tbuckley/cabot-search huggingface dataset:
Abstract 4976: <i>Ex vivo</i> functional characterization and <i>in vivo</i> efficacy validation of human CD40 agonistic antibodies in the human CD40 knock-in model (CD40 HuGEMM)
Authors: Daniel Xianfei He, Lei Zheng, Ruilin Sun, Annie Xiaoyu An, Jian Fei, Henry Qixiang Li, Davy Xuesong Ouyang
Journal: Cancer Research (2019)

Abstract CD40 receptor is a member of TNF-receptor superfamily, broadly expressed on the surface of antigen-presenting cells (APC) including B cells, dendritic cells (DC), macrophages, monocytes, and non-APC like platelets, endothelial cells and even some tumor cells. CD40 is essential for APC activation and signalling via ligation of CD40 ligand located on helper T cells and CD40 on APC to mediate licensing (activating) of APC. Ligation of CD40 on DCs, for example, can induce increased surface expression of costimulatory and MHC molecules, production of pro-inflammatory cytokines, and enhanced T cell activation. CD40 ligation on resting B cells can increase its antigen-presenting function and proliferation. In contrast to its critical role in the induction of effective innate and adaptive immune responses, CD40 signalling on certain malignant cells, particularly B cell lymphomas, triggers tumor apoptosis. The dual function of CD40 signalling provide unique opportunities for the use of agonistic CD40 antibodies in cancer immunotherapy. Indeed, several CD40 monoclonal antibodies are now in different stages of clinical development, some shown promising preliminary results in combination with other cancer immunotherapies. However, we are lacking preclinical models to evaluate efficacy of therapeutic CD40 agonistic antibodies, which usually don’t cross-bind to mouse targets. To fill this gap, we developed a human CD40 knock-in model (CD40 HuGEMM), of which mouse exon 2-5 are replaced by human counterparts. These KI mice express a chimeric CD40 with human extracellular domain &amp; mouse trans-membrane and intracellular sequences. We have characterized the human CD40 expression of CD40 HuGEMM on a broad spectrum of mouse cells, such as lymphocytes, macrophages, DCs, and endothelial cells. In addition, we confirmed that human CD40 antibodies bind to the chimeric m/hCD40 recombinant protein, and lead to increased expression of MHCII on the B cells. Finally, the in vivo efficacy study indicates that human CD40 antibody treatment lead to robust anti-tumor response and contribute to better survival of the mice. Taken together, our CD40 HuGEMM provides a powerful preclinical model to assess the efficacy of the human-specific CD40 agonistic antibodies. It may also serve as a model for proof of concept studies of CD40 agonistic antibodies with other therapies. Citation Format: Daniel Xianfei He, Lei Zheng, Ruilin Sun, Annie Xiaoyu An, Jian Fei, Henry Qixiang Li, Davy Xuesong Ouyang. Ex vivo functional characterization and in vivo efficacy validation of human CD40 agonistic antibodies in the human CD40 knock-in model (CD40 HuGEMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4976.
A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study
Authors: O. Türeci, U. Sahin, H. Schulze-Bergkamen, Z. Zvirbule, F. Lordick, D. Koeberle, P. Thuss-Patience, T. Ettrich, D. Arnold, F. Bassermann, S.E. Al-Batran, K. Wiechen, K. Dhaene, D. Maurus, M. Gold, C. Huber, A. Krivoshik, A. Arozullah, J.W. Park, M. Schuler
Journal: Annals of Oncology (2019)

BackgroundClaudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells.Patients and methodsPatients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile.ResultsFrom September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent.ConclusionsZolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials.ClinicalTrials.gov numberNCT01197885.
Abstract 2566: CYT01B suppresses RAD51 focus formation and induces replication catastrophe following AID induced DNA damage
Authors: Melinda Day, Amber Cyr, Tyler Maclay, Kevin Mills
Journal: Cancer Research (2019)

