tbuckley/cabot-search huggingface dataset:
The intrinsic mitochondrial membrane potential (ΔΨm) impacts the viability of colonic epithelial cells grown under adherence-compromised and hypoxia mimicking conditions.
Authors: Barbara G. Heerdt, Michele A. Houston, Leonard H. Augenlicht
Journal: Cancer Research (2004)

2439  Previous studies have linked transformation of colonic epithelial cells to decreased mitochondrial activity, increased mitochondrial membrane potential (ΔΨm) and defects in proliferation and apoptotic pathways. Using novel isogenic colonic carcinoma cell lines that exhibit stable variations in their intrinsic ΔΨm, we recently demonstrated the significant effect of the ΔΨm on steady state mitochondrial activity and the initiation and integration of growth arrest and apoptotic cascades. Based on these findings, we have proposed an important role for the intrinsic ΔΨm in influencing the probability of colonic tumorigenesis and progression (Heerdt BG, Houston MA, Wilson AJ and Augenlicht LH, Cancer Res. 63: 6311, 2003; Augenlicht LH and Heerdt BG, Nature Genetics, 28:104, 2001; Heerdt BG, Houston MA, Anthony GM and Augenlicht LH, Cancer Res. 58: 2869, 1998). To further dissect this role we have investigated the effect of the intrinsic ΔΨm on the growth properties of colonic epithelial cells. Here we report that although the differences in ΔΨm exhibited by the isogenic cell lines do not effect cell growth under adherent conditions, the intrinsic ΔΨm has a significant impact on the viability of cells grown under adherence-compromised and hypoxia mimicking conditions. Since adherence-independent growth and survival in a hypoxic environment can act as selective pressures for tumor expansion, these data support a role for the intrinsic ΔΨm in defining the probability of colonic tumor formation and progression.
Erratum: Grams ME, Sang Y, Ballew SH, et al, for the Chronic Kidney Disease Prognosis Consortium. Predicting timing of clinical outcomes in patients with chronic kidney disease and severely decreased
Authors: Brad C. Astor, Lawrence J. Appel, Adeera Levin, Mila Tang, Ognjenka Djurdjev, Sankar D. Navaneethan, Stacey E. Jolly, Jesse D. Schold, Joseph V. Nally, David C. Wheeler
Journal: Kidney International (2018)
2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases
Authors: Victoria Furer, Christien Rondaan, Marloes W Heijstek, Nancy Agmon-Levin, Sander van Assen, Marc Bijl, Ferry C Breedveld, Raffaele D"Amelio, Maxime Dougados, Meliha Crnkic Kapetanovic, Jacob M van Laar, A de Thurah, Robert BM Landewé, Anna Molto, Ulf Müller-Ladner, Karen Schreiber, Leo Smolar, Jim Walker, Klaus Warnatz, Nico M Wulffraat, Ori Elkayam
Journal: Annals of the Rheumatic Diseases (2019)

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.
Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression
Authors: Hiromi I. Wettersten, Sara M. Weis, Paulina Pathria, Tami Von Schalscha, Toshiyuki Minami, Judith A. Varner, David A. Cheresh
Journal: Cancer Research (2019)

Abstract Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the coenrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 “don't eat me” signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers. Significance: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvβ3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.
Treatment patterns in men with castration-resistant prostate cancer receiving docetaxel.
Authors: Keith L. Davis, Benjamin Gutierrez, Teresa Maria Zyczynski, James A. Kaye
Journal: Journal of Clinical Oncology (2012)

