Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

HIV and Sexuality Stigma Reduction Through Engagement in Online Forums: Results from the HealthMPowerment Intervention.

HIV and sexuality stigma impede HIV prevention and care efforts. HealthMpowerment.org (HMP) is an interactive mobile phone- and web-based HIV prevention and care intervention for young Black men who have sex with men (YBMSM; ages 18-30) in the United States. HMP included three forums where participants could share their experiences. In this study, we explored whether engaging in stigma-related discussions was associated with changes in YBMSM's stigma-related scores throughout the trial. YBMSM (ages 18-30; N = 238) participating in HMP completed surveys at baseline, and 3 and 6 month follow-ups that included a series of scales focused on HIV and sexuality (internalized homophobia; sexual prejudice) stigma. Sixty-two participants contributed to the forums (1497 posts). We coded instances where YBMSM's conversations were stigma related (915 posts, 61.1%), including discussions of anticipated (74/915, 8.1%), experienced (125/915, 13.7%), internalized (410/915, 44.8%), and/or challenged (639/915, 69.8%) stigma regarding sexuality and HIV. Using a mixed methods approach, we examined whether changes in YBMSM's stigma scores were associated with stigma-related discussions within the forum. We controlled for age, HIV status, income, and educational attainment in these multivariable models. YBMSM who discussed experiencing HIV stigma in the forums reported decreases in perceived HIV stigma over time (b = - 0.37, p ≤ 0.05). YBMSM whose forum posts indicated anticipated HIV stigma reported increases in HIV stigma over time (b = 0.46, p ≤ 0.01). Participants who challenged sexuality-related stigma in forums had lower internalized homophobia (b = - 0.68, p ≤ 0.01) at baseline. YBMSM whose discussions focused on experiencing sexuality-related stigma reported increases in internalized homophobia (b = 0.39, p ≤ 0.01) and sexual prejudice (b = 0.87, p ≤ 0.05) over time. Developing strategies to combat stigma remains a key priority. HMP created an online space where YBMSM could discuss HIV and sexuality stigma. Although a limited number of HMP participants authored the majority of these forum discussions, the discussions were associated with changes in the sample's stigma scores over time. Online interventions (e.g., social media, apps) should consider the inclusion of forums to address stigma and test the efficacy of forums to improve YBMSM's HIV prevention and care continuum outcomes.

The potential of ki67 and p53 assessment in development of individualized targeted therapy in breast cancer patients.

INTRODUCTION: Despite the improvement of diagnostic methods and chemotherapeutic regimens in breast cancer, overall 5-year survival significantly depends on the stage of the disease. Over expression of tumor suppressor gene p53 and the marker for cellular proliferation Ki67 in breast cancer may have prognostic significance. METHODS: We evaluated 675 patients diagnosed with breast cancer at UF Health Jacksonville between January 2000 and June 2007 with up to 5-year follow up. The aim of the study was to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 may predict outcome, the 'hazard' of dying. Cox's proportional hazards models were used to control for age (< 50 vs. ≥ 50), race (white vs. other), lymph node group (negative vs. positive), ER (estrogen receptor) group (negative vs. positive), PR (progesterone receptor) group (negative vs. positive), and tumor type. RESULTS: When only p53 was considered in the model, the hazard of dying was significantly higher for p53 positive compared to p53 negative (HR = 1.32, 95% CI 1.02, 1.70, p = 0.036). When only ki67 was considered in the model, the hazard of dying was significantly higher for ki67 positive compared to ki67 negative (Hazard ratio = 1.64, 95% CI 1.08, 2.49, p = 0.021). Neither of the two markers, nor their interaction was significant when all variables were considered in the model. DISCUSSION: This study confirms the expression of p53 and Ki67 as strong individual indicators of patient outcome. However, when controlling for the other variables, the two markers are not independent predictors. Future studies that will include these markers might help design targeted therapy.

Gas chromatography for in situ analysis of a cometary nucleus V. Study of capillary columns' robustness submitted to long-term reduced environmental pressure conditions.

