bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5567: In vivo administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors
Authors: Smith Melissa , Chin Diana , Chan Szeman , Mahady Sally , Campion Liam , Morgan Caitlin , Patel Shefali , Chu Gerald , Hughes Anna , Bignan Gilles , Connolly Pete , Emanuel Stuart , Packman Kathryn , Luistro Leopoldo L.
Published: September 2020

STING (Stimulator of Interferon Genes) is an important mediator of innate and adaptive immunity that responds to invading cytosolic bacterial and viral pathogens, and double stranded DNA from transformed cells. Activation of the cGAS-STING pathway leads to pleiotropic cytokine (IFN-α, IFN-β, TNF-α, IL-6) production, maturation and activation of macrophages, and MHC class II expressing dendritic cells (DCs) with generation of CD8+ T cells. JNJ-67544412 (JNJ-4412) is a cyclic dinucleotide (CDN) developed as a STING agonist. JNJ-4412 binds both mouse and human STING and is more potent binding all the major human STING alleles than most other STING CDN agonists. JNJ-4412 phosphorylate STING and IRF3 and induces high levels of IFNβ and other cytokines in M1 and M2 macrophages, dendritic cells, and monocytes.

In syngeneic mouse tumor studies, JNJ-4412 was dosed intratumorally (i.t.) on a q3d x 3 or qweekly schedule resulting in significant tumor regression, complete cures and long-lasting antitumor immunity. Body weight loss (<20%) was observed but was transient and recoverable and could be mitigated by utilizing a qweekly schedule with no loss of activity. Proinflammatory cytokines such as IFN-α, IFN-β, IP-10, TNF-α, IL-6 and MCP-1 were detected in tumor and plasma after dosing. Combination studies with anti-PD-1 resulted in enhanced dose-dependent efficacy in treated tumors. In bilateral tumor studies, JNJ-4412 inhibited growth of contralateral un-injected tumors. Pharmacodynamic (PD) and mechanism of action (MOA) studies revealed increased number of CD8+ T cells in the treated tumors; increased apoptosis (cleaved caspase 3); loss of vascularization; decreased tumor cell proliferation and pronounced hemorrhagic necrosis in tumors. Rechallenge of cured mice demonstrated long-lasting antitumor immunity.

Thus, in vivo administration of JNJ-4412 potently activates the STING pathway resulting in inflammatory cytokine induction, activation of dendritic cells, proliferation of CD8+ T cells, increased apoptosis and curative antitumor efficacy with immunologic memory.

Citation Format: Melissa Smith, Diana Chin, Szeman Chan, Sally Mahady, Liam Campion, Caitlin Morgan, Shefali Patel, Gerald Chu, Anna Hughes, Gilles Bignan, Pete Connolly, Stuart Emanuel, Kathryn Packman, Leopoldo L. Luistro. In vivo administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5567.
Abstract 5641: CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager
Authors: El-Murr Nizar , Henry Christophe , Francesconi Elisa , Attenot Florence , Virone-Oddos Angela , Vidard Laurent , Wu Lan , Yang Zhi-Yong , Chiron Marielle
Published: September 2020

SAR442257 (CD38/CD28xCD3) is a trispecific T cell engager designed for the treatment of multiple myeloma (MM). Its cytotoxic activity and anti-tumor efficacy is dependent on the expression of CD38 by malignant plasma cells and the recruitment and activation of T cells via CD3 and CD28. Here we show that MM cells also express CD28 on their membrane and investigate how this expression impacts the cytotoxic activity of the trispecific antibody. Using CRISPR, CD28 knock-out (KO) models were generated from two MM cell lines that have different receptor densities of CD38 and CD28: KMS-11 (CD38 ~3 000/cell; CD28 ~35 000/cell) and RPMI8226 (CD38 ~129 000/cell; CD28 ~84 000/cell). T-cell-mediated cytotoxicity was evaluated in vitro using either effector CD8+ T cells or total PBMC isolated from healthy donors. Binding of SAR442257 to tumor cells in the presence of saturating concentrations of anti-CD38 antibodies was evaluated by flow cytometry using APC-labeled SAR442257 and FITC-labeled anti-CD38 antibodies. In vitro killing assays showed that SAR442257 is active on both CD38 high and CD38 low MM cell lines (EC50 in the pM range for WT cell lines; Table 1). Following CD28 KO, SAR442257 remained active but displayed reduced cytotoxic activity as compared to WT CD38+ CD28+ cells. The reduced cytotoxic activity was noticeable in both CD38 low and CD38 high MM models suggesting that the expression of CD28 by MM cells contributes to the cytotoxic activity of the trispecific antibody. We further show that when other anti-CD38 antibodies are bound to CD38, binding of SAR442257 to tumor cells and T-cell mediated cytotoxicity are rescued by CD28 as evidenced by loss of binding and cytotoxic activity in CD28KO cells. Overall, these data show that SAR442257 is active on both CD38 high and low MM models and that CD28 expressed on MM tumor cells can be directly targeted by SAR442257, enhancing its cytotoxicity and allowing it to bind MM cells when CD38 is occupied by other anti-CD38 antibodies

