A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection

Retrospective data showed that when we administered ledipasvir/sofosbuvir (LDV/SOF) to patients with hepatitis B and C coinfection, there was a modest reduction in hepatitis B surface antigen (HBsAg). Therefore, we hypothesize that similar HBsAg reduction can be seen in hepatitis B virus (HBV) monoinfected subjects. Primary and secondary efficacy endpoints are the decline in HBsAg and HBV DNA at Week 12 from baseline, respectively. We conducted an open-label Phase 2 pilot study to evaluate the safety, tolerability, and antiviral activity of LDV and/or SOF for HBV. Eligible subjects were either suppressed on antivirals (Group B) or inactive chronic HBV (Group A, C, D). Group A and B received LDV/SOF. Group C and D received SOF 400 mg and LDV 90 mg, respectively. All subjects completed the study, and all related adverse events (AEs) were mild. No discontinuations due to AEs or hepatitis flare occurred. At Week 12, HBsAg decline (log₁₀ IU/ml) was similar between Group A (0.399) and B (0.400), less in Group C (0.207), and none in Group D, and there was HBV DNA decline in the inactive chronic HBV groups. LDV and SOF are safe and well tolerated when given to chronic hepatitis B subjects and have modest antiviral activity, particularly when given in combination.     

Automating Angle Measurements on Foot Radiographs in Young Children: Feasibility and Performance of a Convolutional Neural Network Model

Journal of Digital Imaging - Measurement of angles on foot radiographs is an important step in the evaluation of malalignment. The objective is to develop a CNN model to measure angles on...     

Evaluation of beta-tethymustine, a new anticancer compound, in murine tumour models

beta-Tethymustine, 1-[2- {bis(2'-chloroethyl)amino}ethyl]spiro[imidazolidine-4,2'-(1'H),3',4'-dihydronaphthalene]-2,5-dione, has been synthesised and LD50 value determined in Swiss male mice, which was found to be 100.00 mg/kg by single i.p. injection. The following three criteria, namely ascites cell count, ascites fluid measurement and increase in median survival times (MST) of drug-treated (T) over untreated control (C) mice, were studied for evaluation of its antitumour efficacy in vivo in three murine ascites tumours, namely Ehrlich ascites carcinoma (EAC), sarcoma-180 (S-180) and Dalton's lymphoma (DL). At the optimum dose range of 8.0 mg/kg (higher) to 4.0 mg/kg (lower) for 1-7 days treatment following tumour transplantation on day 0, it exhibited a very high percentage of inhibition of both the ascites cell and fluid in these models and displayed excellent ILS(max) value of 80 in EAC, 224 in S-180 and 240 in DL, respectively, showing 'curative' effect (2-3/6 mice having 90 days survival rate). It also demonstrated a high ILS value of 150 with one cure/six mice bearing S-180 for 6 days prior to drug therapy. Screening results were compared with two clinical drugs, cyclophosphamide and 5-fluorouracil, serving as positive controls. Its chemical alkylating activity was compared with nor-HN2 (NSC 10873) and spiromustine (NSC 172112). The results indicate that it possesses greater alkylating activity than nor-HN2 and comparable activity with spiromustine.     

Hormones in male-patients with advanced esophageal-carcinoma

Hormones are believed to play a dominant role as promoters in the growth and development of hormone-dependent cancers. Much less is known about the circulating hormones in male patients with oesophageal cancer. This lack of attention led us to evaluate the role of peptide and steroid hormones (by RIA) in male patients with oesophageal cancer (n=49). Blood samples of patients were collected pretherapeutically and data was compared with age matched controls (n=25). In this retrospective study, significantly high levels of FSH (P<0.02), LH (P<0.001) and prolactin (P<0.001) were observed with concomitant low levels of estradiol (P<0.001), DHEA-S (P<0.02) and testosterone (P<0.001) in patients when compared with respective controls. The patients when grouped according to anatomical site and histological type of the tumor, intergroup variation was not observed in these hormones. From our, study, it seems that hormonal imbalance or altered ratio of peptide and steroid hormones might be playing a significant role in the development and/or progression of oesophageal carcinoma in men.     

Embryonal Rhabdomyosarcoma of tympano-mastoid region

A rare case of Embryonal Rhabdomyosarcoma of the tympanomastoid region with paralysis of VIth and VIIth cranial nerve and development of ipsilateral loss of vision is reported. The case was first clinically diagnosed as a complicated case of C.S.O.M. with petrositis and facial palsy and was operated upon. Histopathological examination in the postoperative period proved it to be a case of Embryonal Rhabdomyosarcoma.     

