bluuebunny/crossref_metadata_2025 huggingface dataset:
Dust from hog confinement facilities impairs Ca2+mobilization from sarco(endo)plasmic reticulum by inhibiting ryanodine receptors
Authors: Tian Chengju , Moore Caronda J. , Dodmane Puttappa , Shao Chun Hong , Romberger Debra J. , Toews Myron L. , Bidasee Keshore R.
Published: January 2013

Individuals working in commercial hog confinement facilities have elevated incidences of headaches, depression, nausea, skeletal muscle weakness, fatigue, gastrointestinal disorders, and cardiovascular diseases, and the molecular mechanisms for these nonrespiratory ailments remain incompletely undefined. A common element underlying these diverse pathophysiologies is perturbation of intracellular Ca2+homeostasis. This study assessed whether the dust generated inside hog confinement facilities contains compounds that alter Ca2+mobilization via ryanodine receptors (RyRs), key intracellular channels responsible for mobilizing Ca2+from internal stores to elicit an array of physiologic functions. Hog barn dust (HBD) was extracted with phosphate-buffered saline, sterile-filtered (0.22 μm), and size-separated using Sephadex G-100 resin. Fractions (F) 1 through 9 (Mw>10,000 Da) had no measurable effects on RyR isoforms. However, F10 through F17, which contained compounds of Mw≤2,000 Da, modulated the [3H]ryanodine binding to RyR1, RyR2, and RyR3 in a biphasic (Gaussian) manner. The Kivalues for F13, the most potent fraction, were 3.8 ± 0.2 μg/ml for RyR1, 0.2 ± 0.01 μg/ml and 19.1 ± 2.8 μg/ml for RyR2 (two binding sites), and 44.9 ± 2.8 μg/ml and 501.6 ± 9.2 μg/ml for RyR3 (two binding sites). In lipid bilayer assays, F13 dose-dependently decreased the open probabilities of RyR1, RyR2, and RyR3. Pretreating differentiated mouse skeletal myotubes (C2C12 cells) with F13 blunted the amplitudes of ryanodine- and K+-induced Ca2+transients. Because RyRs are present in many cell types, impairment in Ca2+mobilization from internal stores via these channels is a possible mechanism by which HBD may trigger these seemingly unrelated pathophysiologies.
Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults
Authors: Radom-Aizik Shlomit , Zaldivar Frank , Haddad Fadia , Cooper Dan M.
Published: January 2013

Natural killers (NK) cells are unique innate immune cells that increase up to fivefold in the circulating blood with brief exercise and are known to play a key role in first-response defense against pathogens and cancer immunosurveillance. Whether exercise alters NK cell gene and microRNA (miRNA) expression is not known. Thirteen healthy men (20–29 yr old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 77% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise challenge. NK cells were isolated from peripheral blood mononuclear cells using a negative magnetic cell separation method. We used Affymetrix U133+2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (false discovery rate < 0.05) was used to determine that exercise significantly altered the expression of 986 genes and 23 miRNAs. Using in silico analysis, we found exercise-related gene pathways where there was a high likelihood of gene-miRNA interactions. These pathways were predominantly associated with cancer and cell communication, including p53 signaling pathway, melanoma, glioma, prostate cancer, adherens junction, and focal adhesion. These data support the hypothesis that exercise affects the gene and miRNA expression pattern in the population of NK cells in the circulation and suggest mechanisms through which physical activity could alter health through the innate immune system.
Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C
Authors: Stout Gerdine J. , Blasco Maria A.
Published: January 2013

Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc−/− mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc−/−-mutant mice and Xpc−/−G1-G3Terc−/− double-mutant mice and exposed them to UV radiation. Chronically UV-exposed Xpc−/− skin displayed shorter telomeres on an average compared with wild-type skin. Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc−/−G1-G3Terc−/− mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening. Cancer Res; 73(6); 1844–54. ©2012 AACR.
Increased CDA Expression/Activity in Males Contributes to Decreased Cytidine Analog Half-Life and Likely Contributes to Worse Outcomes with 5-Azacytidine or Decitabine Therapy
Authors: Mahfouz Reda Z. , Jankowska Ania , Ebrahem Quteba , Gu Xiaorong , Visconte Valeria , Tabarroki Ali , Terse Pramod , Covey Joseph , Chan Kenneth , Ling Yonghua , Engelke Kory J. , Sekeres Mikkael A. , Tiu Ramon , Maciejewski Jaroslaw , Radivoyevitch Tomas , Saunthararajah Yogen
Published: January 2013

Purpose: The cytidine analogs 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase 1 (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application.

