bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of blood biomarkers with glomerular filtration rate in patients with TIA and stroke: population-based study
Authors: Kelly Dearbhla M. , Li Linxin , Burgess Annette I , Poole Deborah L , Duerden Julia M , Rothwell Peter M. 
Published: September 2020

Background and purposeNon-traditional risk factors such as chronic inflammation, oxidative stress and thrombogenic factors are believed to contribute to the excess stroke risk in chronic kidney disease (CKD) by triggering vascular injury and endothelial dysfunction. We aimed to determine how well a panel of biomarkers representative of these factors would correlate with estimated glomerular filtration rate (eGFR) in patients with recent transient ischaemic attack (TIA) or stroke. We also investigated whether eGFR would confound previously reported associations between biomarkers and mortality.MethodsWe studied a panel of 16 blood biomarkers related to inflammation, thrombosis, atherogenesis and cardiac or neuronal cell damage in TIA or ischaemic stroke in a population-based study (Oxford Vascular Study). Biomarker levels were log-transformed and correlated with eGFR, adjusted for age. Cox proportional hazard models were used for survival analysis.ResultsAmong 1297 patients with TIA or stroke, 52.7% (n=684) of patients had CKD (eGFR <60 mL/min/1.73 m2). There was a moderate correlation between log-eGFR and the log-transformed soluble tumour necrosis factor receptor-1 (R2=0.21), attenuating with adjustment for age (R2=0.12). There were moderate-to-strong correlations with markers of cardiac injury, N-terminal pro-brain natriuretic peptide and heart-type fatty acid binding protein (hFABP, R2=0.14 and 0.34, respectively). The strongest correlation after adjustment for age was between hFABP and eGFR (R2=0.20). Adjusting for eGFR did not impact any biomarker associations with mortality.ConclusionsCorrelations between biomarkers related to inflammation and thrombosis with renal dysfunction in the setting of cerebrovascular events were generally modest after adjustment for age, suggesting that putative risk factors such as chronic inflammation or coagulopathy are unlikely to be important stroke mechanisms in patients with CKD.
Efficient Logspace Classes for Enumeration, Counting, and Uniform Generation
Authors: Arenas Marcelo , Croquevielle Luis Alberto , Jayaram Rajesh , Riveros Cristian 
Published: September 2020

We study two simple yet general complexity classes, which provide a unifying framework for efficient query evaluation in areas like graph databases and information extraction, among others. We investigate the complexity of three fundamental algorithmic problems for these classes: enumeration, counting and uniform generation of solutions, and show that they have several desirable properties in this respect.
Both complexity classes are defined in terms of non deterministic logarithmic-space transducers (NL transducers). For the first class, we consider the case of unambiguous NL transducers, and we prove constant delay enumeration, and both counting and uniform generation of solutions in polynomial time. For the second class, we consider unrestricted NL transducers, and we obtain polynomial delay enumeration, approximate counting in polynomial time, and polynomialtime randomized algorithms for uniform generation. More specifically, we show that each problem in this second class admits a fully polynomial-time randomized approximation scheme (FPRAS) and a polynomial-time Las Vegas algorithm (with preprocessing) for uniform generation. Remarkably, the key idea to prove these results is to show that the fundamental problem #NFA admits an FPRAS, where #NFA is the problem of counting the number of strings of length n (given in unary) accepted by a non-deterministic finite automaton (NFA). While this problem is known to be #P-complete and, more precisely, SpanL-complete, it was open whether this problem admits an FPRAS. In this work, we solve this open problem, and obtain as a welcome corollary that every function in SpanL admits an FPRAS.
Virtual conferences
Authors: Krauss Oliver 
Published: September 2020

