Tumor antigens for cancer immunotherapy: therapeutic potential of xenogeneic DNA vaccines

Preclinical animal studies have convincingly demonstrated that tumor immunity to self antigens can be actively induced and can translate into an effective anti-tumor response. Several of these observations are being tested in clinical trials. Immunization with xenogeneic DNA is an attractive approach to treat cancer since it generates T cell and antibody responses. When working in concert, these mechanisms may improve the efficacy of vaccines. The use of xenogeneic DNA in overcoming immune tolerance has been promising not only in inbred mice with transplanted tumors but also in outbred canines, which present with spontaneous tumors, as in the case of human. Use of this strategy also overcomes limitations seen in other types of cancer vaccines. Immunization against defined tumor antigens using a xenogeneic DNA vaccine is currently being tested in early phase clinical trials for the treatment of melanoma and prostate cancers, with proposed trials for breast cancer and Non-Hodgkin's Lymphoma

AVO Analysis of a Weak BSR on the Hikurangi Margin, New Zealand

Gas hydrates occur in deep, cold areas on the Hikurangi margin, New Zealand, generally at water depths of ≥ 600m and ≤ 8oC temperature. In these areas elevated hydrostatic pressures and low temperatures create stable conditions for hydrate formation. The occurrence of Bottom-Simulating Reflections (BSRs) is known to indicate the Base of the Gas Hydrate Stability (BGHS) zone, below which solid hydrates cannot exist due to increasing temperatures of sediments. BSRs in most settings worldwide are thought to be largely caused by free gas at the base of the gas hydrate stability zone. They are characterized by a large negative reflection coefficient due to significant decrease in P-wave velocity attributed to the presence of gas below the BSR. On the Hikurangi margin however, many BSRs appear relatively weak. This study presents the results of Amplitude Variation with Offset (AVO) analysis of a weak BSR beneath Puke Ridge, a thrust ridge on the accretionary wedge east of Gisborne, North Island. Rock-physics modelling is used to interpret the findings. The 05CM04 seismic line has been processed by preserving the amplitude and care has been taken to not bias the variation of reflectivity coefficient with offset. The zero-offset reflection coefficient or AVO intercept (A) is in the range of -0.008 to - 0.015 and the AVO gradient (B) is between -0.015 and -0.03. Rock-physics modelling was employed to determine the possible concentrations of gas and hydrate that can yield the observed reflection coefficients. Negligible hydrate saturation above with a patchy gas distribution of 3% saturation beneath the BSR might explain this pattern. An alternative end-member estimation of 13% saturation of hydrate in a frame-supporting model with no gas beneath it could generate the observed reflection coefficient but it is geologically unlikely. Synthetic modelling reveals that the low reflectivity of the BSR could also be due to the presence of thin layers of more concentrated or evenly distributed gas but this scenario is considered to be geologically unlikely. BSRs beneath some thrust ridges in the southern Hikurangi margin, appear as a series of clearly separated bright spots, which indicate free gas accumulations which when connected mimic the geometry of the seafloor. The most likely lithologic explanation for these high amplitude patches within weak BSRs, is the concept of segmented BSRs which is also seen in the Gulf of Mexico. The bright ―gas‖ anomalies are inferred to correlate with sand-rich high permeability layers while the weak BSR could be due to low saturations of gas in clay-rich low permeability layers. The weak BSR beneath the Puke Ridge is indicative of low and patchy gas saturations in low-permeability reservoir rocks while high amplitude patches found in this area may indicate high-permeability sands that may be attractive reservoir rocks for future gas hydrate production

Impact of Isotype on the Mechanism of Action of Agonist Anti-OX40 Antibodies in Cancer: Implications for Therapeutic Combinations