Experimental design: Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity, and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated patients with MDS (n = 90) and cytarabine-treated patients with acute myeloid leukemia (AML) (n = 76).

Results: By high-performance liquid chromatography (HPLC), plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females than in males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared with high S-phase fraction disease (e.g., MDS vs. AML), because in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female patients with MDS treated with 5-azacytidine/decitabine.

Conclusions: Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res; 19(4); 938–48. ©2012 AACR.
Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models
Authors: Lin Jie , Sampath Deepak , Nannini Michelle A. , Lee Brian B. , Degtyarev Michael , Oeh Jason , Savage Heidi , Guan Zhengyu , Hong Rebecca , Kassees Robert , Lee Leslie B. , Risom Tyler , Gross Stefan , Liederer Bianca M. , Koeppen Hartmut , Skelton Nicholas J. , Wallin Jeffrey J. , Belvin Marcia , Punnoose Elizabeth , Friedman Lori S. , Lin Kui
Published: January 2013

Purpose: We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.

Experimental Design: The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.

Results: GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents.

Conclusions: GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling. Clin Cancer Res; 19(7); 1760–72. ©2012 AACR.
Targeted Degradation of KRAS by an Engineered Ubiquitin Ligase Suppresses Pancreatic Cancer Cell Growth In Vitro and In Vivo
Authors: Ma Yihui , Gu Yumei , Zhang Qiang , Han Yongqing , Yu Shuangni , Lu Zhaohui , Chen Jie
Published: January 2013

KRAS is an attractive pancreatic ductal adenocarcinoma (PDAC) therapeutic target. E3 ligase is thought to be the component of the ubiquitin conjugation system that is directly responsible for substrate recognition. In this study, an engineered E3 ubiquitin ligase (RC-U) was generated to target the KRAS oncoprotein for ubiquitination and degradation. The engineered E3 ubiquitin ligases (RC-U) were constructed (pRC-U and lentivirus-expressing RC-U). After transfecting the pRC-U plasmid into human pancreatic cancer cells, KRAS expression levels were determined. KRAS expression was also evaluated in cells transfected with pRC-U and treated with MG-132 or cycloheximide. Interactions between RC-U and KRAS as well as whether RC-U could ubiquitinate KRAS were investigated. Extracellular signal–regulated kinase 1/2 (ERK1/2) and phosphorylated ERK 1/2 (pERK1/2) levels were examined in pancreatic cancer cells transfected with pRC-U. The effects of RC-U on pancreatic cancer cell growth were assessed. RC-U decreased KRAS protein levels. After pRC-U transfection, KRAS stability was increased in the presence of MG-132. HEK 293T cells were transfected with a mutant KRAS construct together with pRC-U and incubated with cycloheximide to inhibit new protein synthesis. The exogenous mutant KRAS oncoprotein was degraded more quickly. RC-U can bind KRAS and KRAS can be ubiquitinated by RC-U. pERK1/2 protein levels were decreased. RC-U resulted in reduced cell proliferation in vitro and in vivo. KRAS destruction by RC-U occurred through a ubiquitin-dependent, proteasome-mediated degradation pathway. RC-U inhibited pancreatic cancer cell growth in vitro and in vivo. Mol Cancer Ther; 12(3); 286–94. ©2012 AACR.
A Second-Generation 2-Methoxyestradiol Prodrug Is Effective against Barrett's Adenocarcinoma in a Mouse Xenograft Model
Authors: Kambhampati Suman , Rajewski Roger A. , Tanol Mehmet , Haque Inamul , Das Amlan , Banerjee Snigdha , Jha Saheli , Burns Douglas , Borrego-Diaz Emma , Van Veldhuizen Peter J. , Banerjee Sushanta K.
Published: January 2013

2-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. In preclinical models, 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. In an effort to solve this problem, we have now synthesized and tested a new prodrug of 2-ME2 that is water-soluble due to a bioreversible hydrophilic group added at the 3-position and that more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anticancer agent for both in vitro and in vivo studies against Barrett esophageal adenocarcinoma (BEAC) and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through possible disruption of microtubule network. Mol Cancer Ther; 12(3); 255–63. ©2012 AACR.
Genes and ‘In-Vironment’: How Will Our Concepts on the Pathophysiology of Inflammatory Bowel Disease Develop in the Future?
Authors: Fiocchi Claudio
Published: January 2013