With the European Space Agency's Rosetta space mission to comet 67P/Churyumov-Gerasimenko, a gas chromatograph, part of the COmetary Sampling And Composition (COSAC) experiment, travelled for about 10 years in the interplanetary medium before operating at the surface of the cometary nucleus in November 2014. During its journey in space, the instrument was exposed to the constraining conditions of the interplanetary medium, including reduced environmental pressures. In order to estimate the potential influence of this severe condition on the chromatographic capillary columns, their stationary phase and the subsequent separation capability, a set of flight spare columns were kept under reduced environmental pressure in the laboratory for the same duration as the probe sent to the comet. The columns' analytical performances were evaluated recently and compared to the original ones obtained just before the launch of the Rosetta probe. The results presented here show that the chromatographic performances of the spare chromatographic columns were not altered in time. From this result, it can be expected that the flight instrument will perform nominally for the analysis of the first cometary nucleus sample to be collected ever, and that the preparation of the interpretation of the data to be taken at the cometary surface nucleus can be done through calibration of these spare columns, and other spare components of the instrument.

Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.

Loss of transforming growth factor-beta receptor III (TbetaRIII) correlates with loss of transforming growth factor-beta (TGF-beta) responsiveness and suggests a role for dysregulated TGF-beta signaling in clear cell renal cell carcinoma (ccRCC) progression and metastasis. Here we identify that for all stages of ccRCC TbetaRIII expression is downregulated in patient-matched tissue samples and cell lines. We find that this loss of expression is not due to methylation of the gene and we define GATA3 as the first transcriptional factor to positively regulate TbetaRIII expression in human cells. We localize GATA3's binding to a 10-bp region of the TbetaRIII proximal promoter. We demonstrate that GATA3 mRNA is downregulated in all stages, of ccRCC, mechanistically show that GATA3 is methylated in ccRCC patient tumor tissues as well as cell lines, and that inhibiting GATA3 expression in normal renal epithelial cells downregulates TbetaRIII mRNA and protein expression. These data support a sequential model whereby loss of GATA3 expression through epigenetic silencing decreases TbetaRIII expression during ccRCC progression.

Evaluation of nutritional status in advanced metastatic cancer.

Consecutive cancer referrals to a palliative medicine program were evaluated to assess nutritional status using a standard protocol. The study included 352 patients (180 men, 172 women; median age 61 years, range 22-94 years). The most common diagnosis was lung cancer. All had metastatic disease, 139 with gastrointestinal involvement. The most common gastrointestinal symptoms were weight loss ( n=307), anorexia ( n=285), and early satiety ( n=243). Of those with any weight loss, 71% had lost >or0% of their pre-illness weight. The most common factor identified which might have contributed to weight loss was hypophagia ( n=275/307). Men had lost weight more often and to a greater extent than women. Triceps skinfold (TSF) was measured in 337: 51% had values that suggested severe fat deficiency. Upper mid-arm muscle area (AMA) was measured in 349: 30% had evidence of significant muscle mass reduction. The body mass index (BMI) was normal or increased in most patients. Calculated resting energy expenditure (REE) ( n=324) was high in 41%. C-reactive protein was elevated in 74% of those measured ( n=50). We conclude that: (1).most of this group of cancer patients referred to palliative medicine had severe weight loss; (2).there was a gender difference in the severity and type of weight loss; (3).males lost more weight overall and more muscle than females; (4).males with any degree of weight loss had a higher REE than females; (5).a significant correlation existed between the time from diagnosis to death and the severity of weight loss in the prior month; (6).BMI was normal in most patients, suggesting precancer diagnosis obesity; and (7).both TSF and AMA correlated well with body composition of both fat and protein as determined by bioelectrical impedance.

A phase II study of methylphenidate for depression in advanced cancer.

