Rare Presentations of Differentiated Thyroid Cancer Exposing Dr Jekyll and Mr Hyde Nature of an Otherwise Indolent Disease: Case Series.

ABSTRACT: Differentiated thyroid carcinoma (DTC) usually manifests as an indolent cancer with good prognosis. However, rarely uncommon sites of metastatic involvement can worsen the prognosis and require aggressive therapeutic approach. Here in, we describe 5 patients (3 women and 2 men) harboring rare sites of metastatic involvement from DTC including the adrenals, colon, kidneys, urinary bladder, brachial plexus, and superior vena cava with contiguous right atrial involvement. The awareness of such rare sites of involvement from DTC is imperative for treating clinicians to plan individualistic approach in management including multiprong therapies for better patient care.

Cellular and molecular mechanisms of curcumin in prevention and treatment of disease.

Curcumin is a naturally occurring polyphenolic compound present in rhizome of Curcuma longa belonging to the family zingiberaceae. Growing experimental evidence revealed that curcumin exhibit multitarget biological implications signifying its crucial role in health and disease. The current review highlights the recent progress and mechanisms underlying the wide range of pharmacological effects of curcumin against numerous diseases like neuronal, cardiovascular, metabolic, kidney, endocrine, skin, respiratory, infectious, gastrointestinal diseases and cancer. The ability of curcumin to modulate the functions of multiple signal transductions are linked with attenuation of acute and chronic diseases. Numerous preclinical and clinical studies have revealed that curcumin modulates several molecules in cell signal transduction pathway including PI3K, Akt, mTOR, ERK5, AP-1, TGF-ß, Wnt, ß-catenin, Shh, PAK1, Rac1, STAT3, PPARγ, EBPα, NLRP3 inflammasome, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4 and MyD-88. Curcumin has a potential to prevent and/or manage various diseases due to its anti-inflammatory, anti-oxidant and anti-apoptotic properties with an excellent safety profile. In contrast, the anti-cancer effects of curcumin are reflected due to induction of growth arrest and apoptosis in various premalignant and malignant cells. This review also carefully emphasized the pharmacokinetics of curcumin and its interaction with other drugs. Clinical studies have shown that curcumin is safe at the doses of 12 g/day but exhibits poor systemic bioavailability. The use of adjuvant like piperine, liposomal curcumin, curcumin nanoparticles and curcumin phospholipid complex has shown enhanced bioavailability and therapeutic potential. Further studies are warranted to prove the potential of curcumin against various ailments.

Audit of stored strain energy and extent of future earthquake rupture in central Himalaya.

The deadly 25 April 2015 Gorkha earthquake (Mw = 7.8) and aftershocks have partially released the accumulated interseismic strain along the Main Himalayan Thrust (MHT). Postseismic deformation associated with this earthquake is mainly confined to the north of the rupture. This suggests possible occurrence of future large events towards west or south, where MHT is locked. Asperities arising due to heterogeneity in the stress-strain patterns are believed to play a major role in controlling the coseismic rupture propagation. We determine interseismic coupling along the MHT and spatial variations in total strain rate using two decades of GPS, InSAR and sprit leveling data. Further, b-values derived from the seismicity data are used to identify zones of stress accumulation. We demonstrate that the 2015 earthquake ruptured an asperity which hosted high strain and stress accumulation prior to the event. A similar asperity towards west of the epicenter with unreleased strain energy is identified. This could spawn a future large earthquake akin in magnitude to the 2015 Gorkha event. These findings compel a revisit of the seismic hazard assessment of the central Himalaya.

Evidence of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-PSMA-HBED-CC PET/CT.

PURPOSE OF THE REPORT: Prostate-specific membrane antigen (PSMA) overexpression is not restricted to prostate cancer, but it has also been demonstrated in gliomas, lung cancer, and in tumor neovasculature. Systematic studies exploring PSMA uptake in thyroid tumors are lacking. The aim of this pilot study was to assess PSMA expression in patients with metastatic differentiated thyroid cancer (mDTC). MATERIALS AND METHODS: Ten patients of mDTC harboring 32 lesions (5 men; age range, 38-65 years; mean age, 50 years) underwent prospective evaluation with radioiodine (I), F-FDG PET, and Ga-PSMA-HBED-CC PET scans as per the institution protocol. PSMA expression (SUVmax) was compared with F-FDG and I scan findings in all patients. RESULTS: Lesions were radioiodine avid in 8 patients, whereas 2 were classified as thyroglobulin elevation with negative iodide scintigraphy (TENIS) patients. All patients with iodine-avid metastatic disease showed substantial PSMA uptake. PSMA PET detected 30/32 total lesions (93.75%; SUVmax ranging from 4.86 to 101.81 with median SUVmax of 31.35), whereas FDG PET/CT was positive in 23/32 lesions (81.85%). Twenty-one (70%) of 30 lesions that showed PSMA expression were localized to the bones. PSMA localized a lesion in each of the 2 TENIS patients similar to FDG PET scan. CONCLUSIONS: Ga-PSMA-HBED-CC PET/CT is a potentially useful imaging modality in patients of mDTC with most (70%) of PSMA expressing metastasis being localized to the bones. PSMA PET/CT could be useful for identifying patients with limited therapeutic options (eg, TENIS) who might benefit from PSMA-targeted radionuclide therapy.

