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1.  Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer 
Cancer  2013;119(23):10.1002/cncr.28345.
Background
Preclinical studies show that opioids stimulate angiogenesis and tumor progression through the mu opioid receptor (MOR). Although MOR is over-expressed in several human malignancies, the effect of chronic opioid requirement on cancer progression or survival has not been examined in humans.
Methods
We performed a retrospective analysis on 113 patients identified in the Minneapolis VA Tumor Registry (test cohort) and 480 patients from the national VA Central Cancer Registry (validation cohort) diagnosed with stage IV prostate cancer between 1995 and 2010, to examine whether MOR expression or opioid requirement is associated with disease progression and survival. All opioids were converted to oral morphine equivalents (OME) for comparison. Laser scanning confocal microscopy was used to analyze MOR-immunoreactivity in prostate cancer biopsies. The effects of variables on outcomes were analyzed in univariable and multivariable models.
Results
In patients with metastatic prostate cancer, MOR expression and opioid requirement were independently associated with inferior progression-free survival (PFS) (HR 1.65, 1.33–2.07; p<0.001 and HR 1.08, 1.03–1.13; p<0.001, respectively) and overall survival (OS; HR 1.55, 1.20–1.99; p<0.001 and HR 1.05, 1.00–1.10; p=0.031, respectively). The validation cohort confirmed that increasing opioid requirement was associated with worse OS (HR 1.005, 1.002–1.008, p=0.001).
Conclusion
Higher MOR expression and greater opioid requirement are associated with shorter PFS and OS in patients with metastatic prostate cancer. Nevertheless, clinical practice should not be changed until prospective randomized trials show that opioid use is associated with inferior clinical outcomes, and that abrogation of the peripheral activities of opioids ameliorates this effect.
doi:10.1002/cncr.28345
PMCID: PMC3833881  PMID: 24104703
Analgesics; Opioid; Analgesics; Narcotic; Angiogenesis; Disease Free Survival; Disease Progression; Humans; Metastasis; Morphine; Mortality; Neoplasms; Neoplasm Recurrence; Local/prevention & control; Neovascularization; Pathologic; Opioids; Pain; Prostatic Neoplasms; Receptors; Opioid; Receptors; Opioid; mu; Retrospective Studies
2.  The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma 
Nature genetics  2014;46(5):444-450.
Pediatric high-grade glioma (HGG) is a devastating disease with a two-year survival of less than 20%1. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPG (32%), in addition to the previously reported frequent somatic mutations in histone H3, TP53 and ATRX in both DIPG and NBS-HGGs2-5. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, 2, or 3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase/RAS/PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59%, respectively, of pediatric HGGs, including DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.
doi:10.1038/ng.2938
PMCID: PMC4056452  PMID: 24705251
3.  A Phase II Study of the Oral VEGF Receptor Tyrosine Kinase Inhibitor Vatalanib (PTK787/ZK222584) in Myelodysplastic Syndrome: Cancer and Leukemia Group B Study 10105 (Alliance) 
Investigational new drugs  2013;31(5):1311-1320.
Background
Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death.
Methods
Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750–1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity.
Results
The median age was 70.5 years; 51% had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32% had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5%) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15% of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib.
Conclusions
Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.
doi:10.1007/s10637-013-9978-z
PMCID: PMC3773017  PMID: 23700288
Angiogenesis inhibitors; humans; myelodysplastic syndromes; treatment outcome; vascular endothelial growth factor
4.  Unusual lymphoma of lacrimal gland 
Indian Journal of Ophthalmology  2014;62(9):974-975.
doi:10.4103/0301-4738.143971
PMCID: PMC4244757  PMID: 25370412
5.  Upper gastrointestinal barium evaluation of duodenal pathology: A pictorial review 
World Journal of Radiology  2014;6(8):613-618.