Table 1.T cell mediated killing assays. EC50rel, Relative EC50; CI, Confidence interval.EC50rel (pM) [±CI95%]KMS-11RPMI8226WTCD28KOWTCD28KOEffector CD8+ T cells4.1 [2.9 ; 5.9]30.2 [16.9 ; 54.0]0.2 [0.1 ; 0.3]0.5 [0.3 ; 0.8]Total PBMC26.0 [7.8 ; 87]>250032.0 [14.8 ; 69.2]304.0 [118.0 ; 787.0]

Citation Format: Nizar El-Murr, Christophe Henry, Elisa Francesconi, Florence Attenot, Angela Virone-Oddos, Laurent Vidard, Lan Wu, Zhi-Yong Yang, Marielle Chiron. CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5641.
Abstract 5970: Function and regulatory mechanism of GPM6A in hepatocellular carcinoma development and progression
Authors: Li Rui Zong , Xu Gang , Zhu Min Ji , Wu Jian , Wu Jian
Published: September 2020

BACKGROUND: GPM6A is a glycoprotein found in endothelial cells and is considered to be a malignant lymphoma oncogene. However, the role of GPM6A in the development of hepatocellular carcinoma (HCC) is unknown. Through Affymetrix gene expression microarray and bioinformatics analysis, very low GPM6A expression was found in HCC tissue. The present study aims to explore the function and regulatory mechanism of GPM6A in HCC development and progression.

METHODS: Levels of GPM6A expression was determined in various hepatoma cell lines and HCC specimens from different base disorders, and its role on cell proliferation was investigated in GPM6A stably over-expressing cell lines. Modulating effects of a specific miRNA were evaluated with miRNA mimetic transfection.

RESULTS: Much lower GPM6A levels were found in HCC occuring in HBV-infection or nonalcoholic steatohepatitis. TCGA data confirmed that low GPM6A expression in HCC correlates with a poor overall survival and progression-free survival rate (p=0.018 and 0.004). Over-expression of GPM6A inhibited proliferation in SMMC-7721 and MHCC-97H cells by 31% and 30%, respectively (p<0.01), and led to decreased colony formation by 40%. Overexpression of GPM6A was found to significantly reduce wound healing and migration rates in these two cell types. miR-96-5p was expressed at 6 to 61-fold higher in HCC tissues than adjacent tissues (p<0.01); whereas GPM6A gene expression was at 3 to 55-fold lower (p<0.01) in a negative correlation between miR-96-5p levels and GPM6A levels in HCC specimens (r=-0.64, p<0.05). Further experiments demonstrated that miR-96-5p acted directly on the 3'UTR of the GPM6A gene, and transfection of miR-96-5p significantly decreased GPM6A mRNA expression by 50% in two hepatoma cell lines. Moreover, MiR-96-5p transfection promoted proliferation (66%, 59%, p<0.01), migration (10%, 9%, p<0.05) and invasion (557±66 vs. 226±19; 235±36 vs. 153±17, p<0.05-0.01) of SMMC-7721 and MHCC-97H hepatoma cells; whereas the function of oncogenic microRNA-96 was significantly inhibited in GPM6A-overexpressed hepatoma cells.

CONCLUSIONS: GPM6A expression in HCC is commonly suppressed, and correlated to a poor prognosis. Its low expression in HCC tissues is most likely attributed to upregulated miR-96-5p, which may function as an oncolytic regulator through suppressed GMP6A that may block proliferation, cloning formation, migration and invasion of hepatoma cells.

Citation Format: Rui Zong Li, Gang Xu, Min Ji Zhu, Jian Wu, Jian Wu. Function and regulatory mechanism of GPM6A in hepatocellular carcinoma development and progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5970.
Abstract 6011: Mesenchymal stem cells promote PD-L1 expression in lung cancer cells
Authors: Zhao Hui , Yang Hui , Sun Jinqiu , Liang Guoqiang , Zhao Qianqian , Zhang Xiufang , Liang Shengxian , Guo Rui , Zhong Li
Published: September 2020

Background

Effects of mesenchymal stem cells (MSCs) on tumors have been extensively studied in recent years, but results still remain controversial. In this study we investigated the roles of MSCs on the expression of programmed death-ligand 1 (PD-L1) in lung cancer cells. Since overexpression of PD-L1 has been found to attenuate body's immune system against tumor cells, PD-1/PD-L1 blockages have become the most effective immunotherapy to the late stage non-small cell lung cancer (NSCLC). Therefore, understanding the effects of MSCs on PD-L1 expression is critical in managing immunotherapy for NSCLC patients.