It is becoming increasingly evident that the old paradigm of disease pathogenesis where a given genotype would determine a phenotype and this would lead to a particular disease is no longer acceptable. Many novel components are now recognized to be involved in the predisposition, triggering, progression and outcome of chronic inflammatory diseases like inflammatory bowel disease (IBD). Accordingly, investigation of IBD must recognize this complexity and take all potential components into account, if a full understanding of disease pathophysiology is to be reached and truly effective therapies developed based on this new global understanding. Essential to this approach is the notion of functional integration. Groups of functionally related pathogenic components must be assembled and studied as ‘omes’ like, for instance, the genome and the microbiome; at the same time all relevant ‘omes’ must be functionally and meaningfully integrated into the ‘interactome’, while the ‘epigenome’ should be used to dissect and understand the connections underlying the interactome. This is an ideal but also realistic scenario for the immediate future, as some of the ‘omes’ are already being explored in greater depth and their interactions examined through investigation of gene-gene (GXG) and gene-environment (GXE) interactions. Current knowledge of GXG and GXE and their impact on IBD pathogenesis is the focus of this review.
Why and Where to Look in the Environment with Regard to the Etiology of Inflammatory Bowel Disease
Authors: Bernstein Charles N.
Published: January 2013

As inflammatory bowel disease (IBD) continues to emerge with rising prevalence rates in the developed world and rising incidence rates in the developing world, it has become clear that environmental factors play a critical role in disease etiology. While no single environmental factor has been proven to have a definite causative role, there are several leading candidates. Smoking has been shown to adversely impact on the course of Crohn’s disease (CD), but is neither necessary nor sufficient to cause CD. Considering that the countries with the highest smoking rates in the world have among the lowest rates of CD, it is more likely that smoking modulates CD once it is present as opposed to being directly causative. Diet likely plays a role, perhaps by modulating the gut microbiome directly or indirectly by impacting on the gut immune homeostasis. Antibiotics have become ubiquitously prescribed in the developed world and their emergence coincided with the emergence of IBD in the middle of the 20th century. Antibiotic use is also increasing in the developing world, and perhaps by modulating the gut microbiome this may be facilitating the emergence of IBD where it was rare 40 years ago. Finally, personal stress has intestinal physiological and immunological effects and is assuming an increasing role in the management of IBD.
Does Our Food (Environment) Change Our Gut Microbiome (‘In-Vironment’): A Potential Role for Inflammatory Bowel Disease?
Authors: de Wouters Tomas , Doré Joël , Lepage Patricia
Published: January 2013

Human biology can only be fully assessed by combining an analysis of both the host and its surrounding environment. As a part of the environment, the human gastrointestinal tract hosts more than 100 trillion bacteria making up the gut microbiota. The human host provides a nutrient-rich environment while the microbiota provides indispensable functions that humans cannot exert themselves. Shifts in the bacterial makeup of the human gut microbiota have been associated with disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome and obesity. However, since most bacteria inhabiting our gut are not cultivable to date, until recently little was known about their individual functions. Metagenomics, i.e. the analysis of the collective genomes present in a defined ecosystem, gives insight into these specific functions. The first extensive catalogue of the intestinal metagenome outnumbers the size of the human genome by a factor of 150. Recently, 3 distinct ‘types’ of gut composition within the human population have been highlighted. These so-called ‘enterotypes’ are characterized by the dominant genera (Bacteroides, Prevotella and Ruminococcus) and their co-occurring phylogenetic groups. In accordance with the previously described impact of nutritional behavior (diet, probiotics and prebiotics) on specific bacterial populations, an association has been observed between long-term dietary habits and enterotypes. This recent discovery, i.e. that belonging to one or the other enterotype might be modulated by the diet opens up new perspectives in the fields of IBD, nutrition and therapeutic strategies.
Danger-Associated Molecular Patterns and Inflammatory Bowel Disease: Is There a Connection?
Authors: Mueller Christoph
Published: January 2013

