Maximum Body Weight Research Articles

An Essential Role of Maspin in Embryogenesis and Tumor Suppression.

Maspin (SerpinB5) is an epithelial-specific tumor suppressor gene product that displays context-dependent cellular functions. Maspin-deficient mouse models created to date have not definitively established maspin functions critical for cancer suppression. In this study, we generated a mouse strain in which exon 4 of the Maspin gene was deleted, confirming its essential role in development but also enabling a breeding scheme to bypass embryonic lethality. Phenotypic characterization of this viable strain established that maspin deficiency was associated with a reduction in maximum body weight and a variety of context-dependent epithelial abnormalities. Specifically, maspin-deficient mice exhibited pulmonary adenocarcinoma, myoepithelial hyperplasia of the mammary gland, hyperplasia of luminal cells of dorsolateral and anterior prostate, and atrophy of luminal cells of ventral prostate and stratum spinosum of epidermis. These cancer phenotypes were accompanied by increased inflammatory stroma. These mice also displayed the autoimmune disorder alopecia aerate. Overall, our findings defined context-specific tumor suppressor roles for maspin in a clinically relevant model to study maspin functions in cancer and other pathologies. Cancer Res; 77(4); 886-96. ©2017 AACR.

Abstract P4-06-06: Consistent dosing-time dependent tolerability of everolimus (EV) in a pilot study in women with metastatic breast cancers (MBC) and in a mouse chronopharmacology investigation

Abstract Background The molecular circadian clock regulates mTOR activity, the main target of EV. EV use is hampered by adverse events in MBC patients (pts). Knowing the optimal timing of EV oral intake could improve tolerability, thus compliance and treatment efficacy. Objective: To assess the relevance of EV timing for side effects in MBC pts, and to determine the impact of EV timing for body weight, circadian rest-activity pattern, and liver circadian clock in mice. Materials and methods: From 2013 to 2014, 19 MBC pts were treated with EV 10mg plus hormonotherapy at St Louis hospital Breast Cancer unit. Morning or Evening oral intake was prescribed by the medical oncologist in charge of each patient for both EV and hormonotherapy. Side effects were compared according to EV timing. We further investigated whether oral (po) EV timing mattered mice regarding tolerability. EV (5-20 mg/kg/day x 14 days) was administered through oral gavage at 4 circadian times, 6 hours apart to different groups of synchronized male or female B6D2F1 mice (n=32/sex). Body weight change and lethal toxicity were the endpoints. EV effects were further determined on clock gene Per2 expression in the liver of Per2::luciferase (Per2::luc) mice. Per2::luc expression was monitored in freely-moving mice every minute for 3 days before, 5 days during and 3 days after daily EV at one of two timepoints using Real Time-Biolumicorder (RT-BIO, Geneva, Sw). Periods and amplitudes of Per2::luc rhythms were determined with spectral analysis. Results: Nine pts took EV in the morning and 10 in the evening for a median duration of 7.5 months (1.3-19.2 m). Median age was 59 (39-85), median delay between metastatic disease and EV treatment was 52.5 months. Pts had a median of 3 prior lines of treatment for MBC. EV was associated with exemestane (13 pts), or tamoxifen (6 pts). Evening EV was associated with higher occurrence of edema (6 vs 2 pts), fatigue (9 vs 2 pts), and pneumonia (3 vs 0 pts). Equitoxic doses of EV were twice as high in female as compared to male mice. EV timing at the beginning of the light (rest) span resulted in a lethal toxicity rate of 25% in female mice receiving 20 mg/kg/d and 50% in male mice dosed with 10 mg/kg/d). In contrast all the mice treated with EV at the beginning of the dark (activity) span survived, irrespective of dose level. Maximum body weight loss ranged from 5% following EV timing near activity onset to 12% after EV delivery near rest onset, both in males (5 mg/kg/d) and females (10 mg/kg/d) (ANOVA p<0.001). The circadian expression of liver Per2::luc was abolished following EV dosing near rest onset. Per2::luc remained rhythmic in mice receiving EV at the beginning of the activity span. Conclusion: Tolerability was largely improved by the delivery of EV near the onset of the activity span both in women with MBC and in male or female mice. Morning administration of EV could minimize metabolic alterations and fatigue in humans. This timing should further avoid circadian disruption in the liver molecular clocks thus ensure better treatments tolerability. Citation Format: Giacchetti S, Li XM, Ozturk N, Cuvier C, Machowiak J, Arrondeau J, Chang-Marchand Y, Espié M, Okyar A, Lévi F. Consistent dosing-time dependent tolerability of everolimus (EV) in a pilot study in women with metastatic breast cancers (MBC) and in a mouse chronopharmacology investigation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-06.

