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author:("Gupta, parus")
1.  Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression 
Oncotarget  2014;5(7):1812-1828.
HER2, an oncogenic receptor is overexpressed in about 25-30% of breast cancer patients. HER2 has been shown to play role in tumor promotion by having cross-talk with multiple oncogenic pathways in cancer cells. Our results show that Cucurbitacin B (CuB), a triterpenoid steroidal compound inhibited the growth of various breast cancer cells with an IC50 ranging from 18-50nM after 48 and 72 h of treatment. Our study also revealed the significant inhibitory effects of CuB on HER2 and integrin signaling in breast cancer. Notably, CuB inhibited ITGA6 and ITGB4 (integrin α6 & integrin β4), which are overexpressed in breast cancer. Furthermore, CuB also induced the expression of major ITGB1and ITGB3, which are known to cause integrin-mediated cell death. In addition, we observed that TGFβ treatment resulted in the increased association of HER2 with ITGA6 and this association was inhibited by CuB treatment. Efficacy of CuB was tested in vivo using two different orthotopic models of breast cancer. MDA-MB-231 and 4T-1 cells were injected orthotopically in the mammary fat pad of female athymic nude mice or BALB/c mice respectively. Our results showed that CuB administration inhibited MDA-MB-231 orthotopic tumors by 55%, and 4T-1 tumors by 40%. The 4T-1 cells represent stage IV breast cancer and form very aggressive tumors. CuB mediated breast tumor growth suppression was associated with the inhibition of HER2/integrin signaling. Our results suggest novel targets of CuB in breast cancer in vitro and in vivo.
PMCID: PMC4039119  PMID: 24729020
Breast cancer; in vivo; ITGB4; ITGA6; Cucurbitacin B
2.  Combined Prosthesis with Extracoronal Castable Precision Attachments 
Case Reports in Dentistry  2013;2013:282617.
Satisfactory restoration in a patient with a partially edentulous situation can be challenging especially when unilateral or bilateral posterior segment of teeth is missing. Successful restoration can be done with various conventional and contemporary treatment options. One such treatment modality is attachment-retained cast partial dentures. This paper describes a case report of a patient with maxillary bilateral distal extension edentulous span restored with a cast partial denture having an extracoronal castable precision attachment (RHEIN 83 OT CAP attachments system).
doi:10.1155/2013/282617
PMCID: PMC3872092  PMID: 24383011
4.  Metastasis of Breast Tumor Cells to Brain Is Suppressed by Phenethyl Isothiocyanate in a Novel In Vivo Metastasis Model 
PLoS ONE  2013;8(6):e67278.
Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. The chances of brain metastasis are further elevated in patients with HER2 overexpression. In the current study, we evaluated the anti-metastatic effects of phenethyl isothiocyanate (PEITC) in a novel murine model of breast tumor metastasis. The MDA-MB-231-BR (BR-brain seeking) breast tumor cells stably transfected with luciferase were injected into the left ventricle of mouse heart and the migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent imaging system. In order to study the efficacy of PEITC in preventing the number of tumor cells migrating to brain, mice were given 10 µmol PEITC by oral gavage for ten days prior to intra-cardiac injection of tumor cells labeled with quantum dots. To evaluate the tumor growth suppressive effects, 10 µmol PEITC was given to mice every day starting 14th day after intra-cardiac cell injection. Based on the presence of quantum dots in the brain section of control and treated mice, our results reveal that PEITC significantly prevented the metastasis of breast cancer cells to brain. Our results demonstrate that the growth of metastatic brain tumors in PEITC treated mice was about 50% less than that of control. According to Kaplan Meir’s curve, median survival of tumor bearing mice treated with PEITC was prolonged by 20.5%. Furthermore as compared to controls, we observed reduced HER2, EGFR and VEGF expression in the brain sections of PEITC treated mice. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of PEITC in vivo in a novel breast tumor metastasis model and provides the rationale for further clinical investigation.
doi:10.1371/journal.pone.0067278
PMCID: PMC3695065  PMID: 23826254
5.  Comparative Transcriptome Analysis Using High Papaverine Mutant of Papaver somniferum Reveals Pathway and Uncharacterized Steps of Papaverine Biosynthesis 
PLoS ONE  2013;8(5):e65622.
