bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6299: Population kinetics (PopKin) of non-small cell lung cancer (NSCLC) adjuvant therapy
Authors: Stewart David J. 
Published: June 2022

Abstract
Background: Disease-free survival (DFS) and overall survival (OS) follow 1st order kinetics. Curve Popkin assessment yields biological insights. Chemotherapy (chemo) improves outcome in resected NSCLC. We performed adjuvant DFS and OS PopKin assessments.
Methods: We digitized published DFS and OS curves. We used GraphPad Prism for curve exponential decay nonlinear regression analysis (EDNLRA).
Results: We assessed 1 trial with adjuvant osimertinib and 5 with platinum-based postoperative chemo and control arms. With osimertinib, DFS and OS curves were convex on log-linear plots, suggesting rapid tumor regrowth once therapy is discontinued. In chemo trials, 10 of 10 DFS curves and 9 of 10 OS curves fit 2-phase decay EDNLRA models (Table 1). Popkin calculations indicate that of control patients destined to recur, 12% would recur by 2 months after surgery, 22% by 4 months and 31% by 6 months.
Conclusion: PopKin suggests osimertinib delays recurrence rather than preventing it. Combined chemo analyses suggest chemo converts 15% of patients from rapidly to slowly recurring, but many “shifted” patients eventually recur. Hence, chemo may induce reversible tumor senescence rather than eradicating micrometastases. Anti-senescent cell strategies might prove beneficial. Frequent scans are warranted in the 1st postoperative year for early detection of recurrences.
Table 1. EDNLRA of adjuvant chemo and control DFS and OS curves Arm Overall t1/2 a % Fastb Fast group t1/2 c % Slowd Slow group t1/2 e Control DFS 40.1 57 11.0 43 212.7 Chemo DFS 47.2 42 11.7 58 120.8 Control OS 51.9 69 25.8 31 1.3 x 1012 Chemo OSf 61.4 75 45.9 25 1.3 x 1012 aMedian t1/2 (half-life, months) on 1-phase decay EDNLRA. bMedian % of all patients in rapidly recurring/dying subgroup on 2-phase decay EDNLRA. cMedian t1/2 in rapidly recurring/dying subgroup on 2-phase decay EDNLRA. dMedian % in slowly recurring/dying subgroup. eMedian t1/2 in slowly recurring/dying subgroup. fIn 1 study, OS curve did not fit a 2-phase decay model
Citation Format: David J. Stewart. Population kinetics (PopKin) of non-small cell lung cancer (NSCLC) adjuvant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6299.
Abstract ND12: Discovery and First Structural Disclosure of EZM0414: A potent and selective small molecule inhibitor of the histone methyltransferase SETD2
Authors: Kutok Jeffery L. 
Published: June 2022

Abstract
SETD2 is the only known histone methyltransferase (HMT) capable of catalyzing H3K36 trimethylation (H3K36me3). It plays a critical role in several biological processes such as DNA damage repair and B cell development. Dysregulation in H3K36 methylation can occur in B cell malignancies, including multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL), often as a result of mutational events incurred during normal B cell development. For example, 15%-20% of MM patients harbor the high risk (4;14) chromosomal translocation (t), resulting in high expression of the multiple myeloma SET domain (MMSET) gene. MMSET (also known as NSD2) is an HMT that catalyzes H3K36me1 and H3K36me2 formation, which leads to increased levels of H3K36me2 in t(4;14) MM patients. Because H3K36me2 is the substrate of SETD2, we hypothesized that inhibiting SETD2 could target the underlying oncogenic mechanism driven by the dysregulated H3K36 methylation from MMSET overexpression in t(4;14) MM patients, and would establish proof of concept in this and other B cell malignancies (e.g. DLBCL) that may demonstrate dysregulated H3K36me3 or a dependency on SETD2. In this presentation, we will describe the discovery and structure of our clinical candidate EZM0414, a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2; robust anti-tumor effects of SETD2 inhibition with EZM0414 in MM (including t(4;14) MM) and DLBCL preclinical studies; and the outline of the ongoing first-in-human Ph1/1b open-label, multicenter study of EZM0414 in patients with relapsed/refractory MM or DLBCL.
Citation Format: Jeffery L. Kutok. Discovery and First Structural Disclosure of EZM0414: A potent and selective small molecule inhibitor of the histone methyltransferase SETD2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND12.
Abstract PL02-01: The pathogenesis of cancer susceptibility due to inherited DNA repair defects
Authors: Stratton Michael R. 
Published: June 2022

