Vedolizumab as a rescue therapy for patients with medically refractory Crohn's disease.

AIM: Vedolizumab, a monoclonal antibody resulting in gut-selective anti-inflammatory activity, was approved by the US Food and Drug Administration in 2014 for use in patients with Crohn's disease (CD). The aim of this study was to investigate the efficacy of vedolizumab as a rescue therapy when other medical therapies have failed. METHOD: A retrospective review was performed on consecutive patients with CD receiving vedolizumab at the Penn State Hershey IBD Center between May 2014 and March 2016. These patients were unresponsive or intolerant to tumour necrosis factor (TNF) antagonist therapy, and previously would have been candidates for surgery. Outcomes included surgical intervention, clinical response and endoscopic improvement. RESULTS: A total of 48 patients with medically refractory CD receiving vedolizumab were included. The median length of follow-up was 69 weeks (range 15-113 weeks). A majority (81%) of patients previously failed at least two TNF antagonists, and 77% had prior surgery for CD. Surgical intervention was required in 21 (44%) patients and 13 (27%) patients required intra-abdominal operations. At the conclusion of the study, 23 (48%) patients reported continued improvement of symptoms, and 22 of 37 (59%) patients undergoing endoscopy showed improvement. Patients with the inflammatory CD phenotype were more likely to improve clinically and avoid surgery. CONCLUSION: Vedolizumab alone or in combination with immunomodulators or steroids may be used as a rescue therapy in patients with medically refractory CD and may decrease the rate of surgical intervention. Patients with the inflammatory CD phenotype had the best clinical response and decreased need for surgery, suggesting that vedolizumab is most effective in the inflammatory phenotype.

Compliance with Clostridium difficile treatment guidelines: effect on patient outcomes.

Guidelines for the severity classification and treatment of Clostridium difficile infection (CDI) were published by Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) in 2010; however, compliance and efficacy of these guidelines has not been widely investigated. This present study assessed compliance with guidelines and its effect on CDI patient outcomes as compared with before these recommendations. A retrospective study included all adult inpatients with an initial episode of CDI treated in a single academic center from January 2009 to August 2014. Patients after guideline publication were compared with patients treated in 2009-2010. Demographic, clinical, and laboratory data were collected to stratify for disease severity. Outcome measures included compliance with guidelines, mortality, length of stay (LOS), and surgical intervention for CDI. A total of 1021 patients with CDI were included. Based upon the 2010 guidelines, 42 (28·8%) of 146 patients treated in 2009 would have been considered undertreated, and treatment progressively improved over time, as inadequate treatment decreased to 10·0% (15/148 patients) in 2014 (P = 0·0005). Overall, patient outcomes with guideline-adherent treatment decreased CDI attributable mortality twofold (P = 0·006) and CDI-related LOS by 1·9 days (P = 0·0009) when compared with undertreated patients. Compliance with IDSA/SHEA guidelines was associated with a decreased risk of mortality and LOS in hospitalized patients with CDI.

Depressive symptoms are doubled in older British South Asian and Black Caribbean people compared with Europeans: associations with excess co-morbidity and socioeconomic disadvantage.

BACKGROUND: Despite elevated risk profiles for depression among South Asian and Black Caribbean people in the UK, prevalences of late-life depressive symptoms across the UK's three major ethnic groups have not been well characterized. METHOD: Data were collected at baseline and 20-year follow-up from 632 European, 476 South Asian and 181 Black Caribbean men and women (aged 58-88 years), of a community-based cohort study from north-west London. The 10-item Geriatric Depression Scale was interviewer-administered during a clinic visit (depressive symptoms defined as a score of ⩾4 out of 10), with clinical data (adiposity, diabetes, cardiovascular disease, cognitive function) also collected. Sociodemographic, psychosocial, behavioural, disability, and medical history information was obtained by questionnaire. RESULTS: Prevalence of depressive symptoms varied by ethnic group, affecting 9.7% of White European, 15.5% of South Asian, and 17.7% of Black Caribbean participants. Compared with White Europeans, South Asian and Black Caribbean participants were significantly more likely to have depressive symptoms (odds ratio 1.79, 95% confidence interval 1.24-2.58 and 1.80, 1.11-2.92, respectively). Adjustment for co-morbidities had most effect on the excess South Asian odds, and adjustment for socioeconomic position had most effect on the elevated Black Caribbean odds. CONCLUSIONS: Higher prevalence of depressive symptoms observed among South Asian people were attenuated after adjustment for physical health, whereas the Black Caribbean increased prevalence was most explained by socioeconomic disadvantage. It is important to understand the reasons for these ethnic differences to identify opportunities for interventions to address inequalities.