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice

BackgroundH9N2 influenza viruses circulate globally and are considered to have pandemic potential. The hyper-inflammatory response elicited by these viruses is thought to contribute to disease severity. Calcitriol plays an important role in modulating the immune response to viral infections. However, its unknown whether calcitriol can attenuate the inflammatory response elicited by H9N2 influenza virus infection.MethodsHuman lung A549 epithelial cells were treated with calcitriol (100 nM) and then infected with an H9N2 influenza virus, or infected and then treated with calcitriol (30 nM). Culture supernatants were collected every 24 h post infection and the viral growth kinetics and inflammatory response were evaluated. Calcitriol (5 mg/kg) was administered daily by intraperitoneal injection to BABL/c mice for 15 days following H9N2 influenza virus infection. Mice were monitored for clinical signs of disease, lung pathology and inflammatory responses.ResultsCalcitriol treatment prior to and post infection with H9N2 influenza significantly decreased expression of the influenza M gene, IL-6, and IFN-β in A549 cells, but did not affect virus replication. In vivo, we found that calcitriol treatment significantly downregulated pulmonary inflammation in mice 2 days post-infection, but increased the inflammatory response 4 to 6 days post-infection. In contrast, the antiviral cytokine IFN-β was significantly higher in calcitriol-treated mice than in the untreated infected mice at 2 days post-infection, but lower than in untreated infected mice on days 4 and 8 post-infection. The elevated levels of pro-inflammatory cytokines and the decreased levels of antiviral cytokine are consistent with the period of maximum body weight loss and the lung damage in calcitriol-treated mice.ConclusionsThese results suggest that calcitriol treatment might have a negative impact on the innate immune response elicited by H9N2 infection in mice, especially at the later stage of influenza virus infection. This study will provide some novel insights into the use of calcitriol to modulate the inflammatory response elicited by influenza virus infection in humans.

Interleukin-1 receptor type 1 signaling induces excessive inflammatory responses in H1N1 influenza virus infection

Objective To investigate the role of interleukin-1 receptor type 1 (IL-1R1) signaling in H1N1 influenza virus infection. Methods IL-1R1 knockout (IL-1R1-/-) mice and wild type (WT) mice were infected intranasally with 2×104 TCID50 (50% tissue culture infective dose) of influenza virus H1N1 PR8. Changes in clinical signs, survivals and bodyweights of those mice were monitored daily for 14 consecutive days. Three mice from each group were sacrificed at 3, 7 and 14 days post infection (d.p.i), from which whole lungs were harvested. A part of the lobes was fixed in 4% paraformaldehyde for histopathological assessment and the rest were split and stored at -80 centigrade for further analysis. Real-time quantitative PCR and cytometric bead array (CBA) were performed to detect viral loads in lungs and inflammatory cytokines in supernatants of lung homogenates. Results The mice in both groups showed severe symptoms after the infection of PR8. The maximum bodyweight loss of IL-1R1-/- mice [(24.22±0.80) % at 8 d. p.i] was lower than that of WT mice [(28.03±1.51)% at 9 d. p.i] (P<0.05). The IL-1R1-/- mice with PR8 infection showed a higher survival rate (90%) as compared with that of the control group (40%) (P<0.05). No statistical differences in virus loads were observed between the two groups at 3, 7 and 14 d. p.i. The lung weight to body weight ratio of IL-1R1-/- mice [(1.42±0.03) %] was lower than that of WT mice [(1.79±0.08) %] at 3 d. p.i (P<0.05). Pathological changes in IL-1R1-/- mice were less severe than those in WT mice. CBA detection assay revealed that the proinflammatory cytokines in lungs of IL-1R1-/- mice were less than those in WT mice. Conclusion IL-1R1 signaling plays a pathogenic role in mice infected with 2×104 TCID50 of influenza virus PR8 by promoting inflammatory responses. Key words: IL-1R1; Influenza virus; Inflammatory responses

Risk factors for complications of laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass

BackgroundAlthough bariatric procedures are considered safe, yet still they involve a risk of possible perioperative complications. Identification of risk factors for complications would allow for appropriate preoperative optimization of the patient, as well as reasonable postoperative care and early diagnosis and treatment of possible complications. The aim of this study was to determine the risk factors for perioperative complications after laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). Material and methodsA retrospective analysis of prospectively collected data of patients operated for morbid obesity. Regarding postoperative complications defined as adverse events occurring within 30 days of the procedure. Factors associated with patient characteristics and those related to the surgical procedure were determined. 408 patients met inclusion criteria and were submitted to surgical treatment. LSG and LRYGB were performed in 233 and 175 patients, respectively. ResultsComplications were observed in 30 (7.3%) patients. The maximum preoperative body weight and BMI, as well as body weight and BMI on the day of surgery were associated with increased complication rate. The type of the procedure did not influence perioperative complications (LRYGB vs. LSG; OR: 1.14; CI: 0.53–2.44; p = 0.74). Although operative time statistically significantly increased the risk of complications, it did not seem clinically relevant (OR: 1.01; CI: 1.00–1.02; p = 0.003). An increase in the number of stapler firings used significantly increased complication rate only in LSG group. ConclusionLonger duration of LSG and the increase in the number of stapler firings used during LSG should alert a surgeon to an increased risk of postoperative complications. In patients submitted to LRYGB the risk of possible complications increases with BMI.

