Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies

Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE?=?60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2?=?62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov.     

Propranolol for hemangiomas

Objective

Hemangiomas are the most common benign soft tissue tumors occurring in 5–10 % of children at around the age of 1 year and of them 10 % are associated with significant morbidity and entail medical attention. In this study, efficacy and adverse effects of the drug propranolol were observed on hemangiomas.

Methods

Oral propranolol was given to 36 children at a dose of 3 mg/kg/day in three divided doses. Blood pressure and heart rate were recorded during the first 3 h of treatment. Treatment was continued at home and the children were re-evaluated at monthly interval. Photographs were taken in pre- and post-treatment phages and changes of hemangiomas were measured with visual analog scale.

Results

Immediate effects on color and growth were noted in all cases that were especially dramatic in cases of extensive lesions. Clinical evidence of regression was seen within 30 days in all cases and completely regressed within 7 months. Mean duration of treatment was 4.1 months.

Conclusion

Propranolol had a rapid stabilizing effect leading to early regression of hemangiomas when administered orally at a dose of 3 mg/kg/day with good quality safety profile.     

Revisiting potential druggable targets against SARS-CoV-2 and repurposing therapeutics under preclinical study and clinical trials: A comprehensive review

Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the most contagious diseases in human history that has already affected millions of lives worldwide. To date, no vaccines or effective therapeutics have been discovered yet that may successfully treat COVID-19 patients or contain the transmission of the virus. Scientific communities across the globe responded rapidly and have been working relentlessly to develop drugs and vaccines, which may require considerable time. In this uncertainty, repurposing the existing antiviral drugs could be the best strategy to speed up the discovery of effective therapeutics against SARS-CoV-2. Moreover, drug repurposing may leave some vital information on druggable targets that could be capitalized in target-based drug discovery. Information on possible drug targets and the progress on therapeutic and vaccine development also needs to be updated. In this review, we revisited the druggable targets that may hold promise in the development of the anti-SARS-CoV-2 agent. Progresses on the development of potential therapeutics and vaccines that are under the preclinical studies and clinical trials have been highlighted. We anticipate that this review will provide valuable information that would help to accelerate the development of therapeutics and vaccines against SARS-CoV-2 infection.     

Simulation of Electrical and Thermal Properties of Granite under the Application of Electrical Pulses Using Equivalent Circuit Models

Since energy efficiency in comminution of ores is as small as 1% using a mechanical crushing process, it is highly demanded to improve its efficiency. Using electrical impulses to selectively liberate valuable minerals from ores can be a solution of this problem. In this work, we developed a simulation method using equivalent circuits of granite to better understand the crushing process with high-voltage (HV) electrical pulses. From our simulation works, we calculated the electric field distributions in granite when an electrical pulse was applied. We also calculated other associated electrical phenomena such as produced heat and temperature changes from the simulation results. A decrease in the electric field was observed in the plagioclase with high electrical conductivity and void space. This suggests that the void volume in each mineral is important in calculating the electrical properties. Our equivalent circuit models considering both the electrical conductivity and dielectric constant of a granite can more accurately represent the electrical properties of granite under HV electric pulse application. These results will help us better understand the liberation of minerals from granite by electric pulse application.     

Mcl-1 regulates the survival of adult neural precursor cells

Since the discovery of neural precursor cells (NPCs) in the adult mammalian brain, there has been a lot of excitement surrounding the potential for regeneration in the adult brain. For instance, many studies have shown that a significant number of NPCs will migrate to a site of injury and differentiate into all of the neural lineages. However, one of the main challenges affecting endogenous neural regeneration is that many of the NPCs that migrate to the injury site ultimately undergo apoptosis. Therefore, we sought to determine whether myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 protein, would promote the survival of adult NPCs by impeding apoptosis. To do this, we first confirmed that Mcl-1 is endogenously expressed within the adult NPC population using BrdU labeling assays. Next, we conditionally deleted Mcl-1 in adult NPCs using cre/lox technology and expressed Cre from the NPC-specific promoter Nestin. In vitro, cells that had Mcl-1 conditionally deleted had a 2-fold increase in apoptosis when compared to controls. In vivo, we used electroporation to conditionally delete Mcl-1 in adult NPCs and assessed apoptosis at 72h. after electroporation. As in our in vitro results, there was a 2-fold increase in apoptosis when Mcl-1 was conditionally deleted. Finally, we found that Mcl-1 over-expression reduced the endogenous rate of adult NPC apoptosis 2-fold in vitro. Collectively, these results demonstrate that Mcl-1 is crucial for the survival of adult NPCs and may be a promising target for future neural regeneration therapies.