Method

PD-L1 expressions were tested in two NSCLC cell lines, A549 and H1299 using qRT-PCR and Western Blot to qualitatively measure mRNA and protein levels, respectively. MSCs were isolated from umbilical cord blood and co-cultured with A549 and H1299 cells in complete medium using Transwell filters for 24-h, 48-h and 72-h. Then both A549 and H1299 cells were collected and PD-L1 expressions were tested. MSC-Conditioned Medium (MSC-CM) was generated by culturing 80% confluence of MSCs with serum-free medium. After 48 h, the medium was collected as MSC-CM. Both A549 and H1299 were then cultured in MSC-CM for 24-h, 48-h and 72-h, and PD-L1 expressions were measured from these two cell lines separately.

Result

Both MSCs and MSC-CM significantly increased the PD-L1 mRNA levels in the two NSCLC cells, while the MSC-CM had stronger stimulation to PD-L1 expressions (P < 0.0001) comparing to MSCs treatment (P<0.01). A549 cells reached the most significant effect at 48-h, while H1299 cells attended the same effect at 24-h treatment. The similar results were observed with PD-L1 protein levels. Both cell lines showed increased PD-L1 protein expressions after treating with MSCs and MSC-CM, but the augmented scales were smaller than the mRNA levels. The PD-L1 protein expressions in A549 cells increased significantly (p < 0.05) at 48-h when treating with MSCs, while increased much higher when treating with MSC-CM (P < 0.01). H1299 cells also showed the similar increase in PD-L1 protein expressions after 24-h treatment.

Conclusion

Both MSCs and MSC-CM significantly increase PD-L1 expressions in lung cancer cells, which ultimately attenuate the immune system against tumor cells.

Citation Format: Hui Zhao, Hui Yang, Jinqiu Sun, Guoqiang Liang, Qianqian Zhao, Xiufang Zhang, Shengxian Liang, Rui Guo, Li Zhong. Mesenchymal stem cells promote PD-L1 expression in lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6011.
Abstract 6056: A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach
Authors: Gan Xin , Shi Lei , Shan Qianqian , Chen Fei , He Yun , Rong Yiping , Du Qiumei
Published: September 2020

CD73, an ecto-5'-nucleotidase, plays a major role in de-phosphorylation of the extracellular adenosine monophosphate (AMP) to adenosine, which in turn is a potent immunosuppressive metabolite that modulates the immune reaction within the tumor microenvironment (TME). High concentration of adenosine, predominantly signaling through the A2A receptor, suppress innate and adaptive immune cell responses, leading to tumor escape of immune surveillance. Recent studies have shown a significant overexpression of CD73 in solid tumors alongside it's functional upregulation by inflammatory mediators and hypoxia. Thus, inhibition of CD73 enzymatic activity and its surface expression in the TME may improve anti-tumor immune activity.

To test this hypothesis, we designed and developed a fully human antibody with unique structure to recognize CD73. This antibody can block the enzymatic activity of CD73 in addition to reducing the surface expression of CD73. Both enzymatic and non-enzymatic dependent functions of CD73 were significantly dampened. The antibody demonstrates a superior anti-tumor activity over reference antibodies in in-vitro and in-vivo models.

Our findings indicate that the antibody has promising potential as an effective therapy for PD-1/PD-L1 nonresponsive or refractory patients, as well as a broader patient population that may benefit from a unique mechanism of action of CD73-targeting antibody.

Citation Format: Xin Gan, Lei Shi, Qianqian Shan, Fei Chen, Yun He, Yiping Rong, Qiumei Du. A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6056.
Abstract 6535: A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties
Authors: Harper James , Leinster Andrew , Rath Nicola , Burke Shannon , Mulgrew Kathy , Jin Hong , Wilkinson Robert W.
Published: September 2020

Oncolytic viruses offer the potential to be transformative in the treatment of cancers through their ability to selectively infect, replicate in and kill tumors whilst able to potently activate the immune system. Their activity can be further augmented through the addition of transgenes leading to tumor selective gene expression. Our proprietary Newcastle Disease virus (NDV) backbone has previously been demonstrated to have broad oncolytic activity whilst inducing potent anti tumor immune effects in preclinical models. We set out to test whether the incorporation of an IL-12 transgene into the NDV backbone could result in transgene dependent enhancement in anti tumor efficacy. In vitro, the addition of IL-12 into the NDV genome did not alter NDV infectivity in tumor or non-cancer cells compared to the backbone virus and infection of cancer cells resulted in the production of bioactive IL-12. In an immune-deficient xenograft model, a single systemic administration of NDVhuIL-12 resulted in tumor selective replication and local IL-12 production within the tumor microenvironment (TME). In syngeneic tumor models, local tumoral administration of NDVmuIL-12 resulted in the generation of an elevated and more durable type II interferon response compared to NDV-GMCSF; though similar pharmacokinetic profiles were observed. This difference in cytokine response correlated with superior single agent efficacy of NDVmuIL-12 compared to NDV alone in the B16F10 model. Furthermore, NDVmuIL-12 demonstrated anti tumor efficacy in several NDV refractory models, suggesting tumor expression of IL-12 was necessary to drive anti tumor activity in some circumstances. Across all models tested significant changes in the tumor immune microenvironment, previously associated with enhanced anti tumor immunity were observed in NDVmuIL-12 tumours compared to backbone virus alone. There is an abundance of pre-clinical data demonstrating that IL-12 can exert potent anti tumor activity, but its clinical application has been hindered through its toxicity when administered systemically. These data provide evidence that recombinant NDV could be utilised to deliver IL-12 to the TME when administered systemically and that the addition of IL-12 potentiates the anti tumor activity of NDV.

