bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Microbiome and Cancer: Creating Friendly Neighborhoods and Removing the Foes Within
Authors: Parida Sheetal , Sharma Dipali 
Published: November 2020

Abstract
The human body is colonized by the microbial cells that are estimated to be as abundant as human cells, yet their genome is roughly 100 times the human genome, providing significantly more genetic diversity. The past decade has observed an explosion of interest in examining the existence of microbiota in the human body and understanding its role in various diseases including inflammatory bowel disease, neurologic diseases, cardiovascular disorders, and cancer. Many studies have demonstrated differential community composition between normal tissue and cancerous tissue, paving the way for investigations focused on deciphering the cause-and-effect relationships between specific microbes and initiation and progression of various cancers. Also, evolving are the strategies to alter tumor-associated dysbiosis and move it toward eubiosis with holistic approaches to change the entire neighborhood or to neutralize pathogenic strains. In this review, we discuss important pathogenic bacteria and the underlying mechanisms by which they affect cancer progression. We summarize key microbiota alterations observed in multiple tumor niches, their association with clinical stages, and their potential use in cancer diagnosis and management. Finally, we discuss microbiota-based therapeutic approaches.
BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia
Authors: Ramsey Haley E. , Greenwood Dalton , Zhang Susu , Childress Merrida , Arrate Maria P. , Gorska Agnieszka E. , Fuller Londa , Zhao Yue , Stengel Kristy , Fischer Melissa A. , Stubbs Matthew C. , Liu Phillip C.C. , Boyd Kelli , Rathmell Jeffrey C. , Hiebert Scott W. , Savona Michael R. 
Published: November 2020

Abstract

Purpose:
The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity.

Experimental Design:
INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line–derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models.

Results:
INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity.

Conclusions:
Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.
Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional Analyses
Authors: Aggen David H. , Ager Casey R. , Obradovic Aleksandar Z. , Chowdhury Nivedita , Ghasemzadeh Ali , Mao Wendy , Chaimowitz Matthew G. , Lopez-Bujanda Zoila A. , Spina Catherine S. , Hawley Jessica E. , Dallos Matthew C. , Zhang Cheng , Wang Vinson , Li Hu , Guo Xinzheng V. , Drake Charles G. 
Published: November 2020

Abstract

Purpose:
Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, IL1β may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types.

Experimental Design:
Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL1β plus either anti-PD-1 or the multitargeted tyrosine kinase inhibitor (TKI), cabozantinib. We performed comprehensive immune profiling of established RENCA tumors via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing (RNA-seq). Similar analyses were extended to the MC38 tumor model.

Results:
Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA-seq showed that anti-IL1β reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1β plus anti-PD-1 or cabozantinib showed increased antitumor activity that was associated with decreases in immunosuppressive MDSCs and increases in M1-like TAMs.

Conclusions:
Single-cell RNA-seq analyses show that IL1β blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell–independent mechanisms. IL1β is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers
Authors: Tsang Erica S. , Grisdale Cameron J. , Pleasance Erin , Topham James T. , Mungall Karen , Reisle Caralyn , Choo Caleb , Carreira Marcus , Bowlby Reanne , Karasinska Joanna M. , MacMillan Daniel , Williamson Laura M. , Chuah Eric , Moore Richard A. , Mungall Andrew J. , Zhao Yongjun , Tessier-Cloutier Basile , Ng Tony , Sun Sophie , Lim Howard J. , Schaeffer David F. , Renouf Daniel J. , Yip Stephen , Laskin Janessa , Marra Marco A. , Jones Steven J.M. , Loree Jonathan M. 
Published: November 2020

AbstractPurpose:Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.Experimental Design:Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.Results:In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1).Conclusions:Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia
Authors: Nagler Arnon , Labopin Myriam , Dholaria Bhagirathbhai , Angelucci Emanuele , Afanasyev Boris , Cornelissen Jan J. , Sica Simona , Meijer Ellen , Ciceri Fabio , Van Gorkom Gwendolyn , Kröger Nicolaus , Martin Hans , Pioltelli Pietro , Risitano Antonio , Canaani Jonathan , Savani Bipin N. , Sanz Jaime , Mohty Mohamad 
Published: November 2020