Lysine requirements of Korean native ducklings for three weeks after hatch

Dietary lysine content in poultry diets is critical to improve feed utilization efficiency, body protein deposition rate, and carcass traits of growing and finishing poultry. The objective of the current study was to estimate the optimum digestible lysine requirements for maximum growth performance, efficient utilization of nitrogen, and carcass traits of male Korean native ducklings for 3 wk after hatch. A total of 720 one-day-old male Korean native ducklings were used in a completely randomized design having 8 dietary treatments to provide a range of digestible lysine content from 0.44 to 1.07%. Ducklings were randomly allotted to 24 floor pens (6 replicates per treatment and 15 ducklings per pen) and were offered the respective diets on an ad libitum basis for the period of study. Body weight and feed intake were measured weekly to calculate feed conversion ratio. At the termination of the experiment, 2 ducklings per pen were euthanized via cervical dislocation to weigh empty body and drumsticks. The digestible lysine requirement was determined by taking a mean value after fitting the data to both linear-plateau and quadratic-plateau models. Digestible lysine requirements for Korean native ducklings for 3 wk after hatch were estimated to be 0.71, 0.74, 0.65 and 1.01% for maximum body weight, daily gain, and daily feed intake, and for minimum feed conversion ratio, respectively.

Withdrawal from bariatric treatment - an analysis under various demographic conditions.

Documentation of 115 subsequent patients diagnosed with grade 3 obesity, considered eligible for surgical treatment, was analysed since 2015. A subgroup of 68 patients was selected from this group and the included patients who decided to cancel their treatment at various stages. Their history since presentation at the obesity treatment centre, BMI with its history, age, education and place of residence were analysed, followed by a telephone survey. 42 patients were finally contacted. Special attention was placed on the analysis of patients taking into account their place of residence. Patients were divided into inhabitants of rural and urban areas. In the study group of 68 patients, 19 (27.9%) were inhabitants of rural areas and 49 (72.1%) of urban areas. Women accounted for 67.6%, and men for 32.4%. The mean age of patients when they presented for treatment was 43 years. On average, men presented 5 years later compared to women. The mean BMI on qualification for treatment of obesity was 47.6 kg/m2. The mean BMI max - 49.6 kg/m2. There were no differences regarding education in both populations. Despite the lack of differences regarding changes in the BMI since withdrawal from treatment, as many as 63% of patients from rural areas reached the BMI max in this time. There were demographic differences between the degree of obesity observed among patients receiving bariatric treatment, and inhabitants of urban areas were favoured. Patients from rural areas who withdrew from bariatric treatment and were left without medical care significantly more often achieved their maximum body weight, when compared to those living in urban areas. The active participation of physicians, both specialists and general practitioners, in the life of obese patients is imperative.

Length-weight relationships and basic biological information on 64 fish species from lower sections of the Wujiang River, China

Summary The present study provides the length–weight relationships (LWRs) for 64 fish species belonging to eight families from the lower sections of Wujiang River, a tributary of the upper Yangtze River in China. LWRs for eight of these species are unknown to FishBase and new maximum body weights are recorded for 25 species. In addition, some basic biological information on 64 fish species is also summarized. These results will be useful for fishery research, management and conservation in the Wujiang River.

Bodyweight change aids prediction of survival in chronic equine grass sickness.