Citation Format: James Harper, Andrew Leinster, Nicola Rath, Shannon Burke, Kathy Mulgrew, Hong Jin, Robert W. Wilkinson. A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6535.
Abstract 6662: Effects of tumor treating fields (TTFields) on dendritic cells functionality
Authors: Voloshin Tali , Davidi Shiri , Kaynan Noa , Schneiderman Rosa , Volodin Alexandra , Giladi Moshe , Weinberg Uri , Palti Yoram
Published: September 2020

Introduction Tumor Treating Fields (TTFields) are a clinically applied anti-neoplastic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. In this study we evaluated the effects of in vitro TTFields application on dendritic cell (DC) properties that include maturation, phagocytosis, and migration.

Methods Bone marrow cells were flushed from the femurs and tibias of 5-7 week old C57BL/6 mice to generate bone marrow-derived DCs. For the DC maturation assay, TTFields treated cancer cells were added at a ratio of 1:1 for 24 h. DC maturation was analyzed using flow cytometry to assess surface expression of major histocompatibility complex class II (MHC II), CD40, and CD80 activation markers. For the phagocytosis assay, CellTrackerTM Deep Red Dye, pre-stained TTFields treated cancer cells were added at a ratio of 1:1 for 2h and phagocytosis by DCs was evaluated using flow cytometry. DC migration assays were performed using a modified Matrigel coated Boyden chamber either with or without C-C Motif Chemokine Ligand 19 (CCL19), utilized as a chemoattractant.

Results TTFields treated cancer cells were effectively phagocytosed by DCs, while untreated control cells did not show similar outcomes. In addition, activation markers were found to be upregulated in DCs that were co-cultured with TTFields treated cells. This up-regulation was observed for all the costimulatory molecules analyzed. DC migration assays, showed no significant difference in migration rates between untreated and TTFields treated DCs, with or without the chemoattractant CCL19.

Conclusions These in vitro results indicate that TTFields treated cancer cells promote DC elicited phagocytosis and DC maturation. Moreover, in contrast to previous studies reporting that TTFields show an inhibitory effect on cancer cell migration, we demonstrate that TTFields do not impair the migratory properties of DCs.

Citation Format: Tali Voloshin, Shiri Davidi, Noa Kaynan, Rosa Schneiderman, Alexandra Volodin, Moshe Giladi, Uri Weinberg, Yoram Palti. Effects of tumor treating fields (TTFields) on dendritic cells functionality [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6662.
Abstract 744: Volatile organic compounds (VOCs) from exhaled Breath for lung cancer Staging using TD-GC-MS
Authors: Muhammad Kanhar Ghulam , Madeeha Channa , Wei Fu , Xin Xu Lin , Hu Yanjie , Ying Kejing , Liu Jun , Chen Xing
Published: September 2020

Background: Breath analysis is a promising noninvasive screening technique that offers a wide range of probable possibilities to facilitate early diagnosis of lung cancer (LC).

Method: Exhaled breath samples of 352 subjects were analyzed to detect C6∼C30 VOCs through thermal desorption coupled with gas chromatography-mass spectrometry (TD-GC-MS). Data were divided into three categories Lung Cancer (LC), Benign Pulmonary Disease (BPD) and Healthy control (HC). Statistical classification models were used to analyze VOCs to distinguish between HC, BPD and LC patient's early and advanced stages. Receiver operator characteristics (ROC) curves were used to select different VOCs to evaluate the accuracy, specificity, and sensitivity of the diagnostic model.

Results: The analysis resulted that 10,9,11 and 10 VOCs have a significant correlation to discriminate Histology, stage, BPD from LC and HC from LC. The diagnostic model predicted accuracy, sensitivity, and specificity of NSCLC vs. SCLC is 92%, 96% and 90% with area under curve AUC>0.913. As of ROC curve with AUC>0.819 has distinguished Stage I-II vs. stage III-IV with accuracy, sensitivity, and specificity 72%, 84%, and 80%. Whereas the ROC curve with AUC>0.795 has distinguished BPD from LC with accuracy, sensitivity, and specificity 83%, 89%, and 84%. While ROC curve with AUC>0.945, accuracy, sensitivity and specificity 92%, 96%, and 90% have distinguished HC from LC.

