Engineered biomimetic nanoparticle for dual targeting of the cancer stem-like cell population in sonic hedgehog medulloblastoma.

The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood-brain barrier (BBB) penetrance. These challenges signify an unmet need for drug carriers that can cross the BBB and deliver drugs to targeted sites with high drug-loading efficiency and long-term stability. We herein leverage the enhanced stability and targeting ability of engineered high-density lipoprotein-mimetic nanoparticles (eHNPs) to cross the BBB and deliver a SHH inhibitor effectively to the cancer stem-like cell population in SHH MB. Our microfluidic technology enabled highly reproducible production of multicomponent eHNPs incorporated with apolipoprotein A1, anti-CD15, and a SHH inhibitor (LDE225). We demonstrate the dual-targeted delivery and enhanced therapeutic effect of eHNP-A1-CD15-LDE225 via scavenger receptor class B type 1 (SR-B1) and CD15 on brain SHH MB cells in vitro, ex vivo, and in vivo. Moreover, we show that eHNP-A1 not only serves as a stable drug carrier, but also has a therapeutic effect itself through SR-B1-mediated intracellular cholesterol depletion in SHH MB cells. Through the facilitated and targeted cellular uptake of drugs and direct therapeutic role of this engineered biomimetic nanocarrier in SHH MB, our multifunctional nanoparticle provides intriguing therapeutic promise as an effective and potent nanomedicine for the treatment of SHH MB.

Comparative Analysis of Sagittal Condylar Guidance Recorded by Intraoral Gothic Arch Tracing and Panoramic Radiograph in Completely Edentulous Patients.

AIM: To compare the intraoral gothic tracing method with panoramic radiographs in patients requiring complete dentures. MATERIALS AND METHODS: The present study was conducted on 20 edentulous subjects of both genders. Hanau Wide-Vue semi-adjustable articulator was used to record sagittal condylar guidance in all patients. Panoramic radiographs were taken in all patients and Frankfurt horizontal plane was traced on both sides of orthopantomogram (OPG) and second plane was marked by joining the most superior and most inferior point on the glenoid fossa curvature. Frankfort's horizontal plane was crossed with this line to record radiographic condylar guidance angle. NNT software was used to record the condylar guidance angle. RESULTS: Mean ± standard deviation (SD) clinical SCG (25.15 ± 3.24) and radiographic seismocardiography (SCG) (27.54± 5.01) was non significant (p > 0.05) on left side. Mean ± standard deviation (SD) clinical SCG (26.84 ± 3.69) and radiographic SCG (29.3 5 ± 4.58) was significant (p < 0.05) on right side. The SCG did not show difference in values recorded by both methods on both sides. The difference in values in both sides by clinical method and radiographic method was non-significant (p > 0.05). CONCLUSION: There was correlation between sagittal condylar guidance obtained by both intraoral gothic arch method as well as radiographic method done on digital panoramic radiographs. CLINICAL SIGNIFICANCE: Correct centric jaw relation determines the success of the complete denture. Radiographic and clinical methods provide sufficient minute details necessary for the betterment of management.

A new species of Neolebouria Gibson, 1976 (Opecoelidae: Plagioporinae) from the whitecheek monocle bream, Scolopsis vosmeri (Perciformes: Nemipteridae), from the Panjim coast at Goa, with a checklist of parasites previously reported from this fish.

Neolebouria capoori n. sp. (Opecoelidae: Plagioporinae) is described from the whitecheek monocle bream, Scolopsis vosmeri (Bloch) (Perciformes: Nemipteridae) from the Panjim coast on the central west coast of India at Goa. The new species differs from both Neolebouria cantherhini (Li, Qiu & Zhang, 1988) as originally described from Thamnaconus modestus (Günther) (syn. Cantherines modestus Günther ) and Neolebouria confusum (Overstreet, 1969) as originally described from Ocyurus chrysurus (Bloch) by having the cirrus sac surpassing the ventral sucker posteriorly in N. cantherhini and being entirely preacetabular in N. confusum compared to terminating near the midlevel of the ventral sucker in N. capoori n. sp. The new species is most similar to N. confusum, but it further differs from this species by having the vitelline fields terminating near the level of the esophageal bifurcation compared to terminating near the level of the posterior margin of the pharynx, a larger sucker ratio (1:1.7-1:2.0 compared to 1:1.4-1:1.7), a somewhat shorter cirrus sac relative to body length (160-448, representing 9-18% of the body length compared to about 367, representing 22%), and the egg of the new species has a boss at the anopercular end that is not present in N. confusum. This study represents the first report on an opecoelid from S. vosmeri. A review of the parasites reported from S. vosmeri is included.