Like other parts of the gastrointestinal tract (GIT), duodenum is subject to a variety of lesions both congenital and acquired. However, unlike other parts of the GIT viz. esophagus, rest of the small intestine and large intestine, barium evaluation of duodenal lesions is technically more challenging and hence not frequently reported. With significant advances in computed tomography technology, a thorough evaluation including intraluminal, mural and extramural is feasible in a single non-invasive examination. Notwithstanding, barium evaluation still remains the initial and sometimes the only imaging study in several parts of the world. Hence, a thorough acquaintance with the morphology of various duodenal lesions on upper gastrointestinal barium examination is essential in guiding further evaluation. We reviewed our experience with various common and uncommon barium findings in duodenal abnormalities.
doi:10.4329/wjr.v6.i8.613
PMCID: PMC4147442  PMID: 25170399
Barium study; Duodenum; Upper gastrointestinal tract; Small bowel; Pathology
6.  C11orf95-RELA fusions drive oncogenic NF-κB signaling in ependymoma 
Nature  2014;506(7489):451-455.
The nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
doi:10.1038/nature13109
PMCID: PMC4050669  PMID: 24553141
7.  Investigation of Antiarthritic Potential of Plumeria alba L. Leaves in Acute and Chronic Models of Arthritis 
BioMed Research International  2014;2014:474616.
Aim. The present investigation was designed to evaluate antiarthritic potential of fractions of hydroalcoholic extract from leaves of P. alba. Materials and Methods. Plumeria alba L. leaves were extracted with hydroalcohol (30 : 70) to obtain hydroalcoholic extract of P. alba. This extract was further fractionated with solvents ethyl acetate and n-butanol to obtain EAPA and BPA, respectively. These fractions were tested against formaldehyde and Freund's complete adjuvant (FCA) induced arthritis. Arthritis assessment, paw volume, body weight, motor incoordination, and nociceptive threshold were measured. On day 21, the animals were sacrificed and histopathology was done. Results. The 100 and 200 mg/kg doses of EAPA and BPA caused a significant (P ≤ 0.05–0.01) reduction in paw swelling in both models. Erythrocyte sedimentation rate (ESR) and spleen weight decreased significantly (P < 0.01) in arthritic rats treated with extracts. There was significant (P < 0.05) improvement in thymus weight in EAPA treated rats whereas significant (P < 0.01) improvement was also seen in haemoglobin level (Hb) in diclofenac treated group. Motor incoordination and nociceptive threshold were also significantly (P ≤ 0.05–0.01) improved. Conclusion. The present study suggests that Plumeria alba L. has protective activity against arthritis and supports the traditional use of P. alba for rheumatism and other inflammatory diseases.
doi:10.1155/2014/474616
PMCID: PMC4082847  PMID: 25025056
8.  Screening of antiangiogenic potential of twenty two marine invertebrate extracts of phylum Mollusca from South East Coast of India 
Objective
To evaluate the antiangiogenic potential of twenty two marine invertebrate species of Phylum Mollusca from south east coast of India.
Methods
Live specimens of molluscan species were collected and their methanolic extracts were evaluated for preliminary antiangiogenic activity using the in ovo chick chorio-allantoic membrane assay. The extracts were further evaluated for in vivo antiangiogenic activity using chemical cautery induced corneal neovascularization assay in rats and oxygen induced retinopathy assay in rat pups.
Results
In the chick chorio-allantoic membrane assay, four methanolic extracts of marine molluscan species viz. Meretrix meretrix, Meretrix casta, Telescopium telescopium and Bursa crumena methanolic extracts exhibited noticeable antiangiogenic activity at the tested concentration of 200 µg whereby they significantly inhibited the VEGF induced proliferation of new blood vessels. Among these four extracts, the methanolic extract of Meretrix casta exhibited relatively higher degree of antiangiogenic activity with an inhibitiory percentage (64.63%) of the VEGF induced neovascularization followed by the methanolic extracts of Telescopium telescopium (62.02%), Bursa crumena (60.48%) and Meretrix meretrix (47.01%). These four methanolic extracts were further evaluated for in vivo antiangiogenic activity whereby the methanolic extract of Telescopium telescopium exhibited most noticeable inhibition (42.58%) of the corneal neovascularization in rats in comparison to the sham treated group, and also exhibited most noticeable inhibition (31.31%) of the oxygen induced retinal neovascularization in rat pups in comparison to the hyperoxia group that was observed for considerable retinal neovascularization.