The innate immune system is of critical importance for maintaining the local tissue homeostasis in the intestinal mucosa. It must recognize and rapidly respond to microbial antigens and danger signals to provide a first line of host defense. This is primarily accomplished through an array of pattern recognition receptors that are located in distinct (sub)cellular compartments and bind pathogen-associated and danger-associated molecular patterns (PAMPs and DAMPs, respectively). The impact of PAMPs, in particular NOD2/CARD15, in the pathogenesis of Crohn’s disease is widely established. The involvement of DAMPs in the pathogenesis of inflammatory bowel disease (IBD), however, is much less recognized. DAMPs (also known as alarmins) represent non-pathogen-derived molecules, such as intracellular proteins released from damaged and stressed cells. Although the ligand(s) for the triggering receptor expressed on myeloid cells (TREM)-1 have not yet been fully identified, circumstantial evidence indicates that DAMPs are the inducers of the TREM-1-mediated, excessive induction of proinflammatory effects, also seen in patients with active IBD. Blocking the interactions between TREM-1 with its ligand(s) by the administration of a TREM-1-derived antagonistic peptide even attenuates the progression of established colonic inflammation. Hence, DAMPs can contribute to, and exacerbate, colonic inflammation in mouse models of IBD, in particular when they trigger innate immune cells of the intestinal lamina propria. DAMPs and PAMPs, however, may also be required for maintaining intestinal epithelial barrier functions as demonstrated by the enhanced susceptibility for colitis development in mice deficient for the NLRP6 or NLRC4 sensors in inflammasomes in intestinal epithelial cells.
Clinical Risk Factors for Complicated Disease: How Reliable Are They?
Authors: Zallot Camille , Peyrin-Biroulet Laurent
Published: January 2013

Crohn’s disease is a chronic, progressive, destructive disease. Complicated disease can be defined as the presence of bowel damage (stricture, abscess or fistula) and/or the need for surgery. Natural history studies provide invaluable data on the disease course. In population-based cohorts, half of all patients experienced an intestinal complication within 20 years after diagnosis and half of the patients required surgery within 10 years after diagnosis. In Olmsted County, the factors associated with the development of complications were the presence of ileal involvement and perianal disease. The extent of noncolonic disease, current smoking, male gender, penetrating disease behavior and early steroid use were significantly associated with major abdominal surgery. Overall, using various definitions of complicated disease, the predictors of a worse outcome in Crohn’s disease were: extensive small bowel disease, severe upper gastrointestinal disease, rectal disease, perianal lesions, early stricturing/penetrating disease, smoking and a young age at diagnosis. Aggressive ulcerative colitis was recently defined as a disease that is associated with a high relapse rate, the need for surgery, the development of colon cancer or the presence of extraintestinal manifestations. About one tenth of patients still require colectomy for ulcerative colitis at 5 years in the era of biologics. An average of 1.6% of patients with ulcerative colitis was diagnosed with colorectal cancer during 14 years of follow-up in population-based cohorts. A younger age at diagnosis and pancolitis were associated with a worse outcome in ulcerative colitis. The identification of clinical risk factors for complicated disease may be used in future disease-modification trials.
Mucosal Protection by Phosphatidylcholine
Authors: Stremmel Wolfgang , Ehehalt Robert , Staffer Sabine , Stoffels Sabine , Mohr Andrea , Karner Max , Braun Annika
Published: January 2013

The colonic mucus serves a first barrier towards invasion of commensal bacteria in stools to prevent inflammation. One essential component of intestinal mucus is phosphatidylcholine (PC) which represents more than 90% of the phospholipids in mucus indicative for a selective transport of PC into this compartment. It is arranged in lamellar structures as surfactant-like particles which provide a hydrophobic surface on top of the hydrated mucus gel to prevent the invasion of bacteria from intestinal lumen. In ulcerative colitis (UC), the mucus PC content is reduced by 70%, irrespective of the state of inflammation. Thus, it could represent an intrinsic primary pathogenetic condition predisposing to bacterial invasion and the precipitation of inflammation. Since PC was shown to be mainly secreted by the ileal mucosa from where it is assumed to move distally to the colon, the PC content along the colonic wall towards the rectum gradually thins, with the least PC content in the rectum. This explains the start of the clinical manifestation of UC in the rectum and the expansion from there to the upper parts of the colon. In three clinical trials, when missing mucus PC in UC was supplemented by an oral, delayed release PC preparation, the inflammation improved and even resolved after a 3-month treatment course. The data indicate the essential role of the mucus PC content for protection against inflammation in colon.
Topical Therapy
Authors: Gross Volker
Published: January 2013