Parathyroid Cancer Causing Acute Severe Pancreatitis.

Parathyroid carcinoma is a rare disease and accounts for less than 1% of all cases of primary hyperparathyroidism. Many times, parathyroid carcinoma is detected only after surgery. Parathyroid carcinoma as a cause of acute pancreatitis is uncommon. We report this case of acute severe pancreatitis associated with parathyroid carcinoma. Hypercalcemia was found during workup for acute pancreatitis which was due to primary hyperparathyroidism. During surgery, there was a suspicion of parathyroid carcinoma and en bloc resection was done followed by adjuvant radiation therapy. It is important to treat the precipitating factor for acute pancreatitis. Surgery is the mainstay of treatment for parathyroid carcinoma.

Thiazolidine: A Potent Candidate for Central Nervous Systems Diseases.

Thiazolidines are multifaceted molecules and exhibit varied types of biological activities, and also showed anticonvulsants and antidepressants activity. It is the diversified class of heterocyclic compounds. Thiazolidinediones (TZD) has been shown beneficial action in various CNS diseases. The significant mechanism of TZD-induced neuroprotection useful in prevention of microglial activation and cytokine that is responsible for inflammatory condition and chemokine expression. At the molecular level TZDs were also responsible to prevent the activation of pro-inflammatory transcription factors as well as promoting the anti-oxidant mechanisms in the injured CNS. Important SAR, molecular mechanism and potent biological activities with special references to central nervous system are discussed in this article. Various investigations suggest that this moiety pave the way for design and discovery of new drug candidates.

Role of telemedicine technology in endocrine surgery knowledge sharing.

INTRODUCTION: This retrospective study was designed to assess the outcome of telemedicine technology supportive of educational collaboration among endocrine surgery peers and its impact on knowledge and skill development. MATERIALS AND METHODS: The study was carried out in the Department of Endocrine Surgery in collaboration with School of Telemedicine and Biomedical Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, during October 1999-December 2012. Telemedicine activities were divided into various modules (e.g., case/problem-based learning, clinical grand rounds, postgraduate course/continuing medical education/conference). Endocrine surgeons participating in such sessions were divided into two groups (faculty and residents). A multimodule questionnaire was constructed based on a Likert scale (2-7 points) to test various aspects (e.g., technical performance, role in knowledge exchange, skill development, level of satisfaction, and future recommendations). Responses were expressed in proportions, and the chi-squared test was used to find the differences in opinions of the study groups. RESULTS: The questionnaire was sent to 38 surgeons, of whom 36 replied (response rate, 94.74%); of these respondents, 14 were faculty and 22 were residents. More than 80% of participants felt that the technology helped in learning new things and strengthening relations with peers, whereas >90% were of the view that it helped in knowledge exchange and development of skills as well as was helpful in supporting clinical decisions. More than 90% of participants were satisfied and enjoyed using this technology and also were of the opinion that the technology should be integrated into other specialties. Satisfaction with the technology was excellent to good for 94.44% of participants. Both faculty and residents were of the same opinion, and there was no significant difference in their replies. CONCLUSIONS: Knowledge sharing in a collaborative environment using telemedicine technology has been found successful in a low-resource setting and is now adopted in the departmental educational program.

Next generation tyrosine kinase inhibitor (TKI): afatinib.

Afatinib is a recently introduced new tyrosine kinase inhibitor, approved by the USFDA on July 12, 2013. Afatinib is marketed under the trade name Gilotrif and developed by Boehringer Ingelheim GmbH. It is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) carrying EGFR exon 19 deletions or exon 21 (L858R) mutations. Afatinib is a covalent, irreversible inhibitor of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and HER4. Chemically afatinib is a 4-anilinoquinazoline derivative, having an acrylamide warhead. Gilotrif is the formulation of Afatinib di-meleate salt. Presently, afatinib has been approved in the USA, the European Union, Taiwan and Mexico. In this review, we have summarized the chemical characterization of afatinib, its synthesis, patent status, marketed formulation, available crystalline form and current clinical trials.

Prospective study to compare peri-operative hemodynamic alterations following preparation for pheochromocytoma surgery by phenoxybenzamine or prazosin.