Conclusions
The significant antiangiogenic activity evinced by the extract of Telescopium telescopium merits further investigation for ocular neovascular diseases.
doi:10.12980/APJTB.4.2014C701
PMCID: PMC4025331  PMID: 25183067
Marine invertebrate; Mollusca; Antiangiogenic; CAM; Cautery; Retinopathy
9.  Automatic scan triggering software “confused”: Computed tomography angiography in foot arteriovenous malformation! 
Multidetector computed tomography angiography (MDCTA) has become a well-established modality for limb angiography for a variety of indications. The technique of MDCTA depends on the scanner features including the number of detector rows, rotation speeds and single or dual source energy. Integral to a diagnostic quality CTA is the acquisition timing. Various techniques are available for determining the appropriate timing of scan acquisition which includes fixed delay, test bolus and the bolus tracking technique. The transit times of contrast from the aorta to the peripheral arteries shows a wide variability and is dependent upon the inter individual hemodynamic states. The bolus tracking technique is the most preferred one which allows reliable scan timing with acceptable contrast volume and radiation dose. Pitfalls with all these techniques are well described and we report one such technical pitfall in a case of left foot arteriovenous malformation (AVM) where the bolus tracking technique employed for scan triggering failed to initiate acquisition.
doi:10.4103/0971-3026.134387
PMCID: PMC4094961  PMID: 25024519
Arterio-venous malformation; bolus tracking; computed tomography angiography; contrast injection
10.  Mounier-Kuhn syndrome masquerading pulmonary thromboembolism in an elderly male 
Mounier-Kuhn syndrome, also referred to as tracheobronchomegaly, is a rare idiopathic clinical and radiologic disorder characterized by significant tracheobronchial dilation. It results in recurrent lower respiratory tract infections and bronchiectasis. In severe cases, patients may present with acute respiratory distress requiring hospital admission and ventilatory support. Clinical examination and chest radiography may be misleading in these patients as tracheobronchomegaly is easily overlooked on radiographs. We present an interesting report of our patient who presented with acute shortness of breath. A diagnosis of acute pulmonary thromboembolism was suggested by initial evaluation. Computed tomography pulmonary angiography was negative for thromboembolism; however, it revealed diagnosis of this rare disorder.
doi:10.4103/0970-2113.125995
PMCID: PMC3960819  PMID: 24669091
Computed tomography; high resolution computed tomography; Mounier-Kuhn syndrome; tracheobronchomegaly
11.  Variations in superior thyroid artery: A selective angiographic study 
Aim:
To investigate variations in superior thyroid artery (STA) based on digital subtraction angiography (DSA).
Materials and Methods:
Twenty five angiography studies of 15 pts performed between June 2010 and December 2012 were retrospectively evaluated. These patients underwent DSA of the head and neck region as a part of their superselective neoadjuvant intra-arterial chemotherapy protocol for treatment of laryngeal and hypopharyngeal cancers. Depending upon the location of the tumor, unilateral or bilateral arteriograms of common carotid artery (CCA), external carotid artery (ECA), and STA were performed. Arteriograms were evaluated for the site of origin and branching pattern of STA. STA anatomy was ascribed to one of the three branching patterns.
Results:
A total of 25 angiograms were evaluated, including 14 right and 11 left. On the right side, STA was noted to arise from ECA in 10 (71.5%), bifurcation of CCA in 3 (21.5%), and CCA in 1 (7%) patient. Left STA was seen to arise from ECA in 8 (72.5%), bifurcation of CCA in 2 (18.5%), and internal carotid artery (ICA) in 1 (9%) patient. Type III branching pattern (non-bifurcation, non-trifurcation) was found to be the most frequent (52%). Infrahyoid branch was found to be the most consistent in terms of its origin from STA.