Health behaviours, socioeconomic status and diabetes incidence: the Australian Diabetes Obesity and Lifestyle Study (AusDiab).

AIMS/HYPOTHESIS: To identify the impact of socioeconomic status on incident impaired glucose metabolism and type 2 diabetes and to investigate the mediating role of health behaviours on this relationship using national, population-based data. METHODS: The Australian Diabetes Obesity and Lifestyle (AusDiab) Study is a national, population-based, longitudinal study of adults aged 25 years and above. A total sample of 4,405 people provided complete baseline (1999-2000) and 5 year follow-up (2004-2005) data relevant for these analyses. Fasting plasma glucose and 2 h plasma glucose were obtained from an OGTT, and demographic, socioeconomic and behavioural data were collected by interview and questionnaire. Multinomial logistic regression examined the role of socioeconomic position in the development of diabetes and mediation analyses tested the contribution of health behaviours in this relationship. RESULTS: Highest level of education was a stronger predictor of incident impaired glucose tolerance and type 2 diabetes (p = 0.002), compared with household income (p = 0.103), and occupational grade (p = 0.202). Education remained a significant independent predictor of diabetes in fully adjusted models. However, the relationship was attenuated by the health behaviours (smoking and physical activity). Mediation analyses indicated that these behaviours were partial mediators (explaining 27%) of the socioeconomic status-diabetes relationship. CONCLUSION/INTERPRETATION: Smoking and physical activity partly mediate the relationship between low education and type 2 diabetes. Identification of these modifiable behavioural mediators should facilitate the development of effective health promotion campaigns to target those at high risk of developing type 2 diabetes.

High-fidelity conformation of graphene to SiO2 topographic features.

High-resolution noncontact atomic force microscopy of SiO2 reveals previously unresolved roughness at the few-nm length scale, and scanning tunneling microscopy of graphene on SiO2 shows graphene to be slightly smoother than the supporting SiO2 substrate. A quantitative energetic analysis explains the observed roughness of graphene on SiO2 as extrinsic, and a natural result of highly conformal adhesion. Graphene conforms to the substrate down to the smallest features with nearly 99% fidelity, indicating conformal adhesion can be highly effective for strain engineering of graphene.

Characterizing voltage contrast in photoelectron emission microscopy.

A non-destructive technique for obtaining voltage contrast information with photoelectron emission microscopy is described. Samples consisting of electrically isolated metal lines were used to quantify voltage contrast in photoelectron emission microscopy. The voltage contrast behaviour is characterized by comparing measured voltage contrast with calculated voltage contrast from two electrostatic models. Measured voltage contrast was found to agree closely with the calculated voltage contrast, demonstrating that voltage contrast in photoelectron emission microscopy can be used to probe local voltage information in microelectronic devices in a non-intrusive fashion.

Cancer-associated fibroblasts of the prostate promote a compliant and more invasive phenotype in benign prostate epithelial cells.

