Careful regulation of the cell cycle is required for proper replication, cell division, and DNA repair. DNA damage–including that induced by many anticancer drugs–results in cell cycle delay or arrest, which can allow time for repair of DNA lesions. Although its molecular mechanism of action remains a matter of debate, the anticancer ruthenium complex KP1019 has been shown to bind DNA in biophysical assays and to damage DNA of colorectal and ovarian cancer cells in vitro. KP1019 has also been shown to induce mutations and induce cell cycle arrest in Saccharomyces cerevisiae, suggesting that budding yeast can serve as an appropriate model for characterizing the cellular response to the drug. Here we use a transcriptomic approach to verify that KP1019 induces the DNA damage response (DDR) and find that KP1019 dependent expression of HUG1 requires the Dun1 checkpoint; both consistent with KP1019 DDR in budding yeast. We observe a robust KP1019 dependent delay in cell cycle progression as measured by increase in large budded cells, 2C DNA content, and accumulation of Pds1 which functions to inhibit anaphase. Importantly, we also find that deletion of RAD9, a gene required for the DDR, blocks drug-dependent changes in cell cycle progression, thereby establishing a causal link between the DDR and phenotypes induced by KP1019. Interestingly, yeast treated with KP1019 not only delay in G2/M, but also exhibit abnormal nuclear position, wherein the nucleus spans the bud neck. This morphology correlates with short, misaligned spindles and is dependent on the dynein heavy chain gene DYN1. We find that KP1019 creates an environment where cells respond to DNA damage through nuclear (transcriptional changes) and cytoplasmic (motor protein activity) events.

BackgroundThe presenting symptoms and co-morbidities contributing to mortality in young patients (age < 50 years old) with colorectal cancer (CRC) are poorly understood. We reviewed these features in our patient population with non-hereditary early-onset CRC (EO-CRC). Study aimThis study aimed to assess characteristics of patients with a diagnosis of non-hereditary EO-CRC, including presenting symptoms and metabolic disorders contributing to mortality in underserved areas of southwest Virginia. MethodsIn this retrospective observational study, we selected patients aged 18-50 years with a diagnosis of nonhereditary EO-CRC from 2008 to 2016 at Carilion Roanoke Memorial Hospital. The electronic medical record was queried to identify demographic data, medical history, histopathology results, lab values, and mortality. The cumulative risks of symptoms and co-morbid metabolic disorders was estimated using Kaplan-Meier curves. ResultsWe identified 139 patients with non-hereditary EO-CRC (mean age 41.6 ± 6.9 years). Almost half of these patients were obese (BMI > 30), 30.9% had a diagnosis of hypertension, 29% had hyperlipidemia (HLD), and 17.35% had diabetes mellitus type 2 (DM2). Diagnosis was delayed by 4.5 months from initial presentation, and 17% had advanced disease (stage III/IV). Also, 68.5% of patients were symptomatic with one to three symptoms, most commonly with rectal bleeding (45.3%). The chronicity of HLD (≥5 years) was associated with reduced survival in our patients with EO-CRC. The survival of females with multiple metabolic disorders was reduced compared to females with a single metabolic disorder. ConclusionsMultiple symptoms, chronic HLD, and female gender with multiple metabolic disorders were factors associated with poor outcomes in non-hereditary EO-CRC patients.