Conclusions:
Origin of STA is predictable, arising from ECA in more than 70% cases. Branching pattern of STA, following origin from ECA, is, however, highly variable. Knowledge concerning the origin and branching pattern of STA is essential in enhancing precision and decreasing morbidity related to the surgical and interventional radiological head and neck procedures.
doi:10.4103/0971-3026.130701
PMCID: PMC4028919  PMID: 24851008
Anatomic variations; digital subtraction angiography; superior thyroid artery
12.  Triple Helical Recognition of RNA Using 2-Aminopyridine-Modified PNA at Physiologically Relevant Conditions** 
Peptide nucleic acids containing thymidine and 2-aminopyridine (M) nucleobases formed stable and sequence selective triple helices with double stranded RNA at physiologically relevant conditions. The M-modified PNA displayed unique RNA selectivity by having two orders of magnitude higher affinity for the double stranded RNAs than for the same DNA sequences. Preliminary results suggested that nucleobase-modified PNA could bind and recognize double helical precursors of microRNAs.
doi:10.1002/anie.201207925
PMCID: PMC3756501  PMID: 23125029
sequence selective RNA recognition; peptide nucleic acid; PNA; triple helix; modified nucleobases
13.  Choroid plexus papilloma of the third ventricle: A rare infantile brain tumor 
Choroid plexus papilloma (CPP) represents an uncommon pediatric brain tumor with an overall incidence less than 1% of all intracranial tumors. Most of these tumors occur in the lateral ventricles in neonates. Third ventricular location is uncommon, limited to a few case reports. These highly vascular tumors retain the physiological function of choroid plexus and thus lead to overproduction of cerebrospinal fluid (CSF), besides obstructing the CSF pathway. Imaging is fairly sensitive and specific in affording the diagnosis of this tumor. Surgical approaches differ according to the site of tumor and aim is complete removal of tumor. We present an interesting report of an infant who presented to our department for cranial sonography that lead to suspicion of this tumor, later confirmed by other imaging modalities and histopathology.
doi:10.4103/1817-1745.123696
PMCID: PMC3888048  PMID: 24470825
Choroid plexus papilloma; cranial sonography; third ventricular tumors
14.  Triple Helical Recognition of Pyrimidine Inversions in Polypurine Tracts of RNA by Nucleobase-modified PNA 
Peptide nucleic acids containing 2-pyrimidinone (P) and 3-oxo-2,3-dihydropyridazine (E) heterocycles recognized C-G and U-A inversions in a polypurine tract of double helical RNA with high affinity and sequence selectivity at pH 6.25. E-modified PNA bound strongly to bacterial A-site RNA, while no binding was observed to the human A-site RNA.
doi:10.1039/c1cc14706d
PMCID: PMC3757498  PMID: 21909545
15.  Identification of a Potent Combination of Key Plasmodium falciparum Merozoite Antigens That Elicit Strain-Transcending Parasite-Neutralizing Antibodies 
Infection and Immunity  2013;81(2):441-451.