Immunohistochemical localization of receptors for progesterone and oestradiol-17 beta in the implantation site of the rhesus monkey

The aim of the present study was to examine the cellular basis of the involvement of oestradiol and progesterone in blastocyst implantation in the primate. To this end, the cellular distribution of receptors for oestradiol (ER) and progesterone (PR) in fetal trophoblast cells and in endometrial compartments of timed lacunar (pre-villous) and villous stages of placentation in primary implantation sites collected on days 13-22 of gestation were investigated in rhesus monkeys. Both in pre-villous stage tissue and in villous stage tissue, cytotrophoblast cells and syncytiotrophoblast cells and other trophoblast derived cells were PR positive, while they were generally ER negative. Maternal endometrial cells were ER negative, while epithelial cells, stromal cells and vascular endothelial cells in maternal endometrium showed heterogeneous staining patterns for PR depending on their relative location; these patterns, however, correlated well with glandular hyperplasia and differentiation, stromal-decidual transformation and vascular response seen during blastocyst implantation.     

Immunohistological localisation of vascular endothelial growth factor in human endometrium.

Several polypeptide growth factors regulate epithelial and stromal development in endometrium under the influence of estrogen and progesterone, and thereby regulate growth and differentiation of endometrium during menstrual cycle. However, little is known about the angiogenic growth factors that may affect endometrial vasculature throughout each menstrual cycle. Vascular endothelial growth factor (VEGF) is suggestively an important angiogenic growth factor in the female reproductive tract. The aim of the present study was to immunolocalize and assess semi-quantitatively VEGF immunostaining in cells of proliferative phase (n = 3), secretory phase (n = 6) and hyperplastic (n = 6) human endometrial samples. VEGF concentrations were significantly higher in glandular (P < 0.001) and stromal (P < 0.01) compartments of proliferative stage endometrium compared with those in secretory stage and hyperplastic endometrial samples, with no difference in the scores for glandular and stromal compartments between secretory stage and hyperplastic endometrial samples. Generally, glandular expression of VEGF was higher as compared to stromal compartment. Thus, it appears that endometrial VEGF expression and concentration are enhanced by estrogen, and may be correlated with neovascularization and increased vascular permeability during late proliferative period. Additionally, there was no enhancement in VEGF expression in hyperplastic glands, suggesting that regulation of glandular growth and that of angiogenesis in human endometrium operate through different mechanisms.     

Design and models for estimating antagonist potency (pA2, Kd and IC50) following the detection of antagonism observed in the presence of intrinsic activity

The antagonist activity of the metabotropic glutamate receptor ligand (2S,1'S,2'S)-2-methyl-2(carboxycyclopropyl)glycine (MCCG) was examined using the [35S]GTPgammaS binding and forskolin (FSK)-stimulated adenosine 3':5'-cyclic monophosphate (cAMP) assays with recombinant Chinese hamster ovary (CHO) cells expressing the G protein-coupled human subtype 2 metabotropic glutamate (hmGlu2) receptor. Whereas MCCG proved to be a partial agonist in the GTPgammaS binding assay, it not only antagonized the agonist effect of (IS,3R)-ACPD in the cAMP assay but further produced an anomalous increase of the cAMP level relative to baseline. The anomalous MCCG response was also observed following treatment of the cells with MCCG in the absence of added agonist. Determination of the glutamate concentration in the incubate at the start and end of the cAMP reaction revealed the existence of micromolar concentrations of cellularly released glutamate throughout the course of the assay, reaching levels which exceeded its reported affinity for the mGlu2 receptor. Considering MCCG's partial agonist effect in the GTPgammaS binding assay and its pseudo-inverse agonist effect in the cAMP assay, available methods of estimating its antagonist potency were inappropriate since the classical Schild method and the alternative model suggested by Waud both assume the antagonist to lack a concentration-response relationship. We derived an alternate design and models that permit estimation of the pA2 (pAx), Kd and IC50 for antagonists which produce a concentration related effect when applied by themselves. With their use, the data acquired in both assays support the designation of MCCG as a competitive antagonist of the hmGlu2 receptor and provide similar pA2 estimates between assays. In addition, the newly derived models and design permit the determination of antagonist potency for partial and inverse agonists so characterized in studies employing the Schild design.