Abstract
The landscapes of somatic mutation in the genomes of normal human cells have, until recently, been poorly described compared with those of cancer cells. However, advances in technology are now changing this picture and are enabling exploration of the earliest stages of cancer development. In this talk, the patterns of somatic mutation found in normal colorectal epithelial cells are outlined and serve as a backdrop to understanding the pathogenesis of colorectal cancer susceptibility syndromes. Multiple mutational signatures are present in normal colorectal epithelial cells indicating that multiple mutational processes are operative in them during the course of life. Some of these mutational signatures are ubiquitous, present in every colorectal epithelial cell, with mutations generated at constant rates throughout life. Others are sporadic, found only in some cells or in some people, with mutations generated in bursts. Some are of endogenous origins whereas others are caused by exogenous exposures. Several inherited colorectal cancer predisposition syndromes are known to be mediated by DNA repair deficiencies that ultimately generate elevated somatic mutation rates. The results presented here show that in some of these syndromes all normal colorectal cells, and probably all cells in the body, have markedly elevated somatic mutation rates throughout life with mutational signatures not found in healthy individuals. Conversely, in other syndromes normal cells have normal mutation rates with standard mutational signatures but a small minority of cells acquire elevated mutation rates during the course of life. In both scenarios only a small proportion of cells with elevated mutation rates ever become adenomas or carcinomas. The results elucidate the different ways in which elevated somatic mutation rates due to DNA repair deficiencies lead to cancer and potentially offer a new modality contributing to clinical management of colorectal cancer susceptibility. They also provide a new perspective on the role of somatic mutations in ageing.
Citation Format: Michael R. Stratton. The pathogenesis of cancer susceptibility due to inherited DNA repair defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL02-01.
Abstract SY06-03: Development of novel therapeutic strategies to target the DNA damage response in the clinic
Authors: Yap Timothy A. 
Published: June 2022

Abstract
The clinical benefit observed with PARP inhibitors, and their subsequent regulatory approval in multiple tumor indications, have provided clinical proof of concept for a synthetic lethal approach in molecularly selected tumors and beyond. Now, we need to build on the success of such first generation PARP inhibitors through the use of rational evidence-based biomarker-driven strategies in the clinic. We can potentially accomplish this through the development of novel potent PARP1-selective inhibitors, which may lead to an improved therapeutic index and patient benefit, and the development of rational PARP inhibitor combinations with other molecularly targeted agents or immunotherapeutics, taking in consideration potential supra-additive toxicities. Finally, given recent advances in drug discovery efforts, we now have the opportunity to go beyond PARP by drugging other key DNA Damage Response (DDR) targets in the clinic, including ATR, WEE1, DNA-PK, RAD51, POLQ and USP1. I will discuss the progress we have made in the clinic, the potential pitfalls, and the promise that such novel approaches hold in improving patient outcomes.
Citation Format: Timothy A. Yap. Development of novel therapeutic strategies to target the DNA damage response in the clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY06-03.
Abstract SY22-02: Aneuploidy and 3D tissue rigidity
Authors: Discher Dennis 
Published: June 2022

