvae) show similar responses to polystyrene and corn straw diets.

BACKGROUND: Some insects can degrade both natural and synthetic plastic polymers, their host and gut microbes play crucial roles in this process. However, there is still a scientific gap in understanding how the insect adapted to the polystyrene (PS) diet from natural feed. In this study, we analyzed diet consumption, gut microbiota responses, and metabolic pathways of Tenebrio molitor larvae exposed to PS and corn straw (CS). RESULTS: T. molitor larvae were incubated under controlled conditions (25 ± 1 °C, 75 ± 5% humidity) for 30 days by using PS foam with weight-, number-, and size-average molecular weight (Mw, Mn, and Mz) of 120.0, 73.2, and 150.7 kDa as a diet, respectively. The larvae exhibited lower PS consumption (32.5%) than CS (52.0%), and these diets had no adverse effects on their survival. The gut microbiota structures, metabolic pathways, and enzymatic profiles of PS- and CS-fed larvae showed similar responses. The gut microbiota of larvae analysis indicated Serratia sp., Staphylococcus sp., and Rhodococcus sp. were associated with both PS and CS diets. Metatranscriptomic analysis revealed that xenobiotics, aromatic compounds, and fatty acid degradation pathways were enriched in PS- and CS-fed groups; laccase-like multicopper oxidases, cytochrome P450, monooxygenase, superoxidase, and dehydrogenase were involved in lignin and PS degradation. Furthermore, the upregulated gene lac640 in both PS- and CS-fed groups was overexpressed in E. coli and exhibited PS and lignin degradation ability. CONCLUSIONS: The high similarity of gut microbiomes adapted to biodegradation of PS and CS indicated the plastics-degrading ability of the T. molitor larvae originated through an ancient mechanism that degrades the natural lignocellulose. Video Abstract.

Treatment of nanofiltration membrane concentrates integrated magnetic biochar pretreatment with anaerobic digestion.

nanofiltration membrane concentrate (NMC) is an emerging type of wastewater with significant environmental concerns. which can be treated efficiently by an integrated method. In this study, magnetic biochar (MBC) pretreatment integrated with anaerobic digestion (AD) (MBC + AD) was used to treat NMC. Results showed that under the optimal MBC + AD conditions, 79%, 69.4%, 52.9%, and 86.5% of COD, total nitrogen (TN), chromaticity, and light absorbing substances were reduced. For heavy metals removal, 18.3%, 70.0%, 96.4%, 43.8% and 97.5% of Cr (VI), Cd, Pb, Cu and Zn were removed, respectively. LC-MS analysis indicated that p-nitrophenol (4-NP) diethyl and phthalate (DEP) were the main organic pollutants in NMC with a removal rate of 60% and 90%. Compared with single AD, in MBC + AD samples, bacterial activity was improved, and genus DMER64 (23.2%) was dominant. The predominant archaea were Methanocorpusculum (53.3%) and Methanosarcina (25.3%), with microbial restructuring and slight methane generation. Additionally, metabolic pathway prediction revealed that both bacterial and archaeal metabolism were significantly enhanced, contributing to the central functional pathways, namely microbial activity metabolism and biodegradation metabolism. In addition, the significantly increased genera Syner-01, Vulcanibacillus, Methanocorpusculum, and Norank_c_Bathyarchaeia were significantly positively related to metabolic function. This finding demonstrated that MBC + AD enhanced contaminant removal, mainly by regulating bacterial diversity and activity. Moreover, the toxicity of NMC decreased after MBC + AD treatment. This study provides a potential biological strategy for the treatment of membrane concentrates and water recovery.

[Expression of PEPT2 mRNA in lung tissue of rats with pulmonary fibrosis].

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis is a common pathological phenomenon in lung cancer patients after chemotherapy or radiotherapy. It is also a key hindrance to the transport of drugs to lung tissue. Peptide transporters have become a target of the rational design of peptides and peptide drugs. The aim of this study is to investigates the expression of peptide transporter 2 (PEPT2) mRNA in the lungs of rats with bleomycin (BLM)-induced pulmonary fibrosis. METHODS: Fifty healthy adult Sprague-Dawley rats were randomly divided into five groups. One group was untreated (control), the second group was injected with normal saline solution (NS), and the three remaining groups were treated with a single dose of bleomycin to induce pulmonary fibrosis (BLM). Rats from the NS group were killed by exsanguination on day 14. Rats from the BLM group were killed by exsanguination on days 7, 14, and 28. The lung samples were observed under light microscopy and the hydroxyproline concentration was determined. The expression levels of PEPT2 mRNA were measured by RT-PCR. RESULTS: The morphological study showed that collagenous fiber proliferated in the lungs of rats injected with BLM, indicating pulmonary fibrosis. This proliferation was apparent at 14 d post-injection and especially at 28 d post-injection. Hydroxyproline levels increased seven days post-injection compared with the control group and NS group, but there was no significant statistical difference (P>0.05). Hydroxyproline levels significantly increased (P<0.05) 14 d and 28 d post-infection. The change in the lung tissue pathology coincided with the change in hydroxyproline levels. There were no significant changes of pulmonary PEPT2 mRNA expression levels among the different groups (P>0.05). CONCLUSION: PEPT2 is a potential peptide drug target in the treatment of pulmonary fibrosis, although there were no significant changes of PEPT2 mRNA expression in the lungs of rats with bleomycin-induced pulmonary fibrosis.