Adenylate cyclase activator forskolin alleviates intracerebroventricular propionic acid-induced mitochondrial dysfunction of autistic rats

Neuronal mitochondrial dysfunction increases inflammatory mediators and leads to free radical generation and anti-oxidant enzymatic alterations,which are major neuropathological hallmarks responsible for autism.Mitochondrial dysfunction in autism is associated with decreased ATP levels due to reduced levels of cyclic adenosine monophosphate.Rat models of autism were established by intracerebroventricular injection of propionic acid.These rat models had memory dysfunction,decreased muscle coordination and gait imbalance.Biochemical estimation of propionic acid-treated rats showed changes in enzyme activity in neuronal mitochondrial electron transport chain complexes and increases in pro-inflammatory cytokines,oxidative stress and lipid biomarkers.Oral administration of 10,20 and 30 mg/kg adenylate cyclase activator forskolin for 15 days reversed these changes in a dose-dependent manner.These findings suggest that forskolin can alleviate neuronal mitochondrial dysfunction and improve neurological symptoms of rats with autism.This study was approved by the RITS/IAEC,SIRSA,HARYANA on March 3,2014(approval No.RITS/IAEC/2014/03/03).     

Molecular detection of Orientia tsutsugamushi strains circulating in Nagaland

The antigenic heterogeneity of Orientia in India is still unknown in many disease endemic areas. The present study aims to characterize the strains of O. tsutsugamushi circulating in Nagaland, Northeast India. Two patients clinically diagnosed with ST and hospitalized in Mon district hospital, Nagaland were identified from whom eschar tissues were collected. Both patients demonstrated antibodies against O. tsutsugamushi along with positive PCR amplification for 56 ?kDa gene. The prototype strain TA763 shared 90.4% homology with the sequences. Both the sequences formed a distinctive cluster demonstrating 100% similarity with strains identified from Thailand, Vietnam, China and southern parts of India.     

A Phase II Study of Telisotuzumab Vedotin in Patients With c–MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K,NCT03574753)

IntroductionLung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET–positive squamous cell carcinoma (SCC).Patients and MethodsPatients with previously treated SCC with c-MET–positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.ResultsForty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).ConclusionTelisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.     

Evidence to Practice for Mental Health Task-Sharing: Understanding Readiness for Change among Accredited Social Health Activists in Sehore District,Madhya Pradesh,India

Involvement of community health workers (CHWs) within task-sharing to bridge the mental health treatment gap has been proven to be efficacious in randomized controlled trials. The impact of mental health programs based on task-sharing paradigm greatly depends on the performance of CHWs which, in-turn, is influenced by their readiness for change. However, there is dearth of literature assessing the role of readiness for change as an important predicator of CHW performance. The aim of this study is to examine the applicability of the readiness for change model and investigate its cultural and contextual nuances among Accredited Social Health Activists (ASHAs), a cadre of CHWs in India, to understand their engagement in mental health task-sharing. We conducted in-depth, semi-structured interviews with a purposive sample of n?=?12 key informants including ASHAs and other healthcare professionals in Sehore district, India. The interview guide consisted of open-ended questions based on the readiness for change factors including ASHAs’ attitudes towards their role in mental health care, perception of capability to implement mental health task-sharing, of support from the public health system, etc. Framework analysis with a combined inductive-deductive approach was employed to code the data and generate themes. Participants endorsed three readiness for change themes relevant to task-sharing among ASHAs including change valence or value ascribed to task-sharing, change-efficacy or the perceived ability to implement task-sharing, and job valence or value ascribed to their regular job role. In addition, they provided insights into the culturally and contextually salient aspects of these factors. Themes of personal empowerment, gaining respect and trust from community, professional duty, relationship with supervisors, and lack of resources availability were majorly highlighted. This is the first study to qualitatively investigate the applicability of the readiness for change model and its culture- and context-specific nuances among a cadre of non-specialist health workers in India. Our findings posit that implementation science models should strongly consider the culture and context within which they are being applied to enhance fit and relevance. Further, our results should be taken into consideration to adapt and validate measurement tools and build readiness for change in this population.

     

Efficacy of soil-borne Enterobacter sp. for carbofuran degradation: HPLC quantitation of degradation rate

Excessive use of pesticides in agricultural fields is a matter of great concern for living beings as well as the environment across the world, in particular, the third world countries. Therefore, there is an urgent need to find out an effective way to degrade these hazardous chemicals from the soil in an environment-friendly way. In the current project, a bacterial species were isolated through enrichment culture from carbofuran-supplemented rice-field soil and identified as a carbofuran degrader. The rate of carbofuran degradation by this bacterial species was evaluated using reverse-phase high-performance liquid chromatography (RP-HPLC), which confirmed the ability to utilize as a carbon source up to 4 µg/ml of 99% technical grade carbofuran. The morphological, physiological, biochemical characteristics and phylogenetic analysis of the 16S rRNA sequence showed that this strain belongs to the genus of Enterobacter sp. (sequence accession number LC368285 in DDBJ), and the optimum growth condition for the isolated strain was 37°C at pH 7.0. Moreover, an antibiotic sensitivity test showed that it was susceptible to azithromycin, penicillin, ceftazidime, ciprofloxacin, and gentamycin, and the minimal inhibitory concentration value of gentamycin was 400 μg/ml against the bacteria. It shows beyond doubt from the RP-HPLC quantification that the isolated bacterium has the ability to detoxify carbofuran (99% pure). Finally, the obtained results imply that the isolated strain of Enterobacter can be used as a potential and effective carbofuran degrader for bioremediation of contaminated sites through bioaugmentation.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.