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1.  Clinical spectrum of Silver - Russell syndrome 
Contemporary Clinical Dentistry  2013;4(3):363-365.
Silver - Russell syndrome is a clinically and genetically heterogenous condition characterized by severe intrauterine and postnatal growth retardation, craniofacial disproportion and normal intelligence downward curvature of the corner of the mouth, syndactyly and webbed fingers. Diagnosis of Silver - Russell syndrome remains clinical; no definite etiology or specific tests have been established. In the recent years, it has been shown that more than 38% of patients have hypomethylation in the imprinting control region 1 of 11p15 and one-tenth of patients carry a maternal uniparental disomy of chromosome seven. The pathophysiological mechanisms resulting in the Silver - Russell phenotype remain unknown despite the recent progress in deciphering the molecular defects associated with this condition. This case report describes the clinical features of Silver - Russell syndrome in a father and daughter.
PMCID: PMC3793561  PMID: 24124306
Postnatal growth retardation; Silver - Russell syndrome; short stature
2.  A short report on chronic myeloid leukemia from Post Graduate Institute of Medical Education and Research, Chandigarh 
Post Graduate Institute (PGI) Chandigarh is a premier institute of North India. There are approximately 70,000 admissions per year. The adult clinical hematology department sees more than 2000 new patients per year. A preliminary analysis of 299 chronic myeloid leukemia patients registered from January 2001 until December 2007 was done. Out of these, 256 (86%) patients were in chronic phase (CP). The median age at presentation was 40 years. At 6 months of follow-up 95% of patients who were started on Imatinib mesylate based therapy remained in CP. Partial cytogenetic remission was seen in 69% of patients while complete cytogenetic response was seen in only 20% of patients at 6 months on Imatinib mesylate.
PMCID: PMC3902621  PMID: 24516306
Chronic myeloid leukemia; chronic phase; Post Graduate Institute
3.  Hematological Evaluation of Primary Extra Nodal Versus Nodal NHL: A Study from North India 
Primary extra nodal lymphomas (EN-NHL) are different from primary nodal non-Hodgkin’s lymphoma (N-NHL) and are comparatively less common. Hemogram findings and bone marrow involvement is less studied and very few reports are available in the literature. The present study is a retrospective analysis of bone marrow samples evaluated for staging of non-Hodgkin’s lymphoma. The age, sex distribution, clinical features, and site of presentation, hemogram findings, pattern of bone marrow involvement and grade of reticulin fibrosis was noted. These findings were compared with the type of non-Hodgkin’s lymphoma and prognostic information was determined. A total of 647 cases of NHL, which underwent bone marrow examination for staging, over a seven year period, were retrieved and analyzed for all hematological parameters. Prevalence of EN-NHL was 23.5% (152/647), while nodal NHL comprised 76.5% (495/647) of all NHL cases. 90.1% (137/152) cases of EN-NHL were adult patients, out of which 15.3% (21/137) cases showed bone marrow infiltration as compared to 89% (441/495) adult primary nodal NHL cases, of which 39% (175/441) showed bone marrow infiltration. 9.9% (15/152) cases of EN-NHL were pediatric patients, out of which 40% (6/15) showed bone marrow infiltration, while 10.9% (54/495) of nodal NHL cases were pediatric, of which 20.3% (11/54) showed bone marrow infiltration. Hemogram findings were not found useful in predicting bone marrow infiltration in both nodal as well as EN-NHL. 100% (6/6) of pediatric patients had high grade lymphoma as compared to 48% (9/21) of adult patients, showing bone marrow infiltration in EN-NHL group. Reticulin fibrosis also did not reveal relation with grading of NHL. Prognostically EN-NHL of stomach and central nervous system were found to be better than EN-NHL of other sites, as none of these cases showed bone marrow infiltration. EN-NHL can involve various sites and the prognosis depends upon the sites of disease as well as the type of NHL. Moreover, pediatric EN-NHL cases are likely to have poorer prognosis, due to increased risk of bone marrow involvement as compared to their counterparts having primary nodal NHL. Bone marrow infiltration at times cannot be assessed reliably from hemogram findings only and a bone marrow biopsy for staging is mandatory.
