Toxic epidermal necrolysis: an update

Toxic epidermal necrolysis (TEN), also known as Lyell''s syndrome, is a rare, life-threatening dermatological condition that is usually induced by reaction to medications. It is characterized by the detachment of the top layer of skin (the epidermis) from the lower layers of the skin (the dermis) all over the body. There is broad agreement in medical literature that TEN can be considered a more severe form of Stevens Johnson syndrome, and debate whether it falls on a spectrum of disease that includes erythema multiforme. Some authors consider that there is an overlap between the two syndromes (usually between 10% and 30% of skin detachment). This article deals with history, epidemiology, diagnosis, pathophysiology treatment and management of TEN.     

<Emphasis Type="Italic">In Vitro</Emphasis>, Time-Resolved PIV Comparison of the Effect of Stent Design on Wall Shear Stress

The effect of stent design on wall shear stress (WSS) and oscillatory shear index (OSI) was studied in vitro using time-resolved digital particle image velocimetry (DPIV). Four drug-eluting stents [XIENCE V^® (Abbott Vascular), TAXUS^® Liberté^® (Boston Scientific), Endeavor^® (Medtronic), and Cypher^® (J&;J Cordis)] and a bare-metal stent [VISION^® (Abbott Vascular)] were implanted into compliant vessel models, and the flow was measured in physiologically accurate coronary conditions featuring reversal and realistic offsets between pressure and flowrate. DPIV measurements were made at three locations under two different flow rates (resting: Re = 160, f = 70 bpm and exercise: Re = 300, f = 120 bpm). It was observed that design substantially affected the WSS experienced at the vessel walls. Averaged values between struts ranged from 2.05 dynes/cm² (Cypher^®) to 8.52 dynes/cm² (XIENCE V^®) in resting conditions, and from 3.72 dynes/cm² (Cypher^®) to 14.66 dynes/cm² (VISION^®) for the exercise state. Within the stent, the WSS dropped and the OSI increased immediately distal to each strut. In addition, an inverse correlation between average WSS and OSI existed. Comparisons with recently published results from animal studies show strong correlation between the measured WSS and observed endothelial cell coverage. These results suggest the importance of stent design on the WSS experienced by endothelial cells in coronary arteries.     

<Emphasis Type="Italic">IL-10</Emphasis> −1082 G>A: a risk for prostate cancer but may be protective against progression of prostate cancer in North Indian cohort

Background  Chronic intraprostatic inflammation is suspected to play a major role in the pathogenesis of prostate cancer (PCa). Polymorphisms in interleukin-10 (IL-10), a key anti-inflammatory cytokine gene can influence immune response and immune evasion of tumor cells. Its role as an anti-metastatic molecule is also well documented. Methods  Gene promoter polymorphisms in IL-10 (−1082 G>A and −819 C>T) was analyzed in 159 PCa patients and 259 healthy controls to investigate their potential association with susceptibility for PCa. Results  Our results indicated that the heterozygous (GA) and homozygous mutant (AA) genotypes of IL-10 −1082 to be more prevalent among PCa patients in comparison to controls (GA: OR − 2.8, p = 0.011; AA: OR − 2.3, p = 0.037). More patients (92.5%) than controls (82.7%) were positive for the A allele (GA + AA: OR − 2.6, p = 0.015). We observed lower frequency of T(−819)-G(−1082) haplotype in patients without bone metastasis (4.4%, OR − 0.30, p = 0.019) in comparison to PCa patients with bone metastasis (12.6%). Conclusion  Our results support the emerging hypothesis that genetically determined immune activity may play a role in the pathophysiology of PCa. Our findings of high producer of IL-10 −1082 variants suggest initiation of PCa. Future studies in large cohort of different ethnicity PCa groups are warranted to establish definite associations with other cytokine gene polymorphisms.     

GSTM1, GSTM3 and GSTT1 Gene Variants and Risk of Benign Prostate Hyperplasia in North India

Glutathione S-transferases (GSTs) play an important role in detoxification of various toxic compounds like carcinogens in cigarette smoke and tobacco by conjugating to toxic compounds and inactivating their hazardous effect. Variation in Glutathione S-Transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in cancer susceptibility due to various carcinogens. We therefore, investigated association of GSTM1, GSTM3 and GSTT1 variants with susceptibility to benign prostate hyperplasia (BPH) and cigarette, tobacco chewing and alcohol consumption as confounding factors in 141 BPH and 184 healthy controls. Results showed increased risk for BPH susceptibility in patients with GSTM1 null genotype (OR-2.03, p = 0.013) and smoking (OR-3.12, p = 0.028), tobacco chewing (OR-2.54, p = 0.039) and alcohol habits (OR-3.39, p = 0.010). Null genotype of GSTM1 with cigarette, tobacco and alcohol habits predisposed increased risk for BPH.     

Population Pharmacokinetic Analysis of Rivipansel in Healthy Subjects and Subjects with Sickle Cell Disease

BackgroundSickle cell disease is an inherited blood disorder with reduced blood-carrying capacity. It is associated with a tendency to form microclots in blood vessels, leading to painful episodes known as a vaso-occlusive crisis. Rivipansel is a pan-selectin inhibitor being studied for the treatment of a vaso-occlusive crisis in patients with sickle cell disease.MethodsA population pharmacokinetic model of rivipansel plasma and urine concentrations was constructed using a two-compartment model and data from nine different clinical studies. Creatinine clearance was calculated using the Schwartz formula for children and the Chronic Kidney Disease Epidemiology Collaboration formula for adults. Urine volume and concentration of the study drug in urine from subjects in five clinical studies were used to estimate renal and nonrenal clearance.ResultsRivipansel drug concentrations were well described by the model. The post hoc estimates of average steady-state concentrations were predicted to be similar for the adult and pediatric cohorts of the pivotal phase III study. Parameter estimates showed almost exclusively renal excretion of rivipansel, which is consistent with the known properties of the drug.ConclusionsThe pharmacokinetics of rivipansel was well characterized by a two-compartment population pharmacokinetic model. Our results illustrate the important role of simulations in optimizing a potential drug dosing regimen for patients with sickle cell disease and progressive renal impairment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-021-00346-3.     

Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis

Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein‐1 (ZO‐1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.