Due to the health and safety hazard introduced by Covid-19 and the measures of governments around the world restricting travel and large gatherings, most conferences in 2020 have decided to go virtual. This includes the recently held EvoStar conferences, as well as the upcoming Genetic and Evolutionary Computation Conference (GECCO), which many SIGEVO Members are attending regularly.
The following article will attempt to summarize the advantages, disadvantages and challenges that come with such virtual conferences from an attendee's perspective. As they are collected from discussions and personal opinions, take them with a grain of salt, as every experience on a conference is different.
Abstract 10: Sclareol induces apoptosis and inhibits notch signaling in hamster oral carcinogenesis
Authors: Chinnaiyan Aiyavu , Nallu Anandhi , Kathiresan Suresh 
Published: September 2020

Abstract
The Notch signaling pathway is an evolutionarily conserved cell signaling pathway. It plays a central role in cell fate decisions and differentiation. The bioavailability of sclareol has been widely studied due to its anti-carcinogenic and antioxidant effects. However, chemo preventive effects of sclareol on notch signaling in 7, 12-dimethylbenz [a] anthracene (DMBA) induced hamster buccal pouch(HBP) carcinogenesis remain to be fully elucidated. In the present study, tumors were induced by applying 0.5% DMBA topically to HBP thrice a week for 14 weeks and sclareol was orally administered at a dose of 20mg/kg body weight on alternate days of DMBA painting. We analyzed expression of Notch signaling in DMBA induced oral squamous cell carcinoma (OSCC) in experimental oral carcinogenesis and inhibition of notch signaling by sclareol. This study thus observed up regulation of Notch1, Notch2, Jagged1, Hes1 and Hey1 in DMBA alone induced hamsters. Furthermore, oral administration of sclareol led to reduced Notch1, Notch2 activation and expression of Jagged-1 and its downstream targets of Hes-1 and Hey-1 in tumor bearing hamsters. In addition, sclareol treatment increased pro-apoptotic and decreased anti-apoptotic proteins survival indicating apoptosis through activation of caspase 3, and promoting cell death by dysregulation of cyclin D1 levels in tumor bearing hamsters. Immunohistochemical examination showed that Notch intracellular domain accumulates in the nucleus of cells in DMBA induced hamster buccal pouch carcinogenesis, and Jagged1 was found to be dysregulated in sclareol treated tumor animals. In conclusion, the results provide an important new insight of Notch signaling pathway for a potential therapeutic target for oral cancer.
Citation Format: Aiyavu Chinnaiyan, Anandhi Nallu, Suresh Kathiresan. Sclareol induces apoptosis and inhibits notch signaling in hamster oral carcinogenesis [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 10.
Abstract 101: Studies on the flavonoid metabolite 2,4,6-trihydroxybenzoic acid as a CDK inhibitor and anti-proliferative agent: Potential role in cancer prevention
Authors: Sankaranarayanan Ranjini , Valiveti Chaitanya K. , van Slambrouck Severine , Kesharwani Siddharth S. , Kumar D. Ramesh , Seefeldt Teresa , Tummala Hemachand , Gunaje Jayarama B. 
Published: September 2020

