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

Concurrent loss of FTD genes C9orf72 and Grn exacerbates neuroinflammation via autoimmune dysfunction

The majority of familial FTD stems from mutations in Progranulin (GRN gene, PGRN protein) or hexanucleotide (CCCCGG) repeat expansion in C9orf72 gene. Recent studies highlight the key roles of C9orf72 and PGRN in endo-lysosomal trafficking, with their deficiencies causing abnormal microglial activation in the aging brain. Alongside potential interactions between PGRN and C9orf72 in vesicle trafficking, there are documented instances of concurrent mutations in both C9orf72 and GRN genes linked to earlier disease onset and heightened neurodegeneration in familial cases of FTD-ALS spectrum disease. In my thesis work, I hypothesized that simultaneous deletion of C9orf72 and GRN exacerbates neuroinflammation and neurodegeneration. To test this, I generated aging cohorts of wild type (WT), Grn-/-, C9orf72-/-, and Grn-/-;C9orf72-/- mice. Grn-/-;C9orf72-/- mice exhibited heightened microgliosis and astrogliosis, extending beyond the thalamocortical circuit, and disrupted blood-brain barrier. Brain RNA-seq revealed novel transcriptomics signatures of increases in B-cell receptor signaling in Grn-/-;C9orf72-/- mice. CITE-seq and flow cytometry revealed age-dependent clonal expansions of age-associated B cells and activated B cells. PhIP-seq and protein arrays demonstrated that clonally expanded B cells produced autoantibodies that target many neural antigens, including axon guidance protein ROBO3. Together, these results support that concurrent loss-of-function in both C9orf72 and Grn genes intensify neuroinflammation and peripheral immune system defects, thereby synergistically promoting neurodegeneration

Spectral Radiation Analysis Of Premixed Oxy-Syngas And Oxy-Methane Flames

Oxy-fuel combustion has potential to be an impeccable enhancement of current combustion techniques. For a hydrocarbon burning with oxygen the resulting exhaust stream is composed mainly of carbon dioxide and water vapor. This exhaust allows for easier carbon capture and sequestration since the water can be condensed out. Another advantage is the significant reduction of NOx since much of the nitrogen found in air-combustion systems is eliminated. These processes also provide a higher theoretical efficiency which is advantageous. Although beneficial many of the exhaust gas products radiative characteristics are unknown. Motivated by this, this paper focuses on the spectral radiation measurement of oxy-syngas and oxy-methane combustion. This is important for combustion system designers since radiating heat from the flame is the primary source of the heat flux going into the combustor walls. In this experimental study, spectral radiation of premixed oxy-syngas and oxy-methane data was collected from 1.2μm to 5μm wavelengths with varying firing inputs, equivalence ratios, and CO2 recirculation ratios. The study finds that oxy-fuel combustion flame displays 3 to 5 times stronger spectral intensity than a conventional air combustion flame. It is also found from this experimental study that spectral intensity increases 10 to 40 percent at carbon dioxide emission wavelength and 40 to 150 percent at water vapor emission wavelength for hydrogen content increment from 10 to 20 and 20 to 30 percent in syngas mixture. Furthermore, experimental data shows that spectral intensity increases almost 2 to 6 times as firing input increases from 500 W to 1000 W at 250 W intervals for both oxy-syngas and oxy-methane combustion

Neuroimmune dysfunction in frontotemporal dementia: Insights from progranulin and C9orf72 deficiency

Neuroimmune dysfunction is a cardinal feature of neurodegenerative diseases. But how immune dysregulation in the brain and peripheral organs contribute to neurodegeneration remains unclear. Here, we discuss the recent advances highlighting neuroimmune dysfunction as a key disease-driving factor in frontotemporal dementia (FTD). We provide an overview of the clinical observations supporting a high prevalence of autoimmune diseases in FTD patients with mutations in GRN or C9orf72. We then focus on a myriad of evidence from human genetic studies, mouse models, in&nbsp;vitro assays, and multi-omics platform, which indicate that haploinsufficiency in GRN and C9orf72 promotes neuroimmune dysfunction and contributes to neurodegeneration and premature death. These compelling data provide key insights to disease mechanisms, biomarker discovery, and therapeutic interventions for FTD (120 words)