Objective criteria for predicting survival of chronic grass sickness cases are currently lacking. To determine whether the rate and/or magnitude of bodyweight change during hospitalisation of chronic grass sickness cases can provide an objective predictor of survival to discharge from hospital. Clinicians' recorded indication(s) for euthanasia were also reviewed. Single centre retrospective observational study. Case records of all horses admitted for management of chronic grass sickness to The Dick Vet Equine Hospital between 1998 and 2013 were analysed. Case background, survival to hospital discharge, indication(s) for euthanasia, disease duration at admission and bodyweight changes during the hospitalisation period were analysed, and data for survivors and nonsurvivors compared. Percentage weight change was calculated for 7 day intervals up to 28 days (0-7, 7-14, 14-21, 21-28 days) and for entire periods from the first weight recorded (0-7, 0-14, 0-21, 0-28 days). These results were used to estimate survival probability conditional on weight change. The study sample comprised 213 horses, with 114 survivors (53.5%) and 99 (46.5%) nonsurvivors. Compared with nonsurvivors, survivors had significantly lower median maximum bodyweight loss as a percentage of first weight (survivors 5.9%, interquartile range 1.8-13.5; nonsurvivors 12.7%, 6.4-17.3). Throughout all time periods analysed, survivors had significantly lower median bodyweight loss than nonsurvivors, but no specific time period was more predictive of survival. Highest percentages of total bodyweight loss for individual horses were comparable for survivors (36%) and nonsurvivors (37%). Survival prediction curves reporting percentage survival rates for all time periods analysed provided data to aid prediction of chronic grass sickness survival. Overall, nonsurvivors had greater bodyweight loss than survivors. Rapidity and magnitude of bodyweight loss were equally predictive of outcome. Percentage survival prediction curves provide objective data to aid discussion of prognosis, but greater predictive specificity with associated sensitivity is required for clinical decision making in individual cases.

Influence of central obesity in estimating maximal oxygen uptake

OBJECTIVE:To assess the influence of central obesity on the magnitude of the error of estimate of maximal oxygen uptake in maximal cycling exercise testing.METHOD:A total of 1,715 adults (68% men) between 18-91 years of age underwent cardiopulmonary exercise testing using a progressive protocol to volitional fatigue. Subjects were stratified by central obesity into three quartile ranges: Q1, Q2-3 and Q4. Maximal oxygen uptake [mL.(kg.min)-1] was estimated by the attained maximal workload and body weight using gender- and population-specific equations. The error of estimate [mL.(kg.min)-1] and percent error between measured and estimated maximal oxygen uptake values were compared among obesity quartile ranges.RESULTS:The error of estimate and percent error differed (mean ± SD) for men (Q1=1.3±3.7 and 2.0±10.4; Q2-3=0.5±3.1 and -0.5±13.0; and Q4=-0.3±2.8 and -4.5±15.8 (p<0.05)) and for women (Q1=1.6±3.3 and 3.6±10.2; Q2-3=0.4±2.7 and -0.4±11.8; and Q4=-0.9±2.3 and -10.0±22.7 (p<0.05)).CONCLUSION:Central obesity directly influences the magnitude of the error of estimate of maximal oxygen uptake and should be considered when direct expired gas analysis is unavailable.

Abstract C54: Combination of PARP inhibitor talazoparib with etirinotecan pegol exhibits synergistic anti-tumor effect in non-BRCA preclinical cancer models

Abstract Introduction: Talazoparib (BMN 673) is a highly potent and specific PARP1/2 inhibitor (PARPi) that has demonstrated significant clinical activity in patients with germline BRCA mutation ovarian and breast cancer, as well as in patients with small cell lung cancer. Non-clinically, combination of PARPi, including talazoparib, with Topoisomerase 1 (Top1) inhibitors, such as irinotecan, has shown synergy in BRCA1 mutant MX-1 model (Shen et al. 2013; Hoch et al., NCI-AACR-EORTC 2014). Etirinotecan pegol (NKTR-102, pegylated irinotecan) is a long-acting Top1 inhibitor, designed to provide extended drug exposure to the tumor. In preclinical models, NKTR-102 has improved efficacy and tolerability over irinotecan. We therefore hypothesized that the combination of talazoparib with NKTR-102 would be well tolerated and harness the full synergistic potential of combined Top1 and PARP inhibition. Method: In tolerability studies, three dose levels of talazoparib (0.1, 0.2 and 0.3 mg/kg, QDx14) given with NKTR-102 (10 and 50 mg/kg irinotecan-equivalent dose, iv. Q7Dx2), or irinotecan (10, 30 and 60 mg/kg, ip, Q7Dx2) were evaluated in non-tumor-bearing nude mice (Balb/c, n = 4 per group). In efficacy studies, multiple dose levels of a single agent (i.e., talazoparib, NKTR-102, or irinotecan) as well as corresponding dose combinations were evaluated in NCI-H1048 and HT-29 xenograft tumors with wildtype BRCA status (n = 8-10 per group). Tumor volume and body weight were measured twice weekly. Results: For talazoparib and NKTR-102, all combination doses were tolerated, the maximum mean body weight loss reached 6.2% in the high dose group (0.3 mg/kg talazoparib plus 50 mg/kg NKTR-102). For talazoparib and irinotecan, MTD was observed at 0.2 mg/kg BMN 673 plus 30 mg/kg irinotecan. In efficacy studies, single-agent NKTR-102 had dose-dependent anti-tumor activity against NCI-H1048 tumor, while talazoparib showed limited activity with QDx14 dosing schedule. Combination of talazoparib (0.2 or 0.3 mg/kg, QDx14) with NKTR-102 (10 mg/kg, Day 1) exhibited significantly greater anti-tumor effect than either single agent alone. In contrast, combination of talazoparib (0.2 mg/kg, QDx14) with irinotecan (30 mg/kg, Day 1) only had moderate combination effect in the NCI-H1048 model. In HT-29 model, additive anti-tumor effect was also observed for talazoparib + NKTR-102, but not for talazoparib + irinotecan under the same experimental condition. Conclusion: Our data indicate that the combination of NKTR-102 and talazoparib is better tolerated than that of irinotecan and talazoparib, and results in stronger combination anti-tumor activity. The results support potential development of the combination in human studies. Citation Format: Ying Feng, Yuqiao (Jerry) Shen, Leonard E. Post, Steve Doberstein, Deborah Charych, Ute Hoch. Combination of PARP inhibitor talazoparib with etirinotecan pegol exhibits synergistic anti-tumor effect in non-BRCA preclinical cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C54.