Conclusion: This study confirms that TD GC-MS is a sensitive and dependable method to distinguish the VOCs in exhaled breath. We have witnessed significant differences in breath of BPD, HC and LC subjects. Where 10,8,11 and 10 VOCs have distinguished between early from the advance stage, NSCLC from SCLC, BPD from LC and HC from LC. These VOCs has the potential to help improve LC diagnosis and prognosis. However, with the expansion of multi centers to other regions could result in more vital findings and will help improve breath analysis and the diagnosis standard.

Keywords: Breath Analysis, VOC markers, lung cancer, TD-GC-MS.

Citation Format: Kanhar Ghulam Muhammad, Channa Madeeha, Fu Wei, Xu Lin Xin, Yanjie Hu, Kejing Ying, Jun Liu, Xing Chen. Volatile organic compounds (VOCs) from exhaled Breath for lung cancer Staging using TD-GC-MS [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 744.
Abstract CT081: Poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients - a Phase 2 study
Authors: Le Xiuning , Goldman Jonathan , Clarke Jeffrey , Techekmedyian Nishan , Piotrowska Zofia , Chu David , Bhat Gajanan , Lebel Francois , Socinski Mark
Published: September 2020

Introduction and Purpose of Study: Effective and approved therapy for treating non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations is an unmet medical need. Poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants. We evaluated the efficacy and safety of poziotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations (ZENITH20-1) in an independent cohort of a multi-cohort, multi-center Phase 2 study. Methods: Poziotinib (16 mg) was administered orally QD, allowing dose reductions for AEs, with follow up for 24 months. The primary endpoint was objective response rate (ORR), evaluated by central radiographic review using RECIST v1.1. The ORR endpoint was to be met if the lower bound of 95% CI>17% in the As-Treated Population. The secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Safety monitoring was conducted throughout the study. Results: A total of 115 patients with a median age of 61 years (33-83) were enrolled. Patients had received and failed prior therapy (median of 2 [1-9]) with majority receiving both chemo and immunotherapy. The median relative dose intensity was 72% (7-100%) with 65% having dose reductions. 10% of patients discontinued due to related AEs. The ORR was 14.8% (95% CI 8.9%-22.6%), and the DCR was 68.7% (95% CI 59.4%-77.0%). Seventeen patients had a confirmed partial response (PR), 5 patients had unconfirmed PR and 62 (53.9%) patients had stable disease (SD). Overall, 75 (65%) patients had tumor size reductions. The median DoR was 7.4 months (95% CI 3.7-9.7) and the median PFS was 4.2 months (95% CI 3.7-6.6). Safety profile was mechanism related and similar to other 2nd generation tyrosine kinase inhibitors with the most common treatment-related Grade ≥3 AEs (preferred term) being rash (28%), diarrhea (26%), stomatitis (9%) and paronychia (6%). The incidence of treatment-related pneumonitis, an important AE associated with TKIs, was 4%. Conclusion: Although the ORR primary endpoint was not met, poziotinib induced tumor size reduction in the majority (65%) of patients. The tumor size reduction combined with long duration of response demonstrated the clinical activity of poziotinib in treating this patient population. We are further optimizing dosing and AE management.

Citation Format: Xiuning Le, Jonathan Goldman, Jeffrey Clarke, Nishan Techekmedyian, Zofia Piotrowska, David Chu, Gajanan Bhat, Francois Lebel, Mark Socinski. Poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients - a Phase 2 study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT081.
Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade
Authors: Kohlhapp Frederick J. , Haribhai Dipica , Mathew Rebecca , Duggan Ryan , Ellis Paul A. , Wang Rui , Lasater Elisabeth A. , Shi Yan , Dave Nimita , Riehm Jacob J. , Robinson Valerie A. , Do An D. , Li Yijin , Orr Christine J. , Sampath Deepak , Raval Aparna , Merchant Mark , Bhathena Anahita , Salem Ahmed Hamed , Hamel Keith M. , Leverson Joel D. , Donawho Cherrie , Pappano William N. , Uziel Tamar
Published: September 2020

The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti–PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy.

Significance:

The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency–approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.

