Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti–activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody–mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.     

Comparative Evaluation of PCR and Imprint Smear Microscopy Analyses of Skin Biopsy Specimens in Diagnosis of Macular,Papular, and Mixed Papulo-Nodular Lesions of Post-Kala-Azar Dermal Leishmaniasis

Diagnosis of post-kala-azar dermal leishmaniasis (PKDL), particularly the macular form, is difficult when based on microscopy. This study compared the results of nested PCR (91.9% positive samples) with imprint smear microscopy (70.9% positive samples) for 62 PKDL samples. We found that nested PCR, which indicated 87.5% positivity for the macular lesions, compared to 41.6% positivity by imprint smear microscopy, is an efficient method for early diagnosis of PKDL.     

Digital Image Analysis Is a Useful Adjunct to Endoscopic Ultrasonographic Diagnosis of Subepithelial Lesions of the Gastrointestinal Tract

Objective. The purpose of this study was to explore the role of digital image analysis in differentiating endoscopic ultrasonographic (EUS) features of potentially malignant gastrointestinal subepithelial lesions (SELs) from those of benign lesions. Methods. Forty‐six patients with histopathologically confirmed gastrointestinal stromal tumors (GISTs), carcinoids, and lipomas who had undergone EUS evaluation were identified from our database. Representative regions of interest (ROIs) were selected from the EUS images, and features were extracted by texture analysis. On the basis of these features, an artificial neural network (ANN) was built, trained, and internally validated by unsupervised learning followed by supervised learning. Outcomes were the performance characteristics of the ANN. Results. A total of 106, 111, and 124 ROIs were selected from EUS images of 8, 10, and 28 patients with lipomas, carcinoids, and GISTs, respectively. For each ROI, 228 statistical parameters were extracted and later reduced to the 11 most informative features by principal component analysis. After training with 50% of the data, the remainder of the data were used to validate the ANN. The model was “good” in differentiating carcinoids and GISTs, with area under the receiver operating characteristic curve (AUC) values of 0.86 and 0.89, respectively. The model was “excellent” in identifying lipomas correctly, with an AUC of 0.92. Conclusions. Digital image analysis of EUS images is a useful noninvasive adjunct to EUS evaluation of SELs.     

MRI Assessment of Uterine Artery Patency and Fibroid Infarction Rates 6 Months after Uterine Artery Embolization with Nonspherical Polyvinyl Alcohol

Purpose

We have observed significant rates of uterine artery patency after uterine artery embolization (UAE) with nonspherical polyvinyl alcohol (nsPVA) on 6 month follow-up MR scanning. The study aim was to quantitatively assess uterine artery patency after UAE with nsPVA and to assess the effect of continued uterine artery patency on outcomes.

Methods

A single centre, retrospective study of 50 patients undergoing bilateral UAE for uterine leiomyomata was undertaken. Pelvic MRI was performed before and 6 months after UAE. All embolizations were performed with nsPVA. Outcome measures included uterine artery patency, uterine and dominant fibroid volume, dominant fibroid percentage infarction, presence of ovarian arterial collaterals, and symptom scores assessed by the Uterine Fibroid Symptom and Quality of Life questionnaire (UFS-QOL).

Results

Magnetic resonance angiographic evidence of uterine artery recanalization was demonstrated in 90 % of the patients (64 % bilateral, 26 % unilateral) at 6 months. Eighty percent of all dominant fibroids demonstrated >90 % infarction. The mean percentage reduction in dominant fibroid volume was 35 %. No significant difference was identified between nonpatent, unilateral, and bilateral recanalization of the uterine arteries with regard to percentage dominant fibroid infarction or dominant fibroid volume reduction. The presence of bilaterally or unilaterally patent uterine arteries was not associated with inferior clinical outcomes (symptom score or UFS-QOL scores) at 6 months.

Conclusion

The high rates of uterine artery patency challenge the current paradigm that nsPVA is a permanent embolic agent and that permanent uterine artery occlusion is necessary to optimally treat uterine fibroids. Despite high rates of uterine artery recanalization in this cohort, satisfactory fibroid infarction rates and UFS-QOL scores were achieved.     

Evolutionary genetic insights into Plasmodium falciparum functional genes

Complex and rapidly evolving behavior of the human malaria parasite Plasmodium falciparum have always been mysterious to the evolutionary biologists, as the parasite is the most virulent and now becoming the most prevalent malaria parasite species across the globe. With the availability of complete genome sequence of P. falciparum, better understanding of the genome design and evolution could be possible. We herein utilized the available information of all known functional genes from whole genome of P. falciparum and investigate the differential mode of gene evolution. The study comparing P. falciparum functional genes with Plasmodium vivax revealed about 82% of genes to be conserved in the later species and the rest, 18% to be totally unique to P. falciparum. Genetic architectural pattern of functional genes shows absence of introns in about a half of the conserved genes, whereas almost all unique genes have introns. Similarly, distribution of intron number and length were also observed to be different for conserved and unique genes of P. falciparum. Statistically significant positive correlations between total intron length and gene lengths were detected in 11 chromosomes for unique genes, whereas only in three chromosomes for conserved genes. Preference of intron presence in some P. falciparum genes were also detected which provide functional relevance of introns. The study provides, for the first time, a detail evolutionary analysis of functional genes of a devastating malaria parasite. The marked differences in organization of introns between the unique and conserved genes in P. falciparum, and the contribution of introns to genome complexity are some of the hallmarks of the study.     

Association of viral load with HPV16 positive cervical cancer pathogenesis: Causal relevance in isolates harboring intact viral E2 gene

We tested the hypothesis that cervical cancers (CaCx) harbor high HPV16 viral load compared to controls and this is influenced by E2 status and age of subjects. Viral load (natural log transformed values) per 100 ng genomic DNA was estimated (152 cases and 87 controls) by Taqman assay. Median viral load was significantly higher (Mann-Whitney U test) among cases (17.21) compared to controls (9.86), irrespective of E2 status or upon considering E2 status as a covariate in logistic regression model (p < 0.001). Viral load of E2 intact cases (17.80) was significantly higher (p < 0.001) compared to those with disrupted E2 (9.78). At equivalent probability of being a case, viral load was higher among individuals (i) of lower age, irrespective of E2 status, and (ii) with intact E2 but of similar age as those with disrupted E2. Thus viral load in association with E2 status and/or age might be of causal relevance in CaCx pathogenesis.     

Prolactin as a Mitogen in Mammary Cells

Prolactin (PRL) acts as both a mitogen and a differentiating agent in the breast. The decision to respond to PRL as a mitogen by breast cells depends on the hormonal milieu in which the epithelial cell resides. In addition, PRL's action on the breast is regulated (1) at the level of the hormone itself; (2) at the receptor level; (3) at the level of selection of signaling pathway; and, (4) by combinations of these aspects. The development of cell lines containing only one class of the PRL receptors and showing qualitative differences in response and signaling pathways will help in understanding the pleiotropic nature of PRL action.