Mass Spectrometry-Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine.

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.

Replication of a local record keeping method for collecting road crash data in low resource settings: lessons from Bangladesh and Nepal.

BACKGROUND: Police road crash and injury data in low-income and middle-income countries are known to under-report crashes, fatalities and injuries, especially for vulnerable road users. Local record keepers, who are members of the public, can be engaged to provide an additional source of crash and injury data. METHODS: This paper compares the application of a local record keeper method to capture road crash and injury data in Bangladesh and Nepal, assesses the quality of the data collected and evaluates the replicability and value of the methodology using a framework developed to evaluate the impact of being a local record keeper. OUTCOME: Application in research studies in both Bangladesh and Nepal found the local record keeper methodology provided high-quality and complete data compared with local police records. The methodology was flexible enough to adapt to project and context differences. The evaluation framework enabled the identification of the challenges and unexpected benefits realised in each study. This led to the development of an 11-step process for conducting road crash data collection using local record keepers, which is presented to facilitate replication in other settings. CONCLUSION: Data collected by local record keepers are a flexible and replicable method to understand the strengths and limitations of existing police data, adding to the evidence base and informing local and national decision-making. The method may create additional benefits for data collectors and communities, help design and assess road safety interventions and support advocacy for improved routine police data.

Comparative evaluation of A1A2 and A2A2 cow milk-containing diets on biochemical and histological parameters of Wistar rats.

This Research Communication aims to compare the effect of A1A2 and A2A2 cow milk diets on the biochemical and histological parameters of rats. The rats were divided into four groups and fed with a normal diet, A2 milk powder, A1A2 or A2A2 cow milk diets for 90 d. Blood glucose, kidney function, liver function and lipid profile were examined during the experimental period. The study showed an increase in the body weight of the A1A2 group whereas a slight decrease in the A2A2 group, and blood glucose levels increased from d 0 to day 90 in all experimental groups. However, none of these changes were found to be statistically insignificant (P > 0.05). Moreover, no significant changes were recorded in other parameters (serum glutamic pyruvic transferase and serum glutamic-oxaloacetic transaminase for liver function, bilirubin direct, cholesterol, triglycerides, creatinine and uric acid). The histology of the liver, kidney and pancreas also showed no changes in all groups. Overall, this study revealed no significant difference in the nutritional values of A1A2 and A2A2 milk types and hence equally beneficial for health. Although the present study showed no significant difference in the effect of both milk types in 90 d, further studies might be conducted to evaluate their longer term effects.

Wheat as a new host for potato aphid Macrosiphum euphorbiae Thomas (Hemiptera: Aphididae) and construction of its age-stage two-sex life tables.

Wheat (Triticum aestivum L.) is the major global staple food crop that meets the food security demands of various nations across the continents. The recent reduction in wheat production is attributed to several biotic and abiotic factors especially, temperature and rainfall patterns, and pest occurrence. Among insect pests, aphid species are emerging as new pests of economic importance in India and elsewhere. The present investigation identified a new association of Macrosiphum euphorbiae Thomas with the wheat crop. Life table parameters were studied for M. euphorbiae and Rhopalosiphum padi fed on wheat foliage. The total nymphal duration and life cycle duration, respectively, of R. padi (4.76 ± 0.54 and 9.71 ± 1.38 days) and M. euphorbiae (5.84 ± 0.69 and 9.96 ± 1.31 days) were significantly different for these species. The fecundity of the two aphid species was 23.95 ± 8.67 and 11.6 ± 4.10 progeny/female, respectively. Age-specific survival rate (lx), age-specific fecundity (fx), and population age-specific fecundity (mx) were higher in R. Padi compared to M. euphorbiae. Reproductive value (Vxj) was high in R. padi and the duration of reproduction was less, while these parameters showed an opposite trend in M. euphorbiae. The gross reproduction rate (GRR) was found higher in R. Padi (29.17 offspring/adult lifetime) compared to M. euphorbiae (19.58 offspring/adult lifetime). The M. euphorbiae being a pest of solanaceous crops seems to have shifted to a new host, i.e., wheat. This new adaptation strategy to survive for long periods on a wheat crop might pose a serious threat to wheat crop cultivation in near future.

