Introduction Regulatory T cell (Treg)-targeting cancer immunotherapy aims to transiently deplete Treg cells in the tumor microenvironment, without affecting effector T cells (Teff), thus both enhancing anti-tumor activity and avoiding autoimmunity. This study evaluated whether adding E7777 (a new formulation of denileukin diftitox [DD]) improved the efficacy of anti-PD-1 antibody therapy. DD is a recombinant protein containing the hydrophobic and catalytic portions of diphtheria toxin fused to full-length human IL-2. E7777 has the same amino acid sequence and brief circulatory half-life as DD, but with greater purity and potency. Methods Subcutaneous syngeneic murine solid tumor models (colon cancer CT-26 and liver cancer H22) were used to evaluate safety, efficacy, and overall survival with E7777 and anti-PD-1 antibodies, each administered as monotherapy or in concurrent or sequential combination. In Experiment 1, treatments were compared to assess anti-tumor activity at various time points, with tumors excised and dissociated and tumor leukocytes characterized. In Experiment 2, tumor growth, response, and overall survival were characterized for 100 days following a 3-week treatment. Results E7777 administered in combination with anti-PD-1 led to significantly increased anti-tumor activity and durable, extended overall survival compared to either treatment alone. In both tumor models, the Treg cell infiltration induced by anti-PD-1 treatment was counterbalanced by co-treatment with E7777, suggesting potential synergistic activity. Combination therapy showed the most favorable results. Treatment with E7777 was safe and well-tolerated. Discussion Combined E7777 and anti-PD-1 therapy was well tolerated and more effective than monotherapy with either drug.
In this paper various type of full adder circuits with high speed operation have been analyzed. Power Consumption, Speed and Area are important factors of the design aspect of full adder circuit. Many researchers have worked on full adder designs using various technologies. Present paper deals with literature analysis based on full adder designs.
Lurbinectedin was approved on June 15, 2020 by the Food and Drug Administration with the brand name ZEPZELCA as the first systematic approved therapy for patients having Small Cell Lung Cancer (SCLC).In this review, an attempt is made to summarize different aspects of Lurbinectedin, including the pathophysiology, chemistry, chemical synthesis, mechanism of action, adverse reactions, and pharmacokinetics. Special attention is given to various reported clinical trials of lurbinectedin.A comprehensive literature search was conducted in the relevant databases like ScienceDirect, PubMed, ResearchGate and Google Scholar to identify studies. After a thorough study of these reports, significant findings/data were collected and compiled under suitable headings. Important findings related to clinical trials have been tabulated.Lurbinectedin is known to act by inhibiting the active transcription of encoding genes, thereby suppressing tumor-related macrophages with an impact on tumour atmosphere. Lurbinectedin has emerged as a potential drug candidate for the treatment of Small-Cell Lung Cancer (SCLC).
Abstract Whilst the advent of Immune Checkpoint Blockade has revolutionized the management of cancer, a significant proportion of patients have limited or absent response to these therapies. A key cause of this immune insensitivity is the hostile solid tumor microenvironment (TME) dominated by immunosuppressive myeloid cells. We previously identified the acid sensing G protein coupled receptor (GPCR), GPR65, as a primary determinant of these suppressive cells. In mice, genetic deletion of Gpr65 or oral administration of small molecule GPR65 inhibitors in vivo causes a profound repolarization of immunosuppressive tumor associated macrophages, an increase in infiltrating effector cells and potent anti tumor effects in syngeneic models. In TCGA data, across all tumors, patients homozygous for a hypomorphic coding variant in GPR65 (I231L) show increased overall survival, providing compelling genetic evidence of the clinical potential of GPR65 inhibition. To further explore the translational potential of GPR65 we employed a range of techniques to define the human biology of this receptor in different contexts. At the mechanistic level, single cell RNA sequencing (scRNAseq) of human PBMCs obtained from healthy donors demonstrated a pronounced effect of low pH on the myeloid compartment, with a clear polarization of these cells toward an immunosuppressive character and modulation of GPR65 expression. In parallel, pharmacological inhibition of GPR65 in human monocyte derived macrophages exposed to low pH demonstrated that equivalent gene expression changes are primarily due to GPR65 activation. To examine the relevance of these findings to the intact acidic human TME, we performed studies in fresh primary human tumor histocultures from clear cell renal cell carcinoma (ccRCC) patients with immunohistochemically confirmed high macrophage infiltration and carbonic anhydrase 9 (CA9) expression. In these cultures, GPR65 inhibition caused a dose dependent suppression of a geneset closely overlapping with that modulated by GPR65 in primary macrophages. Furthermore, we observed a marked decrease in immune suppressive IL10 secretion with coincident elevation of specific proinflammatory chemokines. Consistent with these findings, in vivo administration of a small molecule GPR65 inhibitor elicited similar changes in human CA9 expressing RCC PDX tumors implanted in myeloid boosted CD34+ stem cell engrafted NCG mice. In summary, inhibition of GPR65 provides a unique and genetically validated approach to favorably modify the immunosupressive TME with features highly conserved between mouse and human contexts. We propose that GPR65 inhibition holds significant clinical promise, with specific evidence around ccRCC as a potential standout indication. Citation Format: Barbara Cipriani, Alastair Corbin, David Miller, Alan Naylor, Faraz Khan, Gavin Milne, Barbara Young, Rupert Satchell, Sourav Sarkar, Mussa Quareshy, Anastasia Nika, Preeti Singh, Gavin Knox, Darryl Turner, Satish Sankaran, Nandini Pal Basak, Toszka Bohn, Tobia Bopp, Surya Koturan, Bo Sun, Benjamin Fairfax, Tom McCarthy, Stuart Hughes. The translational biology of small molecule GPR65 inhibitors: shared effects between mouse models and human primary tumors highlight the unique transformative potential of targeting a genetically validated innate immune checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 668.
