Comparing Patient-Reported Outcomes Among Anti-TNF-Experienced Patients with Crohn's Disease Initiating Vedolizumab Versus Ustekinumab.

BACKGROUND: Primary and secondary non-response to anti-tumor necrosis factor (TNF) therapy is common in patients with Crohn's disease (CD), yet limited research has compared the effectiveness of subsequent biological therapy. OBJECTIVE: We sought to compare the effectiveness of vedolizumab and ustekinumab in anti-TNF-experienced patients with CD, focusing on patient-prioritized patient-reported outcomes (PROs). METHODS: We conducted a prospective, internet-based cohort study nested within IBD Partners. We identified anti-TNF-experienced patients initiating with CD vedolizumab or ustekinumab and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient-Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included patient-reported short Crohn's disease activity index (sCDAI), treatment persistence, and corticosteroid use. Inverse probability of treatment weighting (IPTW) was used to control for a number of potential confounders and incorporated into linear and logistic regression models for continuous and categorical outcomes, respectively. RESULTS: Overall, 141 vedolizumab and 219 ustekinumab initiators were included in our analysis. After adjustment, we found no differences between treatment groups in our primary outcomes of Pain Interference or Fatigue or the secondary outcome of sCDAI. However, vedolizumab was associated with lower treatment persistence (OR 0.4, 95% CI 0.2-0.6) and higher corticosteroid use at follow-up assessment (OR 1.7, 95% CI 1.1-2.6). DISCUSSION: Among anti-TNF experienced patients with CD, Pain Interference or Fatigue was not significantly different 4-10 months after starting ustekinumab or vedolizumab. However, reduced steroid use and increased persistence suggest superiority of ustekinumab for non-PRO outcomes.

Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas.

Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Here, using transcriptomic data for 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we present a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. We confirm pathway dysregulation in separate patient populations, demonstrating the robustness of our approach. Bootstrapping simulations were then applied to assess the biological significance of these alterations. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest, and patterns of metabolic flux, in both common and rare disease sites. Further, we show that Master Metabolic Transcriptional Regulators explain why metabolic differences exist, can segregate patient populations, and predict responders to different metabolism-targeted therapeutics.

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease.

BACKGROUND: The impact of combination therapy on disease-related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well-defined. AIM: To examine the effect of combination therapy on disease outcomes in CD and UC. METHODS: Using a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti-TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD-related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders. RESULTS: We included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63-1.22) or UC (OR: 1.45, 95% CI: 0.63-3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37-0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14-0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45-1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti-TNF biologics. CONCLUSION: The benefit of combination immunomodulator-biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.

Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) on certain immunosuppressants have increased herpes zoster (HZ) risk. AIM: To determine the risk of HZ in IBD and how antitumour necrosis factor-alpha (anti-TNF) agents affect this risk. METHODS: We performed a retrospective cohort and nested case-control study using administrative data from IMS LifeLink(®) Information Assets-Health Plan Claims Database. In the cohort, we identified IBD patients

Colorectal cancer in women: hormone replacement therapy and chemoprevention.

Colorectal cancer (CRC) accounts for 9.4% of new cancer diagnoses among women world-wide. CRC is the third leading cause of incident cancer among women in the United States and has immense impact on morbidity and mortality. We summarize data on CRC pathogenesis and risk in women. We also review the findings from the Women's Health Initiative (WHI) on CRC risk reduction associated with hormone replacement therapy (HRT) use. We then review observational studies since the WHI which evaluated HRT as a chemopreventive agent for CRC among women. The potential mechanisms behind the association between HRT use and CRC are also reviewed. We then discuss the requirements for implementation of chemopreventive agents, and why HRT should not be used for this indication given current knowledge. Further data on the risk-benefit profile of short-term HRT use are needed and will determine whether there is any future role for HRT use in the chemoprevention of CRC.

Effects of external beam irradiation on the TRAM flap: an experimental model.