This article is highlighted in the In This Issue feature, p. 1
Clinical Characteristics and Risk Factors for Mortality due to Bloodstream Infection of Unknown Origin in Hemodialysis Patients: A Single-Center, Retrospective Study
Authors: Shima Hisato , Okamoto Takuya , Tashiro Manabu , Inoue Tomoko , Masaki Chiaki , Tanaka Yusaku , Tada Hiroaki , Takamatsu Norimichi , Wariishi Seiichiro , Kawahara Kazuhiko , Okada Kazuyoshi , Nishiuchi Takeshi , Minakuchi Jun
Published: September 2020

Introduction: Hemodialysis patients are at a high risk of bloodstream infection (BSI). The risk factors for BSI-associated mortality, especially of unknown origin, remain uncertain. BSI of unknown origin is highly prevalent and related to high mortality. The present study aimed to investigate the clinical and microbiological characteristics of BSI and risk factors for BSI-associated mortality, including BSI of unknown origin, in hemodialysis patients. Methods: This study was a single-center, retrospective study conducted from August 2012 to July 2019 in hemodialysis patients with BSI at Kawashima Hospital. Data related to demographics, clinical parameters, BSI sources, causative microorganisms, and initial treatments were collected from the medical records. The predictors for mortality associated with BSI were evaluated by logistic regression. Results: Among 174 patients, 55 (30.9%) had the infection from unknown origin. The most frequent bacterium was Staphylococcus aureus. Low serum albumin level was an independent predictor of mortality due to BSI (odds ratio [OR]: 0.28, 95% confidence interval [CI]: 0.13–0.59). A lower serum albumin level (≤2.5 g/dL) was associated with poorer mortality. Methicillin-resistant Staphylococcus aureus (MRSA) was independently associated with mortality due to BSI of unknown origin (OR: 6.20, 95% CI: 1.04–37.1); 87.5% cases with BSI of unknown origin due to MRSA were not initially administrated anti-MRSA antibiotics, and in such patients, the mortality rate was 85.7%. Conclusions: Serum albumin level of 2.5 g/dL is a cutoff value, which could predict the mortality due to BSI in hemodialysis patients. Considering the high mortality rate of MRSA-associated BSI of unknown origin, wherein no focus of infection was identified in the present study, initial empiric treatment should be considered for MRSA-associated BSI of unknown origin.
Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research
Authors: Nakase Hiroshi , Matsumoto Takayuki , Matsuura Minoru , Iijima Hideki , Matsuoka Katsuyoshi , Ohmiya Naoki , Ishihara Shunji , Hirai Fumihito , Wagatsuma Kouhei , Yokoyama Yoshihiro , Hisamatsu Tadakazu
Published: September 2020

Background: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses. Summary: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts’ opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.
Aging study of a lead-acid storage bank in a multi-source hybrid system
Authors: Laadissi El Mehdi , Khalfi Jaouad , Belhora Fouad , Ennawaoui Chouaib , El Ballouti Abdessamad
Published: September 2020

Autonomous and grid-connected systems play an important role in the
massive integration of renewable energy sources necessary for the global
development of a sustainable society. In this regard, the analysis of the
behavior of electrochemical storage devices such as lead-acid batteries
installed on hybrid energy systems and microgrids in terms of lifespan and economic profitability is an important research subject. The purpose of this article is to present a methodology for calculating the aging rate of a storage battery inserted in a hybrid multisource system. The approach consists in first knowing the solicitations of the battery during a year knowing at every moment its state of charge. This curve is obtained from a dynamic simulator taking into account the intermittences of the sources and the load. The second step is to determine the number of cycles and the depth of discharge of each from the stat of charge. Finally, based on the battery life characteristic given by the manufacturer (cycle number vs. discharge depth), the aging rate of the battery for one year of operation is determined.
Thermal exchange optimization based control of a doubly fed induction generator in wind energy conversion systems
Authors: Mazen Alhato Mohammed , Bouallègue Soufiene
Published: September 2020

This paper presents a novel design method to attain the optimal parameters
of Proportional-Integral (PI) controllers for a Doubly Fed Induction
Generator (DFIG) in wind energy based on a Thermal Exchange
Optimization (TEO) algorithm. Since the gains of PI controllers are usually
selected by classical and tedious trials-errors based procedures, their tuning
for such a wind energy converter is formulated as a constrained nonlinear
optimization problem. Inspired by Newton’s law of cooling, the TEO
algorithm is successfully applied to solve such a control problem under time-
domain performances and operational constraints in order to extract the
maximum available power. In order to assess the performances of the
proposed TEO algorithm, a comparative study between the TEO algorithm
and homologues ones is performed. Moreover, a statistical analysis using
Friedman and Bonferroni-Dunn’s tests indicates that the TEO algorithm
gives very competitive results in comparison to the other reported
metaheuristic algorithms.
Spectrum sensing of wideband signals based on cyclostationary and compressive sensing
Authors: A. AL-Hussain Ali Mohammad , Mahmood Al Azawi Maher Khudair
Published: September 2020