Effects of powdered Montmorency tart cherry supplementation on an acute bout of intense lower body strength exercise in resistance trained males.

BackgroundThe purpose of this study was to examine whether short-term ingestion of a powdered tart cherry supplement prior to and following intense resistance-exercise attenuates muscle soreness and recovery strength loss, while reducing markers of muscle damage, inflammation, and oxidative stress.MethodsTwenty-three healthy, resistance-trained men (20.9 ± 2.6 yr, 14.2 ± 5.4 % body fat, 63.9 ± 8.6 kg FFM) were matched based on relative maximal back squat strength, age, body weight, and fat free mass. Subjects were randomly assigned to ingest, in a double blind manner, capsules containing a placebo (P, n = 12) or powdered tart cherries [CherryPURE®] (TC, n = 11). Participants supplemented one time daily (480 mg/d) for 10-d including day of exercise up to 48-h post-exercise. Subjects performed ten sets of ten repetitions at 70 % of a 1-RM back squat exercise. Fasting blood samples, isokinetic MVCs, and quadriceps muscle soreness ratings were taken pre-lift, 60-min, 24-h, and 48-h post-lift and analyzed by MANOVA with repeated measures.ResultsMuscle soreness perception in the vastus medialis (¼) (p = 0.10) and the vastus lateralis (¼) (p = 0.024) was lower in TC over time compared to P. Compared to pre-lift, TC vastus medialis (¼) soreness was significantly attenuated up to 48-h post-lift with vastus lateralis (¼) soreness significantly lower at 24-h post-lift compared to P. TC changes in serum creatinine (p = 0.03, delta p = 0.024) and total protein (p = 0.018, delta p = 0.006) were lower over time and smaller from pre-lift levels over time compared to P Significant TC group reductions from pre-lift levels were found for AST and creatinine 48-h post-lift, bilirubin and ALT 60-min and 48-h post-lift. No significant supplementation effects were observed for serum inflammatory or anti-inflammatory markers. None of the free radical production, lipid peroxidation, or antioxidant capacity markers (NT, TBARS, TAS, SOD) demonstrated significant changes with supplementation. Changes in TC whole blood lymphocyte counts (p = 0.013) from pre-lift were greater compared to P, but TC lymphocyte counts returned to pre-lift values quicker than P.ConclusionShort-term supplementation of Montmorency powdered tart cherries surrounding a single bout of resistance exercise, appears to be an effective dietary supplement to attenuate muscle soreness, strength decrement during recovery, and markers of muscle catabolism in resistance trained individuals.

Biomechanical assessment of the injury risk of stomping.

Forensic case work as well as literature shows that severe head injuries, e.g., with basilar fractures and cerebral hemorrhages due to stomps can be seen; however, there is no data basis concerning contact forces and potential influencing factors. The objective of this work was to generate a data basis of contact forces in stomping by performing experimental measurements and subsequent statistical analyses. Fifty-five volunteers participated in the present study. Each participant performed several stomps onto force plates with sturdy/soft footwear as well as with/without an elastic layer imitating the scalp. Ground reaction forces induced by jumps were also measured for sturdy and soft footwear. The results show statistically significant dependencies between maximum ground reaction forces and body weight and body height. A statistically significant influence of footwear on stomping force could only be found in tests with an elastic layer and in the jumping setup. Mean maximum stomping forces for the female volunteers were between 4694 and 5970 N; male volunteers were able to produce mean peak stomping forces between 8494 and 9016 N. Jumping forces were approximately twice the stomping forces for both male and female test persons. Regardless of footwear and gender, it can be claimed that a forceful stomp or jump to someone's head supported on the ground can cause facial and skull fractures. Thus, forceful stomps or jumps to someone's head can cause potential fatal injuries independent of footwear, gender, or fitness level.