Abstract
Colorectal cancer (CRC) is the second highest cause of cancer deaths in the United States according to Center for Disease Control. Increasing evidences suggest that a diet rich in fruits and vegetables will reduce incidences of colorectal adenomas. We hypothesize that the natural compounds present in fruits and vegetables, along with their metabolites generated by the gut microbiota, could be responsible for cancer prevention by targeting the cell cycle proteins. Previous studies conducted in the laboratory have identified 2,4,6- Trihydroxybenzoic acid (2,4,6-THBA), one of the degradation products of flavonoids, as a potential chemo-preventive agent mediating its effect through inhibition of cyclin dependent kinases (CDKs). Transport of monocarboxylic acids like 2,4,6-THBA is mediated by the Solute Ligand Carrier (SLC) family of transporters; in particular SLC5A8 and SLC5A12 have been implicated as tumor suppressor proteins that are down-regulated/non-functional in various cancers. In this study, we investigated the ability of the monocarboxylic acid transporter SLC5A8 to transport 2,4,6-THBA into the mammalian cells. Our pilot studies show that the cells expressing SLC5A8 transporters have the capacity to transport 2,4,6-THBA leading to upregulation of p21 and p27 as measured by western blots and qPCR. This was associated with decreased cell number as well as decreased colony formation as measured through clonogenic assays. We suggest that chemo-preventive actions of dietary compounds containing flavonoids may occur through 2,4,6-THBA, contributing largely to the prevention of CRC.
Citation Format: Ranjini Sankaranarayanan, Chaitanya K. Valiveti, Severine van Slambrouck, Siddharth S. Kesharwani, D. Ramesh Kumar, Teresa Seefeldt, Hemachand Tummala, Jayarama B. Gunaje. Studies on the flavonoid metabolite 2,4,6-trihydroxybenzoic acid as a CDK inhibitor and anti-proliferative agent: Potential role in cancer prevention [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 101.
Abstract 1115: Patient-derived explant cultures (PDECs) as a model system for immuno-oncology studies
Authors: Turpin Rita , Munne Pauliina , Suleymanova Ilida , Mustjoki Satu , Pouwels Jeroen , Klefström Juha 
Published: September 2020

Abstract
Despite the great promise of immunotherapy, only relatively few patients show long-term complete remission. In addition, immunotherapy is not effective against every cancer type. Cancer types with low mutational burden such as breast cancer (BCa), for example, are thought to not elicit an immune reaction and are therefore considered non-immunogenic. A major hurdle in the advancement of immunotherapy is the lack of preclinical models that faithfully preserve the tumor microenvironment and recapitulate human disease. We have developed a method to grow 3D cultures of intact fragments of patient-derived tissue (Patient-Derived Explant Cultures; PDECs), which has been used to assess the efficacy of novel treatment regimens on real human tumors (Haikala et al., Nature Comm. 2019; Tervonen et al., Oncogene 2016). PDECs offer many advantages over other cancer model systems; PDECs preserve the human tumor microenvironment, reflect inter- and intra-patient tumor heterogeneity and results are obtained within one week. Up to 16 experimental samples can be obtained from one clinical sample, allowing the same ‘patient' to be experimentally treated with different drug regimens and/or measurement of more than one endpoint.To assess whether PDECs are also a suitable model for IO studies we performed immunoprofiling experiments using FACS, RT-PCR, cytokine profiling and immunofluorescence, showing that the immune-contexture, i.e. the number and activation status of different immune cell types, is similar in PDECs than in the primary tumor they were derived from. Subsequently, we addressed whether the resident immune cells in PDECs were functional. Preliminary data showed that direct T cell activation in PDECs led to apoptosis of cancer cells and invoked a complex immune response, as assessed using cytokine profiling and FACS. Treatment with the immune checkpoint inhibitor anti-PD-1 had more moderate effects. These data reflect the clinical reality where very few BCa patients respond to immune checkpoint monotherapy, but also show that T cells in BCa can be activated to kill the cancer cells, suggesting that with the right treatment strategies, BCa can be targeted with immunotherapy. All in all, our data show that the tumor's immunocontexture is conserved in PDECs and that resident immune cells in PDECs can be activated to attack cancer cells, and thus support the use of PDECs as an ex vivo model system to study immuno-oncology in real human cancers for the development of the immunotherapies of tomorrow.
Citation Format: Rita Turpin, Pauliina Munne, Ilida Suleymanova, Satu Mustjoki, Jeroen Pouwels, Juha Klefström. Patient-derived explant cultures (PDECs) as a model system for immuno-oncology studies [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 1115.
Abstract 1129: CADM1 is a novel serum marker for small cell lung cancer
Authors: Ito Takeshi , Funaki Toko , Tanaka Goh , Nagase Takahide , Murakami Yoshinori 
Published: September 2020

