An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.

Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.

Systematic review of latent tuberculosis infection research to inform programmatic management in Ireland.

The World Health Organisation (WHO) End Tuberculosis (TB) Strategy and the WHO Framework Towards Tuberculosis Elimination in Low Incidence Countries state that latent tuberculosis infection (LTBI) screening and treatment in selected high-risk groups is a priority action to eliminate TB. The European Centre for Disease Prevention and Control (ECDC) advises that this should be done through high-quality programmatic management, which they describe as having six key components. The research aim was to systematically review the literature to identify what is known about the epidemiology of LTBI and the uptake and completion of LTBI screening and treatment in Ireland to inform the programmatic management of LTBI nationally. A systematic literature review was performed according to a review protocol and reported in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Twenty-eight studies were eligible for inclusion and described LTBI screening or treatment performed in one of five contexts, pre-biologic or other immunosuppression screening, people living with HIV, TB case contacts, other vulnerable populations, or healthcare workers. The risk of bias across studies with regard to prevalence of LTBI was generally high. One study reported a complete cascade of LTBI care from screening initiation to treatment completion. This systematic review has described what published research there is on the epidemiology and cascade of LTBI care in Ireland and identified knowledge gaps. A strategy for addressing these knowledge gaps has been proposed.

Ultrasound Image Classification of Thyroid Nodules Using Machine Learning Techniques.

Background and Objectives: Thyroid nodules are lumps of solid or liquid-filled tumors that form inside the thyroid gland, which can be malignant or benign. Our aim was to test whether the described features of the Thyroid Imaging Reporting and Data System (TI-RADS) could improve radiologists' decision making when integrated into a computer system. In this study, we developed a computer-aided diagnosis system integrated into multiple-instance learning (MIL) that would focus on benign-malignant classification. Data were available from the Universidad Nacional de Colombia. Materials and Methods: There were 99 cases (33 Benign and 66 malignant). In this study, the median filter and image binarization were used for image pre-processing and segmentation. The grey level co-occurrence matrix (GLCM) was used to extract seven ultrasound image features. These data were divided into 87% training and 13% validation sets. We compared the support vector machine (SVM) and artificial neural network (ANN) classification algorithms based on their accuracy score, sensitivity, and specificity. The outcome measure was whether the thyroid nodule was benign or malignant. We also developed a graphic user interface (GUI) to display the image features that would help radiologists with decision making. Results: ANN and SVM achieved an accuracy of 75% and 96% respectively. SVM outperformed all the other models on all performance metrics, achieving higher accuracy, sensitivity, and specificity score. Conclusions: Our study suggests promising results from MIL in thyroid cancer detection. Further testing with external data is required before our classification model can be employed in practice.

Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF.

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors.

A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF.

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer-small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF-TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein-protein interactions.

Evolving chronic disease management in HIV care in an era of improved long-term survival.

BACKGROUND: Adults ageing with HIV and on antiretroviral therapy have a greater burden of chronic diseases compared with adults without HIV as reported by Althoff et al. (Curr Opin HIV AIDS 11:527-36, 2016). Therefore, it is important in this clinically stable HIV+ population to monitor and evaluate their risk of chronic kidney disease and intervene when appropriate. The European AIDS Clinical Society (EACS) advise that yearly screening for CKD with eGFR calculation and spot urine protein measurements should be performed (European AIDS Clinical Society Guidelines 2018). The Centre for Excellence for Health, Immunity and Infection (CHIP) have created a validated study calculator to estimate a patient's risk for CKD as reported by Mocroft et al. (PLoS Med 12(3):e1001809, 2015). AIMS: (1) To determine the proportion of patients who had a urinary protein-creatinine ratio checked in 2018; (2) To calculate an eGFR for each patient in our cohort utilizing the Modification of Diet in Renal Disease (MDRD) calculation; (3) To calculate the full chronic kidney disease score in our cohort of patients. METHODS: We undertook a retrospective chart review of 80 HIV-positive patients who attended our weekly clinic in Beaumont Hospital, Dublin, Ireland. RESULTS: In our subset of 31 patients who had all the requirements to estimate their eGFR and full chronic kidney disease risk score, 100% (31/31) of eGFRs calculated were reported as > 90 mL/min/1.73 m2. The median eGFR was 215 mL/min/1.73 m2 (range 95.69-418.08 mL/min/1.73 m2). The average CHIP full chronic kidney disease 5-year risk score for patients developing CKD was 0.91% (95% CI 0.60-1.21%). One patient was identified with a risk score of 5.05% as they had suffered an acute coronary syndrome event in the past. CONCLUSION: Although this audit was small and with limitations, it highlights the importance of collecting relevant and accurate patient data annually to estimate and mitigate the risk of chronic kidney disease in patients with HIV.

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer.

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions.

Mortality Among Unsheltered Homeless Adults in Boston, Massachusetts, 2000-2009.

