Keywords: glioblastoma, spatiotemporal heterogeneity, spatial transcriptomics, multiplex spatial 3D mapping, single cell spatial analysis

Abstract Gliomas are primary brain tumors with a poor prognosis. IDH1R132H exhibits a gain of function mutation leading to 2-hydroxyglutarate (2HG) production. We previously demonstrated, 2-HG mediated epigenetic rewiring is associated with better prognosis and its presence impacts several cellular functions including immune responses and enhanced DNA-damage response in IDH1R132H gliomas harboring p53 and ATRX loss-of-function mutations. Also, IDH1R132H elicits metabolic reprogramming which implies that IDH1R132H could modify the energetic state of gliomas with consequences in tumor biology and therapeutic responses. In this study, RNA-seq and ChIP-seq data revealed human and mouse IDH1R132H gliomas have downmodulated gene ontologies related to mitochondrial metabolism. This was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy for IDH1R132H glioma cells. We also found that IDH1R132H-neurospheres have decreased levels of oxygen consumption and extracellular acidification rates, characteristic of an autophagic/quiescent state when compared to IDH1WT-neurospheres. Analysis of the autophagy pathway revealed that both human and mouse IDH1R132H gliomas have increased expression of pULK1-S555, pATG4b-S383, enhanced conversion of LC3I to LC3II, and decreased expression of pULK1-S757, p62 indicating that IDH1R132H cells have augmented autophagy activity compared to IDH1WT cells. Blocking autophagy selectively impairs the growth of IDH1R132H glioma cells in vitro. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 sensitized IDH1R132H glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory when used in combination with irradiation. Our results thus indicate that the metabolic changes in IDH1R132H glioma cells lead to compromised mitochondrial functions and increased autophagic activity which contributes to their radioresistance, representing a novel therapeutic target for IDH1R132H cells. *Corresponding author: Maria G. Castro: mariacas@med.umich.edu Equal contributions: KB-FN-AM-AM-CT Funding: This work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) Grants: [R37-NS094804, R01-NS122165, R21-NS123879-01 awarded to MGC]; [R01-NS122378, R01-NS122234 awarded to PRL], Ian’s Friends & Chad Tough Foundation.

Abstract The ACTA2 gene, which encodes α-smooth-muscle actin, is known to be involved in contractility and oncogenic transformation. However, the specific role of tumor-associated ACTA2 mesenchymal cells in gliomas is unknown. Using genetically engineered mouse models (GEMM) of glioma, we discovered that ACTA2 expression was increased within oncostreams, which are malignant multicellular structures found in high-grade gliomas. Furthermore, we observed reduced expression of ACAT2 mRNA in IDH-Mut mouse gliomas vs WT tumors. Analyzing human glioma TCGA and CCGA databases revealed a negative correlation between tumor ACTA2 expression and overall survival in glioma patients. ACTA2 mRNA expression was also higher in grade IV and recurrent tumors. To investigate the role of ACTA2 in glioma cells, we created ACTA2 knockdown GEMM of glioma. These mice showed very large increases (~300%) in median survival (NPDS: 253 days, NPAS: 329 days) in comparison to their respective control groups (NPD: 89 days, NPA: 97 days). Glioma neurospheres derived from knockdown tumors confirmed downregulation of ACTA2, and showed reduced cell proliferation compared to controls. Moreover, orthotopic models revealed a decreased potential for tumor development in vivo. To explore the mechanism mediating the effects of ACTA2 downregulation, we conducted RNA-Seq analysis of ACTA2 knockdown neurospheres. This analysis identified approximately 5000 differentially expressed genes, with gene ontology analysis highlighting significant enrichment in biological processes such as cell adhesion, cell communication, and regulation of locomotion. Pathway analysis identified cytokine-receptor interactions, focal adhesion, and NFK-B signaling as the most significant signaling pathways affected by ACTA2 downregulation. Finally, we evaluated the release of cytokines into the cell-conditioned media and found significantly decreased levels of GSCF and GMSCF cytokines in ACTA2 knockdown compared to controls. These findings indicate that ACTA2 expression is a pro-tumoral gene involved in glioma progression and plays an essential role in altering the TME.