Reciprocal interactions between prostate epithelial cells and their adjacent stromal microenvironment not only are essential for tissue homeostasis but also play a key role in tumor development and progression. Malignant transformation is associated with the formation of a reactive stroma where cancer-associated fibroblasts (CAFs) induce matrix remodeling and thereby provide atypical biochemical and biomechanical signals to epithelial cells. Previous work has been focused on the cellular and molecular phenotype as well as on matrix stiffness and remodeling, providing potential targets for cancer therapeutics. So far, biomechanical changes in CAFs and adjacent epithelial cells of the prostate have not been explored. Here, we compared the mechanical properties of primary prostatic CAFs and patient-matched non-malignant prostate tissue fibroblasts (NPFs) using atomic force microscopy (AFM) and real-time deformability cytometry (RT-FDC). It was found that CAFs exhibit an increased apparent Young's modulus, coinciding with an altered architecture of the cytoskeleton compared with NPFs. In contrast, co-cultures of benign prostate epithelial (BPH-1) cells with CAFs resulted in a decreased stiffness of the epithelial cells, as well as an elongated morphological phenotype, when compared with co-cultures with NPFs. Moreover, the presence of CAFs increased proliferation and invasion of epithelial cells, features typically associated with tumor progression. Altogether, this study provides novel insights into the mechanical interactions between epithelial cells with the malignant prostate microenvironment, which could potentially be explored for new diagnostic approaches.

Elevated level of inhibin-alpha subunit is pro-tumourigenic and pro-metastatic and associated with extracapsular spread in advanced prostate cancer.

The biological function of inhibin-alpha subunit (INH alpha) in prostate cancer (PCa) is currently unclear. A recent study associated elevated levels of INH alpha in PCa patients with a higher risk of recurrence. This prompted us to use clinical specimens and functional studies to investigate the pro-tumourigenic and pro-metastatic function of INH alpha. We conducted a cross-sectional study to determine a link between INH alpha expression and a number of clinicopathological parameters including Gleason score, surgical margin, extracapsular spread, lymph node status and vascular endothelial growth factor receptor-3 expression, which are well-established prognostic factors of PCa. In addition, using two human PCa cell lines (LNCaP and PC3) representing androgen-dependent and -independent PCa respectively, we investigated the biological function of elevated levels of INH alpha in advanced cancer. Elevated expression of INH alpha in primary PCa tissues showed a higher risk of PCa patients being positive for clinicopathological parameters outlined above. Over-expressing INH alpha in LNCaP and PC3 cells demonstrated two different and cell-type-specific responses. INH alpha-positive LNCaP demonstrated reduced tumour growth whereas INH alpha-positive PC3 cells demonstrated increased tumour growth and metastasis through the process of lymphangiogenesis. This study is the first to demonstrate a pro-tumourigenic and pro-metastatic function for INH alpha associated with androgen-independent stage of metastatic prostate disease. Our results also suggest that INH alpha expression in the primary prostate tumour can be used as a predictive factor for prognosis of PCa.

Thermodynamics of surface morphology.

Classical thermodynamic descriptions of surfaces treat surface orientation as a thermodynamic degree of freedom and thus allow for the possibility of reversible changes in surface morphology as a function of temperature or impurity concentration. The existence of these transitions has been confirmed experimentally. Advances in surface diffraction and imaging techniques now make it possible to characterize such transitions quantitatively in terms of the atomic structure, and particularly in terms of the behavior of steps on surfaces. Statistical mechanical models can be used to analyze the observations to determine the fundamental energetic parameters governing the observed thermodynamic behavior.

Alpha4beta2 nicotinic receptor status in Alzheimer's disease using 123I-5IA-85380 single-photon-emission computed tomography.

BACKGROUND: Loss of the alpha4beta2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease. OBJECTIVE: To investigate in vivo changes in this receptor using single-photon-emission CT (SPECT) with 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the alpha4beta2 receptor. METHODS: 32 non-smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I-5IA-85380 and perfusion (99mTc-hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation. RESULTS: Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I-5IA-85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD. CONCLUSION: Using 123I-5IA-85380 SPECT we found changes consistent with significant reductions in the nicotinic alpha4beta2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.

Conditional immortalization of human thyroid epithelial cells: a tool for analysis of oncogene action.

