bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB184: Induction of ulk1 regulated autophagy by a novel antipsychotic drug leads to apoptosis in pancreatic cancer cells
Authors: Ramachandran Sharavan , Srivastava Sanjay K. 
Published: July 2021

Abstract
Pancreatic cancer patients have limited treatment options in spite of several advanced treatment strategies. Pancreatic tumors exhibit high basal autophagy compared to other cancers. Several studies including from our lab reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we have demonstrated that pimavanserin (PVT) suppresses pancreatic tumor growth by inducing autophagy-mediated apoptosis. Our results indicated that PVT induced 1.8 - 5 fold autophagy in pancreatic ductal adenocarcinoma (PDAC) cells, as evaluated by increased acridine orange staining. Furthermore, accumulation of double-membrane vesicles (autophagosomes) and formation of autophagolysosomes were observed with PVT treatment. Genomic analysis by R2 &GEPIA database revealed that PDAC patients exhibited reduced levels of autophagy initiator gene, ULK1. PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, and LC3A/B in several pancreatic cancer cells. In addition, phosphorylation of ULK1 atSer757 was inhibited with PVT treatment. Apoptotic effects of PVT in pancreatic cancer cells were validated by increase in cleavage of caspase3. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in pancreatic cancer cells. Our in vivo findings demonstrated that chloroquine abrogated the growth-suppressive effects of PVT by 21% in sub-cutaneously implanted BxPC3 tumor xenografts. Moreover, chloroquine reduced the effects of PVT in inducing the expression of ULK1 and the cleavage of caspase 3 as evaluated by western blotting. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopically implanted PANC1 tumors by 77%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Moreover, long-term administration of PVTdid not altered the clinical chemistry parameters like ALT, AST, total serum protein, calcium, creatinine, BUN, and albumin. Collectively, our results indicate that PVT-mediated pancreatic tumor growth suppression was associated with the induction of autophagy-mediated apoptosis. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for pancreatic cancer therapy.
Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Induction of ulk1 regulated autophagy by a novel antipsychotic drug leads to apoptosis in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB184.
Abstract ND08: Anti-CD25 Mab: Selective depletion of T-regulatory cells
Authors: Kolben Theresa 
Published: July 2021

Abstract
Tregs can suppress anti-tumour immune responses allowing for tumour growth. The negative prognostic impact of Tregs has been shown in several tumor settings. So far, Treg depletion has not been successful in patients, either because relevant Treg depletion was not achieved or because Teff cells have either been impacted or depleted as well. RG6292 has been optimised for ADCC selective depletion of cells with high CD25 density (Treg) and spares effector T cells by preserving IL-2-STAT5 signaling. RG6292 is currently tested in a Ph1 dose escalation study, and is given as monotherapy i.v. Q3W in adult patients with advanced solid tumors. 29 pts have been treated thus far at dose levels ranging from 0.3 mg to 35 mg. A dose dependent peripheral Treg depletion was observed as expected from RG6292 design and a significant flux of activated CD8+T cells as well as increase of PDL1 expression and intensity were observed in 3/3 patients in on-treatment biopsies taken 28 days after initiation of treatment. RG6292 at the doses tested was well tolerated in patients with advanced metastatic solid tumors and yielded encouraging PD effects consistent with its mechanism of action.
Citation Format: Theresa Kolben. Anti-CD25 Mab: Selective depletion of T-regulatory cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND08.
Abstract ND11: The discovery and characterization of ION-537: A next generation antisense oligonucleotide inhibitor of YAP1 in preclinical cancer models
Authors: Macleod A. Robert 
Published: July 2021