Abstract 3524: BAY 1238097, a novel BET inhibitor with strong efficacy in hematological tumor models

Abstract Several BET inhibitors with strong anti-tumor efficacy have been described in the last few years. Most of them are derived from diazepine and azepine scaffolds, but more recently quinazolinones and isoxazoles chemotypes have also been described. We have identified a novel scaffold with strong BET inhibitory activity. Here we describe the biochemical characteristics of BAY 1238097 and its anti-proliferative activity in acute myeloid leukemia (AML) and multiple myeloma (MM) models. In vitro, BAY 1238097 showed strong inhibitory activity (IC50 &amp;lt; 100 nM) in a TR-FRET assay using BET BRD4 bromodomain 1 and an acetylated peptide derived from histone H4. In the NanoBRET assay, the interaction between BRD4, BRD3 or BRD2 and H4 was inhibited with IC50 values of 63 nM, 609 nM and 2430 nM, showing selectivity of the compound for BRD4. A strong reduction of c-Myc transcript and protein levels was observed in treated MOLM-13 (AML) and MOLP-8 (MM) cell lines. ChIP experiments performed in these models additionally revealed that BAY 1238097 prevented binding of BRD4 to c-Myc regulatory regions. In vivo, BAY 1238097 showed strong efficacy in the AML models THP-1, MOLM-13 and KG-1, with T/C between 13 and 20%. Overall, the compound was well tolerated at MTD, with body weight losses of 5-9% at nadir. BAY 1238097 was also active in MM models. Efficacy was observed against a human IGH-cyclin D1 translocated MOLP-8 model with a T/C of 3%, whereas the standard-of-care agents bortezomib and lenalidomide were inactive or poorly active. In this model, BAY 1238097 was well tolerated at 10 mg/kg applied over 14 days, with no body weight loss measured. BAY 1238097 was also active against the FGFR/MMSET translocated model NCIH929, with 19% T/C versus 49% T/C for the standard-of-care lenalidomide. The compound was well tolerated applied at 12 mg/kg for 9 days (maximum body weight loss 6%). Gene expression profiling performed in liver, blood and duodenum of rats treated daily with 2 mg/kg BAY 1238097 for 14 days demonstrated substantial effects on genes involved in cell proliferation and in the immune response in vivo. Altogether, BAY 1238097 is a potent inhibitor of BET binding to histones and has strong anti-proliferative activity in different AML and MM models through down-regulation of c-Myc levels and its downstream transcriptome. Initiation of clinical studies with BAY 1238097 is planned for early 2015. Citation Format: Pascale Lejeune, Tatsuo Sugawara, Kathy A. Gelato, Heidrun Ellinger-Ziegelbauer, Amaury E. Fernandez-Montalvan, Norbert Schmees, Stephan Siegel, Hilmar Weinmann, Volker Gekeler, Annette O. Walter, Matthias Ocker, Stuart Ince, Bernard Haendler. BAY 1238097, a novel BET inhibitor with strong efficacy in hematological tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3524. doi:10.1158/1538-7445.AM2015-3524

Abstract 2424: Association between Chk1 inhibitor AZD7762-mediated modulation of pharmacodynamic biomarkers and potentiation of hypoxia-activated prodrug TH-302 antitumor efficacy in a human tumor xenograft model