The benzylisoquinoline alkaloid papaverine, synthesized in low amount in most of the opium poppy varieties of Papaver somniferum, is used as a vasodilator muscle relaxant and antispasmodic. Papaverine biosynthesis remains controversial as two different routes utilizing either (S)-coclaurine or (S)-reticuline have been proposed with uncharacterized intermediate steps. In an attempt to elucidate papaverine biosynthesis and identify putative genes involved in uncharacterized steps, we carried out comparative transcriptome analysis of high papaverine mutant (pap1) and normal cultivar (BR086) of P. somniferum. This natural mutant synthesizes more than 12-fold papaverine in comparison to BR086. We established more than 238 Mb transcriptome data separately for pap1 and BR086. Assembly of reads generated 127,342 and 106,128 unigenes in pap1 and BR086, respectively. Digital gene expression analysis of transcriptomes revealed 3,336 differentially expressing unigenes. Enhanced expression of (S)-norcoclaurine-6-O-methyltransferase (6OMT), (S)-3′-hydroxy-N-methylcoclaurine 4′-O-methyltransferase (4′OMT), norreticuline 7-O-methyltransferase (N7OMT) and down-regulation of reticuline 7-O-methyltransferase (7OMT) in pap1 in comparison to BR086 suggest (S)-coclaurine as the route for papaverine biosynthesis. We also identified several methyltransferases and dehydrogenases with enhanced expression in pap1 in comparison to BR086. Our analysis using natural mutant, pap1, concludes that (S)-coclaurine is the branch-point intermediate and preferred route for papaverine biosynthesis. Differentially expressing methyltransferases and dehydrogenases identified in this study will help in elucidating complete biosynthetic pathway of papaverine. The information generated will be helpful in developing strategies for enhanced biosynthesis of papaverine through biotechnological approaches.
doi:10.1371/journal.pone.0065622
PMCID: PMC3667846  PMID: 23738019
6.  De Novo Assembly, Functional Annotation and Comparative Analysis of Withania somnifera Leaf and Root Transcriptomes to Identify Putative Genes Involved in the Withanolides Biosynthesis 
PLoS ONE  2013;8(5):e62714.
Withania somnifera is one of the most valuable medicinal plants used in Ayurvedic and other indigenous medicine systems due to bioactive molecules known as withanolides. As genomic information regarding this plant is very limited, little information is available about biosynthesis of withanolides. To facilitate the basic understanding about the withanolide biosynthesis pathways, we performed transcriptome sequencing for Withania leaf (101L) and root (101R) which specifically synthesize withaferin A and withanolide A, respectively. Pyrosequencing yielded 8,34,068 and 7,21,755 reads which got assembled into 89,548 and 1,14,814 unique sequences from 101L and 101R, respectively. A total of 47,885 (101L) and 54,123 (101R) could be annotated using TAIR10, NR, tomato and potato databases. Gene Ontology and KEGG analyses provided a detailed view of all the enzymes involved in withanolide backbone synthesis. Our analysis identified members of cytochrome P450, glycosyltransferase and methyltransferase gene families with unique presence or differential expression in leaf and root and might be involved in synthesis of tissue-specific withanolides. We also detected simple sequence repeats (SSRs) in transcriptome data for use in future genetic studies. Comprehensive sequence resource developed for Withania, in this study, will help to elucidate biosynthetic pathway for tissue-specific synthesis of secondary plant products in non-model plant organisms as well as will be helpful in developing strategies for enhanced biosynthesis of withanolides through biotechnological approaches.
