Kandavel Thennarasu

Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2.

Glioblastoma is the most common and malignant form of primary astrocytoma. Upon investigation of the insulin-like growth factor (IGF) pathway, we found the IGF2BP3/IMP3 transcript and protein to be up-regulated in GBMs but not in lower grade astrocytomas (p < 0.0001). IMP3 is an RNA binding protein known to bind to the 5′-untranslated region of IGF-2 mRNA, thereby activating its translation. Overexpression- and knockdown-based studies establish a role for IMP3 in promoting proliferation, anchorage-independent growth, invasion, and chemoresistance. IMP3 overexpressing B16F10 cells also showed increased tumor growth, angiogenesis, and metastasis, resulting in poor survival in a mouse model. Additionally, the infiltrating front, perivascular, and subpial regions in a majority of the GBMs stained positive for IMP3. Furthermore, two different murine glioma models were used to substantiate the above findings. In agreement with the translation activation functions of IMP3, we also found increased IGF-2 protein in the GBM tumor samples without a corresponding increase in its transcript levels. Also, in vitro IMP3 overexpression/knockdown modulated the IGF-2 protein levels without altering its transcript levels. Additionally, IGF-2 neutralization and supplementation studies established that the proproliferative effects of IMP3 were indeed mediated through IGF-2. Concordantly, PI3K and MAPK, the downstream effectors of IGF-2, are activated by IMP3 and are found to be essential for IMP3-induced cell proliferation. Thus, we have identified IMP3 as a GBM-specific proproliferative and proinvasive marker acting through IGF-2 resulting in the activation of oncogenic PI3K and MAPK pathways.

Clinical characteristics and survival pattern of 1153 patients with amyotrophic lateral sclerosis: Experience over 30 years from India

Amyotrophic Lateral Sclerosis is a progressive disease causing degeneration of upper and lower motor neurons with an average survival of 2 to 3 years. We retrospectively analyzed 1,153 patients of classical sporadic ALS seen over 30 years for the clinical manifestations and survival pattern. There were 855 (74.2%) men and 298 (25.8%) women with a M:F ratio of 3:1. The mean age of onset was 46.2+/-14.1 years (18-85) and the mean duration of illness at evaluation was 17.7+/-20.7 months (0.5-180). Mean age of onset for bulbar onset group was 52.8+/-11.6 and for limb onset was 43.7+/-14.1 (p<0.0001). One third of patients had onset before 40 years of age. The overall median survival duration (MSD) was 114.8+/-25.9(SE) months (3.3-194.4). Survival did not differ between the men [101.7+/-27.4(SE)] and women [118.9+/-6.3(SE)]. Information on death was available in 124 patients. The mean age at death was 52.95 years (25.7-82.6). The MSD for bulbar onset group was 55.9+/-2.9(SE) months and for limb onset group 177.9+/-3.2(SE) (p<0.0001). Gender did not have an effect on the survival period. The clinical manifestations are similar to findings from other developing countries with regards to age of onset, sex ratio and survival. When compared to studies among Caucasians the age of onset was one to two decades earlier and the male preponderance was more. The survival pattern is close to those reported from developing countries particularly from Africa and among Asian immigrants to the West, while it is significantly longer compared to Caucasians who generally have a dismal prognosis. Thus, Indians appear to have a relatively younger age of onset and prolonged survival suggesting the relatively slow course of ALS among Indian patients.

Grade-Specific Expression of Insulin-like Growth Factor–Binding Proteins-2, -3, and -5 in Astrocytomas: IGFBP-3 Emerges as a Strong Predictor of Survival in Patients with Newly Diagnosed Glioblastoma