Activation Induced Cytidine Deaminase (AID) is a DNA-directed cytidine deaminase that plays a critical role in somatic hypermutation and immunoglobulin class switching in activated B- lymphocytes. AID is often ectopically expressed and promotes genomic hypermutation in a range of lymphoid malignancies. Deamination of genomic cytidines results in point mutations, single strand DNA breaks (SSB), and double strand DNA breaks (DSB). The resulting DNA damage stress leads to an obligate dependency on homologous recombination for cellular survival. RAD51 is a critical component of the homologous recombination pathway, forming nucleoprotein filaments at sites of DNA damage or replication fork stalls. RAD51 mediates homologous DNA strand exchange to promote recombinational repair of breaks and damaged replication forks. We have previously shown that RAD51 depletion leads to accumulation of DNA breaks, and ultimately cell death, in AID expressing cells. We now describe the mechanism of action for a novel small molecule, CYT01B, that targets RAD51 mediated recombination. Treatment of AID-expressing cells with CYT01B, attenuates RAD51 focus formation, reduces the nuclear concentration of RAD51, and promotes RAD51 protein degradation. CYT01B reduces homologous recombination activity in cells, culminating in cytologically visible chromosome fragmentation following DNA damage. Finally, CYT01B treated cells undergo replication catastrophe associated with caspase 3/7 activation and persistent PCNA nuclear signal. We conclude that CYT01B is a novel homologous recombination inhibitor, and propose a new synthetic lethality mechanism, induced by CYT01B, mediated by DNA replication stress and replication catastrophe.   Citation Format:  Melinda Day, Amber Cyr, Tyler Maclay, Kevin Mills. CYT01B suppresses RAD51 focus formation and induces replication catastrophe following AID induced DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2566.
Abstract 1502: KRAS RNAi therapy in preclinical models of pancreatic cancer sensitizes tumors to checkpoint blockade by affecting the tumor microenvironment
Authors: Shanthi Ganesh, Serena Shui, Kevin Craig, Weimin Wang, Bob D. Brown, Marc Abrams
Journal: Cancer Research (2019)

Abstract KRAS is one of the most frequently mutated oncogenes in pancreatic cancer. Recent research has revealed that activation of KRAS in cancer cells causes recruitment of immunosuppressive molecules to the tumor microenvironment (TME) and blocks T-cell mediated cytotoxicity. Despite huge progress in our understanding of KRAS and its role in tumorigenesis, direct pharmacological targeting of KRAS has thus far not been achieved. In these studies, we inhibited KRAS directly in tumor-bearing mice, using a potent and specific Dicer substrate siRNA (DsiRNA) formulated in tumor-selective lipid nanoparticles. We demonstrate that intravenously-dosed KRAS DsiRNA treatment results in reduction of multiple immunosuppressive signaling molecules, affecting recruitment of myeloid cells and regulatory T cells (Tregs) to the TME. In addition, effective KRAS inhibition reversed MEK-inhibitor-induced resistance in a model of KRAS mutant human PDAC. These data suggest that KRAS DsiRNA has potential to sensitize treatment-refractory PDAC tumors to both immune checkpoint blockade as well as conventional targeted therapeutics Note: This abstract was not presented at the meeting. Citation Format: Shanthi Ganesh, Serena Shui, Kevin Craig, Weimin Wang, Bob D. Brown, Marc Abrams. KRAS RNAi therapy in preclinical models of pancreatic cancer sensitizes tumors to checkpoint blockade by affecting the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1502.
A randomized, multicenter, open-label controlled phase 2 trial of Foxy-5 as neoadjuvant therapy in patients with WNT5A negative colon cancer
Authors: J. Vermorken, A. Cervantes, P. Morsing, K. Johansson, T. Andersson, N. Lindland Roest, J. Gullbo, R. Salazar
Journal: Annals of Oncology (2019)
Abstract 1224: Correlation of tumor angiogenesis with peripheral ring-enhancement on CT: Its predictive value of chemotherapy responses of colorectal metastatic hepatic tumor
Authors: Hirotaka Okamoto, Shugo Shiba, Hiroshi Iino, Makoto Sudoh, Hiroyuki Wakana, Suguru Maruyama, Kenji Kawashima, Toshio Fukasawa, Daisuke Ichikawa, Hideki Fujii
Journal: Cancer Research (2019)