Blood-stage malaria vaccines that target single Plasmodium falciparum antigens involved in erythrocyte invasion have not induced optimal protection in field trials. Blood-stage malaria vaccine development has faced two major hurdles, antigenic polymorphisms and molecular redundancy, which have led to an inability to demonstrate potent, strain-transcending, invasion-inhibitory antibodies. Vaccines that target multiple invasion-related parasite proteins may inhibit erythrocyte invasion more efficiently. Our approach is to develop a receptor-blocking blood-stage vaccine against P. falciparum that targets the erythrocyte binding domains of multiple parasite adhesins, blocking their interaction with their receptors and thus inhibiting erythrocyte invasion. However, with numerous invasion ligands, the challenge is to identify combinations that elicit potent strain-transcending invasion inhibition. We evaluated the invasion-inhibitory activities of 20 different triple combinations of antibodies mixed in vitro against a diverse set of six key merozoite ligands, including the novel ligands P. falciparum apical asparagine-rich protein (PfAARP), EBA-175 (PfF2), P. falciparum reticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, and Plasmodium thrombospondin apical merozoite protein (PTRAMP), which are localized in different apical organelles and are translocated to the merozoite surface at different time points during invasion. They bind erythrocytes with different specificities and are thus involved in distinct invasion pathways. The antibody combination of EBA-175 (PfF2), PfRH2, and PfAARP produced the most efficacious strain-transcending inhibition of erythrocyte invasion against diverse P. falciparum clones. This potent antigen combination was selected for coimmunization as a mixture that induced balanced antibody responses against each antigen and inhibited erythrocyte invasion efficiently. We have thus demonstrated a novel two-step screening approach to identify a potent antigen combination that elicits strong strain-transcending invasion inhibition, supporting its development as a receptor-blocking malaria vaccine.
doi:10.1128/IAI.01107-12
PMCID: PMC3553821  PMID: 23184525
16.  The Analgesic Potential of Cannabinoids 
Journal of opioid management  2009;5(6):341-357.
Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. Since opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.
PMCID: PMC3728280  PMID: 20073408
pain; cannabinoid; opioid; marijuana; cannabis; HIV/AIDS; cancer
17.  Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models 
Objectives:
To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent.
Materials and Methods:
In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control) or clofilium (3 mg/kg) or chloroquine (21 mg/kg) for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 μM) or chloroquine (300 μM) continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride.
Results:
In these models, prolongation of repolarization during α1-adrenoceptor stimulation produced early after depolarization (EAD) and Torsade de pointes (TdP). Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo). Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc) interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model.
Conclusions:
The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.
doi:10.4103/0976-500X.110892
PMCID: PMC3669570  PMID: 23759957
α1 -Adrenoceptor stimulation; chloroquine; clofilium; torsade de pointes; in vivo rabbit model; ex vivo rabbit model
18.  Novel mutations target distinct subgroups of medulloblastoma 
Nature  2012;488(7409):43-48.
Summary
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. To identify mutations that drive medulloblastoma we sequenced the entire genomes of 37 tumours and matched normal blood. One hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma: several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumours (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
doi:10.1038/nature11213
PMCID: PMC3412905  PMID: 22722829
19.  Recognition of Double Stranded RNA by Guanidine-Modified Peptide Nucleic Acids (GPNA) 
Biochemistry  2011;51(1):63-73.
Double helical RNA has become an attractive target for molecular recognition because many non-coding RNAs play important roles in control of gene expression. Recently, we discovered that short peptide nucleic acids (PNA) bind strongly and sequence selectively to a homopurine tract of double helical RNA via triple helix formation. Herein we tested if the molecular recognition of RNA can be enhanced by α-guanidine modification of PNA. Our study was motivated by the discovery of Ly and co-workers that the guanidine modification greatly enhances the cellular delivery of PNA. Isothermal titration calorimetry showed that the guanidine-modified PNA (GPNA) had reduced affinity and sequence selectivity for triple helical recognition of RNA. The data suggested that in contrast to unmodified PNA, which formed a 1:1 PNA-RNA triple helix, GPNA preferred a 2:1 GPNA-RNA triplex-invasion complex. Nevertheless, promising results were obtained for recognition of biologically relevant double helical RNA. Consistent with enhanced strand invasion ability, GPNA derived from D-arginine recognized the transactivation response element (TAR) of HIV-1 with high affinity and sequence selectivity, presumably via Watson-Crick duplex formation. On the other hand, strong and sequence selective triple helices were formed by unmodified and nucelobase-modified PNAs and the purine rich strand of bacterial A-site. These results suggest that appropriate chemical modifications of PNA may enhance molecular recognition of complex non-coding RNAs.