The rat model of the transverse rectus abdominis musculocutaneous (TRAM) flap was used in the present study to determine the effects of external beam radiation on myocutaneous flap histology and pathophysiology. A total of 57 adult Sprague-Dawley rats underwent a TRAM procedure. A pilot study with 17 animals was first performed to determine proper radiation dosages, and the remaining 40 rats were then used in the definitive study. In half of the definitive study group, the flaps were subjected to fractionated doses of external beam radiation, whereas the other half served as controls. Six weeks after the last radiation dose, all animals were killed and the flaps were harvested for mechanical assessment and histopathologic evaluation. All TRAM flaps survived in both groups. The irradiated and nonirradiated flaps were minimally distinguishable in viscoelastic properties, as well as by histopathologic examination. Growth of the flap in the irradiated animals was significantly diminished (48 percent average surface area increase in irradiated flaps, versus 92 percent increase in nonirradiated flaps, p < 0.05). These findings suggest that the myocutaneous flap is relatively resistant to some of the known adverse affects of radiation on living tissues.

Size transformations of intermediate and low density lipoproteins induced by unesterified fatty acids.

Plasma from individual human subjects is known to contain multiple discrete subpopulations of low (LDL) and intermediate (IDL) density lipoproteins that differ in particle size and density. The metabolic origins of these subpopulations are unknown. Transformation of IDL and larger LDL to smaller, denser LDL particles had been postulated to occur as a result of the combined effects of triglyceride hydrolysis and lipid transfer. However, the presence of multiple small LDL subspecies has been described in patients lacking cholesteryl ester transfer protein. We have characterized an alternative pathway in which size decrements in IDL or LDL are produced in the presence of unesterified fatty acids and a source of apolipoprotein (apo) A-I. Incubation of IDL or LDL subfractions with palmitic acid and either high density lipoproteins (HDL), apoHDL, or purified apoA-I gives rise to apoA-I, apoB-containing complexes that can dissociate into two particles, an apoB-containing lipoprotein with particle diameter 10-30 A smaller than the starting material, and a still smaller species (apparent peak particle diameter 140-190 A) containing lipid and apoA-I but no apoB. The newly formed IDL or LDL are depleted in phospholipid and free cholesterol with no change in apoB-100 as assessed by SDS gel electrophoresis. We hypothesize that this reaction may contribute to the formation of discrete IDL and LDL subpopulations of varying size during the course of hydrolysis of triglyceride-rich lipoproteins in plasma.

Dissociation of high density lipoprotein precursors from apolipoprotein B-containing lipoproteins in the presence of unesterified fatty acids and a source of apolipoprotein A-I.

Incubation of low (LDL), intermediate (IDL), or very low density lipoproteins (VLDL) with palmitic acid and either high density lipoproteins (HDL), delipidated HDL, or purified apolipoprotein (apo) A-I resulted in the formation of lipoprotein particles with discoidal structure and mean particle diameters ranging from 146 to 254 A by electron microscopy. Discs produced from IDL or LDL averaged 26% protein, 42% phospholipid, 5% cholesteryl esters, 24% free cholesterol, and 3% triglycerides; preparations derived from VLDL contained up to 21% triglycerides. ApoA-I was the predominant protein present, with smaller amounts of apoA-II. Crosslinking studies of discs derived from LDL or IDL indicated the presence of four apoA-I molecules per particle, while those derived from large VLDL varied more in size and contained as many as six apoA-I molecules per particle. Incubation of discs derived from IDL or LDL with purified lecithin:cholesterol acyltransferase (LCAT), albumin, and a source of free cholesterol produced core-containing particles with size and composition similar to HDL2b. VLDL-derived discs behaved similarly, although the HDL products were somewhat larger and more variable in size. When discs were incubated with plasma d greater than 1.21 g/ml fraction rather than LCAT, core-containing particles in the size range of normal HDL2a and HDL3a were also produced. A variety of other purified free fatty acids were shown to promote disc formation. In addition, some mono and polyunsaturated fatty acids facilitated the formation of smaller, spherical particles in the size range of HDL3c. Both discoidal and small spherical apoA-I-containing lipoproteins were generated when native VLDL was incubated with lipoprotein lipase in the presence of delipidated HDL. We conclude that lipolysis product-mediated dissociation of lipid-apoA-I complexes from VLDL, IDL, or LDL may be a mechanism for formation of HDL subclasses during lipolysis, and that the availability of different lipids may influence the type of HDL-precursors formed by this mechanism.