UNLABELLED: This study evaluated the use of methylphenidate for depression in advanced cancer DESIGN: Phase II open-label prospective study. ELIGIBILITY CRITERIA: No previous use of methylphenidate or current use of other antidepressants. EVALUATION: Depression and response to treatment were determined by asking the patient: "are you depressed?" Patients were assessed at baseline and at days 3, 5, and 7. TREATMENT: Starting dose was 5 mg at 8:00 a.m. and 12:00 noon. The dose was titrated for lack of response on any of the assessment days. RESPONSE CRITERIA: A negative response to the question: "are you depressed?" RESULTS: Some 41 patients were enrolled and 30 (15 men, 15 women) completed the study. Median age was 68 years (range: 30-90). Methylphenidate was stopped for six patients because of side effects and five were not evaluable; 21 responded to 10 mg/day on day 3; the other nine responded to 20 mg/day on day 5, 29 maintained their positive response through day 7. Anorexia, fatigue, concentration, and sedation also improved in some. All who completed the study had tolerable side effects, none of which caused treatment to stop. CONCLUSIONS: Methylphenidate is effective for depression in advanced cancer A starting dose of 10 mg in divided doses is effective in most patients. Dose escalation may be needed. Improvement occurs within three days. Close monitoring of side effects is recommended.

Dying at home: emergency medications for terminal symptoms.

This article discusses the use of a medication kit at home for terminal symptoms. This innovation has been in place for more than two years at the Hospice of the Cleveland Clinic. There is no previously published information on this innovation in the literature.

Assessment of delirium in advanced cancer: the use of the bedside confusion scale.

We conducted a prospective assessment of 50 consecutive admissions to an acute palliative medicine unit, using the bedside confusion scale (BSCS). Information including age, gender, diagnosis, and the presence or absence of brain metastasis was collected. Possible predisposing factors for delirium were recorded. Forty-one of 50 consecutive admissions were screened. There were 18 men and 23 women with a median age of 65 years (average: 60-75). The most common diagnoses among all were lung and breast cancer. Thirteen patients were delirious (BSCS score of > or = 2), 10 borderline (BSCS score = 1), and 21 normal (BSCS score = 0). Brain metastases and drugs appeared to be the most common predisposing factors of delirium. Forty percent of those that were delirious received haloperidol as symptomatic treatment. The BSCS is simple, portable, valid, quick, and easy to use by any medical team member. Delirium is common in hospitalized patients with advanced cancer.

The terminally ill Muslim: death and dying from the Muslim perspective.

Islam holds life as sacred and belonging to God and that all creatures will die one day. Suicide is forbidden. Muslims believe death is only a transition between two different lives. The terminally ill Muslim desires to perform five ritual requirements. Do not resuscitate (DNR) orders are acceptable. A deceased Muslim must always be buried after being ritually washed and wrapped. There are different Muslim schools of thought, but they are united regarding their views on death and dying.

The business of palliative medicine: management metrics for an acute-care inpatient unit.

For any palliative medicine inpatient unit to be economically viable, certain management metrics need to be followed. Palliative medicine can provide both a compassionate and economical service within the current acute inpatient hospital environment. In this article, we will review the administrative and financial factors we have identified that influence the business of acute palliative medicine.

Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study.

Psychostimulants such as methylphenidate are used for fatigue in cancer patients. We report a prospective, open-label, pilot study of the successful use of methylphenidate to treat fatigue in nine of 11 consecutive patients with advanced cancer. Seven had received radiation or chemotherapy, a median of three weeks (range from one to 30 weeks) prior to methylphenidate. A rapid onset of benefit was noted, even in the presence of mild anemia. Sedation and pain also improved in some. Only one patient had side effects severe enough to stop the medication.

Juvenile male sexual offenders: the quality of motivation system of assessment and treatment issues.

A group of juvenile male sexual offenders (n=100) completed the Quality of Motivation Questionnaire (QMQ) upon entry into a residential treatment facility. The concepts of Quality of Motivation (QM) Theory are presented to explain the QMQ scores. The scores include Disclosure Level, Sources of Motivation, Life Style Characteristics and Power. The results indicate abnormal motivation scores in the area of Disclosure Resistance, Depression, Primary and Learned Sources of Motivation, and all of the Maladaptive Skills Scores. Recommendations of treatment issues for therapists are prioritized according to QM Theory and presented in a treatment plan format called the Personal Development Plan (PDP). Implications for further research with the QMQ include outcome measurement of changes and comparison with non-offender groups.