doi:10.1021/bi201570a
PMCID: PMC3254705  PMID: 22146072
20.  Evaluation of pharmacological activities and assessment of intraocular penetration of an ayurvedic polyherbal eye drop (Itone™) in experimental models 
Background
The polyherbal eye drop (Itone™) is a mixture of aqueous distillates of nineteen traditionally used ingredients that sum up to impart potency to the formulation and make it a useful adjunct in various ocular pathologies. However, as there have been no controlled experimental studies accounting to the above claim, therefore, the present study was designed to evaluate the polyherbal formulation (PHF) for antiangiogenic, anti-inflammatory, anticataract, antioxidant and cytotoxicity in addition to the evaluation of intraocular penetration of PHF in rabbit eyes using LC-MS/MS.
Materials and methods
Antiangiogenic activity of the PHF was evaluated using in ovo chick chorio-allantoic membrane (CAM) assay and in vivo cautery induced corneal neovascularization assay in rats. Anticataract potential was evaluated using steroid induced cataract in developing chick embryos, sodium selenite induced cataract in rat pups and galactose induced cataract in rats. The antioxidant activity was evaluated using di-phenyl picryl hydrazyl (DPPH) radical scavenging assay. Anti-inflammatory activity was evaluated in vitro using inhibition of LTB4 formation in human WBCs and in vivo using carrageenan induced paw edema assay in rats. The cytotoxicity was evaluated against HeLa cancer cell lines using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore evaluation of the intraocular penetration of the PHF was carried out in rabbit eyes via aqueous humor paracentesis and further analysis using LC-MS/MS.
Results
PHF significantly inhibited VEGF induced proliferation of new blood vessels in CAM assay and inhibited the cautery induced corneal neovascularization in rats. Additionally, PHF showed noticeable delay in the progression of cataract in the selenite and galactose induced cataract models whereby the PHF treated lenses were graded for stages II and III respectively. However, the PHF did not show any anticataract activity in the hydrocortisone induced cataract model. Moreover, PHF exhibited anti-inflammatory activity whereby it showed 39.34% inhibition of LTB4 formation and significantly inhibited carrageenan induced paw edema in rats. Eight compounds of PHF viz. camphor, casticin, curcumin-II, quercetin, rosmarinic acid, γ-terpinene, β-pinene and dipentene exhibited transcorneal penetration in rabbit eyes.
Conclusion
The significant antiangiogenic and anti-inflammatory activities evinced by the PHF merits further investigation for ocular neovascular and inflammatory diseases in humans.
doi:10.1186/1472-6882-13-1
PMCID: PMC3542029  PMID: 23280361
Polyherbal; Antiangiogenic; Anti-inflammatory; Anticataract; Antioxidant; Cytotoxicity; LC-MS/MS
21.  Evaluation of Immunization Coverage in the Rural Area of Pune, Maharashtra, Using the 30 Cluster Sampling Technique 
Background:
Infectious diseases are a major cause of morbidity and mortality in children. One of the most cost-effective and easy methods for child survival is immunization. Despite all the efforts put in by governmental and nongovernmental institutes for 100% immunization coverage, there are still pockets of low-coverage areas. In India, immunization services are offered free in public health facilities, but, despite rapid increases, the immunization rate remains low in some areas. The Millennium Development Goals (MDG) indicators also give importance to immunization.
Objective:
To assess the immunization coverage in the rural area of Pune.
Materials and Methods:
A cross-sectional study was conducted in the field practice area of the Rural Health Training Center (RHTC) using the WHO's 30 cluster sampling method for evaluation of immunization coverage.
Results:
A total of 1913 houses were surveyed. A total of 210 children aged 12-23 months were included in the study. It was found that 86.67% of the children were fully immunized against all the six vaccine-preventable diseases. The proportion of fully immunized children was marginally higher in males (87.61%) than in females (85.57%), and the immunization card was available with 60.95% of the subjects. The most common cause for partial immunization was that the time of immunization was inconvenient (36%).