Recovery of thrombopoietin during purification.

A thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) was previously purified by a six-step purification procedure. However, the exact quantity of TSF that was recovered, through the various purification procedures, was unknown because of the absence of a method for establishing a unit of measure of TSF. In the present work dose-response relationships on both the crude TSF preparations and on the more highly purified TSF were determined. TSF units were calculated from the dose-response curves. A unit of TSF is defined as the amount of material (mg) that is required to increase the percentages 35S incorporation into platelets of immunothrombocythemic mice by 50% above the baseline. The results of determining the TSF units on the crude TSF preparation indicated that 0.11 unit (U) of TSF/mg protein was present. Results showed that the specific activity of TSF can be increased to about 3.6 U/mg by a single purification procedure using Sephadex G-75 column chromatography. Increased specific activities were obtained by additional purification steps, i.e., DEAE-cellulose column chromatography, SE-HPLC, DEAE-HPLC, and SDS-PAGE. The purified product appears to have a specific activity of about 11,000 U/mg of protein with 0.00003% of the protein and 1.1% of the TSF recovered from the starting material. Establishing a unit of measure for TSF will allow calculations of its degree of purity, provide a method for quantitation of recoveries of activities after various purification procedures, and allow comparisons of results from different experiments and different laboratories.

Relationship between autonomic and behavioral thermoregulation in the golden hamster.

Preferred ambient temperature (Ta) of male golden hamsters (Mesocricetus auratus) was measured repeatedly by placing the animals in a temperature gradient for 80 min. A total of 180 observations were made during the last 20 min of treatment in the gradient. The mean preferred Ta was 28.2 +/- 0.2 degrees C. In another experiment the same animals were placed in a temperature-controlled chamber for 80 min while metabolic rate, evaporative water loss, thermal conductance, and colonic temperature were measured at Ta's of 14-34 degrees C. The lower critical Ta, the Ta below which metabolic rate increased above the resting level, was 28 degrees C. This Ta corresponds closely to the mean preferred Ta of the hamster when placed in the temperature gradient. Evaporative water loss was minimal at Ta's of 14 and 16 degrees C and increased gradually with increasing Ta. Thermal conductance was minimal between Ta's of 14 and 28 degrees C and then increased sharply with increasing Ta. The data from the hamster are qualitatively similar to the mouse in that the preferred Ta corresponds with the lower critical Ta. It appears that, for these rodents, the control of preferred Ta is critically related to the animal's metabolic requirements.

Temperature regulation in the unrestrained rabbit during exposure to 600 MHz radiofrequency radiation.

Six male New Zealand white rabbits were individually exposed to 600 MHz radiofrequency (RF) radiation for 90 min in a waveguide exposure system at an ambient temperature (Ta) of 20 or 30 degrees C. Immediately after exposure, the rabbit was removed from the exposure chamber and its colonic and ear skin temperatures were quickly measured. The whole-body specific absorption rate (SAR) required to increase colonic and ear skin temperature was determined. At a Ta of 20 degrees C the threshold SAR for elevating colonic and ear skin temperature was 0.64 and 0.26 W/kg, respectively. At a Ta of 30 degrees C the threshold SARs were slightly less than at 20 degrees C, with values of 0.26 W/kg for elevating colonic temperature and 0.19 W/kg for elevating ear skin temperature. The relationship between heat load and elevation in deep body temperature shown in this study at 600 MHz is similar to past studies which employed much higher frequencies of RF radiation (2450-2884 MHz). On the other hand, comparison of these data with studies on exercise-induced heat production and thermoregulation in the rabbit suggest that the relationship between heat gain and elevation in body temperature in exercise and from exposure to RF radiation may differ considerably. When combined with other studies, it was shown that the logarithm of the SAR required for a 1.0 degree C elevation in deep body temperature of the rabbit, rat, hamster, and mouse was inversely related to the logarithm of body mass. The results of this study are consistent with the conclusion that body mass strongly influences thermoregulatory sensitivity of the aforementioned laboratory mammals during exposure to RF radiation.