Satellite sensors acquire massive data to exploit and address numerous human tasks.Due to the physical constraints, the usage of high spatial resolution multispectral (MS) images cannot be acquired by the unique devices.Hence, it is necessary to develop techniques by incorporating the images of MS and the panchromatic (PAN), also called Pan sharpening in remote sensing applications.Hence, this survey analyzes 30 research existing papers in Pan sharpening, which is based on various techniques, like neural network-based techniques, image fusion-based techniques, guided filterbased techniques, and optimization-based techniques.The analysis is based on the publication year of the research paper, research techniques employed, performance evaluation measures, and achievement of the research techniques.Also, the issues in the approaches are explained.Moreover, the future scope is to develop an efficient Pan sharpening technique based on the limitations recognized from the existing research Pan sharpening techniques.
This multipurpose tool allows editors and reviewers to get access to the manuscript for review and to communicate with author. I‟m highly thankful to my Sr.Faculty members - Dr.Bhoomi Sitlani and Dr. Rajeshri Desai Sr.Faculty, staff members – Dr.Nilesh Sainy, Mr.AJAY Mujalde, Mr. Pravin Gurjar, Ms.Pramila Suryavanshi, Mr. Sanju Kayat, Mr.Alpesh Kaul, School Of Commerce, DAVV and their team mebers – Prof. P.K.Gupta, Dr.Rajendra Singh, Dr.Anil Goray, Dr.Amit Kumar Singh, Mr. Alok Anand Jha, Mr. Prathmesh Joshi, Mr. Anand Yadav, Ms. Yashasvi Sharma, Ms.Nancy Shrivastava, Ms. Priya Rathore, Ms.Sakena Banu, Ms.Varsha Vijayvergiya, Dr.Sunita sharma, Dr.Bharti Arya, Dr.Unmekha Tare, Dr. Roopam Agarwal, Dr.Apoorva Shrivastava Dr.Swati Kendulkar, Dr.Avneet Kaur Narang, Ms. Shilpa Arya, Dr.Yogita Maheshwari, Dr. Sona Kanungo, Dr. Bhavna Sharma, Ms. Kratika Pahuja, Mr. Rakesh Khandelwal, Mr. Ashish Joshi for their unending support and love in making the three days National Conference a big success.
In cancer, persistent antigenic challenge leads to T cells acquiring a hyporesponsive cell state, also referred to as T cell exhaustion. We have previously demonstrated that human CD3+ T cells repeatedly stimulated in vitro, via their TCR, develop phenotypical characteristics of exhausted T cell found in vivo, including increased expression of inhibitory receptors PD-1, TIM-3 and LAG-3 and diminished responsiveness to dendritic cell activation and cancer cell cytotoxicity. We showed that PD-1 blockade with nivolumab and treatment with an IKZF3 inhibitor, lenalidomide, reinvigorated the exhausted T cells. We next wished to evaluate if blocking of IKZF3 during the development of T cell exhaustion could protect them from acquiring the exhausted phenotype.
Methods
Human CD3+ T cells, isolated from healthy PBMC donors, were repeatedly stimulated with anti-CD3/anti-CD28 coated beads to mimic chronic antigenic challenge. The stimulations were conducted in the presence or absence of lenalidomide. T cells, both CD4+ and CD8+, were assessed for changes in expression of inhibitory receptors and cytokine release was quantified. Following the final round of TCR stimulation, T cells were co-cultured with allogeneic dendritic cells to determine if their functionality has been altered by lenalidomide treatment. T cell proliferation and IFN-g release were assessed as well as changes in inhibitory receptor expression at the end of the co-culture.