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BackgroundAlcoholic cirrhosis though uncommon in young patients is being reported more frequently and related mortality is also increasing. Study aimTo evaluate risk factors associated with mortality among young patients (<40 years) with alcoholic cirrhosis and older patients (> 40 years old) after their first hospitalization in a tertiary referral academic center. MethodsCarilion clinic's electronic medical record (EPIC) was queried to identify all alcoholic patients hospitalized for the first time with either a new diagnosis of alcoholic cirrhosis or a prior diagnosis of this from 2008 to 2016 with follow-up through June 2018. Information on demographics, comorbidities, lab values, procedures, and mortality was extracted. The cumulative risks of long-term mortality after the first hospitalization were estimated using Kaplan-Meier curves and compared between the two groups; those < 40 years of age and those > 40 years of age. Demographic data, lab values, and comorbidities associated with cirrhosis were assessed using multivariable Cox proportional hazard analysis to determine risk factors associated with long-term mortality. ResultsWe identified 65 young patients out of a total of 325 patients admitted for the first time for alcoholic cirrhosis (mean age: 34.6 ± 4.7 yrs, 72.3% males, 74.4% current alcohol users, 52.3% current smokers, 12.6% current illicit drugs users). The one, three, and five-year cumulative mortality after the first hospitalization was 21.1 %, 31.1%, and 49.7% respectively. The median survival for young patients was longer as compared to the older patients (p<0.001); likely related to high early mortality in older patients who had many other comorbidities. On multivariate Cox proportional hazard analysis, increased age [hazard ratio (HR) 1.03; 95% confidence interval (CI), 1.01-1.05], neutrophils-to-lymphocytes ratio (NLR) at first hospital discharge (HR 1.02; 95% CI, 1.01-1.04), the presence of encephalopathy (HR, 1.93; 95% CI, 1.06-3.55), and initial MELD (model for end-stage liver disease) score (HR, 1.13; 95% CI, 1.08-1.19) were associated with increased risk of mortality. Though the majority of patients endorsed current alcohol and tobacco use before the admission, it was not significantly associated with mortality. ConclusionsFive-year cumulative mortality for patients < 40 years of age with alcoholic cirrhosis after their first hospitalization is 49.7%. Old age, most recent NLR, hepatic encephalopathy, and MELD score on admission were associated with increased late mortality.

IntroductionIdentification of gender-specific prognostic factors in patients with alcoholic liver cirrhosis (ALC) is integral to understanding disease severity and mortality rates. We gathered data on various widely-used laboratory values and comorbid conditions among male and female patients with ALC after initial hospitalization. These individual risk factors were assessed for their relationship with mortality based on gender. MethodsWe performed a retrospective observational study of hospitalized patients with either a new or prior diagnosis of ALC from 2008 to 2016 with follow-up through June 2018. The electronic medical record (EMR) was queried for demographics, comorbidities, lab values, and mortality. The cumulative risks of mortality after the first hospitalization were estimated using Kaplan-Meier curves and compared among both genders. Demographic data, lab values, and comorbidities associated with cirrhosis were assessed using multivariate Cox proportional hazard analysis to determine risk factors associated with mortality. ResultsWe identified 247 male patients (mean age 54.19 ± 13.14 years) and 78 female patients (mean age 51.10 ± 11.60 years) hospitalized at Carilion Clinic with a diagnosis of ALC. About 70% (male) and 46% (female) endorsed alcohol use at the time of admission, 10% (male) and 13% (female) endorsed illicit drug use, and 56% (male and female) endorsed tobacco use. The one-, three-and five-year cumulative mortality after the first hospitalization was 43.4%, 53.2%, and 61.6%, respectively for males and 24.1%, 59.0%, and 67.2%, respectively for females. Median survival for younger male patients with ALC (age < 40 years old) after the first hospitalization was significantly different compared to the older male patients (age > 40 years) (p=0.0009), but age was not a significant factor for survival of female patients.Multivariate analysis further shows that illicit drug use, creatinine level at the time of admission, and age > 40 years had the highest hazard ratios for risk of mortality in male patients. For female patients, history of hepatic encephalopathy (HE) and blood urea nitrogen (BUN) level at the time of discharge were both associated with increased risk of mortality, with a history of HE being associated with a higher hazard ratio for risk of mortality. ConclusionAge, illicit drug use, and creatinine level were risk factors associated with mortality for male patients with ALC but not female patients. Hepatic encephalopathy and BUN were risk factors associated with mortality for female patients. The mortality for male patients was about twice the mortality of female patients at one year, but three-year and five-year mortality was higher in female patients.