Abstract
Sequence differences between normal cells of the same person are increasingly evident (e.g. Yizhak Science 2019), and such somatic variations across different tissues increase from liquid to solid tissues, consistent with similar trends across liquid and solid tumors. Further analyses suggest changes increase with high levels of both replication-division (R=0.24) and the stiffness E of each tissue (R=0.6). Chromosome copy number gains and losses – aneuploidy – follow these trends, which prompted our hypothesis that stiff 3d microenvironments could increase aneuploidy of dividing cells moreso than less confining or microenvironments. We developed a method of live-cell monitoring of changes to chromosome copy numbers and used it to study diverse perturbations, particularly compressed mitosis seen in vivo. Many dividing cells die when squeezed, but rare stem cells and cancer cells show heritable loss of mono-allelic, GFP/RFP-tagged constitutive genes that function as Chromosome-reporters (ChReporters). Flattening spreads mitotic chromatin, favors chromosome mis-segregation, and increases ChReporter loss independent of an established spindle assembly checkpoint. Inhibiting the high level of Topoisomerase in such cells impedes chromosome compaction, division, and ChReporter loss, whereas the proposed tumor suppressor Myosin-IIA stabilizes chromatin against fragmentation, with knockdown increasing ChReporter loss. Solid human tumors and teratomas show similar ChReporter trends in mice, and single-cell-sequencing identifies rare chromosome changes exclusively in normal 3D-infiltrative cells while also relating specific chromosome losses to altered growth and motility. 3D rigidity thus gives rise to heritable aneuploidy as a mechanogenetic change.
Citation Format: Dennis Discher. Aneuploidy and 3D tissue rigidity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY22-02.
Abstract SY30-03: Colorectal cancer screening in underserved populations: COVID, silver linings, and challenges ahead
Authors: Martinez Maria Elena 
Published: June 2022

Abstract
Colorectal cancer (CRC) screening and appropriate follow-up can reduce incidence and mortality, but screening and abnormal test follow-up rates are suboptimal among medically underserved populations. The United States Preventive Services Task Force (USPSTF) recommends CRC screening through a variety of invasive and noninvasive tests for adults aged 50 to 75 years (grade A) and for individuals aged 45 to 49 years (grade B). Evidence-based interventions and other strategies exist to promote CRC screening, but adoption and implementation of these are limited, especially among medically underserved individuals and those receiving care at community health centers (CHCs) in the United States. Aside from low screening uptake, low colonoscopy follow-up of abnormal stool tests is common in CHCs, estimated to be approximately 50%. Lack of colonoscopy completion for abnormal stool tests defeats the purpose of screening because early-stage cancers go undetected, resulting in higher CRC mortality. Reasons for lack of colonoscopy completion are poorly understood. Cancer screening rates have plummeted as a result of the coronavirus disease 2019 (COVID-19) pandemic, resulting in an estimated 10,000 deaths from breast and CRC alone in the U.S. over the next 10 years. The impact of this drop specific to racial/ethnic groups and communities facing barriers prior to the pandemic is unknown. Prior to the onset of the pandemic, the National Cancer Institute invested in CRC screening research as a result of the Cancer Moonshot’s Blue Ribbon Panel recommendation through its Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) initiative. ACCSIS supports research to build the evidence base on multilevel interventions to increase CRC screening, follow-up, and referral to care. Five ACCSIS research projects and a 3-site American Indian project are supported through this initiative, all focusing on underserved populations across the US. This presentation will provide an overview of the key components of the ACCSIS program, challenges faced resulting from the pandemic, and opportunities for overcoming these. In its 2022 report, the President’s Cancer Panel called for equitable cancer screening as a top public health priority. The report emphasizes that overcoming barriers to CRC screening and follow-up among underserved populations must be addressed to ensure that the benefits reach all populations. This provides a timely opportunity to address the extraordinary CRC screening challenges and disparities faced by vulnerable populations.
Citation Format: Maria Elena Martinez. Colorectal cancer screening in underserved populations: COVID, silver linings, and challenges ahead [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY30-03.
Abstract SY42-01: Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche
Authors: Li Linheng 
Published: June 2022