BACKGROUND: Prospective studies comparing the efficacy of selective versus nonselective alpha blockers for preoperative preparation of pheochromocytoma (PCC) are lacking. In this prospective nonrandomized study, we compared the outcome of preoperative preparation with phenoxybenzamine (PBZ) and prazosin (PRZ) in terms of perioperative hemodynamic alterations. METHODS: The study was conducted at a tertiary referral center from July 2010 to December 2012. Thirty-two patients with PCC underwent operation after adequate preparation with PBZ (n = 15) or PRZ (n = 17). Five pediatric and adolescent patients were excluded because of different hemodynamics in this population. Perioperative monitoring was done for pulse rate (PR) and blood pressure(BP) alterations, occurrence of arrhythmias, and time taken to achieve hemodynamic stability. Groups were compared with the Mann-Whitney test, Student's t test, and the χ2 test as applicable. RESULTS: Patients in the two groups were similar in age,gender, 24 h urinary metanephrine and normetanephrine levels, and type of procedure. Patients prepared with PRZ had significantly more intraoperative episodes of transient hypertension (systolic BP ≥ 160 mmHg) and hypertensive urgency (BP >180/110 mmHg) (p 0.02, 0.03, respectively). More patients receiving PRZ suffered from transient severe hypertension (SBP ≥ 220 mmHg) (p 0.03). The PRZ group also had more median maximum SBP (233 mmHg vs PBZ 181.5 mmHg) (p = 0.01) and lesser median minimum SBP (71 mmHg vs PBZ 78 mmHg) (p 0.03). No significant differences were found between the study groups for changes in PR, postoperative BP alterations,occurrence of arrhythmias, and time taken to achieve hemodynamic stability. CONCLUSIONS: PBZ was found superior to PRZ in having fewer intraoperative hemodynamic fluctuations.

The first approved agent in the Glitazar's Class: Saroglitazar.

The new chemical entity (NCE) has been knocked as novel antidiabetic agent, e.g. Saroglitazar. Saroglitazar is a drug for the treatment of Type II diabetes. Saroglitazar is marketed under the trade name Lipaglyn, developed by the Zydus Cadila. Lipaglyn is the first indigenously developed NCE by any Indian pharmaceutical company, ever. Lipaglyn has been approved for the treatment of Type II diabetes by the Drug Controller General of India in June 2013. Lipaglyn is indicated for the patients suffering from diabetes dyslipidemia. It also provides the option of a once-daily oral therapy. Saroglitazar regulates the lipid parameters as well as glycemic control. The present article describes Saroglitazar with its chemical synthesis and patent status with its summary of clinical studies.

3D QSAR and docking studies of various amido and benzyl-substituted 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl analogs as DPP-IV inhibitors.

The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl analogs reported for DPP-IV inhibition using PHASE module of Schrodinger software. The present works also encompass molecular interaction study of 3-amino-4-(2- cyanopyrrolidide)pyrrolidinyl analogs on maestro 8.5 workstation. The Phase study module comprises the five points pharmacophore model (AAHPR.617), consisting two hydrogen bond acceptor (A), one Hydrophobic (H), one Positive(P) and one aromatic ring (R) and with discrete geometries as pharmacophoric feature. The developed pharmacophore model was used to derive a predictive atom-based 3D QSAR model. The obtained 3D QSAR model has an excellent correlation coefficient value (r2=0.9926) along with good statistical significance as shown by high Fisher ratio (F=671.7). The model also exhibits good predictive power, which is confirmed by high value of cross validated correlation coefficient (q2 = 0.7311). The QSAR model suggests that hydrophobic and aromatic characters are crucial for the DPP-IV inhibitory activity. The QSAR model also suggests that the inclusion of hydrophobic substituents would enhance the DPP-IV inhibition. In addition to the hydrogen bond acceptor, hydrophobic character, electro withdrawing character positively contributes to the DPP-IV inhibition. This study provides a set of guidelines for designing compounds with better DPP-IV inhibitory potency.

Antidiabetic activity of alkaloids of Aerva lanata roots on streptozotocin-nicotinamide induced type-II diabetes in rats.