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes

AVO Analysis of a Weak BSR on the Hikurangi Margin, New Zealand

Gas hydrates occur in deep, cold areas on the Hikurangi margin, New Zealand, generally at water depths of ≥ 600m and ≤ 8oC temperature. In these areas elevated hydrostatic pressures and low temperatures create stable conditions for hydrate formation. The occurrence of Bottom-Simulating Reflections (BSRs) is known to indicate the Base of the Gas Hydrate Stability (BGHS) zone, below which solid hydrates cannot exist due to increasing temperatures of sediments. BSRs in most settings worldwide are thought to be largely caused by free gas at the base of the gas hydrate stability zone. They are characterized by a large negative reflection coefficient due to significant decrease in P-wave velocity attributed to the presence of gas below the BSR. On the Hikurangi margin however, many BSRs appear relatively weak. This study presents the results of Amplitude Variation with Offset (AVO) analysis of a weak BSR beneath Puke Ridge, a thrust ridge on the accretionary wedge east of Gisborne, North Island. Rock-physics modelling is used to interpret the findings. The 05CM04 seismic line has been processed by preserving the amplitude and care has been taken to not bias the variation of reflectivity coefficient with offset. The zero-offset reflection coefficient or AVO intercept (A) is in the range of -0.008 to - 0.015 and the AVO gradient (B) is between -0.015 and -0.03. Rock-physics modelling was employed to determine the possible concentrations of gas and hydrate that can yield the observed reflection coefficients. Negligible hydrate saturation above with a patchy gas distribution of 3% saturation beneath the BSR might explain this pattern. An alternative end-member estimation of 13% saturation of hydrate in a frame-supporting model with no gas beneath it could generate the observed reflection coefficient but it is geologically unlikely. Synthetic modelling reveals that the low reflectivity of the BSR could also be due to the presence of thin layers of more concentrated or evenly distributed gas but this scenario is considered to be geologically unlikely. BSRs beneath some thrust ridges in the southern Hikurangi margin, appear as a series of clearly separated bright spots, which indicate free gas accumulations which when connected mimic the geometry of the seafloor. The most likely lithologic explanation for these high amplitude patches within weak BSRs, is the concept of segmented BSRs which is also seen in the Gulf of Mexico. The bright ―gas‖ anomalies are inferred to correlate with sand-rich high permeability layers while the weak BSR could be due to low saturations of gas in clay-rich low permeability layers. The weak BSR beneath the Puke Ridge is indicative of low and patchy gas saturations in low-permeability reservoir rocks while high amplitude patches found in this area may indicate high-permeability sands that may be attractive reservoir rocks for future gas hydrate production

Apolipoprotein A1 as a potential biomarker in the ascitic fluid for the differentiation of advanced ovarian cancers

Context: Primary ovarian cancer and ovarian metastasis from non-ovarian cancers in advanced stage are closely mimicking conditions whose therapeutics and prognosis are different. Objective: To identify biomarkers that can differentiate the two variants of advanced ovarian cancers. Methods: Gel-based proteomics and antibody-based assays were used to study the differentially expressed proteins in the ascitic fluid of fourteen patients with advanced ovarian cancers. Results: Programmed Cell Death 1-Ligand 2, apolipoprotein A1, apolipoprotein A4 and anti-human fas antibody are differentially expressed proteins. Conclusions: Apolipoprotein A1 with a 61.8?ng/ml cut-off is a potential biomarker with the best differentiating statistical parameters

Last-mile delivery of early childhood development services: The role of community health workers in dadra nagar-haveli district

Background: India has the dual challenge of a high prevalence of developmental delay and disabilities in early childhood and a paradoxical underutilization of available intervention services due to limited accessibility and acceptability by their families. Early Childhood Development (ECD) services delivered by community health workers (CHWs) ensure its last-mile delivery to every household. IIts acceptability is improved by including evidence-based, culturally, and contextually sensitive approaches as is done in the International Guide for Monitoring Child Development (IGMCD). The IGMCD is a tool that monitors and supports the development of children under 3 years of age and also enables provision of early intervention services when required. The IGMCD, recognizes caregiver strengths and priorities and helps to build a rapport between caregivers and providers. Clinical Description: We describe six children and their families from Velugam, Dadra-Nagar Haveli district, who received ECD services from CHWs who used the IGMCD package. These cases highlight how the CHWs used the IGMCD package to identify developmental delays, health and psychosocial risk factors to development and provide strategies to caregivers to support their children's development. Management: The CHW used individualized strategies to promote responsive caregiving and enhance opportunities for early learning. In addition, the IGMCD package reinforces health, nutrition, and ECD-directed messages that are provided at the Anganwadi centers. Conclusion: Children and families in underserved communities can receive comprehensive ECD services through CHWs who are trained to deliver the IGMCD