doi:10.1371/journal.pone.0062714
PMCID: PMC3648579  PMID: 23667511
7.  Multiple myeloma presenting as gingival hyperplasia 
Multiple myeloma is a malignant neoplasm that is characterized by a monoclonal proliferation of plasma cells. Oral and maxillofacial manifestations as an initial sign or symptom of multiple myeloma are rare. A 58-year-old male patient presented with generalized gingival enlargement for last 6 months. Based on clinical presentation, a diagnosis of gingival hyperplasia was made. After Phase I therapy, excisional biopsy was taken in anterior mandibular region and excised tissue was sent for histopathological examination. The histopathology report revealed a lining of stratified squamous epithelium with foci of ulceration. The subepithelial zone showed infiltration by sheets of mainly binucleate and multinucleate plasma cells, few cells being less differentiated. Rounded cytoplasmic inclusion bodies were identified in many of these cells. After a series of clinical investigations, a case of “multiple myeloma” was diagnosed. Patient presenting with generalized gingival hyperplasia should be worked up for systemic disease like multiple myeloma.
doi:10.4103/0972-124X.115652
PMCID: PMC3768194  PMID: 24049344
Gingival enlargement; multiple myeloma; plasma cells
8.  Inhibition of EGFR-AKT Axis Results in the Suppression of Ovarian Tumors In Vitro and in Preclinical Mouse Model 
PLoS ONE  2012;7(8):e43577.
Ovarian cancer is the leading cause of cancer related deaths in women. Genetic alterations including overexpression of EGFR play a crucial role in ovarian carcinogenesis. Here we evaluated the effect of phenethyl isothiocyanate (PEITC) in ovarian tumor cells in vitro and in vivo. Oral administration of 12 µmol PEITC resulted in drastically suppressing ovarian tumor growth in a preclinical mouse model. Our in vitro studies demonstrated that PEITC suppress the growth of SKOV-3, OVCAR-3 and TOV-21G human ovarian cancer cells by inducing apoptosis in a concentration-dependent manner. Growth inhibitory effects of PEITC were mediated by inhibition of EGFR and AKT, which are known to be overexpressed in ovarian tumors. PEITC treatment caused significant down regulation of constitutive protein levels as well as phosphorylation of EGFR at Tyr1068 in various ovarian cancer cells. In addition, PEITC treatment drastically reduced the phosphorylation of AKT which is downstream to EGFR and disrupted mTOR signaling. PEITC treatment also inhibited the kinase activity of AKT as observed by the down regulation of p-GSK in OVCAR-3 and TOV-21G cells. AKT overexpression or TGF treatment blocked PEITC induced apoptosis in ovarian cancer cells. These results suggest that PEITC targets EGFR/AKT pathway in our model. In conclusion, our study suggests that PEITC could be used alone or in combination with other therapeutic agents to treat ovarian cancer.
doi:10.1371/journal.pone.0043577
PMCID: PMC3428303  PMID: 22952709
9.  Antitumor activity of phenethyl isothiocyanate in HER2-positive breast cancer models 
BMC Medicine  2012;10:80.
Background
HER2 is an oncogene, expression of which leads to poor prognosis in 30% of breast cancer patients. Although trastuzumab is apparently an effective therapy against HER2-positive tumors, its systemic toxicity and resistance in the majority of patients restricts its applicability. In this study we evaluated the effects of phenethyl isothiocyanate (PEITC) in HER2-positive breast cancer cells.
Methods
MDA-MB-231 and MCF-7 breast cancer cells stably transfected with HER2 (high HER2 (HH)) were used in this study. The effect of PEITC was evaluated using cytotoxicity and apoptosis assay in these syngeneic cells. Western blotting was used to delineate HER2 signaling. SCID/NOD mice were implanted with MDA-MB-231 (HH) xenografts.