Topical therapy with mesalazine and/or corticosteroids is the standard treatment for patients with distal ulcerative colitis. Rectal mesalazine is more effective than rectal systemically active corticosteroids or topically active corticosteroids like budesonide. In patients with mild to moderately active distal ulcerative colitis, topical mesalazine is therefore the treatment of choice. Doses of 1 g or higher are equally effective. The period of treatment is important (4 weeks are more effective than 2 weeks). In the case of nonresponse or nontolerability of rectal mesalazine, rectal budesonide is indicated. The standard dose of budesonide is 2 mg/day. This does not usually induce any corticosteroid-associated adverse events. Treatment with rectal mesalazine plus rectal topically active corticosteroids is even more effective than treatment with either substance alone. To overcome adherence problems with rectal therapy, rectal foam preparations have been developed which are usually better tolerated than enemas.
The Risks and Benefits of Early Immunosuppression and Biological Therapy
Authors: Sands Bruce E.
Published: January 2013

Crohn’s disease and ulcerative colitis are heterogeneous conditions with highly variable courses of disease. Recent studies have focused on the time soon after diagnosis as a potential window of opportunity before which complicated disease behaviors have ensued and in which attaining adequate control of the inflammatory process might improve long-term outcomes. This review covers the use of immune suppression and biological therapy early in the course of inflammatory bowel disease. It includes the rationale for using these medications earlier, the features of early disease that may lead to improved outcomes with early intervention, the most optimal strategies for early treatment, the benefits of early intervention and the risks of this approach. In addition, we discuss the issue of which patients to choose for early intervention through risk stratification.
Stem Cells as Treatment in Inflammatory Bowel Disease
Authors: Hawkey C.J.
Published: January 2013

Background: The Autologous Stem Cell Transplantation International Crohn’s Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn’s disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. Methods: Patients with an impaired quality of life due to active Crohn’s disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophosphamide 4 g/m2 over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 µg/kg daily before randomisation to immediate (after 1 month) or delayed (after 1 year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/kg/day and methylprednisolone 1 mg/kg on days 3–5. The bone marrow was reconstituted by the infusion of an unselected graft of 3–8 × 106/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. Results: Twelve months after stem cell transplantation (early or delayed) the Crohn’s Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229–411) to 161 (85–257, n = 17) compared to 351 (287–443) to 272 (214–331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus 1 after mobilisation. C-reactive protein fell from 16.6 (6.7–32.0) to 6.5 (3.5–12.5) mg/l versus 14 (8.0–27.0) to 9.0 (2.0–23.4) mg/l following mobilisation alone. The Crohn’s Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10–25) to 5 (1–11) following transplantation versus 14 (12–16) to 9 (4–22) following mobilisation. Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy 1 year after transplantation, but so did 1 patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn’s disease activity or a need for surgery occurred in 8 patients. Conclusions: Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn’s disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits.
The Future of Inflammatory Bowel Disease Therapy: Where Do We Go from Here?
Authors: Sandborn William J.
Published: January 2013

There are six important trends that will impact the future of inflammatory bowel disease therapy. (1) Increased use of the biomarkers C-reactive protein (CRP) and fecal calprotectin, and increased imaging with colonoscopy and MRI enterography. (2) Increased use of pharmacokinetics to customize drug dosing for individual patients. Multiple factors impact the pharmacokinetics of monoclonal antibodies including the presence of antidrug antibodies, concomitant immunosuppression and low serum albumin and high CRP concentrations. (3) Evolution of treatment end points from symptoms to deep remission (a combination of both clinical remission and mucosal healing) to the prevention of bowel damage (in Crohn’s disease) and surgery in the short-to-intermediate term and prevention of disability in the longer term. (4) Evolving data demonstrate that azathioprine monotherapy is minimally effective as a disease modification agent in Crohn’s disease. Use of azathioprine as a monotherapy will decline. (5) Combination therapy with azathioprine and infliximab is superior to monotherapy with either agent. Use of combination therapy will increase. (6) There is a rich pipeline of novel therapeutic agents. Treatment strategies that appear particularly appealing include selective anti-integrin therapy with vedolizumab (anti-α4β7), etrolizumab (anti-β7 antibody) and PF-00547,659 (anti-MAdCAM-1 antibody), anti-interleukin 12/23p40 therapy with ustekinumab and Janus kinase 1, 2 and 3 inhibition with toafacitinib.
No Evidence for Effects of a High-Frequency Repetitive Transcranial Magnetic Stimulation Series on Verbal and Figural Fluency and TAP Task Performance in Healthy Male Volunteers
Authors: Schaller Gerd , Lenz Bernd , Friedrich Kerstin , Dygon Dominika , Richter-Schmidinger Tanja , Sperling Wolfgang , Kornhuber Johannes
Published: January 2013