e15165 Background: Docetaxel has been a standard of care for castration-resistant prostate cancer (CRPC) in the US since 2004 (TAX 327), yet little has been reported on its patterns of use in routine practice. To help understand these patterns, a retrospective study was conducted and is reported here. Methods: Medical records from 394 patients treated in the US were reviewed: 48 from oncology (N=344) and 8 from urology (N=50) practices. Inclusion criteria were: CRPC diagnosed between 2004 and 2010; received docetaxel; discontinued docetaxel due to rising PSA, progression of bone lesions, or progression of nodal or visceral metastases. Data were collected from physicians using an internet-based case report form. We evaluated patient demographics, characteristics of the docetaxel regimen and other treatments used until docetaxel discontinuation. Results: Patients had a mean [±SD] age of 66.5 [8.9] years, the majority (63%) were white, and geographic dispersion was similar to the US population. The majority of patients initiated docetaxel between 2008 and 2010. After CRPC diagnosis, 8% of patients initiated another cancer-directed therapy before starting docetaxel. Most (78.9%) patients initiated docetaxel with prednisone, while 18.5% initiated docetaxel alone and 2.6% initiated with other drugs. Half of patients initiated docetaxel within 1 month after CRPC diagnosis, while 25% started ≥6 months later. Other non-chemotherapy treatments used with docetaxel were hormonal therapy (22.8%), radiotherapy (17.3%), and surgery (4.1%). Most patients (75%) received ≥4 docetaxel cycles, half received ≥6 cycles, 25% received ≥8 cycles and 10% received ≥10 cycles. Increased tumor mass, with/without new bone lesions or rising PSA, was the most common reason for docetaxel discontinuation (74% of patients). Conclusions: Concordant with guidelines, docetaxel and prednisone was the preferred first-line chemotherapy regimen in CRPC patients. However, one quarter of patients did not initiate docetaxel until ≥6 months after CRPC diagnosis and total exposure varied considerably, with only 10% receiving ≥10 cycles. Future studies are needed to describe specific reasons for docetaxel delay and sub-maximal exposure in some CRPC patients.
Efficacy of oral amoxicillin–clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial
Authors: Vikas Goyal, Keith Grimwood, Robert S Ware, Catherine A Byrnes, Peter S Morris, I Brent Masters, Gabrielle B McCallum, Michael J Binks, Heidi Smith-Vaughan, Kerry-Ann F O'Grady, Anita Champion, Helen M Buntain, André Schultz, Mark Chatfield, Paul J Torzillo, Anne B Chang
Journal: The Lancet Respiratory Medicine (2019)
Assessment of Machine Learning of Breast Pathology Structures for Automated Differentiation of Breast Cancer and High-Risk Proliferative Lesions
Authors: Ezgi Mercan, Sachin Mehta, Jamen Bartlett, Linda G. Shapiro, Donald L. Weaver, Joann G. Elmore
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Following recent US Food and Drug Administration approval, adoption of whole slide imaging in clinical settings may be imminent, and diagnostic accuracy, particularly among challenging breast biopsy specimens, may benefit from computerized diagnostic support tools. <h3>Objective</h3> To develop and evaluate computer vision methods to assist pathologists in diagnosing the full spectrum of breast biopsy samples, from benign to invasive cancer. <h3>Design, Setting, and Participants</h3> In this diagnostic study, 240 breast biopsies from Breast Cancer Surveillance Consortium registries that varied by breast density, diagnosis, patient age, and biopsy type were selected, reviewed, and categorized by 3 expert pathologists as benign, atypia, ductal carcinoma in situ (DCIS), and invasive cancer. The atypia and DCIS cases were oversampled to increase statistical power. High-resolution digital slide images were obtained, and 2 automated image features (tissue distribution feature and structure feature) were developed and evaluated according to the consensus diagnosis of the expert panel. The performance of the automated image analysis methods was compared with independent interpretations from 87 practicing US pathologists. Data analysis was performed between February 2017 and February 2019. <h3>Main Outcomes and Measures</h3> Diagnostic accuracy defined by consensus reference standard of 3 experienced breast pathologists. <h3>Results</h3> The accuracy of machine learning tissue distribution features, structure features, and pathologists for classification of invasive cancer vs noninvasive cancer was 0.94, 0.91, and 0.98, respectively; the accuracy of classification of atypia and DCIS vs benign tissue was 0.70, 0.70, and 0.81, respectively; and the accuracy of classification of DCIS vs atypia was 0.83, 0.85, and 0.80, respectively. The sensitivity of both machine learning features was lower than that of the pathologists for the invasive vs noninvasive classification (tissue distribution feature, 0.70; structure feature, 0.49; pathologists, 0.84) but higher for the classification of atypia and DCIS vs benign cases (tissue distribution feature, 0.79; structure feature, 0.85; pathologists, 0.72) and the classification of DCIS vs atypia (tissue distribution feature, 0.88; structure feature, 0.89; pathologists, 0.70). For the DCIS vs atypia classification, the specificity of the machine learning feature classification was similar to that of the pathologists (tissue distribution feature, 0.78; structure feature, 0.80; pathologists, 0.82). <h3>Conclusion and Relevance</h3> The computer-based automated approach to interpreting breast pathology showed promise, especially as a diagnostic aid in differentiating DCIS from atypical hyperplasia.
Infographic. Wake up and smell the coffee: caffeine supplementation and exercise performance
Authors: Jozo Grgic, Ivana Grgic, Craig Pickering, Brad J Schoenfeld, David John Bishop, Adam Virgile, Zeljko Pedisic
Journal: British Journal of Sports Medicine (2019)