Abstract
Tumor-initiating stem cells shape microenvironment into an immunosuppressive barrier and a pro-tumorigenic nicheLinheng Li Stowers Institute for Medical Research, Kansas City MO 64110Kansas University of Cancer Center, Kansas City KS 66160
Accumulated evidence supports the concept that tumor-initiating stem cells (TSCs) are at the root of tumor/cancer and are largely responsible for the commonly observed resistance to chemoradiotherapy (CRT) and frequent relapse of disease. How a subset of TSCs, or therapy resistant TSC (TrTSC), survives and supports tumor regrowth post treatment is a fundamental biological question and clinically unsolved problem. Recently, we utilized single-cell RNA-sequencing to identify therapy resistant TSCs (or TrTSCs) in mouse models of CRT-challenged intestinal adenoma, followed by bioinformatics analysis to reveal the bidirectional crosstalk that occurs between TSCs and the tumor microenvironment (TME). The results of the analysis indicate that TSCs shape the TME into an immunosuppressive barrier. Particularly, TrTSCs recruit tumor-associated monocytes and macrophages (TAMMs), which in turn, via Cox-2 dependent prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, induce Akt-mediated phosphorylation of β-catenin and thus enhance the β-catenin activity. Furthermore, we show that enhanced β-catenin signaling upregulates multiple immune-checkpoint genes, thus empowering the immune escape capabilities of TSCs. Taken together, overcoming both the extrinsic immunosuppressive barrier and intrinsic immune escape has the potential to increase the efficacy of checkpoint inhibition therapies against cancers in the future.
Citation Format: Linheng Li. Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY42-01.
Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice
Authors: Karshovska Ela , Mohibullah Rokia , Zhu Mengyu , Zahedi Farima , Thomas Dominique , Magkrioti Christiana , Geissler Claudia , Megens Remco T.A. , Bianchini Mariaelvy , Nazari-Jahantigh Maliheh , Ferreirós Nerea , Aidinis Vassilis , Schober Andreas 
Published: June 2022

Background:
Maladapted endothelial cells (ECs) secrete ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin)—a lysophospholipase D that generates lysophosphatidic acids (LPAs). ENPP2 derived from the arterial wall promotes atherogenic monocyte adhesion induced by generating LPAs, such as arachidonoyl-LPA (LPA20:4), from oxidized lipoproteins. Here, we aimed to determine the role of endothelial ENPP2 in the production of LPAs and atherosclerosis.

Methods:

We quantified atherosclerosis in mice harboring loxP-flanked
Enpp2
alleles crossed with

Apoe
–/–

mice expressing tamoxifen-inducible Cre recombinase under the control of the EC-specific bone marrow X kinase promoter after 12 weeks of high-fat diet feeding.

Results:

A tamoxifen-induced EC-specific
Enpp2
knockout decreased atherosclerosis, accumulation of lesional macrophages, monocyte adhesion, and expression of endothelial CXCL (C-X-C motif chemokine ligand) 1 in male and female

Apoe
–/–

mice. In vitro, ENPP2 mediated the mildly oxidized LDL (low-density lipoprotein)-induced expression of CXCL1 in aortic ECs by generating LPA20:4, palmitoyl-LPA (LPA16:0), and oleoyl-LPA (LPA18:1). ENPP2 and its activity were detected on the endothelial surface by confocal imaging. The expression of endothelial
Enpp2
established a strong correlation between the plasma levels of LPA16:0, stearoyl-LPA (LPA18:0), and LPA18:1 and plaque size and a strong negative correlation between the LPA levels and ENPP2 activity in the plasma. Moreover, endothelial
Enpp2
knockout increased the weight of high-fat diet–fed male

Apoe
–/–

mice.

Conclusions:
We demonstrated that the expression of ENPP2 in ECs promotes atherosclerosis and endothelial inflammation in a sex-independent manner. This might be due to the generation of LPA20:4, LPA16:0, and LPA18:1 from mildly oxidized lipoproteins on the endothelial surface.
Impact of linear infrastructure on South Africa’s primate fauna: the need for mitigation
Authors: Linden Birthe , Cuozzo Frank P. , Sauther Michelle L. , Collinson Jonker Wendy 
Published: June 2022