Background: Study results on cognitive effects of repetitive transcranial magnetic stimulation (rTMS) in healthy people are inconsistent. Moreover, former trials performed exclusively single-session stimulations. This sham-controlled study analyzed the influence of 9 serial high-frequency rTMS on cognition. Methods: 44 young healthy male volunteers received active or sham rTMS. We evaluated verbal fluency tasks, the Ruff Figural Fluency Test and different Test for Attentional Performance tasks (alertness, go/no-go, divided attention, working memory, flexibility) prior to the first stimulation, immediately (within 5–30 min) after stimulation on day 5 and on day 10 (1 day after the last stimulation). Results: Overall, our statistical analyses revealed no significant cognitive effects of serial rTMS. Conclusion: In this sham-controlled study design, 9 serial rTMS over the left dorsolateral prefrontal cortex (targeted by the 5-cm rule) did neither enhance nor impair the assessed cognitive functions in healthy male volunteers.
ZNF804A Genotype Modulates Neural Activity during Working Memory for Faces
Authors: Linden David E.J. , Lancaster Thomas M. , Wolf Claudia , Baird Alison , Jackson Margaret C. , Johnston Stephen J. , Donev Rossen , Thome Johannes
Published: January 2013

Background: Genetic susceptibility to schizophrenia (SZ) has been suggested to influence the cortical systems supporting working memory (WM) and face processing. Genetic imaging studies link the SZ risk variant rs1344706 on the ZNF804A gene to psychosis via alterations in functional brain connectivity during WM, but no work has looked at the effects of ZNF804A on WM with face-processing components. Methods: We therefore investigated healthy controls that were genotyped for rs1344706 with a face WM task during functional magnetic resonance imaging. We suggested that variation at the rs1344706 locus would be associated with similar alterations as patients previously tested using the same WM task for faces. Results: The rs1344706 risk allele was indeed associated with altered activation in the right dorsolateral prefrontal (rDLPFC) cortex. We established that the rDLPFC was activated in a task-dependent manner, suggesting that the differences in activation between rs1344706 genotype groups reflected alterations in task processing. Furthermore, we demonstrated that the rDLPFC region showed significant volumetric overlap with the rDLPFC which had previously been reported to be altered during task processing for patients with SZ. Conclusions: The findings support an association between rs1344706 and alterations in DLPFC activity during WM for faces. We further suggest that WM for faces may be a useful intermediate phenotype in the investigation of genetic susceptibility to psychosis.
Higher Leukocyte Subpopulation Counts in Healthy Smoker Industrial Workers than in Nonsmoker Industrial Workers: Possible Health Consequences
Authors: Mansoor M. Azam , Stakkestad Jacob A. , Drabløs Per Arne
Published: January 2013

Objectives: Cigarette smoke contains free radicals, which cause injury to endothelial cells and oxidize bioactive components in the blood. Neutrophils, a subpopulation of leukocytes, contain the enzyme myeloperoxidase that mediates production of hypochlorous acid during oxidative stress. In this study, we investigated whether smoker industrial workers had significantly higher neutrophil counts than nonsmoker industrial workers. Design and Methods: We collected blood samples from 183 apparently healthy male and 30 female industrial workers. We obtained blood cell counts, measured the concentration of plasma aminothiols and determined the concentration of serum and erythrocyte folate and serum vitamin B12 in the samples. Results: Smoker industrial workers had significantly higher neutrophil, lymphocyte, monocyte, eosinophil and basophil counts than nonsmoker industrial workers (p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001 and p = 0.01, respectively). Mean corpuscular volume and mean corpuscular hemoglobin in smoker industrial workers were higher than in nonsmoker industrial workers (p = 0.001 and p = 0.03). Conclusion: Our study demonstrates that smoker industrial workers have higher neutrophil counts than nonsmoker industrial workers. Therefore, our observations suggest that smokers may become more easily prone to chronic inflammation than nonsmokers. About 84% of the study participants were male subjects; therefore, our findings may be more representative for men than women.
Aberrant Nuclear Repressor Coreceptor 1 Localization in Human Retinoblastoma
Authors: Nazha Bassel , Granner Tamara , Maloney Shawn , Odashiro Alexandre N. , Antecka Emilia , Burnier Jr. Miguel N.
Published: January 2013

