AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Antidepressant Use and Risk of Central Nervous System Metastasis

Thesis (Ph. D.)--University of Rochester.School of Medicine & Dentistry. Dept. of Public Health Sciences, 2015.Central nervous system (CNS) metastasis is the spread of a primary cancer to the CNS and occurs in up to 25% of cancer patients. Antidepressant therapy, used in 15-30% of cancer patients, affects the blood-brain barrier, potentially allowing CNS metastasis. One study found selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, increased CNS metastasis in mice. Our study determined whether antidepressants, and specifically SSRIs, increased the relative odds of CNS metastasis. Using a case-control study design, subjects were identified from the three types of cancers with the highest cumulative incidence of CNS metastasis (excluding lung cancer) at our institution: breast cancer, melanoma, and lymphoma. Our case ascertainment rate was 27.6% resulting in 189 cases (patients with CNS metastasis) and 945 controls (patients without CNS metastasis). Using logistic regression models (Aim 1), we separately estimated the relative odds of CNS metastasis associated with ‘any antidepressant use’ (any antidepressant irrespective of class), ‘any SSRI use’ (SSRI use, nonexclusively), and ‘exclusive SSRI use’ (only SSRI use and no other class of antidepressant), all compared to ‘no antidepressant use’. Using linear regression and only breast cancer controls, we separately estimated the change in white blood cell (WBC) count associated with ‘any antidepressant use’ and ‘any SSRI use’ (Aim 2). Although not statistically significant, the odds of CNS metastasis in breast cancer associated with ‘any SSRI use’ (Aim 1) was greater than 1.0 (OR=1.73, 95% CI = 0.75, 4.04). However, the smaller than expected sample size may, in part, explain the lack of statistical significance. In Aim 2, WBC counts of those breast cancer controls who took SSRIs were 0.75 x 109/L higher than those breast cancer controls who did not take antidepressants (95% CI = 0.01, 1.45). This was the first study to examine the association between antidepressant use and CNS metastasis. Our results found no clear statistically significant associations but suggested an increase in CNS metastasis and WBC count associated with antidepressant use. However, these estimates were imprecise with wide confidence intervals. Future studies, with larger sample sizes, are needed to examine these associations, and perhaps focus specifically on breast cancer patients

Potential biomarkers of temporomandibular joint disorders

Purpose: The purpose of this study was to identify protein markers present in subjects with temporomandibular joint disorders (TMDs) and clicking compared with the levels in controls. Materials and Methods: This was a pilot case-control study, and we report the preliminary results. Samples of joint aspirate collected from patients with TMDs and controls who had undergone surgery for a problem other than TMDs were analyzed using isobaric tags for relative and absolute quantitation (iTRAQ) and biotin-labeled-based protein arrays. The data obtained from these techniques were used to identify the proteins of interest, which were then quantitated using enzyme-linked immunosorbent assay (ELISA). The patient samples studied included joint aspirate collected clinically from the controls and patients and included samples from both the right and the left sides of each patient with a TMD. Results: The 8 TMJ aspirate samples from 6 subjects included 5 aspirate samples from 4 patients and 3 from 2 controls. The greatest standardized protein concentration of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 (EG-VEGF/PK1) and D6 was found in both joints of the controls compared with the levels from the joints of the patients. With 1 exception, the standardized protein concentration was significantly lower in the patients than in the controls. The lower levels of EG-VEGF/PK1 and D6 in the patients compared with the controls suggest that these cytokines might be possible biomarkers for TMDs. Conclusion: In the present pilot study, greater levels of EG-VEGF/PK1 and D6 were found in the controls than in the patients with TMDs. Proteomic analysis of the proteins present in the diseased joints compared with those in the controls might help to identify proteins present when pain or degeneration of the joint occurs. The proteomic information might be useful in the development of future therapies. © 2011 American Association of Oral and Maxillofacial Surgeons

A Retrospective Study of Infection in Patients Requiring Extracorporeal Membrane Oxygenation Support