Symptom control in the pregnant cancer patient.

While much attention has been devoted to cytotoxic drugs and radiation therapy in the pregnant cancer patient, the drugs used for management of symptoms and complications related to cancer during pregnancy have been overlooked. There is substantial overlap between the symptoms of cancer and cancer management and the symptoms related to pregnancy. The mainstay of symptom management is drug therapy and the potential for a drug to be embryotoxic or teratogenic depends on when it is given. In general, drugs not proven safe in pregnancy should be withheld, especially during the first trimester. The few drugs that have been proven to be teratogenic are alcohol, thalidomide, the folic acid antagonists (which includes methotrexate), diethylstilbestrol, and the vitamin A isomers, but there is a good deal of uncertainty about many other therapeutic agents. Placental transport of drugs from mother to fetus must be taken into consideration from the fifth week of gestation to parturition. Although the first trimester is the time of most organ development in the fetus, the brain continues to develop throughout pregnancy and may be damaged later in pregnancy, resulting in diminished intelligence or behavioral problems. This review will focus on the treatment of the most common symptoms of cancer in a pregnant patient and the potential for fetal damage.

Communication in advanced disease.

Communication between physician, patient, and family becomes intense and fraught with problems in the setting of advanced disease. Protocols for end-of-life communication have been developed by various authors, but they have focused primarily on delivery of "bad news" in an individual encounter. This article addresses the need for ongoing conversation throughout the progression from life-prolonging treatment to hospice care. A case study illustrates the utility of this approach.

Development of a clinical fellowship program in palliative medicine.

There has been growing interest in the United States in postgraduate training in palliative medicine. In order for this to proceed in an organized fashion, educational standards need to be developed. We must define what our knowledge base is and what we require of a specialty-trained individual. This article reports the development of the first fellowship program in the United States, with the goal of encouraging further discussion and ultimately obtaining specialty recognition.

Common complications of advanced cancer.

Complications due to cancer and its treatment are common and increase in incidence and severity as the disease progresses. Central nervous system complications affect 15% to 20% of patients, and up to 75% have bone metastases at some point during the disease process. Endocrine abnormalities include hypercalcemia, adrenal insufficiency, and inappropriate antidiuretic syndrome. Hematologic disorders, malignant effusions, and gastrointestinal (GI) problems may cause significant morbidity.

[Leukocyte adhesion on a fibrinogen-coated surface under static conditions: experimentation and creation of a model]. / Adhésion des leucocytes sur une surface recouverte de fibrinogène en conditions statiques: expíence et modélisation]

The adhesion of polymorphonuclear leukocytes (PMNs) on the vascular endothelium is a complex process that occurs during different biological and pathological events and involves numerous molecules. The adhesion cascade is induced after PMN stimulation by various molecular or cellular signals. Fibrinogen is one of the substrates for CD11b/CD18 B2-integrins expressed at the PMN surface; fibrinogen-neutrophil binding is induced by inflammatory reactions. In order to understand this process, we have carried out studies on the basis of preliminary experiments on red blood cells and synthetic particles. The modelization of quiescent PMNs adhesion on a fibrinogen substrate was investigated with a sedimentation cell chamber. Two different physiological conditions were tested: the activated state of PMN by a synthetic pro-inflammatory activator (FMLP). The activated state of PMNs was both quantified by flow cytometry and controlled by fluorescence microscopy. The results suggest that quiescent neutrophils deposit in accordance with the ballistic deposition model. This random adsorption model differs from random sequential adsorption (RSA) in that the cells arriving at the surface are able to roll along cells previously adsorbed introducing the notion of gravitational attraction of cells. The preliminary results obtained with stimulated PMN do not allow to choose between one of this two deposition models. Nevertheless, the qualitative and quantitative effects of FMLP on neutrophils were demonstrated by modifications of adhesion molecules expression.