Compressive sensing is a powerful technique used to overcome the problem of high sampling rate when dealing with wideband signal spectrum sensing which leads to high speed analogue to digital convertor (ADC) accompanied with large hardware complexity, high processing time, long duration of signal spectrum acquisition and high consumption power. Cyclostationary based detection with compressive technique will be studied and discussed in this paper. To perform the compressive sensing technique, Discrete Cosine Transform (DCT) is used as sparse representation basis of received signal and Gaussian random matrix as a sensing matrix, and then 𝓁1- norm recovery algorithm is used to recover the original signal. This signal is used with cyclostationary detector. The probability of detection as a function of SNR with several compression ratio and processing time versus compression ratio are used as performance parameters. The effect of the recovery error of reconstruction algorithm is presented as a function of probability of detection.
Total energy consumption analysis in wireless mobile ad hoc network with varying mobile nodes
Authors: Saad Mohammed Ayad , Alhamdane Hayder Jasim , Ali Adnan Hussein , Alani Sameer , Hashim M. M. , Hasan Bassam
Published: September 2020

The energy protocols that have a mechanisms of shortest path routing considered predominant in the networking scenarios. The interesting matter in the routing protocols designing deal with mobile ad hoc network (MANET) must have an energy efficient network for better network performances. The Performances of such routing protocols that can be assessed will be focused on many metrics like delay, throughput, and packet delivery.  MANET is a distribution network, having no infrastructure and network decentralization. There routing protocols are utilized for detecting paths among mobile nodes to simplify network communication. The performance comparison of three protocols are Optimized Link State Routing (OLSR), the second is Ad hoc On-Demand Distance Vector (AODV), while the third is Dynamic Source Routing (DSR) routing protocols concerning to average energy consumption and mobile node numbers are described thoroughly by NS-3 simulator.  The nodes number is changing between 10 and 25 nodes, with various mobility models. The performance analysis shows that the suggested protocols are superior in relations to the energy consumption for networking data transmission and the performance of the wireless network can be improved greatly.
Predicting fertilizer treatment of maize using decision tree algorithm
Authors: Jahan Nusrat , Shahariar Rezvi
Published: September 2020

Machine learning approaches are progressively successful in image based analysis such as different diseases prediction as well as level of risk assessment etc. In this paper, image based data analysis with machine learning technique were used for fertilizer treatment of maize. We address this issue as our country depend on agricultural field rather than others. Maize has a bright future. To predict fertilizer treatment of maize dataset were comprised of ground coverage region which highlights the green pixels of a maize image. For calculating green pixels from an image we used “Can Eye” tool.  The achievement of machine learning approaches is highly dependent on quality and quantity of the dataset which is used for training the machine for better classification result. For this perseverance, we collected images from the maize field directly. Then processed those images and classified the data into four classes (Less Nitrogen=-N, Less Phosphorus=-P, Less Potassium=-K and NPK) to train our machine using decision tree algorithm to predict fertilizer treatment. We got 93% classification accuracy for decision tree. Finally, the outcome of this paper is the fertilizer treatment of a maize field based on the ground cover percentage, and we implemented this whole work using an android platform because of the availability of android mobile phone throughout the world.
Data mining in web personalization using the blended deep learning model
Authors: Abed Qusay Abdullah , Mohammed Fadhil Osamah , Al-Yaseen Wathiq Laftah
Published: September 2020

In general, multidimensional data (mobile application for example) contain a large number of unnecessary information. Web app users find it difficult to get the information needed quickly and effectively due to the sheer volume of data (big data produced per second). In this paper, we tend to study the data mining in web personalization using blended deep learning model. So, one of the effective solutions to this problem is web personalization. As well as, explore how this model helps to analyze and estimate the huge amounts of operations. Providing personalized recommendations to improve reliability depends on the web application using useful information in the web application. The results of this research are important for the training and testing of large data sets for a map of deep mixed learning based on the model of back-spread neural network. The HADOOP framework was used to perform a number of experiments in a different environment with a learning rate between -1 and +1. Also, using the number of techniques to evaluate the number of parameters, true positive cases are represent and fall into positive cases in this example to evaluate the proposed model.
Web application authentication using ZKP and novel 6D chaotic system
Authors: J. Mohammed Shatha , A. Mehdi Sadiq
Published: September 2020

Text password has long been a dominant approach to user authentication used by a huge quantity of Internet services. Web applications are now widely used for the implementation of a range of significant services. The securing of such applications has thus become a significant process. Currently the frequent use of passwords and the need for them make them more vulnerable to theft or guesswork. In the proposed research, the researcher designed an algorithm that has the ability to perform registration or to access web applications safely. The researcher designed an algorithm in the proposed research, which has the ability to securely perform registration or access web applications. The proposed idea based on the notion of Zero-knowledge proof. A complex generation of random number initiated by proposed novel 6D-Hyper chaotic system. The bottom line is that both parties (web application, user), have a secret number. These two numbers used to do the process of registration without requiring a password. Results from the research showed the importance of the proposed method by which the keys were managed and distributed in a safe and effective way.
Enhancement in resource allocation system for cloud environment using modified grey wolf technique
Authors: Ouhame Soukaina , Hadi Youssef
Published: September 2020