Results
Our results show that treatment of MDA-MB-231 and MCF-7 cells with varying concentrations of PEITC for 24 h extensively reduced the survival of the cells with a 50% inhibitory concentration (IC50) of 8 μM in MDA-MB-231 and 14 μM in MCF-7 cells. PEITC treatment substantially decreased the expression of HER2, epidermal growth factor receptor (EGFR) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr-705. The expression of BCL-2-associated × (BAX) and BIM proteins were increased, whereas the levels of B cell lymphoma-extra large (BCL-XL) and X-linked inhibitor of apoptosis protein (XIAP) were significantly decreased in both the cell lines in response to PEITC treatment. Substantial cleavage of caspase 3 and poly-ADP ribose polymerase (PARP) were associated with PEITC-mediated apoptosis in MDA-MB-231 and MCF-7 cells. Notably, transient silencing of HER2 decreased and overexpressing HER2 increased the effects of PEITC. Furthermore, reactive oxygen species (ROS) generation, mitochondrial depolarization and apoptosis by PEITC treatment were much higher in breast cancer cells expressing higher levels of HER2 (HH) as compared to parent cell lines. The IC50 of PEITC following 24 h of treatment was reduced remarkably to 5 μM in MDA-MB-231 (HH) and 4 μM in MCF-7 (HH) cells, stably overexpressing HER2. Oral administration of 12 μM PEITC significantly suppressed the growth of breast tumor xenografts in SCID/NOD mice. In agreement with our in vitro results, tumors from PEITC-treated mice demonstrated reduced HER2, EGFR and STAT3 expression and increased apoptosis as revealed by cleavage of caspase 3 and PARP. In addition our results show that PEITC can enhance the efficacy of doxorubicin.
Conclusions
Our results show a unique specificity of PEITC in inducing apoptosis in HER2-expressing tumor cells in vitro and in vivo and enhancing the effects of doxorubicin. This unique specificity of PEITC offers promise to a subset of breast cancer patients overexpressing HER2.
doi:10.1186/1741-7015-10-80
PMCID: PMC3412708  PMID: 22824293
apoptosis; doxorubicin; EGFR; ERBB2/HER2; in vivo; mitochondria; STAT3
10.  Expression and Clinicopathological Significance of Estrogen and Progesterone Receptors in Gallbladder Cancer 
ABSTRACT
BACKGROUND:
Clinical significance of sex hormone receptors in gallbladder cancer is not yet established. This study was performed to assess the expression pattern of estrogen and progesterone receptors in benign and malignant gallbladder lesions, and to assess their clinicopathological significance.
METHODS:
Tissue samples from resected gallbladder for cholelithiasis (n = 20) and carcinoma gallbladder (n = 25) were evaluated for estrogen and progesterone receptor (ER, PR) expression by automated immunohistochemistry. Their expression was correlated with different clinicopathological parameters.
RESULTS:
ER expression was significantly high (28%, 95% confidence interval [CI], 14–47) in gallbladder cancer than in chronic cholecystitis (0%; P = .012). PR expression did not differ in two groups (benign 40%, 95% CI, 21.8–61.4; malignant 52%, 95% CI, 33.5–69.9). Metaplastic benign lesions had near significant higher expression of PR (71.4%) than nonmetaplastic lesion (15.9%; P = .062). Their expression did not correlate with gender, age, menopausal status, presence of gallstones, tumor differentiation, and tumor stage.
CONCLUSION:
Female sex hormones play an important role in the gallbladder carcinogenesis. ER and PR may not have prognostic value. Presence of ER in ∼1/3 and PR in 1/2 of patients with carcinoma gallbladder suggests the potential role of antihormonal therapy.
PMCID: PMC3369597  PMID: 22690257
11.  Role of second trimester maternal serum markers as predictor of preeclampsia 
Objectives
To evaluate the variations and potential clinical use of second trimester serum markers as predictor of preeclampsia.
Methods
In a prospective study β HCG, α feto protein and inhibin A levels were estimated in 50 antenatal women in the second trimester (12–24 weeks) by ELISA technique. Results were noted in terms of development of preeclampsia, mean serum levels of all three markers, mode of delivery and fetal outcome.
Resuflts
Out of 50 women, 10 developed preeclampsia (20%). A significant rise of mean serum β HCG level (16130.2 MIU/ml, >2.5 MoM,p <0.001), mean serum AFP level (161.7 ng/ml, >2.5 MoM, P<0.001) and mean inhibin-A level (1248.49 pg/ml, >2.0 MoM, P<0.001) was present in those who developed preeclampsia. Out of 10 preeclamptic women one had IUD, four fetuses were growth retarded, two babies were born before term and six were low birth weight babies, whereas out of 40 normotensive women only five had IUGR, three preterm delivery and 32 delivered at term without and complication.