PMCID: PMC3136672  PMID: 22654298
Bone marrow; Extranodal non-Hodgkin’s lymphoma; Hemogram; Reticulin
4.  Cytogenetic & molecular analyses in adult chronic myelogenous leukaemia patients in north India 
Background & objectives:
Chronic myelogenous leukaemia (CML) is the commonest leukaemia in Asia. There is a paucity data on cytogenetic and molecular analyses of Indian CML patients. This apparently reflects the low availability of cytogenetic and molecular techniques in our country. This study aimed to document various types of BCR-ABL fusion transcripts in different phases of CML and to compare the Ph chromosome positivity/negativity vis-a-vis BCR-ABL fusion transcripts in adult CML patients.
Between June 2004 and February 2009, 208 patients were diagnosed as CML in chronic phase (CP), accelerated phase (AP) and blast crisis (BC), according to standard criteria. Cytogenetic and molecular genetic analyses were performed in all patients. Various types of BCR-ABL hybrid transcripts were compared with phases of CML and cytogenetic abnormalities.
Among 208 CML patients, b3a2 BCR-ABL transcripts were most commonly detected (66.82%) followed by b2a2 (28.84%), b3a2 + b2a2 (3.36%), b3a2 + e19a2 (0.48%) and b2a2 + e19a2 (0.48%). b3a2 transcripts were more frequently detected than b2a2 transcripts, in the whole group of 208 as well as in 183 CML-CP patients (P<0.0001). Ph chromosome was positive in 135 of 139 patients with b3a2 transcripts and 56 of 60 patients with b2a2 transcripts, difference not being significant. Additional cytogenetic abnormalities detected in 3.8 per cent patients in CML-CP and 44 per cent patients in CML-AP/BC, did not show predilection for any BCR-ABL transcript type.
Interpretation & conclusions:
This study documents higher Ph positivity (96.15%) by cytogenetic analysis among CML patients, as confirmed by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in a large patient group from north India. Both the techniques contribute towards understanding the disease biology, and have important implications for diagnosis and management of CML patients.
PMCID: PMC3307183  PMID: 22382182
BCR-ABL fusion transcripts; chronic myelogenous leukaemia; cytogenetic analysis; polymerase chain reaction; reverse transcriptase
5.  A Study on the Expression of BCR-ABL Transcript in Mixed Phenotype Acute Leukemia (MPAL) Cases Using the Reverse Transcriptase Polymerase Reaction Assay (RT-PCR) and its Correlation with Hematological Remission Status Post Initial Induction Therapy 
The MPAL comprise 2–5% of all acute leukemia. The present WHO 2008 classification has separated two groups in MPAL based on t(9;22) positivity and MLL rearrangement.
Aims & Objectives:
The aim of the present pilot study is to note the frequency of BCR-ABL transcript in MPAL cases using the RT-PCR assay and to correlate the status with hematological remission post induction.
Materials & Methods:
A total of 10 MPAL cases classified on Flow-cytometry based on the current WHO 2008 criteria were enrolled. In all the cases Bone marrow or peripheral blood sample in EDTA was processed for molecular studies and the RT-PCR reaction carried out using primers specific to the t (9;22) and t(4;11) translocation. The post induction check marrow slides were also reviewed.
Out of the total 10 MPAL cases, 7/10 (70%) were adult and 3/10 (30%) pediatric cases. A total of 4/10 (40%) cases showed positivity for the t(9;22) transcript and none for t (4;11). Of the 4 positive cases, 3/10(30%) were adult cases and 1/10(10%) pediatric case. The BCR-ABL transcript type in adult cases was b3a2 (p210) in 2/3 (66%) and e1a2 (p190) in 1/3 (33.3%) case. The single pediatric case was positive for b3a2 transcript.