AbstractPurpose:Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor.Experimental Design:We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy.Results:The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P &lt; 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P &lt; 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2–4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival.Conclusions:The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
Immune Infiltrate in the Primary Tumor Predicts Effect of Adjuvant Radiotherapy in Breast Cancer; Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Puttonen Henri A.J. , Sjöström Martin , Holmberg Erik , Chang S. Laura , Feng Felix Y. , Speers Corey , Pierce Lori J. , Lundstedt Dan , Killander Fredrika , Niméus Emma , Kovács Anikó , Karlsson Per 
Published: November 2020

Abstract

Purpose:
Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze whether the immune infiltrate predicts benefit from postoperative radiotherapy in a large randomized breast cancer radiotherapy trial.

Experimental Design:
In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast-conserving surgery (BCS) and postoperative radiotherapy or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods: IHC and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8+ T cells and FOXP3+ T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral and protumoral immune cells, respectively.

Results:
An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant radiotherapy. The interaction between radiotherapy and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses (P = 0.039 and P = 0.035) and was also significant for ipsilateral breast tumor recurrence in the gene expression analyses (P = 0.025).

Conclusions:
Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant radiotherapy. These results may impact decisions regarding postoperative radiotherapy in early breast cancer.
Screening for Pancreatic Ductal Adenocarcinoma: Are We Asking the Impossible?
Authors: Caldwell Katharine E. , Conway Alexander P. , Hammill Chet W. 
Published: November 2020

Abstract
Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. Because of this, significant interest and research funding has been devoted to development of a screening test to identify individuals during a prolonged asymptomatic period; however, to date, no such test has been developed. We evaluated current NIH spending and clinical trials to determine the focus of research on pancreatic cancer screening as compared with other cancer subtypes. Using statistical methodology, we determined the effects of population-based pancreatic cancer screening on overall population morbidity and mortality. Population-based pancreatic cancer screening would result in significant harm to non-diseased individuals, even in cases where a near-perfect test was developed. Despite this mathematical improbability, NIH funding for pancreatic cancer demonstrates bias toward screening test development not seen in other cancer subtypes. Focusing research energy on development of pancreatic screening tests is unlikely to result in overall survival benefits. Efforts to increase the number of patients who are candidates for surgery and improving surgical outcomes would result in greater population benefit.
Prevention Relevance: For patients with pancreatic cancer, early stage detection offers the greatest survival benefit. However, the incidence of pancreatic cancer and associated mortality of pancreatic resections make development of a screening test a difficult, if not impossible, challenge.
Efeito em curto prazo de dois protocolos de hidrocinesioterapia em crianças com síndrome congênita associada à infecção do vírus Zika
Authors: Monteiro Milena Guimarães , Tavares Netto Afonso Rodrigues , Brito Patrícia Meireles , Santos Amanda Jayse da Silva , Mattos Rebeca Maranhão de , Wesiolek Carine Carolina , Lambertz Karla Mônica Ferraz 
Published: November 2020

Objetivo: Avaliar o efeito em curto prazo de dois protocolos de hidrocinesioterapia sobre o tônus muscular e o nível de estresse de crianças com SCZ. Métodos: Estudo cruzado, randomizado e cego, com crianças com microcefalia/SCZ entre 3-36 meses de idade. O tônus foi avaliado pela Escala Modificada de Tardieu(EMT), analisando-se o grau de tônus muscular e a amplitude de movimento articular(ADM); o nível de estresse, através de Escala visual analógica de faces variando desde um estado sem estresse (1) até estresse intenso (4). Dois protocolos de hidrocinesioterapia(Protocolo PI e PII) foram aplicados em ambiente aquático restrito, por 15 minutos com temperatura da água a 37ºC. Resultados: Doze crianças participaram do estudo(média de idade em meses: 23,9+3,97), 58,7% do sexo feminino. Após PI, observamos redução do grau de tônus dos músculos extensores de cotovelo(p=0,03) e joelho(p=0,04); em PII, não houve mudanças significativas no grau de tônus. Não houve mudanças significativas no nível de estresse em PI e PII, porém 83,3% se encontravam sem estresse ou estresse leve antes das intervenções. Conclusões: O protocolo I acarretou redução do grau de tônus muscular em curto prazo quando comparado com PII. Enfatiza-se que os protocolos aplicados são de baixo custo, e podem ser uma opção de técnica não farmacológica viável no acompanhamento terapêutico destas crianças. Ressalta-se que a experiência do fisioterapeuta deve guiar a escolha do protocolo adequado para o objetivo terapêutico de cada criança e a vantagem de ser uma técnica facilmente replicável em ambiente terapêutico e domiciliar.
segmentary mechanical work as a new instrument to postural control evaluation
Authors: Castro Pedro Cláudio Gonsales de , Goroso Daniel Gustavo , Coelho Daniel Boari , Lopes José Augusto Fernandes , Ayres Denise Vianna Machado , Battistella Linamara Rizzo 
Published: November 2020

