DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) repair pathway and the DNA damage response (DDR). DNA-PK has therefore been pursued for the development of anti-cancer therapeutics in combination with ionizing radiation (IR). We report the discovery of a new class of DNA-PK inhibitors that act via a novel mechanism of action, inhibition of the Ku–DNA interaction. We have developed a series of highly potent and specific Ku–DNA binding inhibitors (Ku-DBi’s) that block the Ku–DNA interaction and inhibit DNA-PK kinase activity. Ku-DBi’s directly interact with the Ku and inhibit in vitro NHEJ, cellular NHEJ, and potentiate the cellular activity of radiomimetic agents and IR. Analysis of Ku-null cells demonstrates that Ku-DBi’s cellular activity is a direct result of Ku inhibition, as Ku-null cells are insensitive to Ku-DBi’s. The utility of Ku-DBi’s was also revealed in a CRISPR gene-editing model where we demonstrate that the efficiency of gene insertion events was increased in cells pre-treated with Ku-DBi’s, consistent with inhibition of NHEJ and activation of homologous recombination to facilitate gene insertion. These data demonstrate the discovery and application of new series of compounds that modulate DNA repair pathways via a unique mechanism of action.

Objectives: Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disorder that is associated with high morbidity and mortality in the ICU. It has also been associated with acute liver failure. Design: Retrospective observational study. Setting: Tertiary-care medical ICU. Patients: Thirty-one patients critically ill with hemophagocytic lymphohistiocytosis. Interventions: None. Measurements and Main Results: We performed a comprehensive review of critically ill hemophagocytic lymphohistiocytosis patients admitted to a tertiary-care medical ICU from January 2012 to December 2018. Most patients presented with constitutional symptoms and elevated liver enzymes and thrombocytopenia were common upon hospital admission. ICU admission laboratory and clinical variables were used to calculate Acute Physiology and Chronic Health Evaluation II, hemophagocytic syndrome diagnostic score, and model for end-stage liver disease. Mean age of the cohort was 48.1 years, and 45% were male. The mortality rate was 65% at 28 days and 77% at 1 year. About 28-day survivors were younger, had lower mean Acute Physiology and Chronic Health Evaluation II score (16.5 vs 23.0; p = 0.004), and higher mean hemophagocytic syndrome diagnostic score (249.1 vs 226.0; p = 0.032) compared with nonsurvivors. Survivors were less likely to receive mechanical ventilation, renal replacement therapy, or vasopressor support and were more likely to receive chemotherapy for hemophagocytic lymphohistiocytosis. In this ICU cohort, 29% were diagnosed with acute liver failure, of whom only 22% developed acute liver failure early during their hospital stay. Acute liver failure was associated with a higher model for end-stage liver disease score upon hospital admission. Available histology in those that developed acute liver failure showed massive hepatic necrosis, or histiocytic or lymphocytic infiltrates. Conclusions: Patients admitted to the ICU with hemophagocytic lymphohistiocytosis have a high mortality. Those who survived had lower Acute Physiology and Chronic Health Evaluation scores, had higher hemophagocytic syndrome diagnostic scores, are more likely to receive hemophagocytic lymphohistiocytosis specific chemotherapy, and are less likely to have organ failure. Hemophagocytic lymphohistiocytosis can be associated with acute liver failure especially when model for end-stage liver disease score is elevated upon admission.

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Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein essential for initiation of global-genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene exhibit strong susceptibility to skin cancer due to defective removal via GG-NER of genotoxic, solar UV-induced dipyrimidine photoproducts. However, XPC is increasingly recognized as important for protection against non-dermatologic cancers, not only through its role in GG-NER, but also by participating in other DNA repair pathways, in the DNA damage response and in transcriptional regulation. Additionally, XPC expression levels and polymorphisms likely impact development and may serve as predictive and therapeutic biomarkers in a number of these non-dermatologic cancers. Here we review the existing literature, focusing on the role of XPC in non-dermatologic cancer development, progression, and treatment response, and highlight possible future applications of XPC as a prognostic and therapeutic biomarker.

METHODS: This single center retrospective study included 35 patients over 18 years old who were admitted to our critical care units in the first half of 2015 and received the medication. Patients were divided into two groups; one control group and one group with liver disease as evident by a known diagnosis of liver cirrhosis or abnormal liver function tests indicative of liver disease. RESULTS: Twelve patients had liver disease, with average age of 46.5 years. Average medication duration was 75 hours. The most common indications were delirium in 50% and alcohol withdrawal in 42%. Six patients were extubated, one had a tracheostomy, two were not intubated, and three were terminally weaned. Average length of time from medication discontinuation to extubation was 39.7 hours with average Dexmedetomidine dose of 0.34 mcg/kg/hr. The only side effect was hypotension in one patient. Medication was discontinued in that patient. Twenty-three patients did not have any liver disease, with average age of 47.8 years. Average medication duration was 141 hours. Most common indications were delirium in 83% and alcohol withdrawal in 26%. Thirteen patients were extubated, eight had a tracheostomy, one was terminally weaned, and one was not intubated. Average length of time from medication discontinuation to extubation was 13.5 hours average with Dexmedetomidine dose 0.57 mcg/kg/ hr. Side effects included arrhythmia in two patients (one was life threatening) and hypotension in one patient. Medication was discontinued in all three patients. CONCLUSIONS: Dexmedetomidine was well tolerated in patients with liver disease who received the medication for more than 48 hours. No increase in side effects was noted. This study showed that patients with liver disease required more time before extubation once the medication was discontinued. This can partially be due to the slow metabolism of dexmedetomidine but it can also be affected by slow metabolism of other associated drugs. More controlled randomized studies are needed to test the safety and efficacy in patients with liver disease. CLINICAL IMPLICATIONS: Dexmedetomidine can be used safely in patients with liver disease for more than 48 hours but it can take a longer time for patients to be extubated once the medication is discontinued.