Subramanyeshwar Rao

Electrical conductivity of NiZn ferrites

The electrical conductivity σ of polycrystalline NiZn ferrites of various compositions was investigated from room temperature to the neighbourhood of the Curie temperature. The electrical conduction in these ferrites is explained on the basis of the hopping mechanism. Plots of log(σT) versus 103/T are almost linear and show a transition near the Curie temperature. The activation energy in the ferrimagnetic region is in general less than that in the paramagnetic region.

Electrical conductivity of CoZn ferrites

Abstract The electrical conductivity of mixed CoZn ferrites was studied as a function of composition and temperature. The existence of the single-phase spinel structure was established by X-ray analysis of the specimens. The Seebeck coefficient for these ferrites was determined in order to discuss the conductivity which is explained in terms of the hopping mechanism. Plots of the logarithm of conductivity versus the reciprocal temperature are almost linear and show a transition near the Curie temperature. The activation energy in the paramagnetic region is higher than that in the ferrimagnetic region.

PNUTS Functions as a Proto-Oncogene by Sequestering PTEN

PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility, invasiveness, and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN-associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared with matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.

Evidence for possible non-canonical pathway(s) driven early-onset colorectal cancer in India.

Two genetic instability pathways viz. chromosomal instability, driven primarily by APC mutation induced deregulated Wnt signaling, and microsatellite instability (MSI) caused by mismatch repair (MMR) inactivation, together account for >90% of late‐onset colorectal cancer (CRC). Our understanding of early‐onset sporadic CRC is however comparatively limited. In addition, most seminal studies have been performed in the western population and analyses of tumorigenesis pathway(s) causing CRC in developing nations have been rare. We performed a comparative analysis of early and late‐onset CRC from India with respect to common genetic aberrations including Wnt, KRAS, and p53 (constituting the classical CRC progression sequence) in addition to MSI. Our results revealed the absence of Wnt and MSI in a significant proportion of early‐onset as against late‐onset CRC in India. In addition, KRAS mutation frequency was significantly lower in early‐onset CRC indicating that a significant proportion of CRC in India may follow tumorigenesis pathways distinct from the classical CRC progression sequence. Our study has therefore revealed the possible existence of non‐canonical tumorigenesis pathways in early‐onset CRC in India.

P53 nuclear stabilization is associated with FHIT loss and younger age of onset in squamous cell carcinoma of oral tongue

BackgroundSquamous cell carcinoma of tongue (SCCT) is expected to harbor unique clinico-pathological and molecular genetic features since a significant proportion of patients are young and exhibit no association with tobacco or alcohol.MethodsWe determined P53, epidermal growth factor receptor, microsatellite instability, human papilloma virus infection and loss of heterozygosity status at several tumor suppressor loci in one hundred and twenty one oral SCCT (SSCOT) samples and analyzed their association with clinico-pathological features and patient survival.ResultsOur results revealed a significantly higher incidence of p53 nuclear stabilization in early (as against late) onset SCCOT. FHIT loss was significantly associated with p53 nuclear stabilization and the association was stronger in patients with no history of tobacco use. Samples harboring mutation in p53 DNA binding domain or exhibiting p53 nuclear stabilization, were significantly associated with poor survival.ConclusionOur study has therefore identified distinct features in SCCOT tumorigenesis with respect to age and tobacco exposure and revealed possible prognostic utility of p53.

Distinct genetic aberrations in oesophageal adeno and squamous carcinoma

The two main oesophageal cancer subtypes namely adenocarcinoma and squamous cell carcinoma exhibit interesting clinical, pathological and geographical variations with the former being more common in the West and the latter in Asia.

Primary pulmonary leiomyosarcoma: a case report

Primary pulmonary leiomyosarcoma (PPL) is a very rare tumour. Presentation depends on the site of origin of tumour. Early detection and complete resection result in long-term survival. Complete surgical resection offers the only chance of cure. The role of radiotherapy or chemotherapy is not established.

Prostatic High-Grade Stromal Sarcoma—A Rare Encounter

Prostatic stromal sarcoma is a rare neoplasm, and we present a case of high-grade stromal sarcoma in a 50-year-old male with initial clinical presentation of difficulty in micturition. After initial evaluation by core needle biopsy, diagnosis was established on radical cystoprostatectomy specimen based on morphology and immunohistochemistry.

Abstract 3692: Transcriptome analysis of oral tongue cancer reveals novel insights into wild type and mutant TP53 transcription program