Background/Aims: Nuclear receptor corepressor 1 (NCoR1) is a protein complex with diverse functions in development and tumorigenesis. We investigated the pattern of expression and histopathological correlation of NCoR1 in 41 retinoblastoma tumor samples, 1 retinoblastoma cell line (WERI-Rb-1) and human retinal progenitor cells (hRPCs). Methods: Tissue sections from 41 retinoblastoma cases, the retinoblastoma cell line WERI-Rb-1 and hRPCs were stained with rabbit polyclonal anti-NCoR1 H76 antibody. Percentage and intensity of staining were classified by an ocular pathologist from 0 to 3. The paired t test was used to test for differences. Results: In the nonneoplastic retina, NCoR1 was expressed mainly in cell nuclei. The retinoblastoma tumor cells similarly had nuclear NCoR1 but also had a higher level of cytoplasmic NCoR1 expression compared to all 3 normal retinal cell layers (p < 0.002). In contrast to the normal retina, NCoR1 was mainly expressed in the cytoplasm of the proliferating WERI-Rb-1 cells. This cytoplasmic expression pattern was also seen in the undifferentiated hRPCs. Conclusions: The aberrant cytoplasmic expression of NCoR1 in retinoblastoma appears to be associated with the proliferative and/or dedifferentiated properties of retinoblastoma. Further investigation into the role of NCoR1 in retinoblastoma may provide insight into how therapeutically inhibiting its nucleocytoplasmic shuttling may affect retinoblastoma tumor biology.
Diabetes Mellitus after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Wędrychowicz Anna , Ciechanowska Marta , Stelmach Małgorzata , Starzyk Jerzy
Published: January 2013

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are known to be at risk of developing endocrine abnormalities, but occurrence of diabetes mellitus (DM) is a relatively recent observation. We present a 17.5-year-old girl with DM after high-dose radio- and chemotherapy followed by allogeneic HSCT for the treatment of acute lymphoblastic leukemia, diagnosed when she was 10 years old. In the posttransplantation period, multiple acute and chronic complications occurred. Among them, we observed graft versus host disease requiring corticosteroid therapy, pancreatitis and some endocrine complications like primary hypothyroidism, growth hormone deficiency and hypergonadotropic hypogonadism. DM with some components of metabolic syndrome-like insulin resistance, high arterial blood pressure and dyslipidemia developed during the first year after HSCT. Five years later, a trend towards increased requirement of insulin with deterioration in metabolic control of DM was observed, despite a normal level of C-peptide and negative diabetes autoantibodies. After the addition of metformin to continuous subcutaneous insulin infusion in the therapy of DM, an improvement in metabolic control was observed. Due to the possible mechanism of insulin resistance which is associated with impaired insulin receptors after HSCT procedure, metformin with insulin appears to be effective in the treatment of this type of diabetes.
Risk Factors for Predicting Severe Neutropenia Induced by Amrubicin in Patients with Advanced Lung Cancer
Authors: Watanabe Hiroyuki , Ikesue Hiroaki , Oshiro Marina , Nagata Kenichiro , Mishima Kazuto , Takada Atsushi , Suetsugu Kimitaka , Sueyasu Masanori , Egashira Nobuaki , Harada Taishi , Takayama Koichi , Nakanishi Yoichi , Oishi Ryozo
Published: January 2013

Background: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3–4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m2. The incidence of grade 3–4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01–134.15; p = 0.049), higher AMR doses (40 mg/m2 or more) (OR = 5.98; 95% CI 1.77–23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04–4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.
Reference Range for Fetal Interventricular Septum Area by Means of Four-Dimensional Ultrasonography Using Spatiotemporal Image Correlation
Authors: Nardozza Luciano Marcondes Machado , Rolo Liliam Cristine , Araujo Júnior Edward , Hatanaka Alan Roberto , Rocha Luciane Alves , Simioni Christiane , Ruano Rodrigo , Moron Antonio Fernandes
Published: January 2013

Objective: To determine reference range for fetal interventricular septum area by means of 3-dimensional ultrasonography (3DUS) using the spatiotemporal image correlation (STIC) method. Methods: A prospective, cross-sectional study was conducted on 328 normal pregnant women between the 18th and 33rd gestational weeks. To obtain the interventricular septum area, a virtual plane was used, with the green line (region of interest) adjacent to the external margin of the septum, which was manually delimited. To evaluate the correlation of the septum area with the gestational age, different regression modes were evaluated. The intraclass correlation coefficient was used to evaluate the interobserver reproducibility. Results: The interventricular septum area showed correlation with the gestational age (r = 0.81). The mean increased from 0.47 ± 0.10 cm2 in the 18th week to 2.42 ± 1.13 cm2 in the 33rd week of gestation. The mathematical equation that best represented this correlation was provided by linear regression: interventricular septum area = 0.0511 × gestational age (R2 = 0.095). The interobserver reproducibility was good, with bias of 0.01 cm2, precision of 0.07 cm2 and absolute limits of agreement of -0.14 and +0.15 cm2. Conclusions: Reference range for fetal interventricular septum area were determined by means of 3DUS using STIC in the rendering mode and were shown to be reproducible.
Labyrinthotomy or Vestibulotomy in Anatomic and Congenital Variations of the Oval Window and Facial Nerve
Authors: Al-Mazrou Khalid A. , Bayazit Yildirim A.
Published: January 2013