Cross-sectional Survey on Online Learning during COVID-19 Pandemic in Bangladesh

The educational system across the world had drastically been affected due to the pandemic outbreak of COVID-19. In this circumstance, Teaching and learning shifted from traditional way which involves face-to-face interaction among teachers and students physically in a classroom, to online learning either synchronously or asynchronously. Therefore, the aim of this study is to monitor the level of students’ perception towards online learning during the ongoing COVID-19 pandemic situation. The study adopted the way of quantitative approach by conducting a survey which was collected via a standardized online questionnaire. Data collected from 699 respondents were analyzed using SPSS 23 software. In spite of having been failed to get theoretical and practical experience as well as expected results, majority of the respondents had positive perceptions towards online learning and accepted this as the new method of learning with online application tools. The outcomes of the study will facilitate educational institutions and policy makers to take this online learning process to the next level in a prospective way. Keywords: Online Learning, COVID-19, Pandemic, Bangladesh

Psychometric Properties of the Short-Form Geriatric Depression Scale (GDS-SF) and Its Associated Factors among the Elderly in Bangladesh

Background: This study aimed to (1) evaluate the psychometric properties of a Comprehensive Short-Form Geriatric Depression Scale (GDS-SF) and (2) examine the associated factors of GDS-SF among the elderly. Methods: A cross-sectional study was conducted from November 2019 to April 2020 in Dhaka City Corporation, Bangladesh. Data of 377 elderly were collected, including socio-demographic characteristics, social supports, comorbidities, sleep behaviours, and depression (as measured by the GDS-SF). We used the principal component analysis, correlation analysis, and logistic regression analysis to validate GDS-SF, and explore its associations. Results: The GDS-SF was reliable and homogeneous with Cronbach&rsquo;s alpha = 0.836, and McDonald&rsquo;s Omega = 0.841, with no floor/ceiling effects. The questionnaire demonstrated a good construct validity with item-scale convergent validity and KMO measure of sampling adequacy (0.869 for the total sample, 0.838 for the community subsample, and 0.851 for the slum subsample). In the multivariate model, older people had a higher likelihood of moderate and severe depression (OR, 1.06; 95% CI, 1.00, 1.12; p = 0.048). The likelihood of having moderate and severe depression was lower in men (OR, 0.48; 95% CI, 0.28, 0.85; p = 0.011) and those satisfied with their children&rsquo;s support (OR, 0.17; 95% CI, 0.08, 0.35; p &lt; 0.001), compared with their counterparts, respectively. Conclusions: The GDS-SF is a reliable and valid survey tool for evaluating depression in Bangladeshi older adults. Age, gender, and satisfaction with children&rsquo;s support were predictors of depression

Factors Related To Knowledge On Newborn Danger Signs Among The Recently Delivered Women In Sub-district Hospitals Of Bangladesh

Background: Bangladesh continues to be one of the top ten countries with the highest burden of neonatal mortality. While, most of the neonatal deaths are preventable; health system delays, delayed identification of newborn danger signs, late diagnosis and initiation of treatment are claimed to be the main challenges.Objective: 1) to determine the level of knowledge among the recently delivered women (RDW) about newborn danger signs and 2) to distinguish the factors associated with ability of identifying the danger signs.Methods: A facility based cross-sectional study was conducted in three sub-district hospitals of Bangladesh among 135 RDW between 1 January 2015 and 30 April 2015. Seven key danger signs were identified, and responses were categorized accordingly. Bivariable logistic regression was conducted to determine the likelihood of the association of factors with danger signs identification.Results: About 51% of RDW could identify one key danger sign. Knowledge on "fever'' was the most commonly known danger sign (65%). Middle age (OR 1.67, 95% CI: 1.09 - 2.18), high education (OR 2.37, 95% CI: 1.46 - 2.77), increased parity (OR 1.91, 95% CI: 1.17 - 2.89), and previous hospital delivery (OR 1.79, 95% CI: 1.14 - 2.68) were found associated with the knowl­edge of the danger signs.Conclusion: The findings indicate the immediate need to enhance health education among the RDW about newborn danger signs before their hospital discharge. Community based health education programs can be a cost effective intervention to increase awareness and early recognition of neonatal danger signs

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas.

Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors. Given these findings, we have investigated the impact of IDH mutations on the immunological milieu in LGG. In immortalized normal human astrocytes (NHAs) and syngeneic mouse glioma models, the introduction of mutant IDH1 or treatment with 2HG reduced levels of CXCL10, which was associated with decreased production of STAT1, a regulator of CXCL10. Expression of mutant IDH1 also suppressed the accumulation of T cells in tumor sites. Reductions in CXCL10 and T cell accumulation were reversed by IDH-C35, a specific inhibitor of mutant IDH1. Furthermore, IDH-C35 enhanced the efficacy of vaccine immunotherapy in mice bearing IDH-MUT gliomas. Our findings demonstrate a mechanism of immune evasion in IDH-MUT gliomas and suggest that specific inhibitors of mutant IDH may improve the efficacy of immunotherapy in patients with IDH-MUT gliomas