Proteomic and phosphoproteomic measurements enhance ability to predict ex vivo drug response in AML.

Acute Myeloid Leukemia (AML) affects 20,000 patients in the US annually with a five-year survival rate of approximately 25%. One reason for the low survival rate is the high prevalence of clonal evolution that gives rise to heterogeneous sub-populations of leukemic cells with diverse mutation spectra, which eventually leads to disease relapse. This genetic heterogeneity drives the activation of complex signaling pathways that is reflected at the protein level. This diversity makes it difficult to treat AML with targeted therapy, requiring custom patient treatment protocols tailored to each individual's leukemia. Toward this end, the Beat AML research program prospectively collected genomic and transcriptomic data from over 1000 AML patients and carried out ex vivo drug sensitivity assays to identify genomic signatures that could predict patient-specific drug responses. However, there are inherent weaknesses in using only genetic and transcriptomic measurements as surrogates of drug response, particularly the absence of direct information about phosphorylation-mediated signal transduction. As a member of the Clinical Proteomic Tumor Analysis Consortium, we have extended the molecular characterization of this cohort by collecting proteomic and phosphoproteomic measurements from a subset of these patient samples (38 in total) to evaluate the hypothesis that proteomic signatures can improve the ability to predict response to 26 drugs in AML ex vivo samples. In this work we describe our systematic, multi-omic approach to evaluate proteomic signatures of drug response and compare protein levels to other markers of drug response such as mutational patterns. We explore the nuances of this approach using two drugs that target key pathways activated in AML: quizartinib (FLT3) and trametinib (Ras/MEK), and show how patient-derived signatures can be interpreted biologically and validated in cell lines. In conclusion, this pilot study demonstrates strong promise for proteomics-based patient stratification to assess drug sensitivity in AML.

Discovery and characterization of targetable NTRK point mutations in hematologic neoplasms.

Much of what is known about the neurotrophic receptor tyrosine kinase (NTRK) genes in cancer was revealed through identification and characterization of activating Trk fusions across many tumor types. A resurgence of interest in these receptors has emerged owing to the realization that they are promising therapeutic targets. The remarkable efficacy of pan-Trk inhibitors larotrectinib and entrectinib in clinical trials led to their accelerated, tissue-agnostic US Food and Drug Administration (FDA) approval for adult and pediatric patients with Trk-driven solid tumors. Despite our enhanced understanding of Trk biology in solid tumors, the importance of Trk signaling in hematological malignancies is underexplored and warrants further investigation. Herein, we describe mutations in NTRK2 and NTRK3 identified via deep sequencing of 185 patients with hematological malignancies. Ten patients contained a point mutation in NTRK2 or NTRK3; among these, we identified 9 unique point mutations. Of these 9 mutations, 4 were oncogenic (NTRK2A203T, NTRK2R458G, NTRK3E176D, and NTRK3L449F), determined via cytokine-independent cellular assays. Our data demonstrate that these mutations have transformative potential to promote downstream survival signaling and leukemogenesis. Specifically, the 3 mutations located within extracellular (ie, NTRK2A203T and NTRK3E176D) and transmembrane (ie, NTRK3L449F) domains increased receptor dimerization and cell-surface abundance. The fourth mutation, NTRK2R458G, residing in the juxtamembrane domain, activates TrkB via noncanonical mechanisms that may involve altered interactions between the mutant receptor and lipids in the surrounding environment. Importantly, these 4 activating mutations can be clinically targeted using entrectinib. Our findings contribute to ongoing efforts to define the mutational landscape driving hematological malignancies and underscore the utility of FDA-approved Trk inhibitors for patients with aggressive Trk-driven leukemias.

Identification of research priorities for suicide prevention in Nepal: a Delphi study.