Abstract [Background]The treatment of colorectal cancer (CRC) with metastasis is now widely accepted to be systemic chemotherapy of 5-FU base chemotherapy (FOLFOX or FOLFILI) in combination with molecular antibody. The objective of this study was to determine the significance of tumor angiogenesis in metastatic hepatic tumors in relation to the response of systemic chemotherapy. [Methods]A total of 48 consecutive CRC patients with hepatic metastasis who had been treated with or without hepatic resection were retrospectively reviewed, and factors, such as metastatic tumor angiogenesis and chemotherapy response, were analyzed. Tumor angiogenesis in association with ring-enhancement (RE) on computed tomography (CT) was also microscopically evaluated by microvessel counting (MVD) in sections stained immunochemically with CD34. [Results]The overall response rate after 6 courses of first-line chemotherapy for the liver metastasis with RE on CT was 64% (23/36), whereas the response rate without RE was 25% (3/12), which was significantly different. The survival rate of patients with or without liver resection of all RE-positive tumors was not different, but the survival rate of patients with liver resection was longer than that of patients without liver resection for all RE-negative tumors. Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. [Conclusions]The peripheral RE on CT of the metastatic hepatic tumor was associated with tumor angiogenesis and may predict chemotherapy response. A combination of liver resection with chemotherapy improves the survival of patients who have multiple hepatic metastasis. Citation Format: Hirotaka Okamoto, Shugo Shiba, Hiroshi Iino, Makoto Sudoh, Hiroyuki Wakana, Suguru Maruyama, Kenji Kawashima, Toshio Fukasawa, Daisuke Ichikawa, Hideki Fujii. Correlation of tumor angiogenesis with peripheral ring-enhancement on CT: Its predictive value of chemotherapy responses of colorectal metastatic hepatic tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1224.
Chemotherapy for adult medulloblastoma: Is it necessary for all?
Authors: Mostafa S. El-Haddad, Amr Hawety, Ahmad Farag, Abd Al-Rahman Badawy, Karim Kaled, Shawky El-Haddad
Journal: Journal of Clinical Oncology (2013)

e13025 Background: Medulloblastome is rare in adults and treatment is usually extrapolated from the pediatric age group, the aim of our study is to highlight the importance of chemotherapy both in the concurrent and adjuvant setting in adult medulloblastoma. Methods: Fourty patients between 1995 and 2011 with diagnosis of medulloblastoma were treated at both the department of clinical oncology Cairo University or Nasser Institute Cancer Center, files reviewed for demographic characteristics, radiographic findings, extent of resection, staging, computerized tomography (CT) scans or magnetic resonance (MR), histopathology, treatment received, pattern of recurrence and treament received. All patients treated with craniospinal irradiation with total dose of 36Gy followed by a boost to the posterior fossa till 54Gy. Results: Fourty patient were identified from our medical records 24 (60%) male and 16 (40%) female, mean age 25 year (range = 18 - 45), 2 patients had residual tumor more than 2cm, one patient had leptomeningeal deposits, 13 patients had weekly vincristin 2 mg weekly followed by cisplatin vepside, 27 patients didn’t receive any form of chemotherapy. Five year overall and disease free survival for the whole group was 92% (95% CI: 88-142) , 66% (95% CI: 73-135) respectively, for patients received chemotherapy OAS and DFS was 80% (CI:71-138), and 68% (48-162) for patients didn‘t receive chemotherapy OAS and DFS was 90% (CI:81-161), and 67% (C: 58-101), No statistical significance difference of survival between the two groups. univariate analysis didnt show any statistical significance correlation with chemotherapy.G3 neutropenia was more in the chemotherapy group 6 patients vs. 1 patient in the chemotherapy group. Conclusions: Chemotherapy for adult medulloblastoma should be further investigated as good survival time can be achieved with radiotherapy alone. And recurrence can be still salvage with chemotherapy
Abstract 19011: Predictors of Performing Defibrillation Testing Among Patients Implanted With a Subcutaneous Implantable Cardioverter Defibrillator: A Report From the National Cardiovascular Data Registry
Authors: Daniel J Friedman, Craig Parzynski, Kevin Heist, Andrea M Russo, Joseph G Akar, James V Freeman, Jeptha P Curtis, Sana M Al-Khatib
Journal: Circulation (2017)