Conclusions
A significant positive correlation between second trimester serum markers and development of preeclampsia was observed (p<0.001). Thus with the second trimester serum marker study, prediction of preeclampsia is possible at incipient stage and its adverse pregnancy outcome can be minimized.
doi:10.1007/s13224-011-0014-y
PMCID: PMC3394578
β HCG; alfa feto protein; inhibin A; predictor of preeclampsia; preterm; IUGR
12.  Acinic Cell Carcinoma with Extensive Neuroendocrine Differentiation: A Diagnostic Challenge 
Head and Neck Pathology  2009;3(2):163-168.
Primary salivary gland carcinoma with neuroendocrine differentiation is of rare occurrence, especially so in the parotid gland. Amongst the various reported primary tumors with neuroendocrine differentiation, acinic cell carcinoma (ACC) one such tumor. A 48 year old lady presented with a gradually increasing right infra-auricular swelling for a period of 1 year which enlarged suddenly in a short period. Contrast Enhanced Computed Tomography (CECT) suggested diagnosis of Pleomorphic Adenoma. Fine Needle Aspiration Cytology (FANC) yielded a cystic fluid suggesting a possibility of Warthin’s tumor or Oncocytic lesion. Intraoperative findings were suggestive of a Warthin’s tumor. Initial histopathological examination of the tumor was suggestive of neuroendocrine carcinoma. However, extensive sectioning revealed peripheral islands of ACC. Immunoexpression of S-100, Neuron specific Enolase (NSE), Chromogranin A and Synaptophysin confirmed the diagnosis. The possibility of neuroendocrine differentiation in a primary salivary gland tumor should be kept in mind whenever a salivary gland tumor shows only neuroendocrine histology.
doi:10.1007/s12105-009-0114-5
PMCID: PMC2715458  PMID: 19644544
Neuroendocrine; Acinic cell; Warthin’s; Chromogranin; Carcinoma; Parotid
13.  Pseudogaucher cells obscuring multiple myeloma: a case report 
Cases Journal  2009;2:9147.
Gaucher-like or pseudo-Gaucher cells have been noted in a variety of conditions including acute lymphoblastic leukemia, Hodgkin's disease, thalassemia, and multiple myeloma. They have an eccentric, lobulated nucleus, foamy cytoplasm but lack the tubular inclusions seen in Gaucher cells. The pseudo-Gaucher cells have distinct appearances on electron microscopy which distinguish them from true Gaucher cells.
Increased pseudo-Gaucher cells probably reflects the increased load of leukocyte membrane derived glucosylceramide presented to macrophages under conditions of high cell turnover when the normal pathways for its removal may be saturated.
We present a case of a 72-year-old Indian Aryan female, in which the bone marrow contained sheets of histiocytes with features mimicking gaucher cells. These pseudo-Gaucher cells obscured neoplastic plasma cells causing diagnostic difficulty.
doi:10.1186/1757-1626-2-9147
PMCID: PMC2803944  PMID: 20062664
14.  The Gynecologic Oncology Consult: Symptom Presentation and Concurrent Symptoms of Depression and Anxiety 
Obstetrics and gynecology  2004;103(6):1211-1217.
Objective
To detail the relationship of gynecologic symptoms and sociodemographic variables to depression and anxiety reports among women who were referred to gynecologic oncologists for evaluation.
Methods
Consecutive patients (N = 151) from an National Cancer Institute–designated comprehensive cancer center were accrued and participated on the day of consultation. Patients completed measures assessing depression (Center for Epidemiological Studies Depression Scale) and anxiety (Beck Anxiety Inventory) symptoms, common gynecologic signs/symptoms, and sociodemographic characteristics. Patients were followed up and subsequent diagnoses yielded 73 (48%) cancer and 78 (52%) benign cases.
