Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

Acquisition of taxane resistance by p53 inactivation in ovarian cancer cells.

Ovarian cancer is one of the most common gynecologic malignancies in women and has a poor prognosis. Taxanes are a class of standard first-line chemotherapeutic agents for the treatment of ovarian cancer. However, tumor-intrinsic and acquired resistance to taxanes poses major challenges to improving clinical outcomes. Hence, there is an urgent clinical need to understand the mechanisms of resistance in order to discover potential biomarkers and therapeutic strategies to increase taxane sensitivity in ovarian cancer. Here, we report the identification of an association between the TP53 status and taxane sensitivity in ovarian cancer cells through complementary experimental and informatics approaches. We found that TP53 inactivation is associated with taxane resistance in ovarian cancer cells, supported by the evidence from (i) drug sensitivity profiling with bioinformatic analysis of large-scale cancer therapeutic response and genomic datasets and (ii) gene signature identification based on experimental isogenic cell line models. Further, our studies revealed TP53-dependent gene expression patterns, such as overexpression of ACSM3, as potential predictive biomarkers of taxane resistance in ovarian cancer. The TP53-dependent hyperactivation of the WNT/ß-catenin pathway discovered herein revealed a potential vulnerability to exploit in developing combination therapeutic strategies. Identification of this genotype-phenotype relationship between the TP53 status and taxane sensitivity sheds light on TP53-directed patient stratification and therapeutic discoveries for ovarian cancer treatment.

Clinical features of the predilection and severer sites of intrauterine adhesions. / å®«è ”ç²˜è¿žå¥½å‘å’Œç›¸å¯¹ä¸¥é‡éƒ¨ä½çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Intrauterine adhesions (IUA) refers to the adhesions between the myometrium of the uterine cavity, which is secondary to damage to the basal layer of the endometrium due to trauma or infection. The occurrence of IUA is mainly related to intrauterine operations. Hysteroscopic adhesiolysis (HA) is the standard surgical treatment for IUA. But the recurrence rate of IUA after HA is still high. Importantly, endometrium recovery is difficult, resulting in unsatisfied prognosis for moderate to severer IUA patients. Therefore, it is important to take effective primary preventive measures against the etiology to avoid endometrium damage from medical surgery. In this paper, we discuss and analyze predilection and severer sites of intrauterine adhesions, aiming to provide a basis for how to avoid and reduce injuries during intrauterine operations, such as abortion, dilation and curettage. METHODS: In this study, we retrospectively analyzed the surgical videos of patients who underwent HA for the first time from January 2019 to December 2021 in the Third Xiangya Hospital of Central South University so as to assess the area of adhesions and predilection and severer sites of occurrence of adhesions, and we collected 657 patients who underwent HA for the first time, including 81 patients with total IUA and 576 patients with partial IUA. We counted and analyzed the number and composition ratio of partial IUA patients with severer sites of damage to the lateral wall of the uterine cavity and severerr sites of damage to each segment of the uterine cavity. RESULTS: Among 576 patients with partial IUA, there were 60 patients with no significant difference in the degree of adhesions between the right and left sides, 143 patients with severer adhesions on the left side of the uterine cavity, and 373 patients with severer adhesions on the right side of the uterine cavity. There was a difference in the severity of damage of left and right lateral wall. The proportion of patients with severer adhesions on the right side of the uterine cavity (64.8%) was higher than that of patients with adhesions on the left side of the uterine cavity (24.8%), and there was statistically difference (P<0.05). There was 93 patients with severer adhesions at the fundus or bilateral horn of the uterus, 190 patients with severer adhesions at the middle and upper part of the uterine cavity, 245 patients with severer adhesions at the middle and lower part of the uterine cavity and at the endocervix, and 48 patients with no significant difference in the degree of adhesions in each part. The proportion of patients with severer adhesions at the middle and lower part of the uterine cavity and at the endocervix was higher (42.5%) than those with adhesions in the fundus or bilateral horn of the uterus (16.1%) and in the middle and upper part of the uterine cavity (33.0%), and there were statistically differences (both P<0.05). CONCLUSIONS: The predilection site of IUA is the lateral wall of the uterine cavity. The severer adhesions is in the right lateral wall of the uterine cavity, the middle and lower segments and the endocervix, which may be related to the operating habits of the surgeon. Therefore, gynecologists should minimize damage to the lateral wall of the uterine cavity, especially the right lateral wall in performing uterine operations (more attention should be paid by right-handed physicians). Besides, we should pay attention to protecting the middle and lower segments of the uterine cavity and the endocervix, avoiding maintaining negative pressure to withdraw the uterine tissue suction tube from the uterine cavity during abortion procedures to minimize damage.