Abstract
Small cell lung cancer (SCLC) accounts for about 15% of lung cancer. Although SCLC often responds favorably to combined-modality chemotherapy at the initial treatment, resistant tumors develop rapidly, which makes SCLC one of the representative cancers refractory to any therapeutic approaches. Moreover, molecular targeting therapy has not been developed for SCLC so far. Therefore, novel approaches to the diagnosis and treatment of SCLC on the basis of molecular understanding would be prerequisite to control this refractory cancer. One of the most critical issues of SCLC is its early detection in the initial screening and after chemotherapy. For this purpose, pro-gastrin releasing peptide (ProGRP) and neuron specific enolase (NSE) are widely used for serum markers for detection of SCLC, although combination of ProGRP and NSE can detect at most 60% of SCLC. We have previously demonstrated that CADM1, a member of the immunoglobulin superfamily cell adhesion molecules, is highly expressed in around 75% of SCLC. In addition, SCLC expresses a splicing variant, CADM1v8/9, which is observed specifically in normal testis. Here, we report that the extracellular fragment of CADM1v8/9 is digested by ADM17 and released into cell medium or human serum. So, we generated specific monoclonal antibody against CADM1v8/9 using Cadm1-deficient mice and developed a serum diagnostic marker system for SCLC. Preliminary study shows that CADM1v8/9 detects 47% of SCLC with specificity of 92%, which is independent of and partly overlapped with the cases detected by ProGRP or NSE. CADM1v8/9 can detect 25% of patients with limited disease and 77% of patients with extensive disease of SCLC. Furthermore, the amount of CADM1v8/9 fragments well correlates with the disease activity of SCLC before and after chemotherapy. These findings indicate that detection of CADM1v8/9 in serum from patients is a novel and promising approach to detect and follow up SCLC patients. Since CADM1 is highly expressed in cell membrane of SCLC, CADM1 would also provide a promising target for the treatment of SCLC.
Citation Format: Takeshi Ito, Toko Funaki, Goh Tanaka, Takahide Nagase, Yoshinori Murakami. CADM1 is a novel serum marker for small cell lung cancer [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 1129.
Abstract 1164: Targeted next generation sequencing microbiome assay design
Authors: Ewing Aren 
Published: September 2020

Abstract
Background: Targeted Next Generation Sequencing may provide a lower cost approach for characterizing the Microbiome. Sequencing of 16S rRNA is one approach to characterize microbial diversity. However, 16S sequencing alone is often insufficient to gain species level information. Here we describe the design capabilities of targeted sequencing panels comprising both 16S and species-specific primers using Ion AmpliSeqTM technology. These types assay can be used to understand the composition and diversity of the microbiomes at the species level for human health and other applications.
Method:
Our assays include the capability to customize primers to multiple hypervariable regions of the 16S region. However, 16S alone can still be insufficient in distinguishing highly homologous organisms. To address this we can design species-specific primers that provide high strain coverage and high specificity performance. We have developed and tested example assays that include primers for a variety of species identification. With this approach, we can generate reads from sequencing to report taxonomic classifications and relative abundance for organisms in the sample with high specificity and sensitivity.
Results: We designed many a multiplexed Ion AmpliSeqTM assays including 16S targets and species-specific markers targeting important microbial species that can be adapted to new species of interest. This approach is proven as example of our fixed panels including Ion AmpliSeq Microbiome Health research Panel, Pan Bacterial and Anti-Microbial Resistance (AMR) community panels using the Ion Genestudio S5™ system. With the data generated from the species-specific primers, we identified all the targeted species in the ATCC samples at the Species level. We also created mixed population pools using DNA from clonal isolates of different bacterial strains. We are able to identify most microbes at Genus level with 100% sensitivity using 16S alone. We improved the detection resolution to the Species level through the application of our species-specific primers.
Conclusions: Using the Ion AmpliSeq™ technology, we can create highly sensitive and specific assays for robust characterization of microbiota customized to an individual labs needs. This highly multiplexed PCR approach enables an efficient and affordable means for conducting extensive analyses of the microbiomes having applications in the study of the etiology of phenotypic variability.
For research use only. Not for use in diagnostic procedures.
Citation Format: Aren Ewing. Targeted next generation sequencing microbiome assay design [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 1164.
Abstract 1217A: Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells
Authors: Nishimura Sadaaki , Yashiro Masakazu , Sera Tomohiro , Yamamoto Yurie , Sugimoto Atsushi , Kushiyama Shuhei , Togano Shingo , Kuroda Kenji , Okuno Tomohisa , Ohira Masaichi 
Published: September 2020

Abstract
Background: Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. No driver gene responsible for the malignant potential of SGC has not been identified. Next-generation sequencing (NGS) technology has defined as the genomic landscape of various types of cancers, and has elucidated a number of novel driver mutations of gastric cancer. RHOA and CDH1 are characteristic mutations for SGC, but these mutations are not druggable. Novel molecular target therapy has been necessary for SGC based on its biological behavior.
Objective: We sought to identify the characteristic driver gene which is responsible for SGC.
Methods: DNA was isolated from six human SGC cell lines: OUCM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12, and OCUM-14. The mutational status of 90 cancer-associated genes was examined by next-generation sequencing. The expression level of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) in 708 gastric cancers was examined immunochemically, and the correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were analyzed.
Results: The nonsynonymous mutations of STK11/LKB1 gene were found in three of the six SGC cell lines. Nonsense mutation of STK11/LKB1, which was associated with STK11/LKB1 loss (Y253*), was found in OCUM-12 cells, and missense mutation of STK11/LKB1 (F354L) was found in OCUM-2M cells and OCUM-14 cells. Rapamycin, an inhibitor of STK11/ AMP-activated protein kinase (AMPK)/mammalian target of rapamycin signaling (mTOR), showed inhibitory effects of SGC cells harboring STK11/LKB1 mutation. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth, and nodal involvement, in compared to the high STK11/LKB1 expression group. The 5-year survival rate of patients with low STK11/LKB1 expression was significantly poorer compared to those with high STK11/LKB1 expression (p&lt;0.001). A conditional multivariate analysis showed that STK11/LKB1 expression status was an independent prognostic factor.
Conclusion: SGC cells frequently showed the nonsynonymous mutations of STK11/LKB1. STK11/LKB1 mutation might be responsible for the malignant potential of SGC. STK11/AMPK/mTOR signaling might be one of the therapeutic targets for patients with SGC.1
Citation Format: Sadaaki Nishimura, Masakazu Yashiro, Tomohiro Sera, Yurie Yamamoto, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Kenji Kuroda, Tomohisa Okuno, Masaichi Ohira. Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric 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 1217A.
Abstract 1218: Pimavanserin induces autophagy mediated apoptosis in pancreatic cancer and suppresses pancreatic tumor growth
Authors: Ramachandran Sharavan , Srivastava Sanjay K. 
Published: September 2020

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 can lead 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 apoptosis and reduced the proliferation of pancreatic cancer cells with IC50 ranging between 3-9µM after 24, 48 and 72 hours of treatment. In addition, PVT inhibited the colony formation of pancreatic cancer cells. Treatment of pancreatic cancer cells with increasing concentrations of PVT resulted in a concentration-dependent increase in autophagy as evaluated by acridine orange assay by flow cytometry. PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, LC3B and p62 in a concentration-dependent manner in several pancreatic cancer cells. Apoptotic effects of PVT in pancreatic cancer cells was validated by increase in cleavage of caspase3 and PARP. 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 orthotopicaly implanted PANC1 tumors by 75%. Autophagy and apoptosis was confirmed in the tumors of PVT treated mice by immunohistochemistry and western blotting. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Moreover, long-term administration of PVT did not alter the clinical chemistry parameters like ALT, AST, total serum protein, calcium and albumin. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy and 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. Pimavanserin induces autophagy mediated apoptosis in pancreatic cancer and suppresses pancreatic tumor growth [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 1218.