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Tumor chemotherapy resistance arises frequently and limits high grade serous ovarian cancer (HGSOC) patient survival. Focal adhesion kinase (FAK) is an intracellular protein-tyrosine kinase encoded by PTK2, a gene that is often gained in HGSOC. Canonically, FAK functions at the cell periphery. However, FAK also transits to the nucleus to modulate gene expression. We find that FAK is tyrosine phosphorylated and nuclear localized in HGSOC patient tumors surviving neoadjuvant platinum-paclitaxel chemotherapy and that FAK nuclear accumulation occurs upon sub-cytotoxic cisplatin exposure to ovarian tumor cells in vitro. FAK nuclear localization sequence (NLS) mutational inactivation resulted in tumor cell sensitization to cisplatin in vitro and in vivo relative to wildtype FAK reconstituted ovarian tumor cells. Cisplatin cytotoxicity was associated with elevated extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activation in FAK NLS- cells, cisplatin-stimulated ERK activation was also enhanced upon loss of FAK activity or expression, and cisplatin-stimulated cell death was prevented by an inhibitor of ERK signaling. MAPK phosphastase-1 (MKP1) negatively regulates ERK signaling and cisplatin-induced MKP1 levels were significantly elevated in FAK-WT compared to FAK-NLS- ovarian tumor cells. Notably, small molecule MKP1 inhibition enhanced both cisplatin-stimulated ERK phosphorylation and ovarian tumor cell death. Together, our results show that FAK expression, activity, and nuclear localization limit cisplatin cytotoxicity in part by regulating MKP1 levels and preventing non-canonical ERK/MAPK activation.

Focal adhesion kinase (FAK) functions as a signaling and scaffolding protein within endothelial cells (ECs) impacting blood vessel function and tumor growth. Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine kinase 2) expression, and to test this, we created PYK2 -/- FAK fl/fl mice with tamoxifen-inducible EC-specific Cre recombinase expression. At 11 weeks of age, EC FAK inactivation resulted in increased heart and lung mass and vascular leakage only on a PYK2 -/- background. Surprisingly, ∼90% of PYK2 -/- EC FAK -/- mice survived to 75 weeks of age. Syngeneic melanoma, breast, or lung carcinoma tumors did not grow in PYK2 -/- EC FAK -/- mice, but tumors grew normally in PYK2 -/- EC FAK fl/fl mice lacking Cre. This tumor inhibitory phenotype was associated with abortive EC vessel sprouting, enhanced EC p53 tumor suppressor and p21CIP1 (cyclin-dependent inhibitor 1) expression, and alterations in serum cytokine levels. To discern the role of FAK kinase versus scaffolding activity in ECs, we generated kinase defective (FAK K454R, KD) PYK2 -/- EC FAK fl/KD and PYK2 -/- EC FAK fl/WT (WT, wildtype) mice. Hemizygous EC FAK -/KD expression supported primary tumor growth but not metastasis, implicating EC FAK activity in tumor dissemination. In vitro , hemizygous expression of either WT or KD FAK suppressed EC p21CIP1 levels and cell death observed in primary PYK2 -/- EC FAK -/- ECs. Combined FAK and PYK2 knockdown in tumor cells also increased p21CIP1 and PARP1 (poly ADP-ribose polymerase 1) levels in a p53-associated manner impacting anchorage-independent growth. Together, these results underscore the linkage between PYK2 and FAK loss with p53 activation impacting tumor growth., Impact Statement: PYK2-null combined with endothelial cell-specific FAK transgenic mouse models show that loss of FAK activity limits tumor spread and that genetic or chemical degradation preventing combined FAK-PYK2 expression may be an approach to induce a p53-associated anti-tumor response.

Objective: To construct and apply a risk screening and intervention system for malnutrition in peritoneal dialysis patients based on the Omaha System., Materials and Methods: A total of 75 peritoneal dialysis patients were randomly divided into control (38 cases) and intervention group (37 cases). The control group received routine operation training and health education, and the intervention group implemented a nutritional management plan based on the Omaha System. The modified quantitative subjective comprehensive nutritional scale (MQSGA) score, kidney disease dietary compliance attitude (RAAQ) and behavior (RABQ) score, body mass index (BMI), serum albumin (ALB), prealbumin (PA), and hemoglobin (Hb) were observed., Results: Before intervention, there was no significant difference in these indicators between the two groups (p > 0.05). After 6 months, the MQSGA score in the intervention group was significantly lower than that in the control group (p < 0.05). RAAQ score and RABQ score in the intervention group were higher than those in the control group and (p < 0.05), and the nutritional indicators in the intervention group, such as BMI, ALB, PA, and Hb, were higher than those in the control group (p < 0.05)., Conclusion: A nutritional management plan based on the Omaha System can help improve the nutrition condition of peritoneal dialysis patients, and improve the dietary compliance of chronic kidney disease patients.

SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection., (Copyright © 2024 by The American Association of Immunologists, Inc.)