Importance: Previous studies have shown high mortality rates among homeless people in general, but little is known about the patterns of mortality among "rough sleepers," the subgroup of unsheltered urban homeless people who avoid emergency shelters and primarily sleep outside. Objectives: To assess the mortality rates and causes of death for a cohort of unsheltered homeless adults from Boston, Massachusetts. Design, Setting, and Participants: A 10-year prospective cohort study (2000-2009) of 445 unsheltered homeless adults in Boston, Massachusetts, who were seen during daytime street and overnight van clinical visits performed by the Boston Health Care for the Homeless Program's Street Team during 2000. Data used to describe the unsheltered homeless cohort and to document causes of death were gathered from clinical encounters, medical records, the National Death Index, and the Massachusetts Department of Public Health death occurrence files. The study data set was linked to the death occurrence files by using a probabilistic record linkage program to confirm the deaths. Data analysis was performed from May 1, 2015, to September 6, 2016. Exposure: Being unsheltered in an urban setting. Main Outcomes and Measures: Age-standardized all-cause and cause-specific mortality rates and age-stratified incident rate ratios that were calculated for the unsheltered adult cohort using 2 comparison groups: the nonhomeless Massachusetts adult population and an adult homeless cohort from Boston who slept primarily in shelters. Results: Of 445 unsheltered adults in the study cohort, the mean (SD) age at enrollment was 44 (11.4) years, 299 participants (67.2%) were non-Hispanic white, and 72.4% were men. Among the 134 individuals who died, the mean (SD) age at death was 53 (11.4) years. The all-cause mortality rate for the unsheltered cohort was almost 10 times higher than that of the Massachusetts population (standardized mortality rate, 9.8; 95% CI, 8.2-11.5) and nearly 3 times higher than that of the adult homeless cohort (standardized mortality rate, 2.7; 95% CI, 2.3-3.2). Non-Hispanic black individuals had more than half the rate of death compared with non-Hispanic white individuals, with a rate ratio of 0.4 (95% CI, 0.2-0.7; P < .001). The most common causes of death were noncommunicable diseases (eg, cancer and heart disease), alcohol use disorder, and chronic liver disease. Conclusions and Relevance: Mortality rates for unsheltered homeless adults in this study were higher than those for the Massachusetts adult population and a sheltered adult homeless cohort with equivalent services. This study suggests that this distinct subpopulation of homeless people merits special attention to meet their unique clinical and psychosocial needs.

Tobacco-, alcohol-, and drug-attributable deaths and their contribution to mortality disparities in a cohort of homeless adults in Boston.

OBJECTIVES: We quantified tobacco-, alcohol-, and drug-attributable deaths and their contribution to mortality disparities among homeless adults. METHODS: We ascertained causes of death among 28 033 adults seen at the Boston Health Care for the Homeless Program in 2003 to 2008. We calculated population-attributable fractions to estimate the proportion of deaths attributable to tobacco, alcohol, or drug use. We compared attributable mortality rates with those for Massachusetts adults using rate ratios and differences. RESULTS: Of 1302 deaths, 236 were tobacco-attributable, 215 were alcohol-attributable, and 286 were drug-attributable. Fifty-two percent of deaths were attributable to any of these substances. In comparison with Massachusetts adults, tobacco-attributable mortality rates were 3 to 5 times higher, alcohol-attributable mortality rates were 6 to 10 times higher, and drug-attributable mortality rates were 8 to 17 times higher. Disparities in substance-attributable deaths accounted for 57% of the all-cause mortality gap between the homeless cohort and Massachusetts adults. CONCLUSIONS: In this clinic-based cohort of homeless adults, over half of all deaths were substance-attributable, but this did not fully explain the mortality disparity with the general population. Interventions should address both addiction and non-addiction sources of excess mortality.

Mortality among homeless adults in Boston: shifts in causes of death over a 15-year period.

BACKGROUND: Homeless persons experience excess mortality, but US-based studies on this topic are outdated or lack information about causes of death. To our knowledge, no studies have examined shifts in causes of death for this population over time. METHODS: We assessed all-cause and cause-specific mortality rates in a cohort of 28 033 adults 18 years or older who were seen at Boston Health Care for the Homeless Program from January 1, 2003, through December 31, 2008. Deaths were identified through probabilistic linkage to the Massachusetts death occurrence files. We compared mortality rates in this cohort with rates in the 2003-2008 Massachusetts population and a 1988-1993 cohort of homeless adults in Boston using standardized rate ratios with 95% confidence intervals. RESULTS: A total of 1302 deaths occurred during 90 450 person-years of observation. Drug overdose (n = 219), cancer (n = 206), and heart disease (n = 203) were the major causes of death. Drug overdose accounted for one-third of deaths among adults younger than 45 years. Opioids were implicated in 81% of overdose deaths. Mortality rates were higher among whites than nonwhites. Compared with Massachusetts adults, mortality disparities were most pronounced among younger individuals, with rates about 9-fold higher in 25- to 44-year-olds and 4.5-fold higher in 45- to 64-year-olds. In comparison with 1988-1993 rates, reductions in deaths from human immunodeficiency virus (HIV) were offset by 3- and 2-fold increases in deaths owing to drug overdose and psychoactive substance use disorders, resulting in no significant difference in overall mortality. CONCLUSIONS: The all-cause mortality rate among homeless adults in Boston remains high and unchanged since 1988 to 1993 despite a major interim expansion in clinical services. Drug overdose has replaced HIV as the emerging epidemic. Interventions to reduce mortality in this population should include behavioral health integration into primary medical care, public health initiatives to prevent and reverse drug overdose, and social policy measures to end homelessness.