Abstract
The tumor suppressive Hippo pathway is frequently dysregulated in cancer, resulting in the constitutive activation of YAP1 in a variety of solid cancers including hepatocellular cancer (HCC) and head and neck squamous cell carcinoma (HNSCC) among others. Here, we identified potent next-generation constrained ethyl (cEt) antisense oligonucleotides (ASOs) to selectively target either human or mouse YAP1 and evaluated these in several preclinical models of both HCC and HNSCC. In the genetically engineered mouse (GEM) model of HCC (Salvador KO mice) and in the carcinogen-induced models of HCC (diethylnitrosamine, DEN-induced HCC) systemic treatment with mouse YAP1 ASOs resulted in a marked reduction in YAP1 protein level in (~90% reduction) and strong regressions of established tumors. Interestingly, YAP1 ASO treatment also resulted in significant infiltration of T cells and myeloid lineage cells in the tumors in these immune-competent mouse models of HCC suggesting a role in immune activation. Consistent with this notion, YAP1 ASO treatment in combination with anti-PD1 antibody treatment led to enhanced antitumor activity. In HNSCC, loss of the tumor suppressor FAT1 is a frequent occurrence and results in activation and nuclear localization of YAP1. In a panel of human HNSCC cell lines, proliferation was strongly reduced by human YAP1 ASOs selectively in the cell lines harboring homozygous copy loss or nonsense mutations of FAT1 while minimal antiproliferative activity was observed in cells with wild type FAT1. Importantly, the nuclear localization of YAP1 appeared to be a key determining factor for the sensitivity of human HNSCC cells to YAP1 depletion by ASO. In vivo treatment of mice bearing human CAL33 tumors that harbor FAT1 mutation, YAP1 ASOs greatly reduced YAP1 expression in tumors and suppressed tumor growth in both subcutaneous and orthotopic models. Collectively, these results suggest a potential therapeutic use of YAP1 ASOs in the treatment of both HCC and HNSCC with YAP1 activation as a single agent or in combination with immuno-oncology drugs. Based on these finding broad human ASO clinical candidates screens were performed leading to the selection of ION-537, a potent ASO drug targeting human YAP1 has now advanced into human clinical trials in cancer patients with YAP1 activation.
Citation Format: A. Robert Macleod. The discovery and characterization of ION-537: A next generation antisense oligonucleotide inhibitor of YAP1 in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND11.
Abstract SY17-03: Tumor-associated antigen MUC1 vaccine for colon cancer prevention
Authors: Finn Olivera (Olja) J. 
Published: July 2021

Abstract
For most human cancers, infectious etiology is unknown and preventative vaccines based on viral antigens, such as HPV for cervical cancer, are not a possibility. However, non-viral cancer-associated antigens, self-antigens abnormally expressed on tumors, have been identified as candidates for vaccines. In patients diagnosed with cancer, preexisting immunity to some of these antigens correlates with better disease outcome or reduced risk of recurrence. In transgenic mice or other animal models where they are expressed as self-antigens, immune responses induced to their tumor forms protect from tumor challenge without causing autoimmunity. Therapeutic vaccines that have utilized these antigens have had only marginal efficacy, which extensive research has now attributed to the presence of many immunosuppressive influences in the tumor microenvironment. MUC1 is one such antigen that has been shown effective as a vaccine in preclinical animal models but has had limited immunogenicity and little efficacy as a therapeutic vaccine in numerous clinical trials in many epithelial tumors, including cancer. Hypothesizing that the major difference between the outcome of the vaccine in preclinical models and in clinical trials is likely to be the high level of immune suppression in cancer patients, we began to develop models and MUC1 vaccines for cancer prevention in patients at risk, before immune suppression develops. We determined first that the tumor form of MUC1 was expressed on early premalignant lesions as well and chose premalignant colonic polyps as the first setting for testing the preventative vaccine. Data will be reviewed from a published feasibility study confirming immunogenicity and safety of the MUC1 vaccine in healthy individuals at risk for colon cancer. Data will then be presented from a recently completed unpublished randomized, double blind placebo controlled multi-center prophylactic MUC1 vaccine trial in the same patient population, those with a history of advanced colonic polyps and therefore at increased risk of developing colon cancer.
Citation Format: Olivera (Olja) J. Finn. Tumor-associated antigen MUC1 vaccine for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY17-03.
Abstract 35: Acceptability and Perceived Impact of New Pediatric Patient Navigation Program in Rural Rwanda
Authors: Nguyen Cam , Uwamahoro Pacifique , Benemariya Esperance , Nsanzimana Oscar , Mujyuwisha Louis , Buswell Lori , Lehmann Leslie , Shyirambere Cyprien 
Published: July 2021