STAT3 is required for Smo-dependent signaling and mediates Smo-targeted treatment resistance and tumorigenesis in Shh medulloblastoma.

Sonic hedgehog (Shh)-driven medulloblastoma (Shh MB) cells are dependent on constitutive Shh signaling, but targeted treatment of Shh MB has been ineffective due to drug resistance. The purpose of this study was to address the critical role of signal transducer and activator of transcription 3 (STAT3) in Shh signaling and drug resistance in Shh MB cells. Herein, we show that STAT3 is required for Smoothened (Smo)-dependent Shh signaling and, in turn, is reciprocally regulated by Shh signaling, and demonstrate that STAT3 activity is critical for expression of HCK proto-oncogene, Src family tyrosine kinase (Hck) in Shh MB. We also demonstrate that maintained STAT3 activity suppresses p21 expression and promotes colony formation of Shh MB cells, whereas dual treatment with inhibitors of both Smo and STAT3 results in marked synergistic killing and overcomes drug resistance in vitro of Smo antagonist-resistant Shh MB cells. Finally, STAT3 inhibitor treatment significantly prevents in vivo tumor formation in genetically engineered Shh MB mice. Collectively, we show that STAT3 is necessary to maintain Shh signaling and thus is a potential therapeutic target to treat Shh MB and overcome anti-Smo drug resistance.

Liposome-Imipramine Blue Inhibits Sonic Hedgehog Medulloblastoma In Vivo.

Sonic hedgehog subtype of medulloblastoma (SHH MB) with metastasis or specific clinical or molecular alteration shas a poor prognosis and current therapy results in long-term cognitive impairment in the majority of survivors. Thus, a great need exists for new targeted therapeutic approaches to more effectively treat SHH MB in children. Imipramine blue (IB), a novel molecule with anti-tumor properties, inhibits the NADPH oxidase (NOX) family of enzymes, which are critical for SHH MB survival and treatment resistance. In this study, IB was encapsulated within a liposome to form a liposomal nanoparticle, Liposome-IB (Lipo-IB). This complex has the ability to cross the blood-brain barrier and be preferentially taken up by tumor cells within the brain. We demonstrated in vitro that Lipo-IB treatment caused a dose-dependent decrease in SHH MB cell viability and migration. Short-term administration of single agent Lipo-IB treatment of SHH MB in vivo significantly inhibited tumor growth, reduced the tumor volume, including a complete tumor response, and improved survival compared to control treated mice, without any observable toxicity. We conclude that Lipo-IB is a potential novel nanoparticle-based therapeutic for the treatment of SHH MB that warrants further preclinical safety and efficacy testing for development towards clinical investigation.

Bioinvasion: a paradigm shift from marine to inland ecosystems.

Anisakidosis is one of the most fearsome zoonotic food borne disease in aquaculture. The natural infections by anisakidoids or related variety in freshwater fish are not known, though sporadic experimental reports are available abroad (Butcher and Shamsi 2011). Invasive severity of anisakidoids in fish from Gangetic riverine ecosystems, i.e., in river Ganges at Fatehpur and Allahabad, as well as in river Yamuna at Allahabad, and molecular heterogeneity among these worms have been extensively investigated. The pathways of transmission of non-native alien species due to long distance migratory habits of Rita rita, man-made alterations including dredging in long stretches of the river bed of Ganges to facilitate ballast water transfer mechanism owing to the commercial ship movements between Haldia and Allahabad; and sudden water chemistry (salinity, hardness, alkalinity) alteration (due particularly to rainy period) oriented micro-fauna interchange are identified, and remedial measures suggested.

Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma.

UNLABELLED: Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNP), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation although driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Because both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated postmitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, although their ectopic expression restored the MMP to the nonproliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of Cyclin D2 protein, a marker for proliferation. IMPLICATIONS: This report exposes a novel role for Shh in regulating mitochondrial dynamics and rescue of the metabolic profile of tumor cells to that of nontransformed, nonproliferating cells and represents a potential avenue for development of medulloblastoma therapeutics.

Challenges and future perspectives of T cell immunotherapy in cancer.

Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signalling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer.

Ecological morphotaxometry of trematodes of garfish (Teleostomi: Belonidae) from Gangetic riverine ecosystem in India. III. Principal component analysis in the dynamics of Cephalogonimus yamunii (Upadhyay, Jaiswal, Malhotra and Malhotra, 2012).

