Bispecific antibody based therapeutics: Strengths and challenges

Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent. Approval of two BsAb and three check point blocking mAbs represent a paradigm shift in the use of antibody constructs. Since BsAbs can directly target immune cells to tumors, drug resistance and severe adverse effects are much reduced. The wave of next generation “bispecific or multispecific antibodies” has advanced multiple candidates into ongoing clinical trials. In this review, we focus on preclinical and clinical studies in hematological malignancies as well as discuss reasons for the limited success of BsAbs against solid tumors.     

Consequences of household air pollution on child survival: evidence from demographic and health surveys in 47 countries

Background: Over one-third of the world’s population is exposed to household air pollution (HAP) but the separate effects of cooking with solid fuel and kerosene on childhood mortality are unclear.Objectives: To evaluate the effects of both solid fuels and kerosene on neonatal (0-28 days) and child (29 days-59 months) mortality.Methods: We used Demographic and Health Surveys from 47 countries and calculated adjusted relative risks (aRR) using Poisson regression models.Results: The aRR of neonatal and child mortality in households exposed to solid fuels were 1.24 (95% CI: 1.14, 1.34) and 1.21 (95% CI: 1.12, 1.30), respectively, and the aRR for neonatal and child mortality in households exposed to kerosene were 1.34 (95% CI: 1.18, 1.52) and 1.12 (95% CI: 0.99, 1.27), controlling for individual, household, and country-level predictors of mortality.Conclusions: Kerosene should not be classified as a clean fuel. Neonates are at risk for mortality from exposure to solid fuels and kerosene.     

Resistant Hypertension

Hypertension affects 25 % of all adults worldwide and is a leading risk factor contributing to 62 % of all strokes and 49 % of all cases of heart disease, leading to an estimated 7.1 million deaths a year; equivalent to 13 % of total worldwide deaths. In spite of therapeutic advances, up to 30 % of hypertensive individuals fail to achieve goal blood pressure even with the use of three antihypertensive medications. Resistant hypertension (RH) is a common clinical problem faced by physicians and the incidence is increasing as the population becomes heavier and older. The diagnosis and treatment of RH, is often accompanied by other risk factors such as obesity, sleep apnea, diabetes and chronic kidney disease is important because of the associated increased end organ damage and the subsequent clinical and social impact. Pseudo resistance, lack of blood pressure control due to poor medication adherence or white coat hypertension must be excluded. A successful treatment of RH requires identification of contributing lifestyle factors and eliminating them including the use of multidrug therapy. A potential genetic causes of RH have not been well studied. African American (black) race and certain other ethnic groups are associated with higher prevalence of RH and also poor response to therapy. Studies on RH are limited, in part because of difficulties in enrolling large groups of patients and patient comorbidity, higher cardiovascular risk and other diseases, e.g. sleep apnea, diabetes and chronic kidney disease that can confound the interpretation of study results. This review provides an overview of RH, and its association with risk factors, various ethnic groups, diagnosis and treatment modalities of RH with special emphasis on the relations of the latter with race/ethnicity.     

Effects of resynchronization therapy on sympathetic activity in patients with depressed ejection fraction and intraventricular conduction delay due to ischemic or idiopathic dilated cardiomyopathy

This study assesses the effect of biventricular pacing on sympathetic nerve activity (SNA) in patients with depressed ejection fraction and intraventricular conduction delay (IVCD). Biventricular pacing has been shown to result in hemodynamic improvement in patients with depressed ejection fraction and IVCD. The effect of biventricular pacing on SNA, however, remains unclear. A total of 15 men with a mean ejection fraction of 25 +/- 4% were enrolled. Arterial pressure, central venous pressure and SNA were recorded during 3 minutes of right atrial (RA) pacing and RA-biventricular pacing. Pacing was performed at a rate 5 to 10 beats faster than sinus rhythm, with an atrioventricular interval equal to 100 ms during RA-biventricular pacing. RA-biventricular pacing resulted in greater arterial pressures (p <0.05) than RA pacing (146 +/- 15/83 +/- 11 vs 141 +/- 15/80 +/- 10 mm Hg). There were no differences in central venous pressures between the 2 pacing modes (p = 0.76). SNA was significantly less during RA-biventricular pacing (727 +/- 242 U) than during RA pacing (833 +/- 332 U) (p <0.02). Furthermore, there was a positive correlation between baseline QRS duration and the decrease in SNA noted with RA-biventricular pacing (r = 0.58, p = 0.03). Biventricular pacing results in improved hemodynamics and a decrease in SNA compared with intrinsic conduction in patients with left ventricular dysfunction and IVCD. If the current findings are also present with chronic biventricular pacing, then this form of therapy may have a positive impact on mortality.     

Pubertal augmentation in juvenile rhesus monkey testosterone production induced by invariant gonadotropin stimulation is inhibited by estrogen

CONTEXT: Experimental and epidemiological studies have indicated the adverse impact of changing estrogen [17beta-estradiol (E2)] milieu or of endocrine disrupters on testis development and function. OBJECTIVE: This study examines the direct impact of elevated E2 levels on gonadotropin-induced pubertal testis development and function in the primate. DESIGN: Juvenile monkeys, which have characteristically little endogenous gonadotropin secretion, were treated with pulsatile infusions of recombinant monkey (rm) FSH (rmFSH) and LH (rmLH) in the presence (experiment 1, approximately 100 pg/ml for about 15-20 wk; experiment 2, approximately 400 pg/ml for about 5 wk) or absence (control group) of elevated E2 in the circulation. Changes in circulating concentrations of E2, gonadotropins, testosterone (T), and inhibin B were monitored throughout the study. The number of Leydig cells per testis was determined after immunohistochemical staining for 3-beta hydroxysteroid dehydrogenase in experiment 2. RESULTS: Exogenous gonadotropin treatment produced physiological, episodic, and similar circulating concentrations of FSH and LH in both groups. Exposure to approximately 100 pg/ml of E2 appeared to blunt testicular T production. Exposure to approximately 400 pg/ml of E2 led to a significant (approximately 75%) inhibition of T production together with a marked (approximately 40%) decrease in Leydig cell numbers per testis and a notable inhibition in the growth of the testis. In contrast, E2 exposure had little effect on inhibin B production. CONCLUSIONS: The direct testicular impact of elevated E2 is on Leydig cell number, T production, and testicular growth, but not on inhibin B production. This experimental paradigm provides a powerful primate model for the examination of the direct impact of E2 or other endocrine disrupters on pubertal testicular development.