Background: Insulin-like growth factor (IGF)–binding protein (IGFBP) isoforms have been implicated in the pathogenesis of human neoplasms including glioma. In view of this, we evaluated the expression of IGFBP isoforms (IGFBP-2, -3, and -5) during malignant progression of astrocytoma and their prognostic significance in glioblastoma. Methods: The expression of IGFBP isoforms was analyzed in diffusely infiltrating astrocytomas by real-time quantitative PCR (n = 203) and immunohistochemistry (n = 256). Statistical methods were used to assess their grade-specific expression pattern and mRNA-protein intercorrelation. Survival analyses were done on a uniformly treated, prospective cohort of adult patients with newly diagnosed glioblastoma (n = 136) by using Cox regression models. Results: The mean transcript levels of IGFBP-2 and -3 were significantly higher in glioblastomas (GBM) relative to anaplastic astrocytoma (AA), diffuse astrocytoma (DA), and controls whereas IGFBP-5 mRNA was higher in GBM relative to AA and controls (P < 0.05). By immunohistochemistry, the mean labeling index of all isoforms was significantly higher in GBM compared with AA, DA, and control (P < 0.05). A strong positive correlation was observed between their respective mRNA and protein expressions (P < 0.01). Multivariate analysis revealed IGFBP-3 expression (hazard ratio, 1.021; P = 0.030) and patient age (hazard ratio, 1.027; P = 0.007) to be associated with shorter survival in glioblastoma. Conclusions: This study shows the associations of IGFBP-2, -3, and -5 expression with increasing grades of malignancy in astrocytomas. IGFBP-3 is identified as a novel prognostic glioblastoma biomarker. The strong correlation between their mRNA and protein expression patterns suggests their role in the pathogenesis of these tumors. Impact: IGFBP isoforms have emerged as biomarkers with diagnostic and prognostic utility in astrocytomas. Cancer Epidemiol Biomarkers Prev; 19(6); 1399–408. ©2010 AACR.

Non-motor features in essential tremor

Introduction –  Essential tremor (ET) is increasingly recognized to have several non‐motor manifestations. The aim of this study was to determine the prevalence of non‐motor manifestations in ET and its impact on the quality of life (QOL).

Heart rate variability and outcome in acute severe stroke: role of power spectral analysis.

AbstractIntroduction: Heart rate variability (HRV) is a predictor of outcome in acute myocardial infarction and head trauma. Its efficacy in predicting outcome in stroke has not been well documented. Materials and Methods: Twenty-five patients (mean age 39 years) with acute stroke treated in a stroke intensive care unit were studied. Continuous echocardiogram recorded for a 1-hour period was digitized and stored for off-line analysis. Time and frequency domain HRV measures were derived for the filtered and rectified ECG data for each patient. Clinical and HRV profiles were compared among patients who died or survived. Results: At admission, 16 patients were comatose (Glasgow Coma score <9 at admission), 16 had focal weakness, and all had abnormal brain computed tomography. Of the 25 patients, 11 died, 10 had a poor outcome, and 4 had good outcome. Two variables—low-frequency (LF) spectral power and very low-frequency (VLF) spectral power—correlated with mortality. After adjustment for mechanical ventilation and vasopressor administration, LF, VLF, and Triangular index of RR interval (TINN) correlated with mortality. On multiple regression analysis weighted for mechanical ventilation and vasopressor administration, the eye-opening score on Glasgow Coma Scale and LF spectral power were factors that were independently predictive of mortality. Conclusion: HRV measurements are independent predictors of outcome in acute severe stroke.

Pattern of subclinical pulmonary dysfunctions in Parkinson's disease and the effect of levodopa.

We performed a detailed evaluation of pulmonary function in 53 patients with idiopathic Parkinsons disease (PD) who did not have symptoms of pulmonary or cardiac dysfunction. There was a significant pulmonary dysfunction of restrictive type which partially responded to levodopa. Compared to men, women were more severely affected. Pulmonary function assessment is recommended in PD, irrespective of severity of disease.

Obsessive-compulsive disorder with and without tic disorder: a comparative study from India.

INTRODUCTION Evidence from phenomenological, family, genetic, and treatment studies from Western centers have suggested that tic-related obsessive-compulsive disorder (OCD) could be different from non-tic-related OCD. This study from India investigated the differences in OCD with and without tics, with respect to sociodemographics, symptom profile, and comorbidity, including obsessive-compulsive spectrum disorders, to examine whether the clinical profile of tic-related OCD is similar to that reported previously. METHODS Fifty subjects with OCD and tics (chronic motor tics and Tourette syndrome) were compared with 141 OCD subjects without tics. RESULTS Subjects having OCD with tics tended to be males, and had an earlier onset of illness. They had more of symmetry/aggressive and religious obsessions, and cleaning, ordering/arranging, hoarding, and repeating compulsions and were associated with trichotillomania and hypochondraisis. Stepwise backward (Wald) regression analysis showed that an early age of onset, male gender, aggressive obsessions, cleaning compulsions, and trichotillomania were significantly associated with tic-related OCD. CONCLUSION The findings of this study from India are broadly similar to those reported previously from the West indicating the universality of differences in tic- and non-tic-related OCD. Our findings also support the existing evidence that tics contribute to the heterogeneity of OCD.