Results
We demonstrated that lenalidomide had no impact on T cell viability or CD4+/CD8+ ratio in repeatedly stimulated cultures. Lenalidomide did however affect inhibitory receptor expression and impacted cytokine secretion from chronically stimulated T cells. Lenalidomide led to increased PD-1 expression on CD8+ T cells and LAG-3 expression on CD4+ T cells whereas TIM-3 expression was downregulated on both T cells subsets in the presence of compound. Lenalidomide enhanced production of cytokines in repeatedly stimulated T cells. To assess if lenalidomide-driven changes had any impact on T cell functionality, we cultured lenalidomide-treated and untreated repeatedly activated T cells with allogeneic dendritic cells. Whilst repeatedly stimulated T cells not exposed to lenalidomide showed diminished ability to proliferate and secrete IFN-g, consistent with their exhausted cell state, lenalidomide treated T cells displayed increased IFN-g secretion suggesting that lenalidomide protected repeatedly stimulated T cells from acquiring an exhausted phenotype.
Conclusions
The in vitro assays described herein offer the opportunity to investigate the effect of candidate therapeutics, including combination therapies, on exhausted T cell development and function.
Adoption of online learning tools is still in the nascent stage in India. Use of such tools has been sporadic and patchy at best. The Covid pandemic of 2020 forced the institutions to shut down which resulted in the sudden adoption of such software. The education market in India is dominated by free & open-source software also known as FOSS while proprietary software solutions take a back seat. This research focuses on the impacts of proprietary education software in easing the learning process for children as well as grad-students, and how these tools impact engagement and learnability. Moreover, a retrospective study of an open-source tool present in the market and the comparison of it with the proposed system have been presented. Further, an example of a proposed system of how a simple system can be created in-house and at minimal cost to serve as a proprietary solution for all online educational needs of the pupils has been demonstrated.
Abstract The acidic tumour microenvironment (TME) and the abundance of tumour associated macrophages (TAMs) are key features of solid tumours that drive immune suppression, support tumour growth and limit the efficacy of approved therapies. We identified the pH sensing GPCR, GPR65, as a key determinant of low pH induced immune suppression in human cancers, particularly in TAMs, based on the following observations: 1) cancer patients who are homozygous for a hypomorphic coding variant in GPR65 (I231L) show a statistically significant increase in survival and altered expression of key immune system genes compared to other genotypes; 2) single cell RNA sequencing (scRNAseq) data from multiple solid tumors show that GPR65 and downstream pathway genes are ubiquitously expressed in myeloid and other innate immune cells in human cancers; and 3) low pH acting via GPR65 profoundly alters gene expression in human macrophages in vitro, bringing about a pronounced suppression of proinflammatory cytokines and a marked upregulation of tissue repair genes. These findings identify GPR65 as a novel innate immune check point, and suggest that GPR65 inhibition could be highly beneficial in cancer. Indeed, previous work has shown that genetic ablation of the GPR65 signaling pathway in B16.F10 tumour bearing mice upregulates immunostimulatory genes in TAMs and significantly reduces tumor growth1. Pathios has identified potent and selective antagonists of human GPR65 with excellent oral bioavailability and pharmacokinetics. In line with their potencies in recombinant cell systems, lead molecules are able to inhibit low pH induced cAMP elevations in primary human macrophages with IC50 values in the single digit nM range. In macrophages subjected to acidic conditions, the inhibitory effects on cAMP are accompanied by a reduction in the expression of anti inflammatory and tissue repair genes, and the enhancement of immunostimulatory genes. In particular, GPR65 inhibition counteracts the pronounced low pH induced suppression of key Type I/II interferon (IFN) response genes and chemokines such as CXCL9, CXCL10 and CXCL11. Following oral administration in tumour bearing mice, lead compounds up-regulate the expression of anti-tumor immune response genes at systemic exposures that significantly suppress GPR65 signalling in vitro. Results from tumour growth inhibition studies in mice with our GPR65 inhibitors will be also be presented. In summary, ‘Macrophage Conditioning’ via GPR65 inhibition holds substantial promise as a novel immunoncology strategy to counteract the immunosuppressive effects of the acidic TME on TAMs, and could be deployed either as monotherapy or in combination with T cell checkpoint inhibitors or other standard of care treatments. 1Nat. Immunol. 19:1319 Citation Format: Barbara Cipriani, David Miller, Alan Naylor, Gavin Milne, Barbara Young, Rupert Satchell, Suorav Sarkar, Zoe Smith, Rhoanne McPherson, Anastasia Nika, Preeti Singh, Toszka Bohn, Tobias Bopp, Tom McCarthy, Stuart Hughes. Inhibition of GPR65 counteracts low pH induced immunosuppressive polarization of macrophages: In vitro and in vivo characterization of potent, selective and orally bioavailable small molecule GPR65 antagonists [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 2162.
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)