Discussion & Conclusion:
All the 4 positive MPAL cases presented with high TLC and low platelet count (p<0.05). The positive cases also showed hematological remission at post induction check marrow (blasts<5%). This could partly be explained due to good response to the imatinib added to the treatment protocol.
PMCID: PMC3375663  PMID: 22708039
6.  Incidence of Common Fusion Transcripts in Adult and Pediatric Acute Myeloid Leukemia (AML) Cases: Experience of a Tertiary Care Research institute 
The incidence of common fusion transcripts in AML is 40–45%, but data from Indian sub-continent is limited.
Aims & Objectives
The aim of the present study is to note the incidence of common fusion transcripts of AML1-ETO, PML-RARA and CBFβ-MYH11 in adult and pediatric AML cases.
Materials & Methods
A total of 116 AML cases diagnosed on bone marrow, cytochemistry and Flow-cytometry over a period of 2 year were enrolled and bone marrow samples in EDTA were processed by multiplex RT-PCR assay.
Of 116 cases, 96 (83%) were adult and 20 (17%) pediatric cases. A total of 39/116 (33.6%) cases showed positivity for fusion transcripts of which 28/96 (29.16%) were adult and 11/20 (55%) pediatric cases. Of the 28 positive adult cases, 14/96 (14.58%) were positive for AML1-ETO, 12/96 (12.5%) for PML-RARA and 2/96 (2.08%) for CBFβ-MYH11. In the 11 positive pediatric cases, 6/20 (30%) were positive for AML1-ETO, 3/20 (15%) for PML-RARA and 2/20 (10%) for CBFβ-MYH11.
Discussion & Conclusion
The incidence of the common fusion transcripts in our pilot study is in accordance with that described in western studies. It is important to identify these transcripts as they provide useful prognostic information to the treating clinician.
PMCID: PMC3395706  PMID: 22811791
7.  A Case Series Highlighting the Relative Frequencies of the Common, Uncommon and Atypical/Unusual Hematological Findings on Bone Marrow Examination in Cases of Visceral Leishmaniasis 
Bone marrow aspiration and biopsy still remains as one of the vital tests for confirmation of diagnosis of visceral Leishmaniasis. The aim of the present study is to assess the relative frequency of common, uncommon and atypical hematological findings in cases of Visceral Leishmaniasis.
Materials & Methods:
A total of 16 cases of Leishmaniasis diagnosed on Bone marrow examination over a period of two years (2008–2010), were retrieved from the archives and the peripheral blood smear, bone marrow aspiration smears and trephine biopsies were examined for the common, uncommon and atypical features as described in the literature.
Out of the total of 16 cases, 10 were pediatric and 6 adult cases. The common findings like pancytopenia, peripheral blood monocytosis, increased histiocytes on aspirate smears and granulomas on biopsies were noted in 12/16 (75%), 9/16 (56.25%), 13/16 (81.2%) and 11/16 (69%) cases respectively. Amongst the uncommon findings, hemophagocytosis was noted in 12/16 (75%) cases, plasma cells with inclusions in 6/16 (37.5%) and LD bodies in cells other than histiocytes in 4/16 (25%) cases. The atypical findings included organism aggregates noted in 9/16 (56%) cases, Pelger-Heut cells seen in 4/16 (25%) cases and increased focal vascularity on biopsies in 10/16 (62.5%) cases. The average parasite density (APD) on smears was 3+ and the range of positivity was 1+ to 5+.
The knowledge of these morphological clues can assist us in searching for LD bodies and correctly diagnosing the condition without excessive dependence on unnecessary and sophisticated tests.
PMCID: PMC3212968  PMID: 22084650
8.  Spectrum and Prevalence of Fungi Infecting Deep Tissues of Lower-Limb Wounds in Patients with Type 2 Diabetes ▿  
Journal of Clinical Microbiology  2010;48(6):2097-2102.