Background: Healthcare-associated infections (HAIs) in critically ill patients are a serious public health problem. Extracorporeal membrane oxygenation (ECMO) has been used increasingly for patients with severe cardiac or respiratory failure, but it may increase HAI risk. The goal of our study was to characterize HAIs in ECMO patients at an ECMO referral center. Methods: This institutional review board–approved study identified all consecutive adult ECMO patients admitted to the cardiac surgery intensive care unit (CSICU) between January 1, 2015, and December 31, 2017. Demographic data, diagnosis, ECMO cannulation technique, and survival were collected. Urinary tract infection, pneumonia, and bacteremia incidence during ECMO and within 3 months of decannulation were collected. Outcomes of patients with HAIs were compared with noninfected patients, the CSICU infection incidence, and overall Extracorporeal Life Support Organization survival data. Results: There were 288 ECMO patients and 3396 CSICU admissions during this period. Survival was 72.3% for venoarterial ECMO, 85.3% for venovenous ECMO, and 57.1% for multimodality or veno-arteriovenous ECMO, with discharge survival of 60.2%, 72.0%, and 28.6%, respectively. Bacteremia incidence while cannulated was 6.8% for venoarterial ECMO and 9.3% for venovenous ECMO. Bacteremia occurred in 22 of 288 (7.6%) ECMO patients, compared with 48 of 3109 (1.5%) in non-ECMO CSICU patients, which was statistically significant (P \u3c .002). Bacteremia and pneumonia were associated with decreased VA-ECMO survival, with prolonged overall requirements for ECMO support. Conclusions: Nosocomial ECMO infections are significantly higher than in other CSICU patients. Infection risk remains significant even after decannulation. Infection is associated with increased mortality and longer duration of ECMO support. Further efforts are needed to determine HAI reduction strategies in this high-risk patient population

Outcomes after definitive radiation therapy for localized prostate cancer in a national health care delivery system

Purpose: Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically relevant end points at 10 years among men treated within a national health care delivery system were examined. Methods: National administrative, cancer registry, and electronic health record data were used for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy within the Veterans Health Administration from 2005 to 2015. National Death Index data were used through 2019 for overall and prostate cancer-specific survival and identified date of incident metastatic prostate cancer using a validated natural language processing algorithm. Metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods were estimated. Results: Among 41,735 men treated with definitive radiation therapy, the median age at diagnosis was 65 years and median follow-up was 8.7 years. Most had intermediate (42%) and high-risk (33%) disease, with 40% receiving androgen deprivation therapy as part of initial therapy. Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low-, intermediate-, and high-risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low-, intermediate-, and high-risk disease. The unadjusted overall survival was lower across increasing disease risk categories at 77%, 71%, and 62% for low-, intermediate-, and high-risk disease (p Conclusions: These data provide population-based 10-year benchmarks for clinically relevant end points, including metastasis-free survival, among patients with localized prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high-risk disease in particular suggest that outcomes have recently improved.</p

An empirical investigation of the option value of college enrollment’,

Since the pioneering work of Gary S. Becker and Jacob Mincer, the application of investment theory to the study of individuals&apos; education decisions has become commonplace. People are assumed to weigh short-term costs against future benefits and choose the schooling level that maximizes welfare. This static framework abstracts from uncertainty and suggests that few people should drop out if the marginal earnings gain from graduating is high, as it appears to be. In reality, schooling decisions involve much uncertainty, outcomes often deviate from expectations, and dropout is common. 1 Despite its salience and its importance to investment generally, uncertainty has historically received relatively little attention in the study of education. 2 This paper examines the consequences of educational uncertainty using a structural model in which schooling decisions are sequential and academic ability is learned through grades. Since psychic schooling costs depend on ability, people refine their expectations of them over time. This set-up is analogous to Pindyck&apos;s (1993) model of &quot;technical&quot; cost uncertainty, where the cost of completing a long-term project is revealed only as in