Abstract Background: TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Checkpoint kinase 1 (Chk1) plays a key role in the activation of the DNA damage checkpoint in the cell cycle. We investigated the association between Chk1 inhibitor AZD7762′s-mediated modulation of select downstream pharmacodynamic (PD) biomarkers and potentiation of TH-302 efficacy in the HT29 xenograft model. Material and methods: HT29 ectopic human colorectal xenograft model was employed. Six animals per group were treated with Vehicle (V), TH-302 (T) at 150 mg/kg on Day 1, AZD7762 (A) at 25 mg/kg on Day 1 and 2, or T + A. Two dosing schedules were used in the combination: 1), A was given first, and 4 h and 24 h later, T and A was dosed, respectively (ATA); and 2), T was given first, and 4 h and 24 h later, A was dosed (TAA). The PD biomarkers were evaluated by immunohistochemistry (IHC) on the samples collected on Day 3. In a separate efficacy study, ten animals per group were treated with V, T at 100 mg/kg on Day 1, 4/wk x 2wks, A at 20 mg/kg on Day 1, 2, 4 and 5/wk x 2wks, ATA or TAA combination. Antitumor activity was assessed by tumor growth inhibition (TGI). Results: The biomarker study showed phosphorylated Chk1 (Ser345), γH2AX-positive cells (DNA damage), and Caspase-3 positive cells (apoptosis), were significantly increased in ATA, compared with V, A, T or TAA (p&amp;lt;0.05). ATA-induced DNA damage occurred in 38% cells, which were mainly cancer cells (vs. 3%, 8%, 14% and 24% in V, A, T, and TAA, respectively). 12% of the cells underwent apoptosis after ATA, which was observed mainly in endothelial cells and activated fibroblasts of the tumor stroma. Tumor hypoxia was characterized with pimonidazole IHC and the endogenous marker CA-IX, which showed a strong co-localization of staining. The tumoral hypoxic fraction was reduced after ATA or TAA. In the efficacy study, T or A monotherapy did not show any effect. However, the efficacy was significant in the combination groups, in which ATA yielded TGI of 67%, compared to the TAA of 48%. The dosing schedule dependent antitumor activity was consistent with the PD biomarker observation. Maximal body weight loss in ATA was 1% vs. 6% in TAA. Conclusion: The results suggest that the Chk1 inhibitor A potentiates the efficacy of T in a dose schedule-dependent manner, consistent with dose schedule dependent modulations of PD biomarkers. The detailed mechanistic analysis indicates that the sensitization is due to both disruption of the Chk1 mediated DNA damage checkpoint of the cell cycle and the induction of apoptosis. These studies provide additional support to the preclinical translational rationale for combining TH-302 with Chk1 inhibitors in the clinical trial setting. Citation Format: Jessica D. Sun, Fanying Meng, Qian Liu, Dharmendra Ahluwalia, Wenwu Li, Yan Wang, Deepthi Bhupathi, Charles P. Hart. Association between Chk1 inhibitor AZD7762-mediated modulation of pharmacodynamic biomarkers and potentiation of hypoxia-activated prodrug TH-302 antitumor efficacy in a human tumor xenograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2424. doi:10.1158/1538-7445.AM2015-2424

Fluid accumulation threshold measured by acute body weight change after admission in general surgical intensive care units: how much should be concerning?

BackgroundThe objective of this study (ClinicalTrials.gov: NCT01351506) was to identify the threshold level of fluid accumulation measured by acute body weight (BW) change during the first week in a general surgical intensive care unit (ICU), which is associated with ICU mortality and other adverse outcomes.MethodsFour hundred sixty-five patients were prospectively followed for a 28-day period. The maximum BW change threshold during the first week was evaluated by the maximum percentage change in BW from the ICU admission weight (Max%ΔBW). Daily screening of adverse events in the ICU were recorded. The cutoff point of Max%ΔBW on ICU mortality was defined by considering the area under the receiver operating characteristic (ROC) curve, intersection of the sensitivity and specificity, and the Youden Index. Univariable and multivariable regression analyses were used to demonstrate the associations. Statistical significance was defined as P<0.05.ResultsThe appropriate cutoff value of Max%ΔBW threshold was 5%. Regarding the multivariable regression model, in overall patients, the occurrence of the following adverse events (expressed as adjusted odds ratio [95% confidence interval]) were significantly associated with a Max%ΔBW of >5%: ICU mortality (2.38 [1.25–4.54]) (P=0.008), ICU mortality in patients without renal replacement therapy (RRT) (2.47 [1.21–5.06]) (P=0.013), reintubation within 72 hours (2.51 [1.04–6.00]) (P=0.039), RRT requirement (2.67 [1.13–6.33]) (P=0.026), and delirium (1.97 [1.08–3.57]) (P=0.025). Regarding the postoperative subgroup, a Max%ΔBW value of more than 5% was significantly associated with: ICU mortality (3.87 [1.38–10.85]) (P=0.010), ICU mortality in patients without RRT (6.32 [1.85–21.64]) (P=0.003), reintubation within 72 hours (4.44 [1.30–15.16]) (P=0.017), and vasopressor requirement (2.04 [1.04–4.01]) (P=0.037).ConclusionFluid accumulation, measured as acute BW change of more than the threshold of 5% during the first week of ICU admission, is associated with adverse outcomes of higher ICU mortality, especially in the patients without RRT, with reintubation within 72 hours, with RRT requirement, with vasopressor requirement, and with delirium. Some of these effects were higher in postoperative patients. This threshold value might be an indicator for caution during fluid management in surgical ICU.