Abstract
Purpose: Patient navigation (PN) can promote timely access to care and create seamless flow for patients through the care continuum. PN strategies have not been widely studied in low-income countries or among pediatric cancer patients. We report preliminary acceptability and perceived impact among caregivers and healthcare providers of a new pediatric PN program at a rural hospital in Rwanda.
Methods: From March 2020, patients diagnosed with nephroblastoma were supported by a trained navigator who conducted in-depth education for caregivers, coordinated all appointments, and proactively identified and addressed barriers to care. Caregivers were surveyed and interviewed at the end of their child's treatment; a focus group discussion (FGD) was held with providers six months after implementation. Interviews and FGD were conducted in Kinyarwanda, transcribed and translated to English. Descriptive statistics and the framework method were used to analyze survey and qualitative data, respectively.
Results: At the time of analysis, five patients enrolled in PN had completed treatment. All five caregivers were surveyed; three interviewed. Five providers participated in the FGD. Caregivers found PN helpful in understanding the diagnosis and treatment plan, providing emotional support, and linking them to various providers. Providers observed that treatment processes for nephroblastoma patients have become “smoother,” noting increased adherence to treatment appointments, better care coordination and improved advocacy for social support. While some clinicians worried frequent communications with the navigator would be a burden, caregivers viewed them as a source of motivation to continue treatment, despite numerous challenges. Participants suggested PN be expanded to other diagnoses.
Conclusion: Early data from end-users of our new pediatric PN program demonstrated high acceptability. Clinicians highlighted specific process challenges that were resolved with PN; caregivers appreciated the continuous logistical and emotional support. Further analyses will evaluate the impact of PN on outcomes and expansion of the program to other diagnoses.
Citation Format: Cam Nguyen, Pacifique Uwamahoro, Esperance Benemariya, Oscar Nsanzimana, Louis Mujyuwisha, Lori Buswell, Leslie Lehmann, Cyprien Shyirambere. Acceptability and Perceived Impact of New Pediatric Patient Navigation Program in Rural Rwanda [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 35.
Abstract 78: Breast Cancer in Kumasi: Recent Progress
Authors: Kyei Ishmael ,   International Center For The Study Of Breast Cancer Subtypes Icsbcs Collaborators, Newman Lisa , Davis Melissa 
Published: July 2021

Abstract
Purpose: Breast cancer is the most common malignancy in Ghanaian women and the leading cause of cancer mortality. There have been significant improvements in the management of breast disease over the years through various partnerships and interventions. This work set out to assess one such intervention, led by the International Center for the Study of Breast Cancer Subtypes (ICSBCS) and its impact on the improved management and outcomes of breast cancer.
Methods: The study was conducted at the Komfo Anokye Teaching Hospital from January 2013 to December 2019. Patients with confirmed diagnosis of breast cancer were retrospectively assessed for presentation, mode of tissue diagnosis, immunohistochemistry and staging.
Results: Three Hundred and eleven(311) breast cancer patients were recruited. Only Sixty eight(68)patients were above 60 years. Ninety five percent(95%) of patients were diagnosed by core needle biopsy, a newly implemented modality. Hormone receptor positivity was 30%. Stage III and IV disease accounted for 72% of cases
Conclusion: Significant improvements through ICSBCS training and assistance, led to better core needle biopsy practices and immunohistochemistry, both of which are necessary for treatment decision making, Late stage at presentation still remains a challenge in the management of breast cancer.
Citation Format: Ishmael Kyei, International Center For The Study Of Breast Cancer Subtypes Icsbcs Collaborators, Lisa Newman, Melissa Davis. Breast Cancer in Kumasi: Recent Progress [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 78.
Abstract 81: Studying Ghanian Cancer Genomes Using Cell-free DNA
Authors: Ahuno Samuel , Doebley Anna-Lisa , Ahearn Thomas , Yarney Joel , Titiloye Nicholas , Hamel Nancy , Adjei Ernest , Clegg-Lamptey Joe-Nat , Edusei Lawrence , Awuah Baffour , Song Xiaoyu , Vanderpuye Verne , Abubakar Mustapha , Duggan Maire , Stover Daniel , Nyarko Kofi , Bartlet John , Aitpillah Francis , Ansong Daniel , Gardner Kevin , Bowcock Anne , Caldas Carlos , Foulkes William , Wiafe Seth , Wiafe-Addai  , Garcia-Closas Montserrat , Kwarteng Alexander , Ha Gavin , Figueroa Jonine , Polak Paz ,   On Behalf Of Ghana Breast Health Study Team
Published: July 2021