Glioblastomas multiforme (GBMs) are the most lethal tumors of the brain. Tumoral mesenchymal transformation is a hallmark of GBMs associated with alterations in cellular morphology and dynamic organization. However, little is known about the mechanisms that control this pathological process. Here, we report a comprehensive spatiotemporal study integrating novel intra-tumoral histopathological structures, ‘oncostreams’, with tumor dynamic properties, microenvironment assets and spatial molecular features. Cellular analyses of genetic engineered mouse models of glioma identified that oncostreams are heterogenous structures formed by elongated and aligned neoplastic cells enriched in non-neoplastic cells such as ACTA2+ mesenchymal like cells and CD68+ tumor associated microglia/macrophages (TAM). Deep learning analysis of H&E glioma histological samples from mouse and human gliomas identified that oncostream density correlates with tumor aggressiveness. To determine whether oncostreams fascicles are characterized by a specific gene expression profile, we performed transcriptomic analysis using laser capture microdissection coupled to RNA-sequencing. We found that oncostreams are defined by a transcriptomic signature enriched in mesenchymal genes. Network analyses identified that COL1A1 is a critical gene that regulates oncostream organization and function. Correspondingly, human and mouse high-grade gliomas with high oncostream densities showed prominent alignment of collagen fibers along these fascicles and higher COL1A1 expression compared to low-grade gliomas. To evaluate the functional role of COL1A1 in oncostream formation we generated a COL1A1-deficient GEMM of glioma. We observed that COL1A1 inhibition decreased oncostream formation, impaired tumor cell proliferation and remodeled the tumor microenvironment by diminishing CD68+ TAM cells, CD31+ endothelial vascular proliferation and ACTA2+ perivascular mesenchymal cells, thus increasing animal survival. Further studies, using time lapse confocal imaging in ex vivo glioma explants, and intravital imaging in vivo demonstrated that oncostreams are organized collective dynamic structures present at the tumor core and the invasive tumor border. Oncostreams dynamics increased the intra-tumoral spread of cells within the tumor and foster glioma aggressiveness through collective invasion of the normal brain parenchyma. The analysis of glioma invasion in COL1A1 knockdown tumors exhibited a reduction in collective migration patterns, strongly supporting its importance in tumor progression. We propose that oncostreams represent a novel pathological marker of potential value for diagnosis and COL1A1 depletion within oncostreams is a promising approach and reprogram mesenchymal transformation to reduce the tumor malignancy. Citation Format: Andrea Comba, Syed Faisal, Patrick J. Dunn, Anna E. Argento, Todd C. Hollon, Wajd N. Al-Holou, Maria L. Varela, Daniel B. Zamler, Gunnar L. Quass, Pierre F. Apostolides, Christine E. Brown, Phillip E. E. Kish, Alon Kahana, Celina G. Kleer, Sebastien Motsch, Maria G. Castro, Pedro R. Lowenstein. Spatiotemporal analyses of preclinical glioma models reveal ‘oncostreams’ as dynamic fascicles regulating tumor mesenchymal transformation, invasion, and malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2476.

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.

Glioblastoma (GBM), a high-grade glial tumor, is highly aggressive and is characterized by intra-tumoral heterogeneity and widespread infiltration, impairing therapeutic success. Our laboratory discovered dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal features called “oncostreams” inside GBM tumors that facilitate invasion into the normal brain. We found that collagen 1α1 (Col1A1) is essential for oncostream structure and function. Using in vivo intravital imaging and ex vivo explant glioma models, we established that Col1A1 suppression abolishes oncostreams, reprograms the malignant histopathological phenotype, and extends median survival in mice. However, the signaling through which collagen communicates to maintain an invasion-permissive glioma tumor microenvironment remains unclear. We propose to analyze a poorly understood collagen receptor family -the discoidin domain receptors (DDRs) - which is expressed in glioma and perivascular stromal cells. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) data suggest DDR1/DDR2 overexpression correlates with tumor progression and poor prognosis in glioma patients. Our RNA-seq data further confirm overexpression of DDRs in NPA and NPD glioma compared to the normal brain. Our preliminary data suggests that inhibiting collagen receptors DDR1 or DDR2 sensitizes glioma cells to radiotherapy (IR). DDR1 inhibition completely disrupts oncostreams` structure in the ex vivo explant glioma model. Moreover, pharmacological inhibition of DDR1 combined with irradiation significantly enhances the median survival of NPA (Nras, shP53, shATRX) tumors in an orthotopic mouse glioma model. Furthermore, we are currently testing whether inhibition of DDR1 using a genetically engineered mouse model (GEMM) of glioma called NPAD1 (Nras, shP53, shATRX, shDDR1) will show an increase in overall survival. We hypothesize that blocking collagen receptors DDR1 or DDR2 will control tumor growth, invasion and mediate anti-glioma immunity. This study will eventually uncover a novel therapeutic treatment for GBM, targeting DDR1 and DDR2 in human patients.

