Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.

Two-dimensional Cu-based materials for electrocatalytic carbon dioxide reduction.

Electrocatalytic CO2 reduction reaction (CO2RR) has emerged as a focal point in sustainable energy research, offering the potential for closed carbon cycle. Among numerous catalysts designed for CO2RR, two-dimensional (2D) Cu-based catalysts stand out for their remarkable performance in efficiently converting CO2 into high-value-added C1 and C2+ chemicals. Herein, we discuss the recent progress and challenges in the realm of CO2RR utilizing 2D Cu-based catalysts. The first section introduces various synthetic strategies, emphasizing the features and advantages of different techniques and proposing solutions to existing challenges. The second part outlines the reaction mechanism underlying the production of C1 and C2+ products on Cu-based catalysts, then summarizes applications of different types 2D Cu-based catalysts in CO2RR. Additionally, we evaluate the limitations of 2D Cu-based catalysts and propose improved strategies. Through this exploration of research advances and challenges, we hope to illuminate the path toward developing excellent CO2 electrocatalysts.

Absence of GSTT1 and polymorphisms in GSTP1 and TP53 are associated with the incidence of acne vulgaris.

BACKGROUNDS: Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit affecting most teenagers and numerous adults throughout the world. The present study was designed to assess the association of the presence or absence of GSTM1, GSTT1, and single nucleotide polymorphisms rs1695 in GSTP1 and rs1042522 in TP53 gene with acne vulgaris. METHODS: The cross-sectional case-control study was conducted at the Institute of Zoology from May 2020 to March 2021 and included acne vulgaris patients (N = 100) and controls (N = 100) enrolled in Dera Ghazi Khan district, Pakistan. Multiplex and tetra-primer amplification refractory mutation system-polymerase chain reactions were applied to investigate the genotype in analyzed genes. The association of rs1695 and rs1042522 with acne vulgaris was studied either individually or in various combinations with GATM1 and T1. RESULTS: A significant association of absence of GSTT1 and mutant genotype at rs1695 (GG) and at rs1042522 (CC) in GSTP1 and TP53, respectively, was found to be associated with acne vulgaris in enrolled subjects. Subjects aged 10-25 years and smokers were more susceptible to acne vulgaris. CONCLUSION: Our results suggest that genotypes of glutathione S-transferases (GSTs) and TP53 are involved in protection against oxidative stress and may influence disease progression in acne vulgaris.

Effect of Variable Doses of Zinc Oxide Nanoparticles on Male Albino Mice Behavior.

Zinc oxide nanoparticles (ZnO NPs) have diverse utility these days ranging from being part of nanosensors to be ingredient of cosmetics. Present study was designed to report the effect of variable doses of ZnO NPs on selected aspects of male albino mice behavior. Nano particles were synthesized by sol-gel auto-combustion method (Data not shown here). 10 week old male albino mice were divided into four experimental groups; group A, B and C were orally supplemented with 50 (low dose), 300 (medium dose) and 600 mg/ml solvent/kg body weight (high dose) of ZnO NPs for 4 days. Group D (control) orally received 0.2 M sodium phosphate buffer (solvent for ZnO NPs) for the same duration. A series of neurological tests (Rota rod, open field, novel object and light-dark box test) were conducted in all groups and performance was compared between ZnO NPs treated and control group. Muscular functioning during rota rod test was significantly improved in all ZnO NPs treated mice as compared to control group. While no significant differences in open field, novel object and light-dark box test performance were observed when data from studied parameters of specific ZnO NPs treatment were compared with the control group indicating that applied doses of ZnO NPs did not affect the exploratory, anxiolytic behavior and object recognition capability of adult male albino mice.