The p53 oncoprotein is a tumor suppressor that is stabilized upon various forms of cellular stresses to induce transcription of genes regulating cell cycle arrest or apoptosis. TP53 is the most frequently mutated gene in human cancers and majority of mutations are located in the region encoding the DNA binding domain compromising thereby its transcription activation ability and resulting in loss of function. Recent studies however suggest mutant p53 proteins to exhibit a gain of function property. Specific p53 missense mutations can result in an altered transcription program causing positive regulation of cell proliferation, metastasis and chemoresistance. In our previous studies, we performed comprehensive characterization of squamous cell carcinoma of the oral tongue (SCCOT) with respect to p53, EGFR, Wnt, MSI, LoH of several tumor suppressor loci and HPV status. Mutant p53 was a significant predictor of overall survival and the TP53 codon 72 Proline allele was significantly associated with SCCOT. In order to dissect the role of mutant p53 in tongue cancer, we performed genome wide DNA and RNA profiling of 26 and 40 SCCOT samples, respectively. Both mutant and wild type tumor samples appeared to exhibit comparable levels of DNA copy number alterations. Transcriptome data analyses using a combination of single sample gene set enrichment analysis and comparative marker selection revealed gene sets that could significantly distinguish p53 mutant and wild type tumor samples. Significance analysis of microarrays performed on all genes constituting the differentially enriched gene sets surprisingly identified only two genes to be upregulated in p53 mutant samples at a false discovery rate significantly lower than 10% namely TP53 itself and SMARCD1; the latter a member of the SWI/SNF chromatin remodelling complex. Elevated levels of TP53 transcript in tumors harbouring mutant p53 significantly correlated with levels of ZMAT3, itself induced by p53 and known to stabilize the TP53 transcript. In addition, the analysis revealed several known (ATF3 and others) and novel (GCHFR and others) targets of wild type p53. Differential expression of all targets was validated in additional tongue cancer samples. Ectopic expression of certain (but not all) p53 mutant proteins in p53 null cells induced SMARCD1 (but not canonical wild type p53 targets) while expression of wild type p53 induced GCHFR, ATF3, CDKN1A, etc. (but not SMARCD1). In contrast, p53 stabilization in cells harboring wild type p53 caused elevation of GCHFR, ATF3, CDKN1A, etc., but not of SMARCD1. Validation of novel targets using promoter-luciferase constructs, chromatin immunoprecipitation PCR and a tongue cancer tissue microarray is underway. This is perhaps the first evidence from Head and Neck tumor samples for a gain of function activity of mutant p53. Thus wild type and mutant p53 may support distinct transcription programs in tongue cancer. Citation Format: Raju SR Adduri, Padmavathi Kavadipula, Viswakalyan Kotapalli, Leena Bashyam, Anupama Shirke, Arun kumar Paripati, Swarnalata Gowrishankar, Mukta Srinivasulu, Mohammed Mujtaba Ali, Subramanyeshwar Rao, Snehalatha Dhagam, Mohana Vamsy Chigurupati, Shantveer G. Uppin, Vijaya Tourani, Murali D. Bashyam. Transcriptome analysis of oral tongue cancer reveals novel insights into wild type and mutant TP53 transcription program. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3692.

Abstract 1883: Clinical and molecular genetic analysis of squamous cell carcinoma of the oral tongue

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Squamous cell carcinoma of tongue (SCCT) is a common form of head and neck squamous cell carcinoma (HNSCC) in developing countries, mainly in India. In the last few decades, a steady increase in incidence rate of SCCT has been reported across the world. More importantly, though SCCT is considered to be a tobacco-related late-onset cancer, recent reports indicate an increase in incidence of SCCT in the young and in non-smokers. We analyzed the status of known tumorigenic pathways/genes including TP53, epidermal growth factor receptor (EGFR), microsatellite instability (MSI), CDKN2A, FHIT and human papilloma virus (HPV) infection in 120 surgically resected primary oral SCCT (SCCOT) samples and correlated with clinico-pathological variables and disease specific survival. 78 of 121 (65%) samples exhibited p53 nuclear stabilization confirming earlier reports. Interestingly, p53 nuclear stabilization was more common in young (36/46; 78%) than in older (44/75; 56%) patients (p = 0.0184). Further, PCR based mutation screening of exons 5-8 (encoding the DNA binding domain of p53) revealed mutations in ten of nineteen samples (52.6%) that exhibited p53 nuclear stabilization and in three of fifteen tumors (20%) that did not. We identified a novel 33bp deletion, c.616-648del33, located in exon 5 in a p53 positive tumor from a chronic tobacco chewer. Case control analysis revealed that Proline at TP53 codon 72 increased the risk of SCCOT. Majority of samples (97/121; 80%) exhibited significant EGFR expression though HPV infection was rare (14/106; 13%). MSI was observed in 14/106 (13%) samples, a frequency higher than reported for other populations. Loss of Heterozygosity (LOH) was more frequently observed in CDKN2A (28%) and FHIT (26%). In addition, LOH at FHIT locus was significantly associated with p53 nuclear stabilization (p = 0.0508), especially in non-smokers. A significant difference in survival rate between p53 positive and negative group (p = 0.0056) (Hazard ratio 2.5595) was observed. Though associated with p53 stabilization, FHIT loss did not exhibit significant effect on patient survival. Interestingly, patients exhibiting p53 nuclear stabilization as well as FHIT loss exhibited worse survival. We performed genome-wide DNA copy number and transcript profiling in several SCCOT samples. Interestingly, there was no significant difference in extent and profile of chromosomal instability in p53 positive and negative tumors. Amplifications were detected at chromosomal regions 3q26.1 (PIK3CA), 5p, 8q22 (MYC, RUNX1T1), 11q13 (CCND1) and 20q13 (HNFα). Genome-wide transcript profiling identified novel pathways that appear to drive tumorigenesis in tumors not exhibiting p53 inactivation. Our comprehensive analysis has therefore revealed important insights into the molecular basis for SCCOT and identified prognostic indicators in patients not associated with tobacco use. Citation Format: Raju S. Adduri, Viswakalyan Kotapalli, Rajender K K, Swarnalata Gowrishankar, Saumyadipta Pyne, Mukta Srinivasulu, Subramanyeshwar Rao, Shantveer G. Uppin, Mohammed Mujtaba Ali, Umanath K. Nayak, Snehalatha Dhagam, Mohana Vamsy Chigurupati, Murali D. Bashyam. Clinical and molecular genetic analysis of squamous cell carcinoma of the oral tongue. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1883. doi:10.1158/1538-7445.AM2014-1883