DCE-MR imaging parameters identified significant statistical differences between schwannomas and paragangliomas with AUCs of 0.70–0.99, though no significant differences in ADC values were identified. Vp was the most promising parameter to differentiate the 2 tumor types. BACKGROUND AND PURPOSE: Distinguishing schwannomas from paragangliomas in the head and neck and determining succinate dehydrogenase (SDH) mutation status in paragangliomas are clinically important. We aimed to assess the clinical usefulness of DWI and dynamic contrast-enhanced MR imaging in differentiating these 2 types of tumors, as well as the SDH mutation status of paragangliomas. MATERIALS AND METHODS: This retrospective study from June 2016 to June 2020 included 42 patients with 15 schwannomas and 27 paragangliomas (10 SDH mutation-positive and 17 SDH mutation-negative). ADC values, dynamic contrast-enhanced MRI parameters, and tumor imaging characteristics were compared between the 2 tumors and between the mutation statuses of paragangliomas as appropriate. Multivariate stepwise logistic regression analysis was performed to identify significant differences in these parameters. RESULTS: Fractional plasma volume (P ≤ .001), rate transfer constant (P = .038), time-to-maximum enhancement (P < .001), maximum signal-enhancement ratio (P < .001) and maximum concentration of contrast agent (P < .001), velocity of enhancement (P = .002), and tumor characteristics including the presence of flow voids (P = .001) and enhancement patterns (P = .027) showed significant differences between schwannomas and paragangliomas, though there was no significant difference in ADC values. In the multivariate logistic regression analysis, fractional plasma volume was identified as the most significant value for differentiation of the 2 tumor types (P = .014). ADC values were significantly higher in nonhereditary than in hereditary paragangliomas, while there was no difference in dynamic contrast-enhanced MR imaging parameters. CONCLUSIONS: Dynamic contrast-enhanced MR imaging parameters show promise in differentiating head and neck schwannomas and paragangliomas, while DWI can be useful in detecting SDH mutation status in paragangliomas.

Mutant isocitrate-dehydrogenase 1 ( mIDH1 ) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma–bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, with poor prognosis. Major obstacles hampering effective therapeutic response in GBM are tumor heterogeneity, high infiltration of immunosuppressive myeloid cells, and the presence of the blood-brain barrier. The C-X-C Motif Chemokine Ligand 12/ C-X-C Motif Chemokine Receptor 4 (CXCL12/ CXCR4) signaling pathway is implicated in GBM invasion and cell cycle progression. While the CXCR4 antagonists (AMD3100) has a potential anti-GBM effects, its poor pharmacokinetic and systemic toxicity had precluded its clinical application. Moreover, the role of CXCL12/ CXCR4 signaling pathway in anti-GBM immunity, particularly in GBM-mediated immunosuppression has not been elucidated. Here, we developed a synthetic protein nanoparticle (SPNPs) coated with the cell-penetrating peptide iRGD (AMD3100 SPNPs) to target the CXCR4/CXCL12 signaling axis in GBM. We showed that AMD3100 SPNPs effectively blocked CXCR4 signaling in mouse and human GBM cells in vitro as well as in GBM model in vivo . This results in inhibition of GBM proliferation and induction of immunogenic tumor cell death (ICD) leading to inhibition of GBM progression. Our data also demonstrate that blocking CXCR4 sensitizes GBM cells to radiation, eliciting enhanced release of ICD ligands. Combining AMD3100 SPNPs with radiotherapy inhibited GBM progression and led to long-term survival; with 60% of mice remaining tumor-free. This was accompanied by an anti-GBM immune response and sustained immunological memory that prevented tumor recurrence without further treatment. Finally, we showed that systemic delivery of AMD3100 SPNPs decreased the infiltration of CXCR4 + monocytic myeloid-derived suppressor cells to the tumor microenvironment. With the potent ICD induction and reprogrammed immune microenvironment, this strategy has significant potential for future clinical translation. Graphical abstract Immunological mechanism targeting Glioblastoma (GBM) upon blocking CXCR4 signaling pathway with AMD3100-conjugated nanoparticles (SPNPs). (1) Radiotherapy induces glioma cell death, followed by Damage-associated molecular patterns (DAMPs) release. Dendritic cells (DC) are activated by DAMPs and migrate to the regional lymph node where they prime cytotoxic T lymphocyte immune response. Tumor-specific cytotoxic T cells infiltrate the tumor and attack glioma cells. (2) Glioma cells express CXCR4, as well its ligand CXCL12. CXCL12 induces glioma cell proliferation and, (3) as well as mobilization in the bone marrow of CXCR4 expressing myeloid MDSC, which will infiltrate the tumor, and inhibit tumor-specific cytotoxic T cells activity. GEMM of glioma when treated systemically with SPNPs AMD3100 SPNPs plus radiation, nanoparticles block the interaction between CXCR4 and CXCL12, thus (4) inhibiting glioma cell proliferation and (5) reducing mobilization in the bone marrow of CXCR4 expressing myeloid MDSC, (6) generating a reduced MDSC tumor infiltration, as well as releasing MDSC inhibition over tumor specific cytotoxic T cell response.