Temperature regulation in the mouse and hamster exposed to microwaves in hot environments.

Colonic temperature was measured in naive BALB/c mice and golden hamsters immediately following 90-min exposures to 2450-MHz radiofrequency (RF) radiation at an ambient temperature (Ta) of 32.2 or 35 degrees C (dry air). Exposures were performed in a temperature-controlled waveguide which permitted continuous monitoring of the specific absorption rate (SAR) of RF energy. At a Ta of 32.2 degrees C the threshold SAR for elevating colonic temperature and the SAR resulting in a 0.5 degree C elevation in colonic temperature were, respectively, 4.3 and 6.5 W/kg for the mouse and 0.68 and 1.1 W/kg for the hamster. At a Ta of 35 degrees C these values were 0.12 and 0.63 W/kg for the mouse and 0.46 and 0.8 W/kg for the hamster. The SARs required to elevate body temperature in the mouse and hamster at these relatively warm Ta's are considerably lower than those required at cooler Ta's of 20 to 30 degrees C. Overall, the hamster became hyperthermic at lower SARs than the mouse. Ta's of 35 degrees C and greater are frequently encountered during heat waves in the summer months. Under such stressful environmental conditions where heat loss is impaired, absorption of RF radiation at relatively low SARs may lead to significant hyperthermia which would otherwise be readily dissipated at lower Ta's.

Sulfolane-induced hypothermia enhances survivability in mice.

Mice injected intraperitoneally with sulfolane (tetrahydrothiophene-1,1-dioxide) underwent a significant decrease in metabolic rate and body temperature at ambient temperatures of 20 and 30 degrees C but not 35 degrees C. If given the opportunity, mice treated with sulfolane preferentially sought a cool ambient temperature. When given an LD50 dose of sulfolane (1270 mg/kg), the percentage mortality varied directly with ambient temperature. For example, at 35 degrees C mortality was 75% whereas at 25 degrees C mortality was only 8%. By undergoing an autonomically and behaviorally mediated decrease in body temperature (i.e., regulated hypothermia), sulfolane-treated mice appear to enhance their chance of survival.

Effect of sodium pentobarbital on behavioral thermoregulation in rats and mice.

In this study on behavioral thermoregulation, male Sprague-Dawley rats were given intraperitoneal (IP) injections of sodium pentobarbital in doses of 0, 1, 5, 10 or 15 mg/kg and male CBA/J mice were given doses of 0, 5, 10, 15 or 30 mg/kg. The animals were immediately placed in a temperature gradient which allowed them to select their preferred ambient temperature (Ta). The preferred Ta of rats increased following an injection of 10 mg/kg sodium pentobarbital, whereas, the barbiturate had no effect on the preferred Ta of mice. In another study, male rats and mice were given sodium pentobarbital in doses of 0, 5, 10 and 15 mg/kg and then placed into a temperature-controlled environmental chamber set at 30 degrees C for mice and 25 degrees C for rats (i.e., their approximate preferred Ta when dosed with sodium pentobarbital). Colonic temperatures were taken one hour after injection. Sodium pentobarbital induced dose dependent hypothermia in rats at 25 degrees C and hyperthermia in mice at 30 degrees C. These data suggest a direct or indirect block of heat gain/conserving effectors in rats treated with sodium pentobarbital which results in hypothermia and an appropriate compensatory selection of a warmer Ta.

Brain temperature measurements in rats: a comparison of microwave and ambient temperature exposures.

In an effort to understand microwave heating better, regional brain and core temperatures of rats exposed to microwave radiation (2450 MHz) or elevated air temperatures were measured in two studies. In general, we have found no substantial evidence for temperature differentials, or "hot spots," in the brain of these animals. In the first study, after a 30-min exposure, no temperature differences between brain regions either after microwave or ambient air exposure were found. However, a highly significant correlation between brain and core temperatures was found and this correlation was the same for both microwave and ambient air heating. In the second study, time-temperature profiles were measured in rats exposed to either 30 mW/cm2 or 36.2 degrees C. In this study, the 30-min exposure period was divided into seven intervals and the change in temperature during each period was analyzed. Only the cortex showed significantly different heating rates between the air heating and microwave heating; however, this difference disappeared after the initial 5 min of exposure.