Background: Compared to the transvenous implantable cardioverter defibrillator (ICD), the subcutaneous (S) ICD has a unique shock vector and higher defibrillation energy requirement. In the absence...
Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure
Authors: Christine I Chen, Heather J. Sutherland, Rami Kotb, Michael Sebag, Darrell J White, William Bensinger, Cristina J. Gasparetto, Richard LeBlanc, Christopher P. Venner, Suzanne Lentzsch, Gary J. Schiller, Brea C. Lipe, Aldo Del Col, Michael G. Kauffman, Sharon Shacham, Jacqueline Jeha, Jean-Richard Saint-Martin, Jatin Shah, Nizar J. Bahlis
Journal: Blood (2017)
Abstract 144: Lung Parenchymal Consolidation during typical Kawasaki Disease
Authors: Seiichi Sato
Journal: Circulation (2015)

Introduction: Kawasaki disease (KD) is a systemic vasculitis of childhood throughout the body. We report a patient who complicated by severe pneumonia of lung parenchymal consolidation (LPC) during typical KD clinical course. Case reports: A 7-yr-old male who had a past history of KD at 3-yr-old, visited a general practitioner with fever, sore throat and neck pain. Three days later, after being treated with CTRX/TBPMPI, he was transferred to our hospital because of bilateral lymph nodes swelling and a generalized erythema and rash. On admission he was still febrile and had bilateral conjunctival injections, cervical and axillary lymphadenopathy and markedly reddened pharynx, without edema. We diagnosed him as KD and treated him with aspirin and IVIG at a dose of 2.0g/kg, but the condition worsened; he developed dyspnea and dry cough. Crackles were noted on rt-lung auscultation, along with rt-basal dullness to percussion of the thorax. Chest radiography and a subsequent computed tomography scan revealed disseminated patchy infiltrates and ground-glass alterations with massive pleural effusions on rt-lung, and enlarged axillary and mediastinal lymph nodes. Some kinds of microbiology (including Mycoplasma) and virology (Epstein-Barr virus, cytomegalovirus, parvovirus B19), from all sampled sites (pleural effusion, blood, pharyngeal swab and cerebrospinal fluid), were negative for pathogenic specimens. So we treated him as intractable KD with second-IVIG and m-PSL, which led to the quick resolution of fever and progressive amelioration of pneumonia. Echocardiography showed normal ventricular size and function without coronary artery lesion (CAL). Thereafter, he was finally afebrile. At the first follow-up visit, 1 month after discharge, he had fully recovered. Clinically, echocardiographically and radiographically, no residues were noted. Conclusion: Several manifestations of broncho-pulmonary involvement in KD have been described. But there are very few case of LPC. We should consider the possibility that LPC were secondary to pulmonary arteritis.
Lycopene inhibits growth of human colon cancer cells via suppression of PI-3K/Akt signaling pathways
Authors: Feng-Yao Tang, Chung-Jin Shih, Mei-Pao Lu, Ye-Hsin Chen, Chia-Yeh Lin, Chin-Hua Pan
Journal: Cancer Research (2006)

4789   Lycopene, a major component in tomato, exhibited potential anti-carcinogenic activity. In contrast to most organ systems, the epithelial cells of gastrointestinal tract are exposed to high concentration of lycopene. However, its effects on gastrointestinal epithelium have not been studied well. To study its mechanism of action, we investigated the effects of lycopene on proliferation in human colon cancer cells. Here, we show that lycopene inhibited cell proliferation in HT-29 cells with EC50 value of 10 microM and potently induced cell apoptosis. Treatment of HT-29 cells with lycopene caused suppression of survival signaling pathways, apoptosis and cell cycle arrest. Lycopene caused a decrease in the phosphorylation form of Akt and p27 protein. Lycopene also induced the phosphorylation of p53 and subsequently induced the expression of BAX apoptotic protein. Furthermore, lycopene suppressed the expression of COX-2 and alleviated the progression of malignant colorectal colon cancer cells. In conclusion, lycopene may inhibit the growth of colon cancer cells via suppression of PI-3K/Akt survival signaling pathways and act as a potent new anticancer compound with improved selectivity toward transformed cells.
Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis
Authors: Surbhi Sidana, M. Hasib Sidiqi, Angela Dispenzieri, Francis K. Buadi, Martha Q. Lacy, Eli Muchtar, David Dingli, Suzanne R. Hayman, Wilson I. Gonsalves, Prashant Kapoor, Nelson Leung, Rahma Warsame, Taxiarchis V. Kourelis, Robert C. Wolf, William J. Hogan, Shaji K. Kumar, Morie A. Gertz
Journal: American Journal of Hematology (2019)