BACKGROUND: Suicide is a significant public health concern in Nepal and there is a need for an evidence-based suicide prevention programme to facilitate stakeholders working towards suicide prevention in Nepal. Collaborative research between stakeholders focussing on shared priorities can help to prevent and control suicide. Hence, we aimed to develop a consensus list of research priorities for suicide prevention in Nepal. METHODS: The Delphi expert consensus method was used to elicit the prioritized research questions for suicide prevention in Nepal. Participants comprised suicide prevention experts (psychologists, psychiatrists, psychiatric nurses, researchers and advocates) and people with lived experience. Three rounds of Delphi were conducted; round 1: one to one interviews involving open ended questions used to generate research questions; round 2: ranking of the research questions using a 5-point Likert scale, and round 3: re-ranking of research questions in light of individual and group responses. RESULTS: Forty-two participants participated in round 1 followed by 38 in round 2 and 39 in round 3 . 522 research questions were generated through round 1 which were grouped together and reduced to 33 research questions sent for ranking in round 2. Using a cut off of at least 70% of the panel ranking questions as 'very important' or 'important', 22 questions were retained. These research questions were sent for re-rating in round 3 resulting in a final list of prioritized questions. CONCLUSIONS: This is the first expert consensus study to identify the top research priorities for suicide prevention in Nepal, and used experts in suicide prevention and those with lived experience. A consensus was reached regarding the studies needed to improve suicide data quality, assess the burden and identify factors associated with suicide. A priority driven approach to suicide prevention research may ensure that the research endeavour provides the most useful information for those whose day-to-day work involves trying to prevent suicide.

A qualitative study on gender inequality and gender-based violence in Nepal.

BACKGROUND: Gender inequality and violence are not mutually exclusive phenomena but complex loops affecting each other. Women in Nepal face several inequalities and violence. The causes are diverse, but most of these results are due to socially assigned lower positioning of women. The hierarchies based on power make women face subordination and violence in Nepal. The study aims to explore participants' understanding and experience to identify the status of inequality for women and how violence emerges as one of its consequences. Furthermore, it explores the causes of sex trafficking as an example of an outcome of inequality and violence. METHOD: The study formulated separate male and female groups using a purposive sampling method. The study used a multistage focus group discussion, where the same groups met at different intervals. Six focus group discussions, three times each with male and female groups, were conducted in a year. Thirty-six individuals, including sixteen males and twenty females, were involved in the discussions. The study used constructivist grounded theory for the data analysis. RESULTS: The study participants identify that a power play between men and women reinforce inequality and increases the likelihood of violence for women. The findings suggest that the subjugation of women occurs due to practices based on gender differences, constricted life opportunities, and internalization of constructed differences among women. The study identifies that interpersonal and socio-cultural violence can result due to established differences between men and women. Sex trafficking, as an example of the outcome of inequality and violence, occurs due to the disadvantageous position of women compounded by poverty and illiteracy. The study has developed a concept of power-play which is identified as a cause and consequence of women's subordination and violence. This power play is found operative at various levels with social approval for men to use violence and maintain/produce inequality. CONCLUSION: The theoretical concept of power play shows that there are inequitable power relations between men and women. The male-centric socio-cultural norms and practices have endowed men with privilege, power, and an opportunity to exploit women. This lowers the status of women and the power-play help to produce and sustain inequality. The power-play exposes women to violence and manifests itself as one of the worst expressions used by men.

Home-related and work-related injuries in Makwanpur district, Nepal: a household survey.

OBJECTIVE: To describe the epidemiology of home-related and work-related injuries, their mechanisms, inequalities and costs associated with these injuries. METHODS: A household survey was undertaken in three palikas of Makwanpur district between April and June 2019. Data were collected electronically on non-fatal injuries that occurred in the previous 3 months and fatal injuries that occurred in the previous 5 years. FINDINGS: 17 593 individuals were surveyed from 3327 households. Injury rates were 8.0 per 1000 population for home injuries and 6.4 per 1000 for work-related injuries; 61.0% of home injuries were among women and 69.9% of work-related injuries among men. Falls were the cause of 48% home injuries, affecting 50.9% of men and 46.5% of women. Burns/scalds were higher in women than men, affecting 17.4% of women reporting home injuries. Cuts and piercings accounted for 39.8% of all work-related injuries and 36.3% were falls. Injury incidence varied by ethnic group: home injuries were highest in Brahmin (12.0 per 1000) and work-related injuries highest in Rai groups (21.0 per 1000). The total mean costs (transport and treatment) of work-related injury was US$143.3 (SD 276.7), higher than for home injuries (US$130.4, SD 347.6). The number of home (n=74, 64.9%) and work-related (n=67, 77.9%) injuries were higher in families below the poverty line than families in the next income bracket (home: n=22, 19.3%; work: n=11, 12.8%). CONCLUSIONS: Home-related and work-related fall injuries are common. The inequalities in injury identified in our study by rurality, age, sex, income level and ethnic group can help target injury prevention interventions for vulnerable groups.