Thermoregulation in mice following acute chlordimeform administration.

CBA/J mice were injected intraperitoneally (i.p.) with the formamidine insecticide chlordimeform (CDM) while colonic temperature, preferred ambient temperature (Ta), and lethality were monitored. In the first experiment there was a dose-dependent decrease in colonic temperature when measured 60 min after administering CDM doses of 0, 15, 30, 60, and 75 mg/kg. The hypothermic effect of CDM was more pronounced at a Ta of 20 degrees C than at 30 degrees C. In the second experiment, CDM at doses greater than 30 mg/kg caused a dose-dependent reduction in preferred Ta from the normal value of approx. 30 degrees C to approx. 22 degrees C. Thus, the CDM-treated mouse lowered body temperature by selecting a cool Ta which accelerated the hypothermic effect. In the final experiment, a 90 mg/kg i.p. injection of CDM (the approximate LD50 dose) caused 10% and 0% mortality at a Ta of 20 and 30 degrees C, respectively, and 80% mortality at a Ta of 35 degrees C. It is concluded that the physiological and behavioral response to CDM administration, i.e., selecting a cool Ta and lowering body temperature, may be beneficial to survival.

Studies on the purification of thrombopoietin from kidney cell culture medium.

A thrombocytopoiesis-stimulating factor (TSF) has been purified from human embryonic kidney (HEK) cell culture medium. In the initial purification step, crude HEK cell culture medium was fractionated with saturated ammonium sulfate (step I). The proteins precipitated by 40% to 60% and 60% to 80% ammonium sulfate saturation increased the percent of sulfur 35 incorporation into platelets of assay mice (P less than 0.01). The ammonium sulfate-precipitated proteins that contained significant TSF activity were further refined on Sephadex G-75 columns (step II). The fraction containing the highest specific activity (greatest 35S incorporation into platelets of assay mice per milligram of protein) was further purified by diethylaminoethyl (DEAE)-cellulose column chromatography (step III). TSF activity was eluted from the columns between 0.3 and 1.0 mol/L NaCl. Additional Sephadex chromatography of post-DEAE-chromatographic preparations further increased the purity of the TSF (step IV). TSF from this four-step procedure was further processed on a DEAE-high-performance liquid chromatography (HPLC) column (step Va) or size exclusion (SE)-HPLC columns (step Vb). After HPLC, the activity was localized in a region corresponding to a retention time of 6 to 8 minutes for the DEAE-HPLC, but longer times were found after SE-HPLC. TSF was further purified by additional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and SE-HPLC (step VI). The final product had significant TSF activity and represented a purification of approximately 500,000-fold. It was also shown that the isoelectric pH of partially purified TSF was 4.7 and the molecular weight of the more highly purified preparation was approximately 32,000. After extraction by a combination of chromatographic procedures, a single homogeneous product was obtained.

Effect of sulfolane on behavioral and autonomic thermoregulation in the rat.

Sulfolane (tetrahydrothiophene 1,1-dioxide), a commonly used extraction solvent, promotes rapid changes in the thermoregulatory system. Colonic temperature, skin temperature, metabolic rate, and preferred ambient temperature (Ta) were measured over an 8-h period in the Sprague-Dawley rat following an intraperitoneal injection of sulfolane at 800 mg/kg or of physiological saline. At Ta values of 15 and 25 degrees C, sulfolane caused a significant inhibition in metabolic rate and reduction in colonic temperature, which lasted over the 8-h measuring period. At both Ta values, metabolic rate tended to recover approximately 4 h after sulfolane injection. Colonic temperature recovered with time but was still significantly reduced at 8 h postinjection. Tail skin temperature was unaffected. Preferred Ta in the sulfolane-treated rat was not significantly different from the controls. In spite of their hypothermic condition, the sulfolane-treated animals did not select a warm Ta. Since sulfolane toxicity appears to be greater with increased tissue temperature, the sulfolane-induced hypothermia may enhance survival of the rat following exposure to toxic levels of sulfolane.