Abstract In appropriately selected patients with AL amyloidosis, autologous stem cell transplant (ASCT) is an established treatment modality with excellent outcomes and decreasing transplant related mortality (TRM) over time. We report on 15‐year overall survival (OS) in 159 patients undergoing ASCT from 1996 to 2003, with median follow up of 17.1 years. Day 100 TRM was 13.2% (n = 21). The OS of ≥15 years was observed in 30% (47/159) of patients. Patients surviving ≥15 years were younger (53 vs 56 years, P = .02), less likely to have lambda as the involved light chain (62% vs 78%, P = .03) and were less likely to have heart involvement (32% vs 56%, P = .005). Median OS of patients with heart involvement vs not was 4.0 vs 11.1 years, P = .006 and actuarial 15‐year OS was 23% vs 43%, respectively. A higher proportion of patients with OS ≥15 years received full‐dose melphalan conditioning (81% vs 61%, P = .01), and achieved day 100 complete response (CR) (64% vs 24%, P &lt; .001). Median OS amongst patients who achieved CR vs not was 19.3 vs 5.4 years, P &lt; .001. Heart involvement, receiving full‐dose melphalan and achieving CR remained independent predictors of OS. AL amyloidosis and related complications were the cause of death in 52% of patients overall (1‐5 years post‐transplant: 81%; 5‐10 years: 62% and 10‐15 years: 55%). These results reinforce the key role of ASCT in AL amyloidosis. With improvements in TRM and more options for relapsed disease, we expect the long‐term survival post‐transplant to improve significantly in the future.
Abstract 202: STAT1 regulates B7H3 mediated angiogenesis in medulloblastoma
Authors: Ian J. Purvis, Janardhan Avilala, Maheedhara R. Guda, Sujatha Venkataraman, Rajeev Vibhakar, Andrew J. Tsung, Kiran K. Velpula, Swapna Asuthkar
Journal: Cancer Research (2019)

Abstract B7-H3 (CD276), an immune checkpoint member of the B7/CD28 family, plays a key role in the repression of the immune response by cancer cells. B7-H3 is overexpressed on tumor and tumor-associated cells, making it an interesting therapeutic target. B7-H3 also appears to play a role outside of immune evasion, contributing to the progression of cancer via invasion/migration, angiogenesis, and metastasis. Our previous data has confirmed the presence of B7-H3 in highly aggressive Myc+ medulloblastoma (MB) tumors. Data-mining studies revealed that B7-H3 is correlated with Myc expression in Group 3 and 4 MBs, and is associated with worse patient outcomes. miR-29, a tumor suppressor, has been shown downregulating the expression of B7-H3 in various cancers. We have shown that miR-29 can reduce the angiogenesis abilities of D283 and D425 cells by downregulating B7-H3 in vitro. Subsequent RNA-sequencing analysis of miR-29-transfected D283 cells revealed upregulation of STAT1 activity. Immunoblot analysis and real-time PCR of D283 and D425 cells demonstrated increased expression of p-STAT1, when transfected with miR-29 plasmid. Treatment with all-trans retinoic acid induced p-STAT1 expression, with a concomitant decrease in the expression of B7-H3 and MMP-9. This preliminary data revealed a novel role for STAT1 in potentially regulating B7-H3, and consequently, angiogenesis and metastasis in MB. To date, the role of STAT1 in MB progression has not been fully investigated, and so our results provide a new avenue for developing potential treatments for aggressive MB tumors. Citation Format: Ian J. Purvis, Janardhan Avilala, Maheedhara R. Guda, Sujatha Venkataraman, Rajeev Vibhakar, Andrew J. Tsung, Kiran K. Velpula, Swapna Asuthkar. STAT1 regulates B7H3 mediated angiogenesis in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 202.