To overcome the difficulty of assessing oncogene action in human epithelial cell types, such as thyroid, which have limited proliferative potential in culture, we have explored the use of temperature-sensitive (ts) mutants of simian virus 40 (SV40) early region to create conditionally immortalized epithelial cell lines. Normal primary cultures of human thyroid follicular cells were transfected with a plasmid containing the SV40 early region from mutant tsA58. Expanding epithelial colonies were observed after 2 to 3 months, all of which grew to greater than 200 population doublings without crisis. All showed tight temperature dependence for growth. After switch-up to the restrictive temperature (40.5 degrees C), no further increase in cell number was seen after 1 to 2 days. However, DNA synthesis declined much more slowly; the dissociation from cell division led to marked polyploidy. Viability was maintained for up to 2 weeks. Introduction of an inducible mutant ras gene into ts thyroid cells led, as expected, to morphological transformation at the permissive temperature when ras was induced. Interestingly, this was associated with a marked reduction in net growth rate. At the restrictive temperature, induction of mutant ras caused rapid cell death. These results demonstrate the utility of a ts SV40 mutant to permit the study of oncogene action in an otherwise nonproliferative target cell and reveal important differences in the interaction between ras and SV40 T in these epithelial cells compared with previously studied cell types.

Generalized survival in step fluctuations.

The properties of the generalized survival probability, that is, the probability of not crossing an arbitrary location R during relaxation, have been investigated experimentally (via scanning tunneling microscope observations) and numerically. The results confirm that the generalized survival probability decays exponentially with a time constant tau(s) (R). The distance dependence of the time constant is shown to be tau(s) (R) = tau(s0) exp[-R/w (T)], where w2 (T) is the material-dependent mean-squared width of the step fluctuations. The result reveals the dependence on the physical parameters of the system inherent in the prior prediction of the time constant scaling with R/L(alpha), with L the system size and alpha the roughness exponent. The survival behavior is also analyzed using a contrasting concept, the generalized inside survival S(in) (t,R), which involves fluctuations to an arbitrary location R further from the average. Numerical simulations of the inside survival probability also show an exponential time dependence, and the extracted time constant empirically shows (R/w)(lambda) behavior, with lambda varying over 0.6 to 0.8 as the sampling conditions are changed. The experimental data show similar behavior, and can be well fit with lambda = 1.0 for T = 300 K, and 0.5 < lambda < 1 for T = 460 K. Over this temperature range, the ratio of the fixed sampling time to the underlying physical time constant, and thus the true correlation time, increases by a factor of approximately 10(3). Preliminary analysis indicates that the scaling effect due to the true correlation time is relevant in the parameter space of the experimental observations.

Spatial first-passage statistics of Al/Si(111)-(square root 3 x square root 3) step fluctuations.

Spatial step edge fluctuations on a multicomponent surface of Al/Si(111)-(square root 3 x square root 3) were measured via scanning tunneling microscopy over a temperature range of 720-1070 K, for step lengths of L=65-160 nm. Even though the time scale of fluctuations of steps on this surface varies by orders of magnitude over the indicated temperature range, measured first-passage spatial persistence and survival probabilities are temperature independent. The power law functional form for spatial persistence probabilities is confirmed and the symmetric spatial persistence exponent is measured to be theta=0.498+/-0.062 in agreement with the theoretical prediction theta=1/2. The survival probability is found to scale directly with y/L, where y is the distance along the step edge. The form of the survival probabilities agrees quantitatively with the theoretical prediction, which yields exponential decay in the limit of small y/L. The decay constant is found experimentally to be y(s)/L=0.076+/-0.033 for y/L

p49/STRAP, a Serum Response Factor Binding Protein (SRFBP1), Is Involved in the Redistribution of Cytoskeletal F-Actin Proteins during Glucose Deprivation.

The functional decline that usually accompanies adult aging also encompasses cellular changes including cytoplasmic architecture. In addition to their role in cytoskeletal structure, actin microfilaments have important roles in various cellular processes, including cell-to-cell communication and intracellular signaling. Age-related diseases and late-stage cellular morphological appearances often correlate with altered f-actin structure, which has been observed most notably in cancer. What remains less clear are the molecular pathways that may be involved in normal and premature aging-induced f-actin changes. We report herein that p49/STRAP, a serum response factor binding protein (SRFBP1), is increased with normal aging and appears to be sensitive to low glucose-exposure. Our study results suggest that increased levels of p49/STRAP expression tend to correlate with f-actin redistribution genes, particularly cofilin, while siRNA-mediated knockdown of p49/STRAP resulted in a reduction of thymosin-ß4. Furthermore, with the redistribution of f-actin, we observed an increase in the intermediate filament vimentin, compatible with the notion that vimentin may be increased due to its greater role in cytoskeletal dynamics during advancing population doubling levels (PDLs) and in response to a low-glucose exposure. Taken together, these data suggest that p49/STRAP may play a role in glucose-deprivation associated cytoskeletal changes.

Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.

A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer.

We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.

Experimental induction of parathyroid adenomas in the rat.

Neonatal inbred Wistar albino rats were given either 5 or 10 microCi radioiodine (131I) within 24 hours of birth. After weaning, animals were placed on diets high, normal, or deficient in vitamin D3 (cholecalciferol) for periods up to 2 years. In animals aged 12 months and older, adenomas were found in 0 of 67 unirradiated controls, in 22 of 67 given 5 microCi 131I, and in 25 of 67 given to microCi 131I. The incidence of tumors in irradiated animals was highest (55%) in those on a low-vitamin D diet and lowest (20%) in those on a high-vitamin D diet. Plasma calcium levels were significantly increased by the high-vitamin D diet, but the low-vitamin D diet did not lead to any significant decrease as compared to the calcium levels of the normal vitamin D diet group. Small but significant calcium increases were found in tumor-bearing animals. These findings indicate that parathyroid tumors in the rat can be induced by radiation and that their incidence is strongly influenced by dietary vitamin D content. The possibility that metabolites of vitamin D3 may influence parathyroid growth and tumor formation directly is discussed.

Prolongation of fibroblast life span associated with epithelial rat tumor development.

We have examined the proliferative behavior in culture of stromal cells of fibroblast morphology taken from various stages in the development of experimentally induced epithelial tumors in the rat thyroid. In this model long-term stimulation by an elevated level of serum thyroid stimulating hormone leads first to hyperplasia, then to multiple benign, and finally malignant tumors. Fibroblasts from hyperplastic glands, despite having already undergone more divisions in vivo, consistently showed a longer life span than normal fibroblasts in culture, averaging 16 compared with six divisions before senescing. In the three tumor bearing glands studied, all cultures have undergone more than 40 divisions (in one case over 70) and none has yet shown signs of senescence. We conclude that the life span of thyroid fibroblasts observed in culture has been reset to a higher limit by growth stimulation in vivo and furthermore that this limit may be lost altogether in fibroblasts associated with epithelial tumors.

N-myc expression in neoplasia of human thyroid C-cells.

In view of the frequent reports of the increased expression of myc oncogenes in several neuroendocrine tumor types, we have investigated c- and N-myc expression in human medullary carcinoma, a malignant tumor derived from the neuroendocrine "C"-cell subpopulation of the thyroid gland. In situ nucleic acid hybridization was used to permit analysis not only of tumors but also of normal C-cells which form a tiny, scattered, minority of the thyroid epithelial cell population. N-myc expression was readily demonstrable in 6 of 21 tumor samples and c-myc in one case, whereas neither N- nor c-myc mRNA was ever detected in normal C-cells. We conclude that N-myc expression is a specific feature of C-cell tumors and is not merely a differentiation marker of their cell of origin. The data therefore strengthen the hypothesis that myc oncogene activation plays a role in neuroendocrine neoplasia.