tbuckley/cabot-search huggingface dataset:
Quality of life: a deconstruction for clinicians
Authors: M. Koller, W. Lorenz
Journal: Journal of the Royal Society of Medicine (2002)

Quality of life has been an issue in medical research for more than twenty years1, and many authorities now regard it as a key measurement in clinical trials2,3. Yet the concept remains controversial. In the clinical world, scepticism is exemplified by a comment by Wulff in the JRSM:


‘Scientists may use rating scales and visual analogue scales to measure pain, and they may even invent scoring systems quantifying types of handicaps; but when they talk about measuring quality of life they have gone too far’4.


This statement reflects a two-world model of medicine and of human experience in which objective facts are clearly distinguished from subjective values4,5. It can be seen as a reaction to the World Health Organization's concept of health and of quality of life that invites us to mix facts and values non-systematically:


‘Quality of life is defined as an individual's perception of their position in life in the context of the culture and value system in which they live and in relation to their goals, expectations and standards and concerns. It is a broad ranging concept affected in a complex way by the person's physical health, psychological state, level of independence, social relationships, and their relationship to salient features of their environment’6.
Visual prediction: Psychophysics and neurophysiology of compensation for time delays
Authors: Romi Nijhawan
Journal: Behavioral and Brain Sciences (2008)

A necessary consequence of the nature of neural transmission systems is that as change in the physical state of a time-varying event takes place, delays produce error between the instantaneous registered state and the external state. Another source of delay is the transmission of internal motor commands to muscles and the inertia of the musculoskeletal system. How does the central nervous system compensate for these pervasive delays? Although it has been argued that delay compensation occurs late in the motor planning stages, even the earliest visual processes, such as phototransduction, contribute significantly to delays. I argue that compensation is not an exclusive property of the motor system, but rather, is a pervasive feature of the central nervous system (CNS) organization. Although the motor planning system may contain a highly flexible compensation mechanism, accounting not just for delays but also variability in delays (e.g., those resulting from variations in luminance contrast, internal body temperature, muscle fatigue, etc.), visual mechanisms also contribute to compensation. Previous suggestions of this notion of "visual prediction" led to a lively debate producing re-examination of previous arguments, new analyses, and review of the experiments presented here. Understanding visual prediction will inform our theories of sensory processes and visual perception, and will impact our notion of visual awareness.
Expression and functional significance of Twist1 in hepatocellular carcinoma: Its role in vasculogenic mimicry
Authors: Tao Sun, Nan Zhao, Xiu-lan Zhao, Qiang Gu, Shi-wu Zhang, Na Che, Xing-hui Wang, Jing Du, Yi-xin Liu, Bao-cun Sun
Journal: Hepatology (2009)

The up-regulation and nuclear relocation of epithelial-mesenchymal transition (EMT) regulator Twist1 have been implicated in the tumor invasion and metastasis of human hepatocellular carcinoma (HCC). The term vasculogenic mimicry (VM) refers to the unique capability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. However, the relationship between Twist1 and VM formation is not clear. In this study, we explored HCC as a VM and EMT model in order to investigate the role of Twist1 in VM formation. We first examined the expression of Twist1 in human HCC samples and cell lines and found that Twist1 was frequently overexpressed in the nuclear relocation occurring in VM-positive HCCs (13/18 [72%]). Twist1 nuclear expression was likewise significantly associated with VM formation. Clinicopathological analysis revealed that both VM and Twist1 nuclear expressions present shorter survival durations than those without expression. We consistently demonstrated that an overexpression of Twist1 significantly enhanced cell motility, invasiveness, and VM formation in an HepG2 cell. Conversely, a knockdown of Twist1 by the short hairpin RNA approach remarkably reduced Bel7402 cell migration, invasion, and VM formation. Using chromatin immunoprecipitation, we also showed that Twist1 binds to the vascular endothelial (VE)-cadherin promoter and enhances its activity in a transactivation assay.The results of this study indicate that Twist1 induces HCC cell plasticity in VM cells more through the suppression of E-cadherin expression and the induction of VE-cadherin up-regulation than through the VM pattern in vivo and in a three-dimensional in vitro system. Our findings also demonstrate a novel cogitation in cancer stem-like cell differentiation and that related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis.
Chemoprevention of Breast Cancer
Authors: Joyce A. O'Shaughnessy
Journal: JAMA (1996)