Abstract
South Africa’s extensive linear infrastructure network (which includes roads and power lines) is severely impacting the country’s historically recognised five primate species: greater or thick-tailed bushbaby (Otolemur crassicaudatus), southern lesser bushbaby (Galago moholi), chacma baboon (Papio ursinus), vervet monkey (Chlorocebus pygerythrus) and samango monkey (Cercopithecus albogularis). We present South African mortality data from two different linear infrastructure types on a country wide scale, over a long-term sampling period. Using primate road mortality and power line electrocution data acquired from different data sources, we compare and discuss different mortality data collection methodologies, the resulting data quality and identify current limitations in understanding the direct impacts of linear infrastructure which have important implications for primate conservation planning. Between 1996-2021 a total of 483 primate mortalities were recorded on roads and power lines, the majority on the former. Vervet monkeys were most severely impacted by both linear infrastructure types whereas lesser bushbabies experienced the least number of mortalities. Both data sets showed numerous incidents where more than one individual was killed (roadkill: 4%, up to four killed in one incident; electrocutions: 13%, up to six killed in one incident). GPS coordinates were available for 61% of roadkill records and for 65% of electrocution records. Age or sex of carcasses were not available for electrocution records and only available for 11% of roadkill records. Although South Africa leads the African continent regarding roadkill and electrocution data collection, there are still areas in the collection protocol that can be improved and projects implementing mitigation measures (e.g. canopy bridges) to reduce primate roadkill are lacking. We argue that the mortality data presented here should form the basis for future mitigation implementation and recommend that linear infrastructure be more prominently recognised as a direct threat when developing national and international Red Lists.
Studying Muslim Minorities in Subsaharan Africa: Preliminary Remarks
Authors: Schulz Dorothea E. 
Published: June 2022

Abstract
The introduction to the special issue on Muslim minorities in Subsaharan Africa argues that a focus on the circumstances and challenges faced by them opens up productive lines of inquiry into forms of religious coexistence and plurality, in Subsaharan Africa and elsewhere. Starting from a conceptual reflection on different forms of religious plurality, the article enters a plea for more a sustained reflection on the effects of state regulation of religious coexistence and how it is lived in everyday life. To this effect, the introduction invites readers to take the different case studies of the special issue as a way to assess and compare the genealogies and legacies of state regimes of religious governance in Subsaharan Africa.
Elevated parathyroid hormone one year after kidney transplantation is an independent risk factor for graft loss even without hypercalcemia
Authors: Okada Manabu , Tominaga Yoshihiro , Sato Tetsuhiko , Tomosugi Toshihide , Futamura Kenta , Hiramitsu Takahisa , Ichimori Toshihiro , Goto Norihiko , Narumi Shunji , Kobayashi Takaaki , Uchida Kazuharu , Watarai Yoshihiko 
Published: June 2022

Abstract
Background
Hypercalcemic hyperparathyroidism has been associated with poor outcomes after kidney transplantation (KTx). However, the clinical implications of normocalcemic hyperparathyroidism after KTx are unclear. This retrospective cohort study attempted to identify these implications.

Methods
Normocalcemic recipients who underwent KTx between 2000 and 2016 without a history of parathyroidectomy were included in the study. Those who lost their graft within 1 year posttransplant were excluded. Normocalcemia was defined as total serum calcium levels of 8.5–10.5 mg/dL, while hyperparathyroidism was defined as when intact parathyroid hormone levels exceeded 80 pg/mL. The patients were divided into two groups based on the presence of hyperparathyroidism 1 year after KTx. The primary outcome was the risk of graft loss.

Results
Among the 892 consecutive patients, 493 did not have hyperparathyroidism (HPT-free group), and 399 had normocalcemic hyperparathyroidism (NC-HPT group). Ninety-five patients lost their grafts. Death-censored graft survival after KTx was significantly lower in the NC-HPT group than in the HPT-free group (96.7% vs. 99.6% after 5 years, respectively, P < 0.001). Cox hazard analysis revealed that normocalcemic hyperparathyroidism was an independent risk factor for graft loss (P = 0.002; hazard ratio, 1.94; 95% confidence interval, 1.27–2.98).

Conclusions
Normocalcemic hyperparathyroidism 1 year after KTx was an independent risk factor for death-censored graft loss. Early intervention of elevated parathyroid hormone levels may lead to better graft outcomes, even without overt hypercalcemia.