The prevalence rate and spectrum of fungi infecting deep tissues of diabetic lower-limb wounds (DLWs) have not been previously studied. Five hundred eighteen (382 male and 136 female) consecutive patients with type 2 diabetes hospitalized due to infected lower-limb wounds were enlisted in this study. Deep tissue (approximately 0.5- × 0.5-cm size) taken perioperatively from the wound bed was cultured for fungi. Fungi was found in 27.2% (141/518) of the study population. Candida parapsilosis (25.5%), Candida tropicalis (22.7%), Trichosporon asahii (12.8%), Candida albicans (10.6%), and Aspergillus species (5.0%) were the most predominant fungal isolates. Of the fungal isolates, 17.7% were resistant to itraconazole, 6.9% were resistant to amphotericin B, 6.9% were resistant to voriconazole, 3.9% were resistant to fluconazole, and 1.5% were resistant to flucytosine. Of the population, 79.7% (413/518) had bacterial infection in deep tissue. The predominant isolates were Enterococcus faecalis (14.1%), Staphylococcus aureus (12.2%), and Pseudomonas aeruginosa (10.8%). Mixed fungal and bacterial infections were seen in 21.4% of patients, while 5.8% had only fungal infection and 58.3% had only bacterial infections. Another 14.5% had neither bacteria nor fungi in the deep tissue. Patients with higher glycosylated hemoglobin levels had significantly more fungal infections. Our study reveals that deep-seated fungal infections are high in DLWs. In the context of delayed wound healing and amputation rates due to DLWs, it is important to study the pathogenicity of fungi in deep tissues of DLWs and their possible contribution to delayed wound healing. The role of antifungal agents in wound management needs to be evaluated further.
PMCID: PMC2884499  PMID: 20410345
9.  Array comparative genomic hybridisation (aCGH) analysis of premenopausal breast cancers from a nuclear fallout area and matched cases from Western New York 
British Journal of Cancer  2005;93(6):699-708.
High-resolution array comparative genomic hybridisation (aCGH) analysis of DNA copy number aberrations (CNAs) was performed on breast carcinomas in premenopausal women from Western New York (WNY) and from Gomel, Belarus, an area exposed to fallout from the 1986 Chernobyl nuclear accident. Genomic DNA was isolated from 47 frozen tumour specimens from 42 patients and hybridised to arrays spotted with more than 3000 BAC clones. In all, 20 samples were from WNY and 27 were from Belarus. In total, 34 samples were primary tumours and 13 were lymph node metastases, including five matched pairs from Gomel. The average number of total CNAs per sample was 76 (range 35–134). We identified 152 CNAs (92 gains and 60 losses) occurring in more than 10% of the samples. The most common amplifications included gains at 8q13.2 (49%), at 1p21.1 (36%), and at 8q24.21 (36%). The most common deletions were at 1p36.22 (26%), at 17p13.2 (26%), and at 8p23.3 (23%). Belarussian tumours had more amplifications and fewer deletions than WNY breast cancers. HER2/neu negativity and younger age were also associated with a higher number of gains and fewer losses. In the five paired samples, we observed more discordant than concordant DNA changes. Unsupervised hierarchical cluster analysis revealed two distinct groups of tumours: one comprised predominantly of Belarussian carcinomas and the other largely consisting of WNY cases. In total, 50 CNAs occurred significantly more commonly in one cohort vs the other, and these included some candidate signature amplifications in the breast cancers in women exposed to significant radiation. In conclusion, our high-density aCGH study has revealed a large number of genetic aberrations in individual premenopausal breast cancer specimens, some of which had not been reported before. We identified a distinct CNA profile for carcinomas from a nuclear fallout area, suggesting a possible molecular fingerprint of radiation-associated breast cancer.
PMCID: PMC2361621  PMID: 16222315
amplification; array CGH; breast cancer; deletion; radiation
10.  A Systematic Approach to Design and Prepare Solid Dispersions of Poorly Water-Soluble Drug 
AAPS PharmSciTech  2014;15(3):641-657.