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

The prevention of - and first response to - injuries in Nepal: a review of policies and legislation.

BACKGROUND: Injuries, the cause of an estimated 4.5 million deaths annually and many more disabilities worldwide each year, are the predictable outcome of particular circumstances. One of the most effective ways to prevent injuries is through policy and legislation. The aim of this research study was to identify and critically review all policy and legislation in Nepal that had the potential to prevent injuries. METHODS: We identified legislation and policy that met inclusion criteria through a stakeholder meeting, networks and contacts, and websites and electronic resources. Each included document was critically reviewed to identify areas of strength and opportunities for improvement. We compared the included documents against WHO's recommendations of known effective interventions. RESULTS: Sixty-two documents met the inclusion criteria for this review. Of these, 24 (38.7%) were exclusively related to road injuries, 11 (17.7%) to occupational injuries, 6 (9.7%) to injuries in the home and 5 (8.1%) to injuries at school; 30 (48.4%) documents included text related to the first response to injuries. Of 127 strategic recommendations by WHO that provided an area for policy or legislative focus, 21 (16.5%) were considered adequately met by Nepali policy and legislation, 43 (33.9%) were considered partially met and 63 (49.6%) were not met. CONCLUSION: We drew five conclusions from this critical policy review, which we have related to recommendations as follows: widening the scope of legislation and policy for injury prevention to emphasize injuries occurring at home or school; addressing the causes of injuries and promoting proven preventive measures; greater clarity on both individual and institutional roles and responsibilities; trustworthy data and quality evidence to inform decision-making; and financial investment and capacity-strengthening for injury prevention and first response. The current system of federal governance in Nepal has potential for strengthening injury prevention and first response at the central, provincial and local levels.

Establishing injury surveillance in emergency departments in Nepal: protocol for mixed methods prospective study.

BACKGROUND: Globally, injuries cause more than 5 million deaths annually, a similar number to those from HIV, Tuberculosis and Malaria combined. In people aged between 5 and 44 years of age trauma is the leading cause of death and disability and the burden is highest in low- and middle-income countries (LMICs). Like other LMICs, injuries represent a significant burden in Nepal and data suggest that the number is increasing with high morbidity and mortality. In the last 20 years there have been significant improvements in injury outcomes in high income countries as a result of organised systems for collecting injury data and using this surveillance to inform developments in policy and practice. Meanwhile, in most LMICs, including Nepal, systems for routinely collecting injury data are limited and the establishment of injury surveillance systems and trauma registries have been proposed as ways to improve data quality and availability. METHODS: This study will implement an injury surveillance system for use in emergency departments in Nepal to collect data on patients presenting with injuries. The surveillance system will be introduced in two hospitals and data collection will take place 24 h a day over a 12-month period using trained data collectors. Prospective data collection will enable the description of the epidemiology of hospital injury presentations and associated risk factors. Qualitative interviews with stakeholders will inform understanding of the perceived benefits of the data and the barriers and facilitators to embedding a sustainable hospital-based injury surveillance system into routine practice. DISCUSSION: The effective use of injury surveillance data in Nepal could support the reduction in morbidity and mortality from adult and childhood injury through improved prevention, care and policy development, as well as providing evidence to inform health resource allocation. This study seeks to test a model of injury surveillance based in emergency departments and explore factors that have the potential to influence extension to additional settings.

Colostrum knowledge among Saudi mothers in Jeddah, Saudi Arabia.