Estimated right ventricular systolic time intervals for the assessment of right ventricular function in acute respiratory distress syndrome.

Right ventricular (RV) systolic time intervals (STIs) have been shown to accurately reflect RV function in patients with acute respiratory distress syndrome (ARDS). The measurement of RVSTIs requires phonocardiography to define the time of RV end systole. If RV end-systolic pressure (RVESP) can be derived from peak pulmonary artery (PA) systolic pressure, then the time of RV end systole, and hence, RVSTIs can be deduced without phonocardiography. We tested this possibility. In 34 patients with ARDS, RVESP was determined on the PAP curve at RV end systole, which was defined by phonocardiography. The ratios of RVESP/peak PA systolic pressure were obtained in each patient, the mean of which was 0.90 +/- 0.006. With an application of this value, the estimated RVSTIs were determined in other groups of patients. Right ventricular end-systolic pressure was estimated from the peak PA systolic pressure by multiplying 0.9. Then the point of RV end systole was determined on the electrocardiographic tracing that coincided with the point of RVESP on the PAP curve by simultaneous display of electrocardiograph and PAP curve. Total electromechanical systole was measured from the onset of the QRS complex to the point of RV end systole on the electrocardiograph. The onset of RV ejection was defined by PAP curve. The validity of this estimated RVSTIs was tested by comparing with the measured RVSTIs. By Bland-Altman analysis, the mean difference in RVSTIs between the two methods was 0.007, and bias was 0.0036, suggesting close agreement. The estimated RVSTIs can be used to accurately assess RV function.

A vascular endothelial growth factor receptor-2 kinase inhibitor potentiates the activity of the conventional chemotherapeutic agents paclitaxel and doxorubicin in tumor xenograft models.

Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 microM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition, JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs doxorubicin and paclitaxel in xenograft models when administered orally in combination therapy. An orally available angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of cancer and preventing metastasis.

Proteases as drug targets.

The effective management of AIDS with HIV protease inhibitors, or the use of angiotensin-converting enzyme inhibitors to treat hypertension, indicates that proteases do make good drug targets. On the other hand, matrix metalloproteinase (MMP) inhibitors from several companies have failed in both cancer and rheumatoid arthritis clinical trials. Mindful of the MMP inhibitor experience, this chapter explores how tractable proteases are as drug targets from a chemistry perspective. It examines the recent success of other classes of drug for the treatment of rheumatoid arthritis, and highlights the need to consider where putative targets lie on pathophysiological pathways--regardless of what kind of therapeutic entity would be required to target them. With genome research yielding many possible new drug targets, it explores the likelihood of discovering proteolytic enzymes that are causally responsible for disease processes and that might therefore make better targets, especially if they lead to the development of drugs that can be administered orally. It also considers the impact that biologics are having on drug discovery, and in particular whether biologically derived therapeutics such as antibodies are likely to significantly alter the way we view proteases as targets and the methods used to discover therapeutic inhibitors.

The Kenneth B. Schwartz Center at Massachusetts General Hospital hematology-oncology department: hope for the homeless.

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient and support to caregivers and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum during which caregivers discuss a specific cancer patient, reflect on the important psychological issues faced by patients, their families, and their caregivers, and gain insight and support from their fellow staff members. A homeless man with head and neck cancer presents to the emergency room: a sad and familiar story. But this story is redeemed by his 35-year friendship with a priest, a man whose unconditional love and support became critical to the patient's care and treatment. The patient had lived for 30 years in homeless shelters, had problems with alcohol abuse, and was notoriously noncompliant with medical caregivers. He could not speak due to his disease, was illiterate with limited intellectual capacity, and had neither a job nor a family. Despite huge and apparently insurmountable problems for the patient, the oncology team was able to carve out a package of care, successfully communicate, and mobilize a support network to allow successful completion of chemoradiation therapy. The team developed a strong commitment to his care and an affectionate bond, which very positively affected all of those involved. We discuss issues of access to cancer care, and the special problems presented by homeless patients.