CONTEXT: The roots of Aerva lanata Linn. (Amaranthaceae) (AL) are employed traditionally as an antihyperglycaemic in the Ayurvedic system of medicine. OBJECTIVE: The present investigation is focus for identification and isolation of the bioactive compound from methanol roots extract of AL against streptozocin-nicotinamide induced elevated serum glucose level in rats. MATERIALS AND METHODS: The methanol extract of the roots was fractionated using different solvents. The partially purified alkaloid basified toluene fraction (PPABTF) showed the presence of alkaloids. The fraction (10 and 20 mg/kg) was tested for oral glucose tolerance test (OGTT) and in non-insulin-dependent diabetes mellitus (NIDDM)-induced elevated serum glucose level in rats. The fraction was also subjected to high performance thin layer chromatography (HPTLC) for the determination of content of individual alkaloids. RESULTS: Single oral administration of PPABTF (10 and 20 mg/kg) after 20 h caused a significant (p < 0.01) reduction in the serum glucose level (mg/dl). On other hand, PPABTF normalised plasma glucose levels after 2 weeks of repeated oral administration in diabetic rats (p < 0.01). HPTLC analysis on PPABTF showed the presence of three known alkaloids. The fraction was further subjected to column chromatography and the compounds identified by ultraviolet, infrared, mass spectroscopy and nuclear magnetic resonance, as canthin-6-one derivatives. CONCLUSION AND DISCUSSION: The PPABTF in the dose of 20 mg/kg showed significant effects on streptozotocin-nicotinamide induced type-II NIDDM in rats. The activity may be due to the presence of alkaloids like canthin-6-one derivatives.

3D QSAR and docking study of gliptin derivatives as DPP-IV inhibitors.

The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 46 xanthine derivatives reported for DPP-IV inhibition using PHASE module of Schrodinger software. The present works also encompasses molecular interaction of 46 xanthine ligand through maestro 8.5 software. The QSAR study comprises AHHR.7 pharmacophore hypothesis, which elaborates the three points, e.g. one hydrogen bond acceptor (A), two hydrophobic rings (H) and one aromatic ring (R). The discrete geometries as pharmacophoric feature were developed and the generated pharmacophore model was used to derive a predictive atom-based 3D QSAR model for the studied data set. The obtained 3D QSAR model has an excellent correlation coefficient value (r(2)= 0.9995) along with good statistical significance which is indicated by high Fisher ratio (F= 8537.4). The model also exhibits good predictive power confirmed by the high value of cross validated correlation coefficient (q(2) = 0.6919). The QSAR model suggests that hydrophobic character is crucial for the DPP-IV inhibitory activity exhibited by these compounds and inclusion of hydrophobic substituents will enhance the DPP-IV inhibition. In addition to the hydrophobic character, electron withdrawing groups positively contribute to the DPP-IV inhibition potency. The findings of the QSAR study provide a set of guidelines for designing compounds with better DPP-IV inhibitory potency.

Ligand-based pharmacophore detection, screening of potential gliptins and docking studies to get effective antidiabetic agents.

Three-dimensional pharmacophore hypothesis was established based on a set of known DPP-IV inhibitor using PharmaGist software program understanding the essential structural features for DPP-IV inhibitor. The various marketed or under developmental status, potential gliptins have been opted to build a pharmacophore model, e.g. Sitagliptin (MK- 0431), Saxagliptin, Melogliptin, Linagliptin (BI-1356), Dutogliptin, Carmegliptin, Alogliptin and Vildagliptin (LAF237). PharmaGist web based program is employed for pharmacophore development. Four points pharmacophore with the hydrogen bond acceptor (A), hydrophobic group (H), Spatial Features and aromatic rings (R) have been considered to develop pharmacophoric features by PharmaGist program. The best pharmacophore model bearing the Score 16.971, has been opted to screen on ZincPharmer database to derive the novel potential anti-diabetic ligands. The best pharmacophore bear various Pharmacophore features, including General Features 3, Spatial Features 1, Aromatic 1 and Acceptors 2. The PharmaGist employed algorithm to identify the best pharmacophores by computing multiple flexible alignments between the input ligands. The multiple alignments are generated by combining alignments pair-wise between one of the gliptin input ligands, which acts as pivot and the other gliptin as ligand. The resulting multiple alignments reveal spatial arrangements of consensus features shared by different subsets of input ligands. The best pharmacophore model has been derived using both pair-wise and multiple alignment methods, which have been weighted in Pharmacophore Generation process. The highest-scoring pharmacophore model has been selected as potential pharmacophore model. In conclusion, 3D structure search has been performed on the "ZincPharmer Database" to identify potential compounds that have been matched with the proposed pharmacophoric features. The 3D ZincPharmer Database has been matched with various thousands of Ligands hits. Those matches were screened through the RMSD and max hits per molecule. The physicochemical properties of various "ZincPharmer Database" screened ligands have been calculated by PaDELDescriptor software. The all "ZincPharmer Database" screened ligands have been filtered based on the Lipinski's rule-of-five criteria (i.e. Molecular Weight < 500, H-bond acceptor ≤ 10, H-bond donor ≤ 5, Log P ≤ 5) and were subjected to molecular docking studies to get the potential antidiabetic ligands. We have found various substituted as potential antidiabetic ligands, which can be used for further development of antidiabetic agents. In the present research work, we have covered rational of DPP-IV inhibitor based on Ligand-Based Pharmacophore detection, which is validated via the Docking interaction studies as well as Maximal Common Substructure (MCS).