Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

Hepsin, a transmembrane serine protease abundant in renal endothelial cells, is a promising therapeutic target against several cancers, particularly prostate cancer. It is involved in the release and polymerization of uromodulin in the urine, which plays a role in kidney stone formation. In this work, we design new potential hepsin inhibitors for high activity, improved specificity towards hepsin, and promising ADMET properties. The ligands were developed through a novel hierarchical pipeline. This pipeline explicitly accounts for off-target binding to the related serine proteases matriptase and HGFA (human hepatocyte growth factor activator). We completed the pipeline incorporating ADMET properties of the candidate inhibitors into custom multi-objective optimization functions. The ligands designed show excellent prospects for targeting hepsin the blood stream and the urine and thus enable key experimental studies. The computational pipeline proposed is remarkably cost-efficient and can be easily adapted for designing inhibitors against new drug targets.

Effect of Fermented Papaya Preparation on Doxorubicin Induced Myocardial Toxicity.

Many antitumor drugs cause “on treatment” cardio toxicity or introduce a measurable risk of delayed cardiovascular events. The problem of anthracycline-induced cardio toxicity has been around for some 40 years. Doxorubicin (DOX) is an anthracycline derivative used as an anticancer agent. However, its clinical use is limited due to its severe cardio toxic manifestations. The present aim is to evaluate the protective role of Fermented Papaya Preparation (FPP) in combating doxorubicin induced cardio-toxicity/oxidative stress. Female Wistar rats were pretreated with FPP (100 mg/kgbw or 250 mg/kgbw) or saline daily for 28 consecutive days followed by doxorubicin (10 mg/kgbw) induction for next 2 days. Results indicated that pretreatment with FPP significantly decreased serum levels of CK-MB and LDH cardiac marker enzymes. Further, FPP supplementation significantly increased SOD, GSH-Px and GSH (p<0.05) while decreased Malondialdehyes and Catalase levels in heart. Histological observations demonstrated that FPP pretreatment attenuated DOX induced myofribillar derangement and vascular congestion in heart tissue. Thus our results suggest that FPP exhibits significant preclinical potential in combating DOX induced oxidative stress.

Langerhans Cell Histiocytosis Presenting with Hypopigmented Macules.

Langerhans cell histiocytosis (LCH) is a complex disease characterized by proliferation of the Langerhans cells. The clinical course is variable and ranges from a solitary lytic bone lesion or skin lesion with complete remission to a multisystem disorder with possible lethal outcome. The diagnosis is suspected by clinical signs and symptoms and radiological features commonly in craniofacial bones and skin lesions. Diagnosis is confirmed by biopsy and immunohistochemical studies. We present case of a 8 year old child presenting with proptosis, diabetes insipidus and hypopigmented macules on chest and back showing bilateral distribution which is a rare presentation. Skin biopsy revealed the diagnosis of Langerhans cell histiocytosis.

Alterations of tear function tests in 50 patients with unilateral pterygium / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To determine tear function tests values,Schirmer Ⅰ test(S Ⅰt),tear film break-up time(TBUT)in patients with pterygium.METHODS:A total of 100 eyes(50 with primary pterygium and 50 without pterygium)of 50 patients who fulfilled the inclusion criteria were evaluated for S Ⅰt and TBUT.RESULTS:The mean S Ⅰ t value in eyes with pterygium was 19.6±11.6(range 1-40)mm and in control eyes without pterygium was 17.2±10.6(range 1-35)mm.S Ⅰ tresults were abnormal in 20 eyes(40%)with pterygium and in 21 eyes(42%)without pterygium(control);the difference was not statistically significant(P= 0.75).The difference between the groups was not statistically significant(f= 1.453,P=0.15).The TBUT in eyes with pterygium was 7.4±5.1(range 2-20)seconds and in control eyes without pterygium was 13.4±6.1(range 2-25)seconds.The difference between the groups was statistically significant(f = 8.029,P＜0.01).The TBUT was abnormal in 39 eyes(78%)with pterygium and in 16 control eyes(32%);the difference was statistically significant(P＜0.01).CONCLUSION:There was no significant difference in S Ⅰ t in eyes with pterygium compared to eyes without pterygium.There is reduction of TBUT in eyes with pterygium.

Bone marrow morphological changes in patients of chronic myeloid leukemia treated with imatinib mesylate.

Background: Imatinib mesylate has shown promising results in chronic myeloid leukemia (CML) in all phases. This drug is an effective treatment for patients with CML in chronic phase as it induces hematological remission in nearly all patients and cytogenetic responses in many. The bone marrow changes produced by this drug are different from the treatment modalities used earlier in CML. Materials & Methods: We studied 80 patients of CML on treatment with Imatinib at doses of 400-800 mg per day. Morphological and cytogenetic evaluation (Ph analysis) of bone marrow aspirates was done at six months of treatment. Result: In our study, 95% (76 out of 80) patients showed complete hematological response and 63.3% showed major cytogenetic response at the end of six months of treatment. The most commonly observed changes in the bone marrow aspirates at the end of six months of therapy were in the form of reduction in the cellularity, reduction in the M: E ratio to a mean of 2:1, presence of relative erythroid hyperplasia, normalization of megakaryocytic morphology and variable increase in the bone marrow lymphocytes. None of these changes had significant correlation with the patient's Ph status. Conclusion: We advise study of trephine biopsies to overcome the often-faced problem of hemodiluted aspirates in these cases and evaluation of sequential bone marrows to check the durability of these morphological changes and their correlation with the cytogenetic response with emphasis on cytogenetic changes other than Ph positivity.