Cloud computing is an advanced technology which provides services with the help of internet. These services work under the rule of pay and gain. The services consist of hardware and software used in different fields of life. Due to growth of cloud computing the number of users are increased and their demand for better services also  increased with the passage of time. Cloud computing faces different issues. One of them is resource scheduling. In this paper a new technique is used for improvement of scheduling in cloud computing. The improvement took place in GWO algorithm. Two main sections of this algorithm are modified, which are local search section and fitness function value. The above proposed technique is used to improve three main parameters of scheduling that are energy consumption, throughput and average network executation time in VM for cloud computing. The  techniques results are compared with ABC algorithm and GWO algorithm. The results show that proposed algorithm improves in the three main parameters  of scheduling for cloud computing.
An approach for enhancing data confidentiality in Hadoop
Authors: Kareem Shahab Wahhab , Yousif Raghad Zuhair , Jihad Abdalwahid Shadan Mohammed
Published: September 2020

The amount of data processed and stored in the cloud is growing dramatically. The traditional storage devices at both hardware and software levels cannot meet the requirement of the cloud. This fact motivates the need for a platform which can handle this problem. Hadoop is a deployed platform proposed to overcome this big data problem which often uses MapReduce architecture to process vast amounts of data of the cloud system. Hadoop has no strategy to assure the safety and confidentiality of the files saved inside the Hadoop distributed File system(HDFS). In the cloud, the protection of sensitive data is a critical issue in which data encryption schemes plays avital rule. This research proposes a hybrid system between two well-known asymmetric key cryptosystems (RSA, and Paillier) to encrypt the files stored in HDFS. Thus before saving data in HDFS, the proposed cryptosystem is utilized for encrypting the data. Each user of the cloud might upload files in two ways, non-safe or secure. The hybrid system shows higher computational complexity and less latency in comparison to the RSA cryptosystem alone.
Near-lossless image compression using an improved edge adaptive hierarchical interpolation
Authors: Sinshahw Yenewondim Biadgie
Published: September 2020

In medical and scientific imaging, lossless image compression is recommended because the loss of minor details subject to medical diagnosis can lead to wrong diagniosis. On the other hand, lossy compression of medical images is required in the long run because a huge quantity of medical data needs remote storage. This, in turn, takes long time to search and transfer an image. Instead of thinking lossless or lossy image compression methods, near-loss image compression mehod can be used to compromise the two conflicting requirements. In the previous work, an edge adaptive hierarchical interpolation (EAHINT) was proposed for resolution scalable lossless compression of images. In this paper, it was enhanced for scalable near-less image compression. The interpolator of this arlgorithm swiches among one-directional, multi-directional and non-directional linear interpolators adaptively based on the strength of the edge in a 3x3 local casual context of the current pixel being predicted. The strength of the edge in local window was estimated using the variance of the the pixels in the local window. Although the actual predictors are still linear functions, the switching mechanism tried to deal with non-linear structures like edges. Simulation results demonstrate that the improved interpolation algorithm has better compression ratio over the the exsisting the original EAHINT algorithm and JPEG-Ls image compression standard. 
A robust watermarking algorithm for medical images
Authors: Nagm Ahmed , Safy Mohammed
Published: September 2020

Integrated healthcare systems require the transmission of medical images between medical centres. The presence of watermarks in such images has become important for patient privacy protection. However, some important issues should be considered while watermarking an image. Among these issues, the watermark should be robust against attacks and does not affect the quality of the image. In this paper, a watermarking approach employing a robust dynamic secret code is proposed. This approach is to process every pixel of the digital image and not only the pixels of the regions of non-interest at the same time it preserves the image details. The performance of the proposed approach is evaluated using several performance measures such as the Mean Square Error (MSE), the Mean Absolute Error (MAE), the Peak Signal to Noise Ratio (PSNR), the Universal Image Quality Index (UIQI) and the Structural Similarity Index (SSIM). The proposed approach has been tested and shown robustness in detecting the intentional attacks that change image, specifically the most important diagnostic information.
Trayectorias institucionales, diagnósticos psiquiátricos y violencias combinadas en un estudio de caso
Authors: Guemureman Silvia , Bianchi Eugenia
Published: September 2020

(analítico) Se abordan las categorías de trayectorias institucionales, diagnósticos psiquiátricos y violencias, a través de un estudio de caso de un adolescente declarado penalmente responsable y luego condenado por la comisión de delitos en Ciudad de Buenos Aires (1993-2005), a través de su expediente tutelar abierto en los juzgados de menores, desde que era menor no punible hasta su mayoría de edad. El análisis se complementa con las sentencias definitivas y normativa relacionada. El objetivo es analizar este expediente desde el concepto de trayectorias, hipotetizando que estas no son lineales, deterministas ni reduccionistas, sino que se componen en una densa trama de circunstancias y experiencias. Los resultados se organizan en tres vectores: diagnósticos psiquiátricos, trayectorias institucionales y violencias. El artículo busca contribuir teórica y metodológicamente a los estudios sociales de juventudes.