Caffeine has been used as a performance-enhancing aid by athletes for many years. The first known study to explore the effects of caffeine ingestion on exercise performance dates back to 1907.1 Until recently, however, findings on this topic remained equivocal, despite a large number of published studies over the last 30 to 40 years.2 There are many possible reasons for the discrepant results between these studies, but one likely issue could be a common use of relatively small samples. To reconcile the equivocal evidence on this topic and overcome the low statistical power of individual studies, researchers have started to use meta-analytical methods. Meta-analysis is a statistical method that allows pooling of results from studies that address a similar research question.3 

Given that meta-analytical …
A successful prime-boost immunization strategy in a tumor model: Targeting tyrosinase in melanoma
Authors: Stacie M. Goldberg, Jose A. Guevara-Patino, Jason P. Gardner, Stephanie C. Montgomery, Miguel-Angel Perales, Gerald P. Donovan, William C. Olson, Jedd D. Wolchok
Journal: Cancer Research (2004)

1260  Background: Immunization with plasmid DNA encoding xenogeneic orthologues of differentiation antigens is a means to overcome immunologic tolerance to these otherwise poorly immunogenic self antigens. Previously, we have shown that immunization of C57BL/6 mice with human tyrosinase-related proteins 1 and 2 results in the induction of either antibody or CD8+ T-cell responses (respectively), capable of protecting mice from challenge with syngeneic B16 melanoma. In the current study, we investigated immunization of mice with xenogeneic human tyrosinase DNA and have found that while this induces both antibodies and T-cells, it provides only minimal tumor protection. One strategy that has been successfully employed in infectious disease models is heterologous prime-boost immunization in which recombinant viral vectors are used to boost the DNA vaccine encoding the same antigen. Methods: We first determined the optimal regimen of plasmid DNA alone to be used for priming. Then, using a replication-deficient alphavirus vector (AVV), we tested different combinations of priming with DNA or AVV and then boosting with AVV to examine the effect on antibody production, T-cell response, and tumor protection. Results: Using DNA alone, we found that T-cell responses to newly identified mouse tyrosinase epitopes were generated only when mice were immunized with the xenogene (human tyrosinase). In addition, T-cell responses increased with repeated doses of DNA. In contrast, potent antibody and T-cell responses were induced when alphavirus vectors encoding either mouse or human tyrosinase were used as single agents and a significant delay in tumor growth was observed. Similarly, a heterologous prime-boost regimen utilizing DNA prime and virus boost showed a more marked protection from tumor challenge over DNA vaccination alone. Conclusions: We have demonstrated that alphavirus vectors encoding self or xenogeneic tumor antigens induce potent immune responses and tumor protection when administered either alone or in a heterologous prime-boost approach following DNA priming.
Transcriptional regulation and prostate cancer risk loci.
Authors: Robert J. Klein, Xing Xu, Wasay Hussain, James Farber, Riina-Minna Vaananen, Pekka Taimen, Joseph Vijai, James E. Hayes, Hans Lilja, Kim Pettersson, Mark A. Rubin, Francesca Demichelis, Kenneth Offit
Journal: Journal of Clinical Oncology (2013)