<h3>CASE REPORT</h3> A 46-year-old woman was found on mammography to have a solid 1-cm mass in her right breast. Excisional biopsy identified a fibroadenoma, and 3 foci of cribriform ductal carcinoma in situ (DCIS) with necrosis were incidentally noted, in addition to areas of lobular neoplasia and atypical ductal hyperplasia (ADH). The surgical margins were clear of DCIS, and her right breast was treated with radiotherapy. This patient's 50-year-old sister had recently been diagnosed with breast cancer. With lobular and ductal neoplasia placing this patient at increased risk of developing breast cancer in her other breast, the patient questioned her physicians regarding the appropriateness of her taking tamoxifen as a chemopreventive agent and whether any genetic studies could be done on her breast tissue to more accurately predict the risk of her developing a second malignancy. The biopsy showed that this woman is at high risk for developing breast cancer
Obesity and Cancer: A Gut Microbial Connection
Authors: Naoko Ohtani, Shin Yoshimoto, Eiji Hara
Journal: Cancer Research (2014)

Multiple epidemiological studies have revealed that excess bodyweight, such as in people who are overweight or obese (defined by a body mass index higher than 25 kg/m(2)), is a major risk factor for not only diabetes and cardiovascular diseases but also cancer. Effective strategies for obesity prevention are therefore needed for cancer prevention. However, because the prevalence of excess bodyweight in most developed countries has been increasing markedly over the past several decades, with no signs of abating, alternative approaches are also required to conquer obesity-associated cancer. Therefore, we sought to understand the molecular mechanisms underlying obesity-associated cancer. Although several phenomena have been proposed to explain how obesity increases cancer risk, the exact molecular mechanisms that integrate these phenomena have remained largely obscure. Recently, we have traced the association between obesity and increased cancer risk to gut microbiota communities that produce a DNA-damaging bile acid. The analyses also revealed the role of cellular senescence in cancer, which we have been studying for the past few decades. In this review, we provide an overview of our work and discuss the next steps, focusing on the potential clinical implications of these findings.
Inflammatory bowel disease in pregnancy
Authors: E M Alstead
Journal: Gut (2003)

Women and men with inflammatory bowel disease (IBD) frequently express concerns about fertility and pregnancy. The evidence suggests that women with IBD can expect to have a normal pregnancy outcome provided they have inactive disease. They have an increased risk of having a small or premature baby but the majority will have a normal outcome of pregnancy. The commonly used drugs appear to be safe and well tolerated in pregnancy. There remains a need for further studies in this area to help in the difficult decisions about the management of IBD around the time of conception and during pregnancy.
Molecular determinants of responses to myocardial ischemia/reperfusion injury: focus on hypoxia-inducible and heat shock factors
Authors: N Chi
Journal: Cardiovascular Research (2004)