The objective of the present study was to define a systematic approach to design and prepare solid dispersions of poorly water-soluble drug. The systematic approach can be defined in four phases. In the first phase, glass forming ability is assessed, and in the second phase, probable excipients are screened. The screened excipients are evaluated (third phase) for glass transition temperatures (Tg) and miscibility studies according to Florey–Huggins interaction parameter. The predicted excipients are used to prepare the solid dispersion and evaluated for Tg and any interactions using Fourier transfer infrared studies (fourth phase), and the findings are correlated with phase three predictions. For this investigation, cilostazol (CIL) was selected as model drug, which was classified as a poor glass former. As per the physical chemical properties of CIL, ten excipients, both polymeric and non-polymeric, were selected and screened. Out of these, povidone, copovidone, hypromellose and Eudragit EPO were found theoretically miscible with CIL. After going through phase 2 to phase 4, only povidone, copovidone and hypromellose were confirmed as polymer of choice for preparing the solid dispersion of CIL with a prediction of better physical solid-state stability on the basis of good miscibility between drug and carrier.
PMCID: PMC4037479  PMID: 24563175
amorphous; cilostazol; glass transition temperature; miscibility; solid dispersions; solubility parameters
11.  Lobulated capillary haemangioma: a common lesion in an uncommon site 
BMJ Case Reports  2013;2013:bcr2012008535.
Pyogenic granuloma (PG) is a well-known localised granulation tissue overgrowth. It remains an aetiopathological enigma, with trauma, inflammatory and infectious agents being the suspected causative factors. It is a relatively common benign mucocutaneous lesion occurring intraorally or extraorally and is more common in women in the second decade of their lives than in men. Although it is a common lesion it may present with varying clinical features that sometimes may mimic more serious lesions such as malignancies. The clinical diagnosis of such lesion can be quite challenging. This case report drives attention towards the uncommon location of PG of lobular capillary haemangioma type occurring on anterior palate. Surgical excision of the lesion was planned because of the discomfort attributed to large size of the lesion and hindrance in mastication.
PMCID: PMC3604419  PMID: 23417947
12.  Image Diagnosis: Weber Syndrome: A Rare Presentation of Acute Leukemia—A Case Report and Review of the Literature 
The Permanente Journal  2015;19(1):83-85.
For two weeks before presentation, a 13-year-old boy had fever, fatigue, and breathlessness, and painless lymphadenopathy on both sides of his neck, axilla, and groin. He developed drooping of the right upper eyelid. Non-contrast computed tomography scans of the head showed multiple hemorrhages.
PMCID: PMC4315385  PMID: 25663211
13.  Study of Insulin Resistance in Subclinical Hypothyroidism 
Thyroid hormones influences glucose homeostasis. The association of insulin resistance in overt hypothyroidism is well proven, but very less information is available about insulin action on subclinical hypothyroidism.
This study was done to evaluate the association between thyroid hormones and insulin resistance in subclinical hypothyroidism (SCH).
Materials and Methods
Thirty subjects diagnosed as SCH and 30 age matched euthyroids were included. Serum TSH, FT3, FT4, fasting plasma glucose and insulin were estimated. Homeostasis Model Assessment was used to assess insulin resistance (HOMA- IR).
Results and Conclusion
Serum TSH levels were significantly increased in SCH (14.20 ± 5.23 μU/ml) when compared with euthyroids (2.24 ±1.43μU/ml; P< 0.0001). Serum FT3, FT4 levels in SCH (2.96±0.80 pg/ml & 1.15 ± 0.52 ng/dl) were within the normal range.
The mean insulin levels were significantly elevated in SCH (9.07±3.41 μU/ml) when compared with euthyroids (5.28± 2.18 μU/ml; P-value < 0.0001).
The mean HOMA IR was significantly elevated in SCH (2.03 ± 0.95) when compared with euthyroids (1.05±0.45, P-value < 0.0001).
TSH levels positively and moderately correlated with insulin (r= 0.43 P=0.03) and HOMA IR (r =0.48; P= 0.01). FT3 levels negatively and strongly correlated with insulin (r= -0.5, P=0.004) and moderately with HOMA IR (r= -0.38, P= 0.04). FT4 levels negatively and weakly correlated with insulin and IR (r= - 0.11, P=0.54; r= - 0.07, P=0.69 respectively).
To conclude, SCH is associated with insulin resistance. Hence there is an increased risk of insulin resistance associated disorders such as metabolic syndrome, cardiovascular events in SCH.
PMCID: PMC4286301  PMID: 25580384
Subclinical hypothyroidism (SCH); Insulin resistance (HOMA IR)
14.  Cardiovascular risks and brain function: a functional magnetic resonance imaging study of executive function in older adults 
Neurobiology of aging  2013;35(6):1396-1403.
Cardiovascular (CV) risk factors, such as hypertension, diabetes, and hyperlipidemia are associated with cognitive impairment and risk of dementia in older adults. However, the mechanisms linking them are not clear. This study aims to investigate the association between aggregate CV risk, assessed by the Framingham general cardiovascular risk profile, and functional brain activation in a group of community-dwelling older adults. Sixty participants (mean age: 64.6 years) from the Brain Health Study, a nested study of the Baltimore Experience Corps Trial, underwent functional magnetic resonance imaging using the Flanker task. We found that participants with higher CV risk had greater task-related activation in the left inferior parietal region, and this increased activation was associated with poorer task performance. Our results provide insights into the neural systems underlying the relationship between CV risk and executive function. Increased activation of the inferior parietal region may offer a pathway through which CV risk increases risk for cognitive impairment.
PMCID: PMC4282177  PMID: 24439485
Cardiovascular risk; Framingham risk score; fMRI; Brain function; Executive function; Older adults
15.  Development and Clinical Evaluation of sdaA Loop-Mediated Isothermal Amplification Assay for Detection of Mycobacterium tuberculosis with an Approach To Prevent Carryover Contamination 
Journal of Clinical Microbiology  2014;52(7):2662-2664.
A rapid and sensitive loop-mediated isothermal amplification assay for the sdaA gene of Mycobacterium tuberculosis was developed using a dUTP-uracil-N-glycosylase (dUTP-UNG) strategy to prevent carryover contamination. Evaluation of the assay using clinical specimens (n = 648) showed high specificity (97.2%) and sensitivity (100%), demonstrating its potential as a diagnostic test for tuberculosis, especially in resource-limited settings.
PMCID: PMC4097723  PMID: 24789191
16.  Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation 
Cancer research  2013;74(1):341-352.
Currently only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TICs) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2 or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2 targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of breast cancer patients than they currently reach.
PMCID: PMC3917843  PMID: 24177178
breast cancer; tumor-initiating cells; HER2/HER3 signaling; neuregulin; lapatinib
17.  Rapidly progressive renal failure in a patient with extranodal non-Hodgkin's lymphoma 
Indian Journal of Nephrology  2015;25(1):43-45.
A 60-year male was admitted with advanced renal failure and bilaterally enlarged kidneys. Kidney biopsy revealed diffuse interstitial infiltration by CD20 + lymphomatous cells suggestive of diffuse large B-cell, non-Hodgkin's lymphoma. Bone marrow examination was negative for malignant cells. Positron emission tomography-computed tomography showed uniformly diffuse and avid flurodeoxy glucose uptake in both kidneys, multiple hypodense areas of both lobes of liver, and axial and appendicular skeleton. Patient was treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone, became afebrile and serum creatinine normalized.
PMCID: PMC4323911
Primary renal lymphoma; complication; rapidly progressive renal failure
18.  HET0016, a Selective Inhibitor of 20-HETE Synthesis, Decreases Pro-Angiogenic Factors and Inhibits Growth of Triple Negative Breast Cancer in Mice 
PLoS ONE  2014;9(12):e116247.