1554 Background: While genome-wide association studies (GWAS) have identified numerous loci at which common single nucleotide polymorphisms (SNPs) are clearly associated with the risk of developing prostate cancer, the mechanism by which these variants influence disease is not clear. Based on the observation that regions of the genome with marks of transcriptional regulatory elements harbor SNPs that are more likely to be under negative selective pressure, we hypothesized that many prostate cancer associated SNPs, or their correlated proxies in linkage disequilibrium, function by altering regulation of nearby genes through alteration of transcription factor binding sites. Two predictions of this hypothesis are that there will be an enrichment of prostate cancer risk SNPs or their proxies in regulatory elements in prostate tissue and that some of these SNPs will correlate with the expression levels of nearby genes. Methods: To test the first prediction, we compared the number of prostate cancer risk SNPs (or their proxies) that overlap with DNase hypersensitive sites in the LNCaP prostate cancer cell line with randomly selected SNPs matched for allele frequency, distance from nearby genes, and local gene density. To test the second prediction, we asked if any of the known prostate cancer risk SNPs are associated with mRNA expression levels of nearby genes. Results: We found a four-fold enrichment of real prostate cancer risk SNPs overlapping with DNase hypersensitive sites versus the random set (p=0.03) at an r 2 threshold of 0.95. In both tumor and benign prostate tissue, we found that a recently identified prostate cancer risk SNP is associated with expression levels of IRX4, a transcription factor previously implicated only in cardiac development. Conclusions: These data support the hypothesis that many GWAS-identified risk SNPs alter transcriptional regulation of nearby genes.
The global identification of non coding RNA regulated by p53
Authors: Reo Maruyama, Minoru Toyota, Fumio Aoki, Yasushi Sasaki, Hiromu Suzuki, Hirofumi Akashi, Hiroaki Mita, Masashi Idogawa, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino
Journal: Cancer Research (2007)

4433  Transcription of p53 target genes is controlled by binding of p53 to its response element (p53RE). We have been extracted all p53REs in the human and mouse genome and developed our own p53RE database. We succeeded in predicting and identifying novel p53 target genes using comparative genomic approach (Cancer Res, 2006). Recently non protein coding RNA (including micro RNA) has gotten a lot of attention and some research shows that even a half of all transcript in the mouse is non-protein coding RNA. In this study, focusing on the new area of transcript, we try to identify non coding RNAs (ncRNAs) which are regulated by p53 using whole genome in silico analysis.  To this end, we first determined 21,744 regions for analysis using public EST and gene annotation database available. These regions are functionally unknown and include many transcripts whose ORF are too short to code proteins. We next used our own p53RE database to get 55,807 p53REs which are located within 10kb of the putative transcription start sites of these regions. Then we evaluated the value of each p53RE by its sequence, location, conservation and so on. Finally we predicted 66 putative targets considering all the various factors together.  To assess the validity of the p53 target genes predicted by the computational analysis, their responsiveness to p53 was examined by RT-PCR and real time RT-PCR in several cancer cell lines. Sixteen genes were up-regulated by p53.  Among them, we focused on one gene and further analyzed its function. We confirmed that the gene is transcriptionaly upregulated by p53 by ChIP assay and reporter assay and the gene is upregulated by exogenous and endogenous p53 induction in several cell lines. Furthermore, its overexpression slightly suppressed colony growth in several cancer cell lines, therefore the gene might have potential tumor suppressive function. Interestingly, the gene has no ORF long enough for coding protein, so it might be functional ncRNA. We have found a lot of ncRNAs regulated by p53, and functional analysis is currently underway. We would like to introduce some new findings in this meeting.
MESNA (2-mercaptoethane sulfonate) is effective in inducing lymphocyte progression through cell cycle in patients with advanced cancer of different sites
Authors: Clelia Madeddu, Roberto Serpe, Giulia Gramignano, Antonio Macciò, Giovanni Mantovani
Journal: Cancer Research (2006)