During the past several years much new evidence has accumulated regarding the molecular and biochemical mechanisms underlying cardiac responses to hypoxia and to ischemia/reperfusion injury. Studies have involved cell culture, and ex vivo and in vivo preparations. This review focuses on regulation of two transcription factors that are thought to be important in these processes, hypoxia-inducible factor1α (HIF-1α) and heat shock factor (HSF). Both of these molecules are expressed acutely and chronically in response to hypoxia and ischemia/reperfusion, and both have numerous targets that comprise part of integrated response to ischemic injury aimed at promoting cell survival. Emphasis is placed on new mechanisms of action that regulate HIF-1α, HSF, and heat shock proteins as key responses to hypoxia and ischemia, and possible approaches to therapy based on these data are discussed.
A novel TNFRSF1A splice mutation associated with increased nuclear factor appaB (NF- B) transcription factor activation in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS)
Authors: S M Churchman, L D Church, S Savic, L R Coulthard, B Hayward, B Nedjai, M D Turner, R J Mathews, E Baguley, G A Hitman, H C Gooi, P M D Wood, P Emery, M F McDermott
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To characterise and investigate the functional consequences of a novel <i>TNFRSF1A</i> splice site mutation causing tumour necrosis factor receptor associated periodic syndrome (TRAPS) in a 16-year-old male patient and his mother. <h3>Methods:</h3> Mutational DNA screening was performed in the patient and his mother. Western blotting was used to analyse protein expression levels of TNFR1. A multiplex bead immunoassay was used to quantify serum levels of range of cytokines, and an ELISA-based transcription factor assay to measure nuclear factor (NF)-κB transactivation. Serum levels of soluble TNFR1 (sTNFR1) were measured by ELISA and fluorescence-activated cell sorting (FACS) analysis used to measure monocyte TNFR1 cell surface expression. <h3>Results:</h3> A novel mutation, c.472+1G&gt;A (C158delinsYERSSPEAKPSPHPRG), involving a splice site in intron 4 of <i>TNFRSF1A</i>, was found in the proband and affected mother leading to a 45 nucleotide insertion of intronic DNA into the mRNA, resulting in an in-frame insertion of 15 amino acids in the mature TNFR1 protein and a deletion of a cysteine residue C129 (158) in cysteine rich domain (CRD)3. The patients had reduced serum sTNFR1 and surface expression levels of TNFR1, with marked increases in pro- and anti-inflammatory cytokine. Their peripheral blood mononuclear cells (PBMC) had increased basal NF-κB activation compared with healthy controls and also had increased p50 nuclear expression following tumour necrosis factor (TNF) stimulation compared with PBMC from healthy controls, as well as T50M (T79M) and C88R (C117R) patients with TRAPS and patients with rheumatoid arthritis (RA). <h3>Conclusion:</h3> A novel, TRAPS causing, <i>TNFRSF1A</i> splice site mutation is associated with decreased sTNFR1 levels, cell surface and whole cell extract expression and increased NF-κB transcription factor activation.
The endurance athletes heart: acute stress and chronic adaptation
Authors: Keith George, Greg P Whyte, Danny J Green, David Oxborough, Rob E Shave, David Gaze, John Somauroo
Journal: British Journal of Sports Medicine (2012)

The impact of endurance exercise training on the heart has received significant research and clinical attention for well over a century. Despite this, many issues remain controversial and clinical interpretation can be complex of biomarkers of cardiomyocyte insult. This review assesses the current state of knowledge related to two areas of research where problems with clinical decision making may arise: (1) the impact of chronic endurance exercise training on cardiac structure, function and electrical activity to the point where the athletic heart phenotype may be similar to the expression of some cardiac pathologies (a diagnostic dilemma referred to as the 'grey-zone') and (2) the impact of acute bouts of prolonged exercise on cardiac function and the presentation of biomarkers and cardiomyocyte insult in the circulatory system. The combination of acute endurance exercise stress on the heart and prolonged periods of training are considered together in the final section.
NONRENAL COMPLICATIONS OF THE NEPHROTIC SYNDROME
Authors: George A. Kaysen
Journal: Annual Review of Medicine (1994)