The attributes of multivariate analyses were applied to infer peculiarity in distribution dynamics of Cephalogonimus yamunii Upadhyay et al. (J Parasit, 2012) in Xenentodon cancilla under influence of interionic interactions amongst hydrobiological factors. Non-parametric Mann-Whitney's Test χ(2) statistic was significant for the effect of Dissolved Oxygen and magnesium. The temperature optimum 23-27 °C was concluded for expression of peak prevalence and mean intensity during change in water temperature between autumn and winter periods. The dominant Ist component (PC1 (p) ) from Principal Component Analysis of monthwise response of infection data by C. yamunii in X. cancilla was further confirmed by Scree Plot of Eigenvalues and Factor Loadings Plot to identify the critical impact of hardness of water on infection prevalence and mean intensity. The findings of larger PC1 (p) positive coefficients comprehensively substantiated predominating hardness factor, under the influence of enhanced Dissolved Oxygen and optimum thermal effect. Therefore, the role of multifactorial etiology is a definite possibility.

Ecological morphotaxometry of trematodes of garfish (Teleostomi: Belonidae) from Gangetic riverine ecosystem in India. II. Correlation of seasonality and host biology with distribution pattern of Cephalogonimus yamunii n.sp.

The seasonality influence on the biology and distribution dynamics of Cephalogonimus yamunii n.sp. in Xenentodon cancilla (Teleostomi: Belonidae) was reflected during 2 years' investigations. The highest infection prevalence appeared to be in late summer. Size, weight, and sex-biased population dynamics of trematode was well marked in Gangetic riverine ecosystem. The biostatistical non-parametric Mann-Whitney χ (2) test values were significant for dissolved oxygen and magnesium. The distribution of infection data on Poisson series ruled out overdispersion because good agreement was observed (P < 0.01).

Ecological morphotaxometry of trematodes of garfish (Teleostomi: Belonidae) from Gangetic riverine ecosystem in India. I. Morphology and taxometric assessment of Cephalogonimus yamunii n.sp.

A new endoparasitic fluke, Cephalogonimus yamunii n.sp. is described from the intestine of freshwater fish Xenentodon cancilla (Belonidae). The worms could be differentiated from C. amphiumae (Chandler 1932), C. apognichthysi (Gupta and Puri 1982), C. hanumanthai (Agrawal and Agarwal 1984), C. salamandrus (Dronen and Lang 1974), C. simhai (Singh 2010) and C. vesicaudus (Nickerson 1912) in a unipartite seminal vesicle, genital pore subterminal anteriorly, opening at the hind end of oral sucker, equatorial or sub-equatorial testes, besides other morphological attributes of shorter body and pharynx, larger oesophagus and oral sucker, smaller ventral sucker, testes, cirrus sac and ovary, and a terminal excretory pore. Taxometric substantiation has been presented by using Polythetic Divisive Classificatory System, and ecological attributes have been evaluated to validate specific distribution patterns in population dynamics of the new species in simultaneous contributions.

NK cells: immune cross-talk and therapeutic implications.

Increased evidence of cross-talk between NK cells and other immune cells has enhanced the possibilities of exploiting the interplay between the activation and inhibition of NK cells for immunotherapeutic purposes. The battery of receptors possessed by NK cells help them to efficiently detect aberrant and infected cells and embark on the signaling pathways necessary to eliminate them. Endogenous expansion of NK cells and their effector mechanisms are under exploration for enhancing adoptive immunotherapy prospects in combination with immunostimulatory and cell-death-sensitizing treatments against cancer, viral infections and other pathophysiological autoimmune conditions. Various modes of NK cell manipulation are being undertaken to overcome issues such as relapse and graft rejections associated with adoptive immunotherapy. While tracing the remarkable properties of NK cells and the major developments in this field, we highlight the role of immune cooperativity in the betterment of current immunotherapeutic approaches.

Taxometric analysis of helminthes of marine fishes. 1. Pedunculacetabulum spinatum n.sp., from Chorinemus mandetta and Wenyonia rhincodonti n.sp., from Rhincodon typus.

The investigations include report of two new worms from marine fishes of Central West Coast of Goa in Arabian Sea. A trematode, Pedunculacetabulum spinatum n.sp. from Chorinemusmandetta and Wenyonia rhincodoni n.sp. from sharks, Rhincodon typus have been described and compared with closer species. The systematics of genus Pedunculacetabulum Yamaguti (Japan J Zool 6:1-112, 1934) has been discussed with detailed evidence of taxometric significance to reinstate this genus.

Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth.

Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immunosurveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape is still incomplete. Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T-cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T-cell immunity and suppress tumor growth.