3884  Objective This study aimed to assess the ability of intravenous (i.v.) formulation of 2-mercaptoethane sulfonate (MESNA) and MESNA oral formulation (ATC V034AF01), when added into cultures of peripheral blood mononuclear cells (PBMCs) isolated from advanced stage cancer patients (pts) to induce PBMCs progression through the cell cycle, namely from G0/G1 to S phase. The ability of MESNA was compared to the antioxidants Alpha Lipoic Acid (ALA) and N-Acetyl Cysteine (NAC) the efficacy of which was demonstrated in our previously published studies. Additionally, we assessed the most significant clinical indexes of disease progression such as stage and ECOG-PS and the biological parameters of cancer cachexia (IL-1β, IL-6, TNFα, C-reactive protein CRP, fibrinogen, leptin) and of oxidative stress (OS), such as reactive oxygen species (ROS) and Glutathione Peroxidase (GPx). Patients and Methods Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs, isolated from 35 stage IV cancer pts with tumors at different sites and 10 controls, with or without ALA 0.001 mM or NAC 0.004 mM or i.v. formulation MESNA or ATC V034AF01 (the last two at concentrations of 1000, 750, 500, 350, 200 μM) was studied. The concentrations used of i.v. formulation MESNA or ATC V034AF01 were in the same range of those achievable in the plasma (approximately 350 μM) after in vivo administration. Results Either i.v. formulation MESNA (350 μM) or ATC V034AF01 (at all concentrations tested) enhanced significantly the progression from G0/G1 to S phase of cancer PBMCs, whilst no significant effect was observed on control PBMCs. We also confirmed the ability of ALA or NAC to enhance significantly the cell cycle progression of cancer PBMCs. The addition into cultures of ATC V034AF01 (350 μM) induced a cell cycle progression from G0/G1 to S phase significantly higher (+ 46.57%) in comparison to that induced by i.v. formulation MESNA 350 μM (+10.84%), ALA (+10.31%) and NAC (+13.16%). Moreover, IL-1 β, IL- 6, TNFα, CRP, fibrinogen and ROS were significantly higher whereas leptin and GPx were significantly lower in cancer pts than controls. Baseline leptin correlated positively, whilst IL-1β, IL-6 and TNFα correlated negatively, with the extent of the increase of PBMCs entering into S phase when stimulated with antioxidants. Conclusion Advanced cancer pts exhibit both a high grade OS and an immune impairment similar to that observed in chronic inflammation. Both i.v. formulation MESNA and ATC V034AF01 enhanced significantly the progression from G0/G1 to S phase of cancer PBMCs, thus suggesting their potential role in the functional restoration of the immune system in advanced cancer pts. Our data warrant clinical investigations with MESNA both i.v. and orally in adequate clinical trials with the aim to reverse cancer-related immune impairment. Supported by: MIUR, NRP No. 2004067078, Rome, Italy.
Low Peripheral Blood NK Cell Count Is Associated with Worse Clinical Outcome in Patients with Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: Results from the Frontline Phase 3 GALLIUM and GOYA Trials
Authors: Magdalena Klanova, Mikkel Z. Oestergaard, Marek Trněný, Wolfgang Hiddemann, Robert Marcus, Laurie H. Sehn, Umberto Vitolo, Alexandra Bazeos, Valentin Goede, Harald Zeuner, Andrea Knapp, Denis Sahin, Nathalie Danesi, Christopher Bolen, Susan Robson, Jeffrey M. Venstrom, Tina Nielsen, Günter Fingerle-Rowson
Journal: Blood (2017)