▪ Abstract The nephrotic syndrome is a consequence of urinary loss of intermediate-sized plasma proteins and the resulting homeostatic responses to those losses. Plasma protein composition is changed greatly. Pathphysiologic changes are a consequence of the nature of the proteins lost and of the proteins that are increased in plasma to replace them. Plasma oncotic pressure (π) falls because of the replacement of relatively small plasma proteins by larger ones. Decreased π increases transudation of fluid into the interstitum and favors edema. This is exacerbated by causing renal insensitivity to atrial natriuretic factor (ANF), primary renal sodium retention, and plasma volume expansion. Many proteins lost in the urine, such as erythopoietin and IgG, are not defended by increased synthesis. Their loss may result in reduced immunity, anemia, and endocrinopathies. Albumin synthesis can be increased by dietary protein augmentation; however, urinary protein losses also increase, offsetting any palliative effect of increased albumin synthesis on albumin stores. The synthesis of many other proteins secreted by the liver is also increased, causing an elevation in plasma levels of several large proteins, including lipoproteins and elements of the coagulation cascade. This results in hyperlipidemia and, in conjunction with the urinary loss of smaller proteins that impede coagulation, a hypercoagulable state. Lipoprotein catabolism is also reduced as a consequence of proteinuria contributing to increased lipid levels.
Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension
Authors: Nicolas Picard, Katja Trompf, Chao-Ling Yang, R. Lance Miller, Monique Carrel, Dominique Loffing-Cueni, Robert A. Fenton, David H. Ellison, Johannes Loffing
Journal: Journal of the American Society of Nephrology (2013)

The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelch-like 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na+ uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1−/−) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1−/− mice. Compared with WT mice, I-1−/− mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity.
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
Authors: Charles S Fuchs, Jiri Tomasek, Cho Jae Yong, Filip Dumitru, Rodolfo Passalacqua, Chanchal Goswami, Howard Safran, Lucas Vieira dos Santos, Giuseppe Aprile, David R Ferry, Bohuslav Melichar, Mustapha Tehfe, Eldar Topuzov, John Raymond Zalcberg, Ian Chau, William Campbell, Choondal Sivanandan, Joanna Pikiel, Minori Koshiji, Yanzhi Hsu, Astra M Liepa, Ling Gao, Jonathan D Schwartz, Josep Tabernero
Journal: The Lancet (2013)
Phase I Trial of Intravesical Docetaxel in the Management of Superficial Bladder Cancer Refractory to Standard Intravesical Therapy
Authors: James M. McKiernan, Puneet Masson, Alana M. Murphy, Manlio Goetzl, Carl A. Olsson, Daniel P. Petrylak, Manisha Desai, Mitchell C. Benson
Journal: Journal of Clinical Oncology (2006)

Purpose Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent. Patients and Methods This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging. Results Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression. Conclusion Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.
Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer
Authors: Jinsheng Yu, William D. Shannon, Mark A. Watson, Howard L. McLeod
Journal: Clinical Cancer Research (2005)

Abstract The exact mechanism responsible for large variation of response to chemotherapy remains unclear. This study profiled the gene expression for the entire irinotecan pathway to provide insights into individualized cancer therapy. The RNA expressions of 24 irinotecan pathway genes were measured in paired tumor and normal tissues from 52 patients with Dukes' C colorectal cancer using a real-time quantitative reverse transcription-PCR assay. The relative expression levels across the 24 pathway genes varied considerably, with a 441-fold range from highest to lowest expression levels for the tumor tissues and a 934-fold range for the normal tissues. Interpatient variability was also quite large, with a 33.6 median fold change in the tumor tissue genes and a 30.1 median fold change in the normal tissue genes. Six of the 24 irinotecan pathway genes had dramatically lower expression levels in the tumor samples than did the genes in the normal tissues (median range, 1.28-4.39 folds; P = 0.001-0.029). Eight genes had significantly higher levels (median range, 1.35-2.42 folds; P = 0.001-0.011). Using hierarchical clustering, three gene clusters and three patient groups were observed with high similarity indices by the RNA expressions in colorectal tumors. The three patient groups had no unique clinical pathologic features but could be differentiated by the statistically significant differences in RNA expression level of seven genes. Our study indicates that gene expression profiling could be valuable for predicting tumor response to chemotherapy and for tailoring therapy to individual cancer patients.
Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy
Authors: Maciej Lech, Regina Gröbmayr, Mi Ryu, Georg Lorenz, Ingo Hartter, Shrikant R. Mulay, Heni Eka Susanti, Koichi S. Kobayashi, Richard A. Flavell, Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2013)

The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M(-/-) kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-α blockade with etanercept partially prevented renal atrophy in IRAK-M(-/-) mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage- and TNF-α-dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration.