Unraveling the cytotoxic potential of Temozolomide loaded into PLGA nanoparticles

BACKGROUND: Nanotechnology has received great attention since a decade for the treatment of different varieties of cancer. However, there is a limited data available on the cytotoxic potential of Temozolomide (TMZ) formulations. In the current research work, an attempt has been made to understand the anti-metastatic effect of the drug after loading into PLGA nanoparticles against C6 glioma cells. Nanoparticles were prepared using solvent diffusion method and were characterized for size and morphology. Diffusion of the drug from the nanoparticles was studied by dialysis method. The designed nanoparticles were also assessed for cellular uptake using confocal microscopy and flow cytometry. RESULTS: PLGA nanoparticles caused a sustained release of the drug and showed a higher cellular uptake. The drug formulations also affected the cellular proliferation and motility. CONCLUSION: PLGA coated nanoparticles prolong the activity of the loaded drug while retaining the anti-metastatic activity

Trauma from Occlusion: Practical Management Guidelines

Occlusal trauma is trauma to the periodontium from functional or parafunctional force’s causing damage to the teeth and its attachment apparatus by exceeding its adaptive and reparative capacities. Occlusal instability is a common cause for trauma from occlusion, resulting in numerous complications. It often leads to interference which reflexively shifts or slides the jaw forward on one or both the side to find a spot where most teeth come together. This action protects the teeth from injury caused by chewing on just one tooth. Overtime, this shift can cause a whole host of problems from TMJ pain, post restorative complications, headache, tooth sensitivity, recession, broken and loss of teeth and orofacial pain. These occlusal interferences and bite discrepancies are treatable with minimally invasive dentistry. Occlusal equilibration is a therapy that is used when the cause of trauma is due to occlusal instability. This involves the reshaping of the teeth where the improper biting surfaces are located. The key lies in decoding the cause, but often treatment is only directed towards the effects. Only a thorough evaluation and occlusal analysis will lead to a definitive diagnosis that will help in better anticipation of the damages

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Rare Case of Sino-Nasal Rosai Dorfman Disease

ABSTRACT : Introduction: Rosai-Dorfman disease (RDD) is a very rare nonneoplastic lymphoproliferative disease with unknown etiology and pathogenesis. It was originally described as sinus histiocytosis with massive lymphadenopathy(SHML). Approximately 43% of Rosai-Dorfman disease show extra nodal involvement wherein the possible sites are skin, CNS, ear, orbit and rarely nose and paranasal sinuses. Definitive diagnosis can be performed by histopathological examination, which shows emperipolesis. The sinus histiocytes are strongly reactive for S-100 protein and CD68, but negative for CD1a. Case Report: The current study presents the case of a 29 year old male patient who had complaints of nasal obstruction since 5 months. Diagnostic Nasal Endoscopy showed mass completely filling both nasal cavities. Histopathological examination concluded the diagnosis of Rosai-Dorfman Disease and Immunohistochemistry (IHC) stained positive for S-100 and CD68, while negative for CD1a, of the surgical specimen after surgical excision by Functional Endoscopic Sinus Surgery. Follow up was done after a week, monthly for 6 months and a year for recurrence Discussion: Extranodal RDD, although rarely seen, should be considered in nasal cavity. Even though there is no ideal protocol in the treatment, surgical excision should be considered if there is a functional disorder

Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth.

Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by the healthier neighbors. The precise connection between proteotoxic stress and competitive cell survival remains largely elusive. Here, we reveal the function of an endoplasmic reticulum (ER) and Golgi localized protein Rer1 in the regulation of protein homeostasis in the developing Drosophila wing epithelium. Our results show that loss of Rer1 leads to proteotoxic stress and PERK-mediated phosphorylation of eukaryotic initiation factor 2α. Clonal analysis showed that rer1 mutant cells are identified as losers and eliminated through cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc-overexpression that causes overgrowth, albeit under high proteotoxic stress. Our results suggest that increased levels of Rer1 provide cytoprotection to Myc-overexpressing cells by alleviating the proteotoxic stress and thereby supporting Myc-driven overgrowth. In summary, these observations demonstrate that Rer1 acts as a novel regulator of proteostasis in Drosophila and reveal its role in competitive cell survival