Abstract
Purpose: Analysis of cell free DNA could provide a rapid and non-invasive approach to detect cancer and provide new molecular insights in many African countries where expert pathology is lacking. Hence, we tested whether whole-genome sequencing of cfDNA (WGS-cfDNA) could identify somatic alterations that drive breast cancer.
Methods: We conducted a pilot on 15 Ghanaian women (median age 49.5 years) recruited as part of the Ghana Breast Health Study. cfDNA was extracted and subjected to WGS at 30x and 0.1x. ichorCNA software was used to predict copy number alterations and ctDNA fractions.
Results: We found extensive amplification and deletion of multiple chromosomal regions including those with oncogenes and tumor suppressor genes associated with breast cancer. Similar copy number alterations for selected breast cancer genes were observed with 0.1x and 30x cfDNA-WGS with increasing concordance between the two instruments as the ctDNA fraction increases. We observed a high frequency (&gt;50%) of copy number gain in 3/5 regions and potential target genes for the amplification (chr8p11-12 [ZNF703] n=8, 53.3%; chr8q24.2 [MYC] n=9, 60%; chr19q12 [CCNE1] n=9, 60%), which were in agreement to previous observations among African-American (AA) ancestry compared to European-American (EA) ancestry in TCGA datasets.
Conclusion: Our data provided evidence that ctDNA-based genomic studies are possible and ctDNA analysis could be a tool for future molecular oncology studies in Africa for cancer etiology, surveillance and clinical trials.
Citation Format: Samuel Ahuno, Anna-Lisa Doebley, Thomas Ahearn, Joel Yarney, Nicholas Titiloye, Nancy Hamel, Ernest Adjei, Joe-Nat Clegg-Lamptey, Lawrence Edusei, Baffour Awuah, Xiaoyu Song, Verne Vanderpuye, Mustapha Abubakar, Maire Duggan, Daniel Stover, Kofi Nyarko, John Bartlet, Francis Aitpillah, Daniel Ansong, Kevin Gardner, Anne Bowcock, Carlos Caldas, William Foulkes, Seth Wiafe, Wiafe-Addai, Montserrat Garcia-Closas, Alexander Kwarteng, Gavin Ha, Jonine Figueroa, Paz Polak, On Behalf Of Ghana Breast Health Study Team. Studying Ghanian Cancer Genomes Using Cell-free DNA [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 81.
Salt-Inducible Kinase 3 Promotes Vascular Smooth Muscle Cell Proliferation and Arterial Restenosis by Regulating AKT and PKA-CREB Signaling
Authors: Cai Yujun , Wang Xue-Lin , Lu Jinny , Lin Xin , Dong Jonathan , Guzman Raul J. 
Published: July 2021

Objective:
Arterial restenosis is the pathological narrowing of arteries after endovascular procedures, and it is an adverse event that causes patients to experience recurrent occlusive symptoms. Following angioplasty, vascular smooth muscle cells (SMCs) change their phenotype, migrate, and proliferate, resulting in neointima formation, a hallmark of arterial restenosis. SIKs (salt-inducible kinases) are a subfamily of the AMP-activated protein kinase family that play a critical role in metabolic diseases including hepatic lipogenesis and glucose metabolism. Their role in vascular pathological remodeling, however, has not been explored. In this study, we aimed to understand the role and regulation of SIK3 in vascular SMC migration, proliferation, and neointima formation.

