Moreover, the addition of poly ADP-ribose polymerase inhibitors further potentiates the K+CS antitumor effect K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in generalγ-Glutamyl carboxylase GGCX is an integral membrane protein that catalyzes posttranslational carboxylation of a number of vitamin K-dependent VKD proteins involved in a wide variety of physiologic processes, including blood coagulation, vascular calcification, and bone metabolism Naturally occurring GGCX mutations are associated with multiple distinct clinical phenotypes However, the genotype-phenotype correlation of GGCX remains elusive Here, we systematically examined the effect of all naturally occurring GGCX mutations on the carboxylation of 3 structure-function distinct VKD proteins in a cellular environment GGCX mutations were transiently introduced into GGCX-deficient human embryonic kidney 293 cells stably expressing chimeric coagulation factor, matrix Gla protein MGP, or osteocalcin as VKD reporter proteins, and then the carboxylation efficiency of these reporter proteins was evaluated Our results show that GGCX mutations differentially affect the carboxylation of these reporter proteins and the efficiency of using vitamin K as a cofactor Carboxylation of these reporter proteins by a C-terminal truncation mutation R704X implies that GGCX's C terminus plays a critical role in the binding of osteocalcin but not in the binding of coagulation factors and MGP This has been confirmed by probing the protein-protein interaction between GGCX and its protein substrates in live cells using bimolecular fluorescence complementation and chemical cross-linking assays Additionally, using a minigene splicing assay, we demonstrated that several GGCX missense mutations affect GGCX's pre-messenger RNA splicing rather than altering the corresponding amino acid residues Results from this study interpreted the correlation of GGCX's genotype and its clinical phenotypes and clarified why vitamin K administration rectified bleeding disorders but not nonbleeding disordersTraumatic brain injury-induced coagulopathy TBI-IC causes life-threatening secondary intracranial bleeding Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood We report results of a study designed to test the hypothesis that von Willebrand factor VWF released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by gt;50 and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury  https//wwwselleckchemcom/products/bay-3827html  A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBIGlucocorticoid GC resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia T-ALL cells Genes identified in the screen interfere with cyclic adenosine monophosphate cAMP signaling and are underexpressed in GC-resistant or relapsed ALL patients Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 PGE2 increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL
  Loss of sleep or disturbance of sleep-wake cycles has been related to metabolic impairments However, few studies have investigated the association between daily sleep duration and hyperuricemia
 
  We investigated daily sleep duration daytime napping and nocturnal sleep with hyperuricemia risk
 
  We cross-sectionally analyzed data from the China Multi-Ethnic Cohort CMEC, Yunnan region A total of 22 038 participants aged 30 to 79 years were recruited in 2018 Hyperuricemia was defined as serum uric acid SUA above 70 mg/dL in men and above 60 mg/dL in women Outcomes were associations between daily sleep duration and hyperuricemia
 
  We found that the longest daytime napping duration was associated with a higher risk of hyperuricemia in the crude model odds ratio [OR] [95 CI], 222 [188-261], P lt; 001 and in a multivariable adjustment model OR, 169; 95 CI, 141-201, P lt; 001 after adjusting for demographic, sleep habits, and metabolic risk factors The association was moderately attenuated with additionally adjusted for serum creatinine OR, 154; 95 CI, 128-186, P lt; 001 Longer daytime napping duration was also related to higher risk of hyperuricemia combined with metabolic syndrome MetS Respondents in the group with daytime napping duration greater than or equal to 90 minutes presented with a higher risk of hyperuricemia combined with MetS OR, 139; 95 CI, 106-179; P lt; 001 in the fully adjusted model We did not observe any relation between nocturnal sleep duration and risk of hyperuricemia in the study
 
  Longer daytime napping duration but not nocturnal sleep duration was independently associated with risk of hyperuricemia in a Chinese population
 Longer daytime napping duration but not nocturnal sleep duration was independently associated with risk of hyperuricemia in a Chinese population