Exploration of dimensions of psychopathology in neuroleptic-naı̈ve patients with recent-onset schizophrenia/schizophreniform disorder

Previous studies have suggested that schizophrenic psychopathology segregates into three orthogonal dimensions, viz., psychosis, negative and disorganization. Most of these reports were based on studies on medicated patients with varying degrees of chronicity. The present study aimed at exploring the dimensionality of psychopathology rated on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in a sample of 43 neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder. Principal Components Analysis (PCA) of SANS and SAPS global ratings, excluding inattention but including inappropriate affect as a separate global rating, revealed that the symptoms segregated into three dimensions, viz., negative (affective flattening, alogia, avolition anhedonia and inappropriate affect), psychosis (delusions and hallucinations) and disorganization (positive formal thought disorder and bizarre behavior). Cumulatively these three dimensions explained 74.07% of the variance. The results suggest that the three dimensions of schizophrenic psychopathology are valid even in neuroleptic-naïve, recent-onset patients with schizophrenia/schizophreniform disorder. PCA of the SANS and SAPS individual items revealed similar findings, but psychotic symptoms loaded under two components, thus yielding a four-factor solution; however, this observation needs to be confirmed in a larger sample of neuroleptic-naïve schizophrenic patients.

Sex differences in Indian patients with obsessive-compulsive disorder

Sex has been postulated as one of the factors mediating heterogeneity in obsessive-compulsive disorder (OCD). This study investigated the sex differences in OCD with respect to sociodemographics, symptom profile, and comorbidity including spectrum disorders. Two hundred thirty-one subjects diagnosed with OCD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria were included in the study. The subjects were evaluated by extensive clinical and semistructured interviews by expert clinical psychiatrists, and diagnosis was made by consensus. Male (n = 166) and female (n = 65) subjects with OCD were compared with respect to the data obtained. Males with OCD tended to have an earlier onset and had more symmetry/religious obsessions and miscellaneous compulsions. Males also showed a tendency to have attention deficit hyperactivity disorder. Female subjects were more likely to be married, have cleaning compulsions and be associated with trichotillomania. The findings support the hypothesis that there are sex differences in OCD, but the results are only partly comparable with other studies, suggesting that the phenotypic expression of OCD is possibly dependent on a complex interaction among biologic, personal, and cultural factors.

A Fourteen Gene GBM Prognostic Signature Identifies Association of Immune Response Pathway and Mesenchymal Subtype with High Risk Group

Background Recent research on glioblastoma (GBM) has focused on deducing gene signatures predicting prognosis. The present study evaluated the mRNA expression of selected genes and correlated with outcome to arrive at a prognostic gene signature. Methods Patients with GBM (n = 123) were prospectively recruited, treated with a uniform protocol and followed up. Expression of 175 genes in GBM tissue was determined using qRT-PCR. A supervised principal component analysis followed by derivation of gene signature was performed. Independent validation of the signature was done using TCGA data. Gene Ontology and KEGG pathway analysis was carried out among patients from TCGA cohort. Results A 14 gene signature was identified that predicted outcome in GBM. A weighted gene (WG) score was found to be an independent predictor of survival in multivariate analysis in the present cohort (HR = 2.507; B = 0.919; p<0.001) and in TCGA cohort. Risk stratification by standardized WG score classified patients into low and high risk predicting survival both in our cohort (p = <0.001) and TCGA cohort (p = 0.001). Pathway analysis using the most differentially regulated genes (n = 76) between the low and high risk groups revealed association of activated inflammatory/immune response pathways and mesenchymal subtype in the high risk group. Conclusion We have identified a 14 gene expression signature that can predict survival in GBM patients. A network analysis revealed activation of inflammatory response pathway specifically in high risk group. These findings may have implications in understanding of gliomagenesis, development of targeted therapies and selection of high risk cancer patients for alternate adjuvant therapies.