Objectie: Calculate the mechanical work (W), applying the total mechanical work (Wtot) and segmental work (Wseg) as a new complementary evaluation resource of the postural control mechanisms in subjects undergoing motor and visual disturbance. Methods: Ten healthy adult male volunteers were selected with ages 25.6 (±2.26) years, whose height was 1.69 (± 0.25) m and body weight was 68.22 (± 0.25) kg. Kinematic data of trunk extension with eyes open and blindfolded were captured with a frequency of 200 Hz. This way the post perturbation interval has been selected and the Wseg (i.e. trunk, head, etc) and the total mechanical work (Wtot) calculated, which were obtained by means of total integral mechanical energy. Results: The statistical analyzing of information was done by paired-data Student's t test. There has been no significant difference (p<0,08) for the Wtot during the post perturbation interval. On the other hand, there has been a significant difference (p<0.05) in the post perturbation interval of Wseg. However, there were significant differences in interval (p<0.05). This difference is related to Wseg of head (Whead) and lower limbs (Wleg and Wthigh ) in the post-perturbation interval with early range of [0. 60] ms and [0. 100] ms after the self-perturbation. Conclusion: These differences that were found in Whead between the two conditions can be associated with modulations of the vestibulo-ocular-motor system. On the other hand, the differences that were found in Wleg and Wthigh can be associated with somato-sensory adjustment mechanisms.
Traditional Attenuation of Inequality: Neutral Meaning of Body Size among the Yorùbá of Southwestern Nigeria
Authors: Ibrahim Fausat M. , Jegede Ayodele S. 
Published: November 2020

Abstract
Body size is a profound ground of inequality in modern global society. Moreover, constructions of body size are racially polarized, with blacks being reputed for venerating large body. Proceeding with a triangulation of qualitative methods, this phenomenological study featured forty-two in-depth interviews, eight focus group discussions and eighteen key informant interviews among men and women of varying body sizes in two of the six states of southwestern Nigeria. Findings reflect dominantly neutral meaning of body size among the Yorùbá. This neutrality is dominantly reflected in the literal questioning of meaning that Yorùbá attach to body size, and who becomes a king in Yorùbá land but partially neutral in acceptability of prospective son or daughter in-law. Divinity, orí (fate), ìwà (good behavior) and ọmọlúàbí (good person) are among phenomena that counts in discerning people’s worth. Meaning attached to body size is opposed to common-place attitude to body size, making this attitude to be profane while meaning is solemn. This meaning is tremendously in favour of optimum health, and attenuating inequality, for which even black societies are perpetrating in the globalized world. Traditional Yorùbá value of human person is irrespective of body size.
Contributions of cholinergic receptor muscarinic 1 and CYP1A2 gene variants on the effects of plasma ratio of clozapine/N-desmethylclozapine on working memory in schizophrenia
Authors: Islam Farhana , Maciukiewicz Malgorzata , Freeman Natalie , Huang Eric , Tiwari Arun , Mulsant Benoit H , Pollock Bruce G , Remington Gary , Kennedy James L , Müller Daniel J , Rajji Tarek K 
Published: November 2020

