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Diagnosis and Treatment
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
In a recent report by Fridell et al. [21], it is reported that for T1DM patients with uraemia, PAK should be the preferred pancreatic transplant procedure. As per the report, it is stated that on grafting terms, PTA is better than SPK because it is widely accepted that a living donor renal transplantation has a better allograft result and patient compliance as compared to a cadaveric donor. This is because in SPK, both the pancreas and kidney are usually from cadaveric donors. It was reported, however, that the risk of pancreatic graft rejection was similar in both PAK and SPK. In PAK, the baseline immunosuppressive drugs that are already in action might help in the better acceptance of a pancreas. However, as patients awaiting PAK are already immunosuppressed, they have a very high chance of acquiring a post-surgical infection. Secondly, a second surgical procedure is definitely not patient compliant for those awaiting PAK. A few centres, however, completely eliminated the need for a second surgery by performing simultaneous cadaveric pancreas transplantation living donor kidney grafting (SPLK) and have achieved excellent results. Although the rate of graft rejection has seen a significant decrease in the case of PAK in the last 20 years, it is almost the same for SPK. However, the administration of newer immunosuppressive drugs (anti-thymocyte antibodies and mycophenolate mofetil) without any calcineurin inhibitors has made the grafts safer and longer lasting.
Gastrointestinal Tract
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Judit E. Markovits, Graham R. Betton, Donald N. McMartin, Theresa Boulineau
New promising biomarkers of GI toxicity were identified in rats treated with a PAK-4 inhibitor. Preliminary findings indicated the utility of plasma citrulline and fecal miRNA194, at least in the model used (John-Baptiste et al. 2012). In follow-up studies, using PAK4 inhibitors as well as a heat shock protein 90 inhibitor and an NSAID, miRNA194 and miR-215 appeared to be quantitative, noninvasive, and sensitive biomarkers for drug-induced intestinal toxicity (Kalabat et al. 2017).
Pigmented nonmelanocytic skin lesions
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Elvira Moscarella, Simonetta Piana, Caterina Longo, Giuseppe Argenziano
They typically present as pink to red macules, with a variably scaly surface. Less frequently, AKs may present a clinically visible pigmentation, pigmented AK (PAK). PAK can be difficult to differentiate from other pigmented lesions, such as melanoma and lentigo maligna melanoma, SL, early SK, and LPLK. In the context of actinically damaged skin, characterized by the presence of mottled pigmentation, discriminating between benign macules and pigmented tumors may be challenging; thus, histopathologic confirmation is frequently required in the diagnosis of PAK in order to exclude melanoma.
Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response
Published in International Journal of Radiation Biology, 2023
Muzaffer Dukel, Kayahan Fiskin
P21‐activated kinases (PAKs) are serine/threonine kinases that have the capability to promote oncogenic signaling pathways including directional motility, invasion, metastasis, cell cycle progression, and angiogenesis (Ye and Field 2012; Radu et al. 2014). The upregulation of PAKs in tumors is referred to as leading to resistance to anticancer drug-induced cell death in tumors (Marlin et al. 2009; Lu et al. 2017). Moreover, the overactivation of PAKs causes anti-apoptotic actions that prolong cell survival (Molli et al. 2009). Besides, PAKs have several vital roles during numerous cellular processes that can be distinguished during cancer development. PAK4 and PAK5 mutations are linked to colon and lung cancers, while PAK1 is overexpressed in both gene and protein levels or hyperactivated in colon cancer (Dummler et al. 2009). On the other hand, an early study indicated that PAK4 is required for anchorage-independent cell growth and it is overexpressed in colon cancer cells (Callow et al. 2002). In addition, changes to PAK1 mRNA, protein, and activity have been reported in a variety of human malignancies, including breast (Li et al. 2008), glioblastoma (Aoki et al. 2007), liver (Ching et al. 2007), kidney (O’Sullivan et al. 2007), prostate (Goc et al. 2013), and pancreas (Yeo et al. 2017). Moreover, PAK1 and PAK4 have been reported to be involved in a large number of oncogenic properties, including anti-apoptosis and metastasis, and, not surprisingly, this kinase is recognized as a potential target for the treatment of human cancers such as colon cancer (Carter et al. 2004; Liu et al. 2008).
S1P in the development of atherosclerosis: roles of hemodynamic wall shear stress and endothelial permeability
Published in Tissue Barriers, 2021
Christina M Warboys, Peter D Weinberg
Exposure of endothelial cells to S1P results in rapid actin polymerization and dynamic reorganization of the actin cytoskeleton, forming a prominent cortical actin band29,33,36,37,41 that is essential for the barrier-enhancing effects of S1P.29 Several studies have also shown that Rac GTPase is rapidly activated in response to S1P29,38,39,41 and that this depends on the activation of PI3K and recruitment of Tiam1, a Rac1 guanine nucleotide exchange factor.37 Rac plays a critical role in mediating S1P-induced cytoskeletal remodeling via activation of p21-associated Ser/Thr kinase (PAK).29,41 PAK may act at several levels to promote the dynamic reorganization of the cytoskeleton into dense peripheral bands that strengthen barrier function. Myosin light chain (MLC) can be phosphorylated by PAK61 and indeed phosphorylated MLC has been shown to localize to peripheral bands in response to S1P.29,36 PAK also phosphorylates and activates LIM kinase (LIMK), which inhibits cofilin (an actin severing protein) thus preventing actin depolymerization and promoting the formation of actin filaments.62
Clinical Evaluation of P21 Activated Kinase 1 (PAK1) Activation in Gliomas and Its Effect on Cell Proliferation
Published in Cancer Investigation, 2021
Akkanapally Venu, Balasubramanian Archana, Rahul Kanumuri, Veena Kumari Vuttaradhi, Lawrence D’Cruze, Sowmiya Murugan, Krishnamurthy Ganesh, Duvuru Prathiba, Mayya Alexandrovna Dymova, Suresh Kumar Rayala, Ganesh Venkatraman
In current literature, widely growing evidences proclaim that p21-activated kinase 1 (PAK1) acts as a significant player in cancer cell proliferation, survival, and invasiveness (12). PAK1 is a serine/threonine protein kinase which is a downstream mediator of Rho family small Guanosine Tri Phosphatases (GTPase) mainly Rac1 and Cdc42 (13,14) that manifests a fundamental role in cell motility, shape, survival and cytoskeletal rearrangement (15–17). Recent reports indicate the fact that PAK1 dysregulation at genomic or protein level may contribute to tumorigenesis of ovarian, breast, bladder, liver, colorectal, lung and brain cancers (18–25). Furthermore, PAK1 has proved to be connected with tamoxifen resistance in breast cancer cells (26), resistance to inhibitors utilized in lymphoma (27), renal cell carcinoma (28), pancreatic cancer cells (29) and non-small cell lung carcinoma (30) along with radio-resistance in lung adenocarcinoma (31). First evidence on PAK1 association with glioma published in 2007 by Hiroshi Aoki et al. (18), who had reported that phosphorylated cytoplasmic PAK1 was associated with poor survival rate in patients with glioblastoma. A contemporary systemic review described a detailed meta-analysis of PAK1 correlation with disease prognosis in solid tumors (32). However, a conclusive role of PAK1 in glioblastoma has yet to be determined. Hence evaluating PAK1 expression in various grades of astrocytomas may shed some light on better understanding of its role in tumorigenesis and therapeutic resistance. Subsequently, this may pave a way for development of potential therapeutic drug targets.