OBJECTIVE: To assess the knowledge level of Saudi women about colostrum for the newborns. METHODS: The cross-sectional study was conducted from October 2015 to June 2016 at the Gynaecological Clinics of King Abdulaziz University Hospital, Jeddah, Saudi Arabia and comprised lactating mothers in the community. Data was collected using a pretested questionnaire. Data was analysed using SPSS 22. RESULTS: Of the 552 mothers, 301(54.5%) were age >30 years. The source of information about colostrum was friends and family for 367(66.67%) subjects. Overall, 367(66%) had high knowledge about colostrum. A significant correlation was detected between age and knowledge about colostrum composition and duration (p<0.05); as well as between educational level and colostrum composition, colour and form (p<0.05). A significant association between occupational status and knowledge about colostrum colour and form was also noted (p<0.05). CONCLUSIONS: Saudi mothers were found to have a good knowledge about colostrum and its benefits.

Heterogeneity in HIV and cellular transcription profiles in cell line models of latent and productive infection: implications for HIV latency.

BACKGROUND: HIV-infected cell lines are widely used to study latent HIV infection, which is considered the main barrier to HIV cure. We hypothesized that these cell lines differ from each other and from cells from HIV-infected individuals in the mechanisms underlying latency. RESULTS: To quantify the degree to which HIV expression is inhibited by blocks at different stages of HIV transcription, we employed a recently-described panel of RT-ddPCR assays to measure levels of 7 HIV transcripts ("read-through," initiated, 5' elongated, mid-transcribed/unspliced [Pol], distal-transcribed [Nef], polyadenylated, and multiply-sliced [Tat-Rev]) in bulk populations of latently-infected (U1, ACH-2, J-Lat) and productively-infected (8E5, activated J-Lat) cell lines. To assess single-cell variation and investigate cellular genes associated with HIV transcriptional blocks, we developed a novel multiplex qPCR panel and quantified single cell levels of 7 HIV targets and 89 cellular transcripts in latently- and productively-infected cell lines. The bulk cell HIV transcription profile differed dramatically between cell lines and cells from ART-suppressed individuals. Compared to cells from ART-suppressed individuals, latent cell lines showed lower levels of HIV transcriptional initiation and higher levels of polyadenylation and splicing. ACH-2 and J-Lat cells showed different forms of transcriptional interference, while U1 cells showed a block to elongation. Single-cell studies revealed marked variation between/within cell lines in expression of HIV transcripts, T cell phenotypic markers, antiviral factors, and genes implicated in latency. Expression of multiply-spliced HIV Tat-Rev was associated with expression of cellular genes involved in activation, tissue retention, T cell transcription, and apoptosis/survival. CONCLUSIONS: HIV-infected cell lines differ from each other and from cells from ART-treated individuals in the mechanisms governing latent HIV infection. These differences in viral and cellular gene expression must be considered when gauging the suitability of a given cell line for future research on HIV. At the same time, some features were shared across cell lines, such as low expression of antiviral defense genes and a relationship between productive infection and genes involved in survival. These features may contribute to HIV latency or persistence in vivo, and deserve further study using novel single cell assays such as those described in this manuscript.

Prevalence and associated factors of domestic violence among pregnant women attending routine antenatal care in Nepal.

AIMS: The primary aim of this study was to assess the prevalence of domestic violence (DV) and its associated factors among pregnant women in Nepal. The secondary aims were to investigate disclosure of DV by women to health-care personnel and to assess whether health-care personnel had asked women about their experience of DV. METHODS: This cross-sectional study included 2004 pregnant women between 12 and 28 weeks of gestation attending routine antenatal care at two hospitals in Nepal from August 2014 to November 2015. In this study, DV was defined as fear of a family member and/or an experience of physical, emotional or sexual violence. Associated risk factors were analysed using logistic regression analyses. RESULTS: Twenty-one per cent of the women had experienced DV; 12.5% experienced fear only, 3.6% violence only and 4.9% experienced both violence and fear. Less than 2% per cent reported physical violence during pregnancy. This study found that just 17.7% had ever been asked by health-care personnel about DV, and of the women who had reported DV, only 9.5% had disclosed their experience to health-care personnel. Women of young age and low socio-economic status were more likely to have experienced DV. Women who reported having their own income and the autonomy to use it were at significantly lower risk of DV compared to women with no income. CONCLUSIONS: A substantial proportion of women reported having experienced DV. Victims had rarely disclosed their experience of DV to health-care personnel. This study underlines the importance of integrating systematic assessment of DV in antenatal care.