Background: Clozapine has heterogenous efficacy in enhancing working memory in schizophrenia. We have previously hypothesized that this is due to opposing effects of clozapine and its metabolite, N-desmethylclozapine, at the muscarinic M1 receptor and demonstrated that a lower clozapine/ N-desmethylclozapine ratio is associated with better working memory than clozapine or N-desmethylclozapine levels alone. Aims: In this study, we expanded the above hypothesis to explore whether genetic variation in the cholinergic receptor muscarinic 1 gene, encoding the M1 receptor, affects the relationship between clozapine/ N-desmethylclozapine and working memory. Further, we explored whether CYP1A2 gene variants affect the ratio of clozapine/ N-desmethylclozapine and by this, working memory performance. Methods: We evaluated two functionally significant single nucleotide polymorphisms, rs1942499 and rs2075748, in cholinergic receptor muscarinic 1, with the haplotype T-A associated with lower transcriptional activity than the haplotype C-G. Further, we examined CYP1A2 *1F, with *1F/*1F conferring high inducibility in the presence of smoking. Results: In a sample of 30 patients with schizophrenia on clozapine monotherapy, clozapine/ N-desmethylclozapine was correlated with working memory only in non-carriers of the haplotype T-A of the cholinergic receptor muscarinic 1 gene. Interaction of CYP1A2 genotype and smoking status significantly affected clozapine concentrations, but there were no significant effects of CYP1A2 genotype and smoking status on the relationship between clozapine/ N-desmethylclozapine on working memory. Conclusions: Our finding that the relationship between clozapine/ N-desmethylclozapine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of cholinergic receptor muscarinic 1) supports a cholinergic mechanism underlying this relationship.
Elevated serum granzyme B levels are associated with disease activity and joint damage in patients with rheumatoid arthritis
Authors: Qiao Junjie , Zhou Meng , Li Zheng , Ren Jie , Gao Guanghan , Zhen Jumei , Cao Guanglei , Ding Lixiang 
Published: November 2020

Objectives Little is known about the roles of granzyme B in rheumatoid arthritis (RA). We aimed to evaluate the serum level of granzyme B in patients with RA and determine relationships with clinical features and joint destruction of RA. Methods We enrolled 100 patients with RA, 50 patients with osteoarthritis (OA), and 50 healthy controls (HC). Granzyme B serum concentrations were measured by ELISA; we then analyzed associations between granzyme B levels, clinical features, and joint destruction by calculating Sharp scores and disease activity as measured by Disease Activity Score-28 based on erythrocyte sedimentation rate (DAS28-ESR) in patients with RA. Results Compared with HC and patients with OA, serum granzyme B levels in patients with RA were remarkably elevated. Serum granzyme B levels did not differ between patients with OA and HC. Granzyme B levels correlated with ESR, rheumatoid factor, swollen joint counts, joint erosion scores, total Sharp scores, and DAS28-ESR. Moreover, patients with RA with high disease activity had higher granzyme B levels. Conclusions Serum granzyme B levels were elevated significantly in patients with RA and correlated positively with disease activity and joint destruction. Serum granzyme B may have potential applications in laboratory evaluation of patients with RA.
Market differences and adjustment speed of debt, equity, and debt maturity
Authors: Tekin Hasan 
Published: November 2020

This article investigates the role of market differences and the global financial crisis 2007–2009 (GFC) on the adjustment speed of debt issuance, equity issuance, and debt maturity. The sample of 9731 firm-years from highly regulated Main Market (MAIN) and slightly unregulated Alternative Investment Market (AIM) in the United Kingdom was used. Employing system generalized methods of moments, the findings show that AIM firms have a faster adjustment speed of debt and equity before the GFC than MAIN firms. However, it is vice versa after the GFC because AIM firms face greater problems in accessing finance due to the shrinkage of bank credits during the recession. Besides, MAIN firms have faster adjustments on long-term debt over the time, whereas AIM firms have faster adjustment speed of trade credits. Overall, investors should consider market differences and recessions to take accurate decisions on debt-equity and debt maturity to invest where and when. JEL Classification: C26, G01, G32