A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors. HET0016 effects were analyzed on MDA-MB-231 derived breast cancer in mouse and in vitro cell line. MDA-MB-231 tumor cells were implanted in animals’ right flank and randomly assigned to early (1 and 2), starting treatments on day 0, or delayed groups (3 and 4) on day 8 after implantation of tumor. Animals received HET0016 (10 mg/kg) treatment via intraperitoneal injection for 5 days/week for either 3 or 4 weeks. Control group received vehicle treatment. Tumor sizes were measured on days 7, 14, 21, and 28 and the animals were euthanized on day 22 and 29. Proteins were extracted from the whole tumor and from cells treated with 10 µM HET0016 for 4 and 24 hrs. Protein array kits of 20 different cytokines/factors were used. ELISA was performed to observe the HIF-1α and MMP-2 protein expression. Other markers were confirmed by IHC. HET0016 significantly inhibited tumor growth in all treatment groups at all-time points compared to control (p<0.05). Tumor growth was completely inhibited on three of ten animals on early treatment group. Treatment groups showed significantly lower expression of pro-angiogenic factors compared to control at 21 days; however, there was no significant difference in HIF-1α expression after treatments. Similar results were found in vitro at 24 hrs of HET0016 treatment. After 28 days, significant increase of angiogenin, angiopoietin-1/2, EGF-R and IGF-1 pro-angiogenic factors were found (p<0.05) compared to control, as well as an higher intensity of all factors were found when compared to that of 21 day’s data, suggesting a treatment resistance. HET0016 inhibited tumor growth by reducing expression of different set of pro-angiogenic factors; however, a resistance to treatment seemed to happen after 21 days.
PMCID: PMC4280215  PMID: 25549350
19.  Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma 
Biomedical Optics Express  2014;6(1):98-111.
Multimodal spectral imaging (MSI) based on auto-fluorescence imaging and Raman micro-spectroscopy was used to detect basal cell carcinoma (BCC) in tissue specimens excised during Mohs micrographic surgery. In this study, the MSI algorithm was optimized to maximize the diagnosis accuracy while minimizing the number of Raman spectra: the segmentation of the auto-fluorescence images was optimized according to the type of BCC, sampling points for Raman spectroscopy were generated based on auto-fluorescence intensity variance and segment area, additional Raman spectra were acquired when performance of the segmentation algorithm was sub-optimal. The results indicate that accurate diagnosis can be achieved with a sampling density of ~2,000 Raman spectra/cm2, based on sampling points generated by the MSI algorithms. The key benefit of MSI is that diagnosis of BCC is obtained based on intrinsic chemical contrast of the tissue, within time scales similar to frozen-section histopathology, but without requiring laborious sample preparation and subjective interpretation of stained frozen-sections.
PMCID: PMC4317116  PMID: 25657878
(170.0170) Medical optics and biotechnology; (170.5660) Raman spectroscopy; (170.4580) Optical diagnostics for medicine; (170.1870) Dermatology
20.  Closing the Loop: Modelling of Heart Failure Progression from Health to End-Stage Using a Meta-Analysis of Left Ventricular Pressure-Volume Loops 
PLoS ONE  2014;9(12):e114153.
The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for the classification of heart failure (HF) are descriptive but lack precise and objective measures which would assist in categorising such patients. Our aim was two fold, firstly to demonstrate quantitatively the progression of HF through each stage using a meta-analysis of existing left ventricular (LV) pressure-volume (PV) loop data and secondly use the LV PV loop data to create stage specific HF models.
Methods and Results
A literature search yielded 31 papers with PV data, representing over 200 patients in different stages of HF. The raw pressure and volume data were extracted from the papers using a digitising software package and the means were calculated. The data demonstrated that, as HF progressed, stroke volume (SV), ejection fraction (EF%) decreased while LV volumes increased. A 2-element lumped parameter model was employed to model the mean loops and the error was calculated between the loops, demonstrating close fit between the loops. The only parameter that was consistently and statistically different across all the stages was the elastance (Emax).
For the first time, the authors have created a visual and quantitative representation of the AHA/ACC stages of LVSD-HF, from normal to end-stage. The study demonstrates that robust, load-independent and reproducible parameters, such as elastance, can be used to categorise and model HF, complementing the existing classification. The modelled PV loops establish previously unknown physiological parameters for each AHA/ACC stage of LVSD-HF, such as LV elastance and highlight that it this parameter alone, in lumped parameter models, that determines the severity of HF. Such information will enable cardiovascular modellers with an interest in HF, to create more accurate models of the heart as it fails.