Approach and Results:

We observed that SIK3 expression was low in contractile aortic SMCs but high in proliferating SMCs. It was also highly induced by growth medium in vitro and in neointimal lesions in vivo. Inactivation of SIKs significantly attenuated vascular SMC proliferation and up-regulated p21
CIP1
and p27
KIP1
. SIK inhibition also suppressed SMC migration and modulated actin polymerization. Importantly, we found that inhibition of SIKs reduced neointima formation and vascular inflammation in a femoral artery wire injury model. In mechanistic studies, we demonstrated that inactivation of SIKs mainly suppressed SMC proliferation by down-regulating AKT (protein kinase B) and PKA (protein kinase A)-CREB (cAMP response element-binding protein) signaling. CRTC3 (CREB-regulated transcriptional coactivator 3) signaling likely contributed to SIK inactivation-mediated antiproliferative effects.

Conclusions:
These findings suggest that SIK3 may play a critical role in regulating SMC proliferation, migration, and arterial restenosis. This study provides insights into SIK inhibition as a potential therapeutic strategy for treating restenosis in patients with peripheral arterial disease.
Digital Peripheral Arterial Tonometry and Cardiovascular Disease Events: The Framingham Heart Study
Authors: Cooper Leroy L. , Wang Na , Beiser Alexa S. , Romero José Rafael , Aparicio Hugo J. , Lioutas Vasileios-Arsenios , Benjamin Emelia J. , Larson Martin G. , Vasan Ramachandran S. , Mitchell Gary F. , Seshadri Sudha , Hamburg Naomi M. 
Published: July 2021

Background and Purpose:
Novel noninvasive measures of vascular function are emerging as subclinical markers for cardiovascular disease (CVD) and may be useful to predict CVD events. The purpose of our prospective study was to assess associations between digital peripheral arterial tonometry (PAT) measures and first-onset major CVD events in a sample of FHS (Framingham Heart Study) participants.

Methods:
Using a fingertip PAT device, we assessed pulse amplitude in Framingham Offspring and Third Generation participants (n=3865; mean age, 55±14 years; 52% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia. The PAT ratio (relative hyperemia index) was calculated as the post-to-pre occlusion pulse signal ratio in the occluded arm, relative to the same ratio in the control (nonoccluded) arm, and corrected for baseline vascular tone. Baseline pulse amplitude and PAT ratio during hyperemia are measures of pressure pulsatility and microvascular function in the finger, respectively. We used Cox proportional hazards regression to relate PAT measures in the fingertip to incident CVD events.

Results:

During follow-up (median, 9.2 years; range, 0.04–10.0 years), 270 participants (7%) experienced new-onset CVD events (n=270). In multivariable models adjusted for cardiovascular risk factors, baseline pulse amplitude (hazard ratio [HR] per 1 SD, 1.04 [95% CI, 0.90–1.21];
P
=0.57) and PAT ratio (HR, 0.95 [95% CI, 0.84–1.08];
P
=0.43) were not significantly related to incident composite CVD events, including myocardial infarction or heart failure. However, higher PAT ratio (HR, 0.76 [95% CI, 0.61–0.94];
P
=0.013), but not baseline pulse amplitude (HR, 1.15 [95% CI, 0.89–1.49];
P
=0.29), was related to lower risk for incident stroke. In a sensitivity analysis by stroke subtype, higher PAT ratio was related to lower risk of incident ischemic stroke events (HR, 0.68 [95% CI, 0.53–0.86];
P
=0.001).

Conclusions:
Novel digital PAT measures may represent a marker of stroke risk in the community.