The human papillomavirus (HPV) associated infections are the hallmark of cervical and neck cancer. Almost all the cases of cervical cancer (CC) and 70% of oropharyngeal cancer (OC) are, more or less, caused by the persistent infection of HPV. CC is the fourth most common cancer globally, and is commenced by the persistent infection with human papillomaviruses (HPVs), predominantly HPV types; 16 and 18. In the light of the above facts, there is an immediate requirement to develop novel preventive and innovative therapeutic strategies that may help in lower occurrences of HPV mediated cancers. Currently, only radiation and chemical-based therapies are the treatment for HPV mediated neck cancer (NC) and CC. Recent advances in the field of immunotherapy are underway, which are expected to unravel the optimal treatment strategies for the growing HPV mediated cancers. In this review, we decipher the mechanism of pathogenesis with current immunotherapeutic advances in regressing the NC and CC, with an emphasis on immune-therapeutic strategies being tested in clinical trials and predominantly focus on defining the efficacy and limitations. Taken together, these immunological advances have enhanced the effectiveness of immunotherapy and promises better treatment results in coming future.

BACKGROUND:Lymphatic Filariasis (LF) is one of the incapacitating and mosquito-borne sicknesses that on progression may prompt a few recognizable types of clutters like extreme lymphedema, hydrocele, and elephantiasis.METHODS:Antigenic preparations of B. malayi adult (BmA), S. cervi adult parasites and microfilariae (mf) total parasite extract were used to analyze the serological reactivity profile with human infectious sera collected from endemic areas of Bancroftian filariasis by performing Western blot and ELISA analysis. Sera from healthy human subjects were also included in the study to determine the variation incurred in the reactivity due to the filariasis infection. Gelelectrophoresis analysis of the crude-extract of BmA revealed seven protein bands while more than ten bands were recognized in S. cervi.RESULTS:our results represent a clear variation in protein patterns among the crude-antigens. ELISA results showed highest prevalence of IgG, IgM and IgG4 antibodies against all antigen preparations when recorded among microfilaraemic chronic infected patients. In both the antigenic preparations, the positive reactions were in the order of microfilaraemic>endemic normal>chronic>acute>nonendemic normal subjects. All sera of Mf+ patients were uniformly positive, while sera of both chronic and endemic normal subjects showed less reactivity.CONCLUSION:In the present study, we endeavoured to establish the extent of cross-reactivity of antigens derived from animal filarial parasites such as B. malayi and S. cervi with W. bancrofti filariasis sera of human patients. Besides, we further analyzed antibody-isotype profile of IgG, IgG4 and IgM in various human infection sera of bancroftian filarial subjects reactive to heterologous parasite antigens derived from adult worms of S. cervi from bovine and B. malayi from bovine and jirds.

Emergent technologies based on spintronics demand the unprecedented control on magnetic anisotropy. Here we present the control on magnetic anisotropy of SmFeO3 by the means of Tm(3+)doping at Sm(3+)site. A series of nano particles of Sm1-xTmxFeO3 (X = 0, 0.3, 0.5, 0.7, 1) orthoferrite have been synthesized by sol-gel auto-combustion method and phase purity was confirmed by the X-ray diffraction pattern. The crystallographic information obtained from Rietveld refinement and Raman spectroscopy confirmed the changes in oxygen octahedra with the change in doping percentage of Tm3+ ion in SmFeO3. Temperature dependent dc magnetization measurement implies the tuning of spin reorientation temperature from 480 K to 80 K as a function of Tm3+ ion doping concentration. The room temperature magnetic isotherm confirms the canted antiferromagnetic character of nano particles. Sm0.7Tm0.3FeO3 shows the spin reorientation at room temperature which might be used in room temperature spintronics devices. (C) 2019 Elsevier B.V. All rights reserved.