PMCID: PMC4257583  PMID: 25479594
21.  Molecular Targets and Treatment of Meningioma 
Meningiomas are by far the most common tumors arising from the meninges. A myriad of aberrant signaling pathways involved with meningioma tumorigenesis, have been discovered. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. An understanding of the genetic and molecular profile of meningioma would provide a valuable first step towards developing more effective treatments for this intracranial tumor. Chromosomes 1, 10, 14, 22, their associated genes, and other potential targets have been linked to meningioma proliferation and progression. It is presumed that through an understanding of these genetic factors, more educated meningioma treatment techniques can be implemented. Future therapies will include combinations of targeted molecular agents including gene therapy, si-RNA mediation, proton therapy, and other approaches as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas. This review provides an overview of the current knowledge of the genetic, signaling and molecular profile of meningioma and possible treatments strategies associated with such profiles.
PMCID: PMC4255716  PMID: 25485306
Meningioma; Tumorgenesis; Molecular genetics; NF2; Merlin; Proliferation
22.  Reply: ‘Central retinal artery occlusion and cerebral stroke' 
Eye  2013;27(12):1422-1423.
PMCID: PMC3869518  PMID: 24097117
23.  A Novel Approach for Restoration of Hemisectioned Mandibular Second Molar with Modified Tunnel Restoration: A Case Report 
Hemisection refers to sectioning of a mandibular molar into two halves followed by removal of the diseased root and its coronal portion. Hemisection of a mandibular molar may be a suitable treatment option when the decay is restricted to one root and the other root is healthy. The retained root is endodontically treated and the furcation area is made self-cleansable. Retained tooth structure is restored as premolar which helps to reduce the masticatory load. Hemisection of mandibular molar was often referred to as premolarization. Studies showed that the remaining coronal structure influenced the fracture resistance of endodontically treated maxillary first premolars. Clinical experience showed the viability of tunnel restoration as an alternative to class II conventional cavity preparation in initial proximal lesion. This article discusses a case that presents the novel technique involved in restoration of the remaining hemisected tooth using modified tunnel restoration.
PMCID: PMC4253278  PMID: 25478460
Hemisection; Mandibular molars; Root canal treatment; Tunnel restoration
24.  Impacted Teeth: A Radiographic Pictorial Essay 
PMCID: PMC4253297  PMID: 25478479
Impaction; Radiographic essay; Radiography of impaction; Types of impaction
25.  The influence of finishing/polishing time and cooling system on surface roughness and microhardness of two different types of composite resin restorations  
The aim of this study was to evaluate the effect of finishing time and polishing time on surface roughness and microhardness of nanofilled and hybrid resin composites.
Materials and Methods:
Hundred disk composite specimens from micro hybrid composite and nanohybrid composite were prepared, 50 for each type of composite. The specimens were divided into five groups according to the time of finishing and polishing (immediate, 15 min, 24 h and dry). Composite under the Mylar strip without finishing and polishing was taken as the control group. Surface roughness was measured with environmental scanning electronic microscope (ESEM) and microhardness was determined using Vickers Microhardness Tester. Data collected were statistically analyzed by t-test and one-way analysis of variance (ANOVA) followed by Turkey's post hoc test.
Smooth surface with low hardness was obtained for the group under Mylar strip without finishing and polishing. The highest roughness was recorded for delayed finishing and polishing for both composites. Immediate finishing and polishing increased the surface hardness more than that in the control group in both types of composites. Dry finishing reduced the hardness significantly for micro hybrid composite, but resulted in the highest surface hardness for nanofilled composite.
Immediate finishing and polishing under coolant resulted in the best surface smoothness and hardness values in micro hybrid composite; however, immediate dry finishing and polishing gave the best smoothness and hardness values in nanohybrid composite.
PMCID: PMC4278109  PMID: 25558457
Microhardness; resin composite; roughness

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