Conclusion:
Sustained efforts are required to achieve universal coverage of immunization in the rural area of Pune district.
doi:10.4103/2249-4863.109945
PMCID: PMC3894018  PMID: 24479044
30 cluster sampling technique; coverage evaluation; dropout; primary immunization
23.  Evaluation of a Novel Hexavalent Humanized Anti-IGF-1R Antibody and Its Bivalent Parental IgG in Diverse Cancer Cell Lines 
PLoS ONE  2012;7(8):e44235.
A major mechanism of monoclonal antibodies that selectively target the insulin-like growth factor type 1 receptor (IGF-1R) to inhibit tumor growth is by downregulating the receptor, regardless whether they are capable (antagonistic) or incapable (agonistic) of blocking the binding of cognate ligands. We have developed and characterized a novel agonistic anti-IGF-1R humanized antibody, hR1, and used the Dock-and-Lock (DNL) method to construct Hex-hR1, the first multivalent antibody comprising 6 functional Fabs of hR1, with the aim of enhancing potency of hR1. Based on cross-blocking experiments, hR1 recognizes a region of cysteine-rich domain on the α-subunit, different from the epitopes mapped for existing anti-IGF-1R antibodies, yet hR1 is similar to other anti-IGF-1R antibodies in downregulating IGF-1R and inhibiting proliferation, colony formation, or invasion of selected cancer cell lines in vitro, as well as suppressing growth of the RH-30 rhabdomyosarcoma xenograft in nude mice when combined with the mTOR inhibitor, rapamycin. Hex-hR1 and hR1 are generally comparable in their bioactivities under the in-intro and in-vivo conditions investigated. Nevertheless, in selective experiments involving a direct comparison of potency, Hex-hR1 demonstrated a stronger effect on inhibiting cell proliferation stimulated by IGF-1 and could effectively downregulate IGF-1R at a concentration as low as 20 pM.
doi:10.1371/journal.pone.0044235
PMCID: PMC3432068  PMID: 22952934
24.  Morphine promotes renal pathology in sickle mice 
Patients with sickle cell disease (SCD) are often treated with opioids for severe pain. Although opioids are known to have renal-specific effects, their role in nephropathy in SCD remains unknown. Because a subset of patients receives opioids for long periods of time, we examined the influence of chronic morphine treatment on mice with pre-existing renal disease expressing varying amounts of sickle hemoglobin. Morphine treatment for 3–6 weeks resulted in a variety of defects in renal morphology observed using light and electron microscopy. Notably, morphine induced glomerular pathology, resulting in increased glomerular volume, mesangial expansion, mesangial cell proliferation, parietal cell metaplasia, podocyte effacement, and microvillus transformation. Cystic tubulopathy and hemeoxygenase-1 expression and activity were also increased in morphine-treated mice. Naloxone, a non-selective opioid receptor (OR) antagonist, ameliorated these effects. Functionally, the urine albumin to creatinine ratio was increased following acute as well as chronic morphine treatment. These results suggest that clinically relevant doses of morphine induce renal pathology and that OR antagonists may be effective for ameliorating morphine-induced renal disease.
doi:10.2147/IJNRD.S33813
PMCID: PMC3413037  PMID: 22888269
mesangial cell; morphine; nephropathy; pain; podocyte; sickle cell disease
25.  A Novel Retinoblastoma Therapy from Genomic and Epigenetic Analyses 
Nature  2012;481(7381):329-334.
SUMMARY
Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of the RB1 gene. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated RB1’s role in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. Here we show that the retinoblastoma genome is stable, but multiple cancer pathways can be epigenetically deregulated. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, RB1 inactivation may allow preneoplastic cells to acquire multiple hallmarks of cancer through epigenetic mechanisms, resulting directly or indirectly from RB1 loss. These data provide novel targets for chemotherapeutic interventions of retinoblastoma.
doi:10.1038/nature10733
PMCID: PMC3289956  PMID: 22237022

Results 1-25 (60)