Background: Nanotechnology-based therapies are emerging as a promising new anticancer approach. Early clinical studies suggest that nanoparticle-based therapeutics can show enhanced efficacy while reducing side effects minimal, owing to targeted delivery and active intracellular uptake. Methods: To overcome the problems of gene and drug delivery, nanotechnology based delivery system gained interest in the last two decades. Encouraging results from Nano formulation based drug delivery systems revealed that these emerging restoratives can efficiently lead to more effective, targeted, selective and efficacious delivery of chemotherapeutic agents to the affected target cells. Results: Nanotechnology not only inhibits targeted gene products in patients with cancer, but also taught us valuable lessons regarding appropriate dosages and route of administrations. Besides, nanotechnology based therapeutics holds remarkable potential as an effective drug delivery system. We critically highlight the recent findings on nanotechnology mediated therapeutics strategies to combat hepatocellular carcinoma and discuss how nanotechnology platform can have enhanced anticancer effects compared with the parent therapeutic agents they contain. Conclusion: In this review, we discussed the key challenges, recent findings and future perspective in the development of effective nanotechnology-based cancer therapeutics. The emphasis here is focused on nanotechnology-based therapies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with hepatocellular carcinoma

Nano-sized drug delivery systems (NDDS) have been widely exploited to achieve targeted delivery of pharmaco-materials. Traditional pharmaceutical approaches, implied in the synthesis of nano-formulations, are obscure owing to the incompatible physico-chemical properties of the core drug as well as some other factors crucial in development of NDDS. Infact, most of the existing methods used in development of NDDS rely on usage of additives or excipients, a special class of chemicals. Barring few exceptions, the usage of synthetic excipients ought to be curtailed because of several associated undesirable features. Such issues necessitate strategies that lead to development of the synthetic excipient free drug delivery system. Plant based extracts have great potential to induce synthesis of nano-sized particles. Considering this fact, here we propose a prototype employing orange fruit juice (OJ) to facilitate bio-mediated synthesis of nano-sized supra-molecular assemblies of 5-fluorouracil (5-FU), a potent anticancer drug. The as-synthesized 5-FU Nanoparticles (NPs) retained the anti-neoplastic efficacy of the parent compound and induced apoptosis in cancer cells. The novel 5-FU NPs formulation demonstrated enhanced efficacy against DMBA induced experimental fibrosarcoma in the mouse model when compared to the micro-sized crystals of parent 5-FU drug.

BACKGROUNDUnderstanding of cervical cancer severity is still an important health issue across the world, especially for developing countries. Cancer or abnormal growth of the cell is one of the major health problems of the world. There are about two hundred types of malignancies reported till date. An updated statistic of all the main types of cancer and pathophysiology of cervical cancer is a significant need for designing the future treatment strategy.OBJECTIVEIn this review, a brief update on cancer, its causes and different types has been discussed along with updated statistics of patient's mortality. A brief overview of cervical cancer and its pathophysiology has been discussed with special emphasis on its causative agent, human papilloma virus (HPV). A brief introduction and update on genetics, molecular pathogenesis and prevalence of HPV and its role in cervical cancer have been added.CONCLUSIONThis review delivered an updated status of cervical cancer and provide novel therapeutic approaches for targeting HPV. The detailed molecular and genomic information of the HPV help the researchers to develop more effective and efficacious therapeutic strategies and preventive vaccines that will significantly contribute to the control and anticipation of cervical cancer. Ultimately this may open new vistas to get rid of this deadly disease and may offer significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer in the affected nations.

Lymphatic filariasis (LF) is a chronic and debilitating disease that affects people in tropical and sub-tropical areas of Asia, Africa, and Western Pacific. It is one of the leading community health problems in some of the endemic districts in India including Hardoi district of Uttar Pradesh. The disease is caused by the parasites Wuchereria bancrofti (W. bancrofti), Brugia malayi (B. malayi) and Brugia timori (B. timori), transmitted by the vector Culex, Anopheles and other mosquitoes. This cross-sectional survey study was carried out in rural areas, where its inhabitants vary in socio-economic status, from low to middle-income class. 12 villages of Hardoi district, Uttar Pradesh, India were included. The aim was to see the impact of age and gender on various clinical forms of LF and in estimating its economic and social implications. 260 LF affected people in different parts of Hardoi district were surveyed. The results revealed that the Mass Drug Administration (MDA) coverage reached more than 90%. The overall Microfilaria rate had been reduced, however the prevalence of elephantiasis increased with the progression of age and was found to be highest among people of > 70 years of age, regardless of their gender.