An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: implications for acute kidney injury.

Acute kidney injury (AKI) causes severe morbidity, mortality, and chronic kidney disease (CKD). Mortality is particularly marked in the elderly and with preexisting CKD. Oxidative stress is a common theme in models of AKI induced by ischemia-reperfusion (I-R) injury. We recently characterized an intracellular isoform of matrix metalloproteinase-2 (MMP-2) induced by oxidative stress-mediated activation of an alternate promoter in the first intron of the MMP-2 gene. This generates an NH2-terminal truncated MMP-2 (NTT-MMP-2) isoform that is intracellular and associated with mitochondria. The NTT-MMP-2 isoform is expressed in kidneys of 14-mo-old mice and in a mouse model of coronary atherosclerosis and heart failure with CKD. We recently determined that NTT-MMP-2 is induced in human renal transplants with delayed graft function and correlated with tubular cell necrosis. To determine mechanism(s) of action, we generated proximal tubule cell-specific NTT-MMP-2 transgenic mice. Although morphologically normal at the light microscopic level at 4 mo, ultrastructural studies revealed foci of tubular epithelial cell necrosis, the mitochondrial permeability transition, and mitophagy. To determine whether NTT-MMP-2 expression enhances sensitivity to I-R injury, we performed unilateral I-R to induce mild tubular injury in wild-type mice. In contrast, expression of the NTT-MMP-2 isoform resulted in a dramatic increase in tubular cell necrosis, inflammation, and fibrosis. NTT-MMP-2 mice had enhanced expression of innate immunity genes and release of danger-associated molecular pattern molecules. We conclude that NTT-MMP-2 "primes" the kidney to enhanced susceptibility to I-R injury via induction of mitochondrial dysfunction. NTT-MMP-2 may be a novel AKI treatment target.

α1A-Subtype adrenergic agonist therapy for the failing right ventricle.

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α1-adrenergic receptors (α1-ARs), in particular the α1A-subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α1A-subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg-1·day-1). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α1A-subtype is a potential therapeutic target to treat the failing RV.NEW & NOTEWORTHY Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α1A-adrenergic receptor subtype agonist A61603. Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the α1A-subtype is a therapeutic target to treat RV failure.

Osteogenic changes in kidneys of hyperoxaluric rats.

Many calcium oxalate (CaOx) kidney stones develop attached to renal papillary sub-epithelial deposits of calcium phosphate (CaP), called Randall's plaque (RP). Pathogenesis of the plaques is not fully understood. We hypothesize that abnormal urinary environment in stone forming kidneys leads to epithelial cells losing their identity and becoming osteogenic. To test our hypothesis male rats were made hyperoxaluric by administration of hydroxy-l-proline (HLP). After 28days, rat kidneys were extracted. We performed genome wide analyses of differentially expressed genes and determined changes consistent with dedifferentiation of epithelial cells into osteogenic phenotype. Selected molecules were further analyzed using quantitative-PCR and immunohistochemistry. Genes for runt related transcription factors (RUNX1 and 2), zinc finger protein Osterix, bone morphogenetic proteins (BMP2 and 7), bone morphogenetic protein receptor (BMPR2), collagen, osteocalcin, osteonectin, osteopontin (OPN), matrix-gla-protein (MGP), osteoprotegrin (OPG), cadherins, fibronectin (FN) and vimentin (VIM) were upregulated while those for alkaline phosphatase (ALP) and cytokeratins 10 and 18 were downregulated. In conclusion, epithelial cells of hyperoxaluric kidneys acquire a number of osteoblastic features but without CaP deposition, perhaps a result of downregulation of ALP and upregulation of OPN and MGP. Plaque formation may additionally require localized increases in calcium and phosphate and decrease in mineralization inhibitory potential.