Objective: To present the results of our experience with labyrinthotomy or vestibulotomy in cases where the oval window is blocked by the facial nerve and in the presence of bilateral congenital agenesis of the oval window, respectively. Study design: Retrospective analysis of the records of the patients operated in two different centers. Methods: Between 2007 and 2012, 5 ears of 4 patients who were operated on in two different clinics with a presumptive diagnosis of otosclerosis were included in the study. There were 3 female patients and 1 male. The ages ranged from 10 to 26 (mean 19 years). All patients had unilateral conductive hearing loss except 1 (10-year-old girl or patient 1). Pure tone averages were calculated at the frequencies 0.5, 1, 2 and 4 kHz both pre- and postoperatively according to the Committee on Hearing and Equilibrium 1995 Guidelines for the Evaluation of Results of Treatment of Conductive Hearing Loss. All patients underwent a middle ear exploration and postoperatively the initial audiological examination was performed after 6 months. Results: Retrospective analysis revealed that vestibulotomy or labyrinthotomy was performed in 5 ears of 4 patients. Postoperative dizziness was encountered in 2 patients who had vestibulotomy due to oval window agenesis, which ceased spontaneously at 1 month postoperatively. The perioperative period was otherwise uneventful. None of the patients had sensorineural hearing loss or deterioration of hearing. There was a significant improvement in hearing after the operation. A 28-dB improvement in the mean air conduction pure tone thresholds was achieved. Conclusion: Vestibulotomy and labyrinthotomy are safe and effective procedures in terms of hearing restoration, which can be applied in cases of congenital agenesis of the oval window or obstruction of the oval window by the facial nerve.
Prognostic Significance of Serum Levels of Vascular Endothelial Growth Factor and Insulin-Like Growth Factor-1 in Advanced Gastric Cancer Patients Treated with FOLFOX Chemotherapy
Authors: Oh Sung Yong , Kwon Hyuk-Chan , Kim Sung Hyun , Lee Suee , Lee Ji Hyun , Graves Christian A. , Camphausen Kevin , Kim Hyo-Jin
Published: January 2013

Background: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy. The insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX). Methods: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1 plus leucovorin 20 mg/m2 over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m2 and 22 h of continuous infusion of 600 mg/m2 on days 1–2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays. Results: There was a significant correlation between the serum level of VEGF and Lauren’s classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377–3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome. Conclusion: A high level of serum VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen.
Dynamin-Related Protein-1 Controls Fusion Pore Dynamics During Platelet Granule Exocytosis
Authors: Koseoglu Secil , Dilks James R. , Peters Christian G. , Fitch-Tewfik Jennifer L. , Fadel Nathalie A. , Jasuja Reema , Italiano Joseph E. , Haynes Christy L. , Flaumenhaft Robert
Published: January 2013

Objective—

Platelet granule exocytosis serves a central role in hemostasis and thrombosis. Recently, single-cell amperometry has shown that platelet membrane fusion during granule exocytosis results in the formation of a fusion pore that subsequently expands to enable the extrusion of granule contents. However, the molecular mechanisms that control platelet fusion pore expansion and collapse are not known.

Methods and Results—

We identified dynamin-related protein-1 (Drp1) in platelets and found that an inhibitor of Drp1, mdivi-1, blocked exocytosis of both platelet dense and α-granules. We used single-cell amperometry to monitor serotonin release from individual dense granules and, thereby, measured the effect of Drp1 inhibition on fusion pore dynamics. Inhibition of Drp1 increased spike width and decreased prespike foot events, indicating that Drp1 influences fusion pore formation and expansion. Platelet-mediated thrombus formation in vivo after laser-induced injury of mouse cremaster arterioles was impaired after infusion of mdivi-1.

Conclusion—

These results demonstrate that inhibition of Drp1 disrupts platelet fusion pore dynamics and indicate that Drp1 can be targeted to control thrombus formation in vivo.