Evolving cancer resistance to anti-PD-1/PD-L1 antibodies in melanoma: Comprehensive insights with future prospects.

Immunotherapy has transformed the treatment of advanced melanoma. However, up to two-thirds of patients experience disease progression after initially achieving a response to immunotherapy. Furthermore, most research has focused on cutaneous melanoma rather than acral or mucosal melanoma, although the latter predominates in Asian populations. In this review, we examine and summarize current definitions of resistance to immunotherapy and the epidemiology of resistance to PD-1 inhibition. We also review the available literature on molecular mechanisms of resistance, including how the tumor mutational landscape and tumor microenvironments of immunotherapy-resistant acral and mucosal melanomas may influence resistance. Finally, we review strategies for overcoming resistance to PD-1 inhibition and summarize completed studies and ongoing clinical trials. Our review highlights that improving the understanding of resistance mechanisms, optimizing existing therapies and further studying high-risk populations would maximize the potential of immunotherapy and result in optimized treatment outcomes for patients with melanoma.

Nanoassembly-Mediated Exendin-4 Derivatives to Decrease Renal Retention.

An Exendin-4 analogue that was conjugated with 68Ga exhibited an excellent diagnostic effect on insulinoma in clinical practice. On account of its low molecular weight and short hydration radius, 68Ga-Exendin-4 showed high accumulation in kidney tissues. Nanoparticle-mediated strategies have attracted much attention due to polyvalent properties and the size amplification effect. In this study, Exendin-4 derivatives of radionuclide nanodevices were developed and evaluated. The Exendin-4 derivatives consisting of a ternary block recombinant protein were purified by an inverse transition cycle (ITC) and allowed to self-assemble into a nanodevice under physiological conditions. Our results showed that the nanoassemblies of Exendin-4 derivatives formed homogeneous spherical nanoparticles, exhibited outstanding affinity for insulinoma cells, and could be deposited in insulinoma tissues in vivo. The nanoassembly-mediated Exendin-4 derivatives showed fivefold reduced renal retention and exhibited an outstanding tumor-suppression effect.

A rare germline BMP15 missense mutation causes hereditary ovarian immature teratoma in human.

Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte-specific RNA sequencing revealed that abnormal activation of the H-Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.

Driving factors and grouping paths of rural sports development in China - A qualitative comparative analysis based on fuzzy sets.

The development of rural sports depends on many factors, but the complex causal relationship between various factors and the level of rural sports development is not clear. Using data envelopment analysis (DEA) and fuzzy set qualitative comparative analysis (fsQCA), this study aims to examine the driving role of various factors on rural sports development and construct various grouping paths to improve the level of rural sports development in China. The results shows that the area of fitness venues and social capital participation are sufficient conditions for the development of rural sports in China. Resource endowment through government fing, social capital participation and the construction of sports venues and facilities is the key driving factor for rural sports development in China. There are four grouping paths for the high-quality development of rural sports, which are divided into three configurations by combining the grouping characteristics: the state-social capital jointly controlled type driven by economic development and the resource endowment driven by the modernization of the agriculture promotes production and the grassroots organizations that are supported by the advantage of resource endowment. The results of the study highlight the complex causal relationships and key driving factors of rural sports development in China, highlight the differences in rural sports development patterns in different regions, and provide new ideas and guidelines for improving the level and quality of rural sports development.

Combining photodynamic therapy and cascade chemotherapy for enhanced tumor cytotoxicity: the role of CTT2P@B nanoparticles.

The mitochondria act as the main producers of reactive oxygen species (ROS) within cells. Elevated levels of ROS can activate the mitochondrial apoptotic pathway, leading to cell apoptosis. In this study, we devised a molecular prodrug named CTT2P, demonstrating notable efficacy in facilitating mitochondrial apoptosis. To develop nanomedicine, we enveloped CTT2P within bovine serum albumin (BSA), resulting in the formulation known as CTT2P@B. The molecular prodrug CTT2P is achieved by covalently conjugating mitochondrial targeting triphenylphosphine (PPh3), photosensitizer TPPOH2, ROS-sensitive thioketal (TK), and chemotherapeutic drug camptothecin (CPT). The prodrug, which is chemically bonded, prevents the escape of drugs while they circulate throughout the body, guaranteeing the coordinated dispersion of both medications inside the organism. Additionally, the concurrent integration of targeted photodynamic therapy and cascade chemotherapy synergistically enhances the therapeutic efficacy of pharmaceutical agents. Experimental results indicated that the covalently attached prodrug significantly mitigated CPT cytotoxicity under dark conditions. In contrast, TPPOH2, CTT2, CTT2P, and CTT2P@B nanoparticles exhibited increasing tumor cell-killing effects and suppressed tumor growth when exposed to light at 660 nm with an intensity of 280 mW cm-2. Consequently, this laser-triggered, mitochondria-targeted, combined photodynamic therapy and chemotherapy nano drug delivery system, adept at efficiently promoting mitochondrial apoptosis, presents a promising and innovative approach to cancer treatment.