Results
Descriptive analyses revealed that the cancer group was significantly older (52 versus 45 years) than the benign group, and variables correlated with age also differed significantly, with the cancer sample more likely to be postmenopausal, unemployed, and if employed, working fewer hours per week. Importantly, the groups did not differ on reports of depressive, anxiety, or gynecologic symptoms. Hierarchical multiple regression analyses, collapsing across groups, yielded significant correlates of emotional distress. Women who were older, without a spouse/partner, and who had more gynecologic symptoms had higher levels of both depressive and anxiety symptoms. Among the women who did have a partner, those with relationships of longer duration reported lower levels of depression/anxiety
Conclusion
Reports of clinically significant depressive (42%) and anxiety symptoms (30%) were high. The number of gynecologic symptoms was reliably correlated with emotional distress. Age and absence of partner may have conferred added vulnerability. For those women with partners, lengthier relationships appeared to offer protection from both depressive and anxiety symptoms.
doi:10.1097/01.AOG.0000127983.70739.d8
PMCID: PMC2746486  PMID: 15172854
15.  Acinic Cell Carcinoma with Extensive Neuroendocrine Differentiation: A Diagnostic Challenge 
Head and Neck Pathology  2009;3(2):163-168.
Primary salivary gland carcinoma with neuroendocrine differentiation is of rare occurrence, especially so in the parotid gland. Amongst the various reported primary tumors with neuroendocrine differentiation, acinic cell carcinoma (ACC) one such tumor. A 48 year old lady presented with a gradually increasing right infra-auricular swelling for a period of 1 year which enlarged suddenly in a short period. Contrast Enhanced Computed Tomography (CECT) suggested diagnosis of Pleomorphic Adenoma. Fine Needle Aspiration Cytology (FANC) yielded a cystic fluid suggesting a possibility of Warthin’s tumor or Oncocytic lesion. Intraoperative findings were suggestive of a Warthin’s tumor. Initial histopathological examination of the tumor was suggestive of neuroendocrine carcinoma. However, extensive sectioning revealed peripheral islands of ACC. Immunoexpression of S-100, Neuron specific Enolase (NSE), Chromogranin A and Synaptophysin confirmed the diagnosis. The possibility of neuroendocrine differentiation in a primary salivary gland tumor should be kept in mind whenever a salivary gland tumor shows only neuroendocrine histology.
doi:10.1007/s12105-009-0114-5
PMCID: PMC2715458  PMID: 19644544
Neuroendocrine; Acinic cell; Warthin’s; Chromogranin; Carcinoma; Parotid
16.  A rare coexistence of concurrent breast hemangioma with fibroadenoma: a case report 
Cases Journal  2009;2:7005.
We report the case of a 38-year-old Asian, Indian female with capillary hemangioma breast in coexistence with the commonly occurring fibroadenoma. Clinical examination of the breast revealed a 4 cm diameter lump. Mammography revealed a well defined slightly hypoechoic lesion with smooth contours. A lumpectomy was performed. Histopathology confirmed the diagnosis of a completely encapsulated fibroadenoma coexistent with a capillary hemangioma in the adjacent breast tissue. The rarity of literature on breast hemangioma especially capillary type with coexisting fibroadenoma deserves mention.
doi:10.1186/1757-1626-2-7005
PMCID: PMC2740063  PMID: 19829893
17.  Fibroma with minor sex cord elements: a case report and review of the literature 
Cases Journal  2008;1:264.
Introduction
Ovarian fibroma is a rare neoplasm and the one with focal proliferations of sex cord type elements is rarer. Histopathological importance lies in the recognition of this entity due to the diagnostic dilemmas that these tumors can pose. To the best of our knowledge only 9 cases of ovarian fibroma with minor sex cord elements have been documented in world literature till date.
Case presentation
We report the case of a 65-year-old Indian female who presented with postmenopausal bleeding and pain abdomen. An ultrasound scan of the abdomen revealed a right ovarian mass. Histologically, the ovarian tumor was a fibroma with minor sex cord elements.
Conclusion
Clinical manifestations of a hyperestrogenic state in postmenopausal female should raise suspicion of this entity in the mind of a physician. Also a thorough evaluation of an ovarian fibroma would help detection of minor sex cord elements within the tumor and thus be a stepping stone for better evaluation of the pathogenesis and clinical behaviour of these tumors. A close follow up of the patient should be done as hyperestrogenemia may predispose to endometrial cancer.
doi:10.1186/1757-1626-1-264
PMCID: PMC2579288  PMID: 18947409

Results 1-17 (17)