SU‐E‐I‐86: Ultra‐Low Dose Computed Tomography Attenuation Correction for Pediatric PET CT Using Adaptive Statistical Iterative Reconstruction (ASiR™)

Purpose:To develop ultra‐low dose computed tomography (CT) attenuation correction (CTAC) acquisition protocols for pediatric positron emission tomography CT (PET CT).Methods:A GE Discovery 690 PET CT hybrid scanner was used to investigate the change to quantitative PET and CT measurements when operated at ultra‐low doses (10–35 mAs). CT quantitation: noise, low‐contrast resolution, and CT numbers for eleven tissue substitutes were analyzed in‐phantom. CT quantitation was analyzed to a reduction of 90% CTDIvol (0.39/3.64; mGy) radiation dose from baseline. To minimize noise infiltration, 100% adaptive statistical iterative reconstruction (ASiR) was used for CT reconstruction. PET images were reconstructed with the lower‐dose CTAC iterations and analyzed for: maximum body weight standardized uptake value (SUVbw) of various diameter targets (range 8–37 mm), background uniformity, and spatial resolution. Radiation organ dose, as derived from patient exam size specific dose estimate (SSDE), was converted to effective dose using the standard ICRP report 103 method. Effective dose and CTAC noise magnitude were compared for 140 patient examinations (76 post‐ASiR implementation) to determine relative patient population dose reduction and noise control.Results:CT numbers were constant to within 10% from the non‐dose reduced CTAC image down to 90% dose reduction. No change in SUVbw, background percent uniformity, or spatial resolution for PET images reconstructed with CTAC protocols reconstructed with ASiR and down to 90% dose reduction. Patient population effective dose analysis demonstrated relative CTAC dose reductions between 62%–86% (3.2/8.3−0.9/6.2; mSv). Noise magnitude in dose‐reduced patient images increased but was not statistically different from pre dose‐reduced patient images. Conclusion: Using ASiR allowed for aggressive reduction in CTAC dose with no change in PET reconstructed images while maintaining sufficient image quality for co‐localization of hybrid CT anatomy and PET radioisotope uptake.

A neuron-specific deletion of the microRNA-processing enzyme DICER induces severe but transient obesity in mice.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis.

Ultralow dose computed tomography attenuation correction for pediatric PET CT using adaptive statistical iterative reconstruction.

To develop ultralow dose computed tomography (CT) attenuation correction (CTAC) acquisition protocols for pediatric positron emission tomography CT (PET CT). A GE Discovery 690 PET CT hybrid scanner was used to investigate the change to quantitative PET and CT measurements when operated at ultralow doses (10-35 mA s). CT quantitation: noise, low-contrast resolution, and CT numbers for 11 tissue substitutes were analyzed in-phantom. CT quantitation was analyzed to a reduction of 90% volume computed tomography dose index (0.39/3.64; mGy) from baseline. To minimize noise infiltration, 100% adaptive statistical iterative reconstruction (ASiR) was used for CT reconstruction. PET images were reconstructed with the lower-dose CTAC iterations and analyzed for: maximum body weight standardized uptake value (SUVbw) of various diameter targets (range 8-37 mm), background uniformity, and spatial resolution. Radiation dose and CTAC noise magnitude were compared for 140 patient examinations (76 post-ASiR implementation) to determine relative dose reduction and noise control. CT numbers were constant to within 10% from the nondose reduced CTAC image for 90% dose reduction. No change in SUVbw, background percent uniformity, or spatial resolution for PET images reconstructed with CTAC protocols was found down to 90% dose reduction. Patient population effective dose analysis demonstrated relative CTAC dose reductions between 62% and 86% (3.2/8.3-0.9/6.2). Noise magnitude in dose-reduced patient images increased but was not statistically different from predose-reduced patient images. Using ASiR allowed for aggressive reduction in CT dose with no change in PET reconstructed images while maintaining sufficient image quality for colocalization of hybrid CT anatomy and PET radioisotope uptake.

Influence of Feeding Frequency on Growth performance and Body Indices of Goldfish (Carrassius auratus)

A total of forty goldfish (Carrassius auratus) with an average weight of 20 g per fish were stocked in individual glass aquaria having 50-L water holding capacity. There were 4 experimental feeding regimens A, B, C, and D having once twice, thrice and four times per day, respectively. All the groups received Nova Aquarium Fish Food @ 2% bodyweight which was equally spaced in treatment groups. The body weight, body and caudal lengths, and girth were recorded at the start of the experiment. The trial continued for 8 weeks. Group B yielded the maximum weight gain whereas group D yielded lowest weight (P<0.05). Feed Conversion Ratio (FCR) was better in Feed A and depreciated with increasing frequency (P<0.05). Caudal fin showed significant correlation with weight (+ 0.548; P<0.001) and length (- 0.792; P<0.0001). A positive correlation of dissolved oxygen (DO; P<0.001) and salinity (P<0.0001) showed with temperature. Salinity showed positive significant correlation with temperature (P<0.05). Consequently, feeding frequency twice per day is better for maximum body weight gain however better feed efficiency can be obtained at feed frequency once per day. However goldfish require genetic improvement for its rearing at commercial scale.