The impact of proprioceptive neuromuscular facilitation (PNF) on physical function in assisted-living older adults (73-94 years old) was studied. A 5-week pretraining period consisting of weekly visits by trainers to participants preceded a 10-week training period of warm-up, PNF exercises, and cool-down. Training progressed from 1 set of 3 repetitions to 3 sets of 3 repetitions. Assessments were conducted at baseline (T1), postpretraining (T2), and posttraining (T3). Eleven of 14 volunteer participants completed the study. Physical function was assessed by range of motion (ROM), isometric strength, and balance and mobility measures. Repeated-measures ANOVA identified 6 measures (sit-to-stand, shoulder- and ankle-flexion ROM, and hip-extension, ankle-flexion, and ankle-extension strength) with statistically significant differences. With the exception of hip-extension strength, these measures were statistically significant from T2 to T3 in post hoc univariate tests. Results indicate that PNF flexibility training can improve ROM, isometric strength, and selected physical-function tasks in assisted-living older adults.

The study objective was to determine whether N retention was improved with supplemental Zn above NRC concentrations with or without ractopamine hydrochloride inclusion. Angus crossbred steers (n = 32, 485 ± 26 kg BW) with Genemax gain scores of 4 or 5 were utilized in a 2 × 2 factorial arrangement (8 steers/treatment). Steers were blocked by BW to a finishing diet with 1 of 2 mineral supplementation strategies (ZNTRT), no supplemental Zn (analyzed 32 mg Zn/kg DM; CON) or supranutritional Zn (CON + 60 ppm ZnSO4 + 60 ppm Zn-amino acid complex; analyzed 145 mg Zn/kg DM; SUPZN), fed 56 days in pens equipped with GrowSafe bunks and assigned to β-agonist (BA) supplementation strategies of 0 (NON) or 300 mg steer-1 d-1 ractopamine hydrochloride (RAC) fed the last 30 d before harvest. Initial 56-d ADG was not affected by ZNTRT (P = 0.66), but DMI was greater in CON vs. SUPZN (P < 0.01). On day 56 (day 1 of BA supplementation), steers (4 groups; 8 steers/group; 2 steers/treatment) were moved to metabolism crates and adapted for 10 d, followed by 5 d of total fecal and urine collection. Total retention of Zn, Mn, Fe, Cu, and N were calculated. Data were analyzed as a 2 × 2 factorial arrangement, with group as a fixed effect and the 3-way interaction of ZNTRT × BA × group as random. No interactions between ZNTRT and BA were noted for any data (P ≥ 0.19). Collection DMI did not differ among treatments (P ≥ 0.23); however, Zn intake was lesser in CON vs. SUPZN (P < 0.01). Fecal and urinary Zn excretion and Zn and Mn retention were lesser in CON vs. SUPZN (P ≤ 0.03); however, Zn retention was not different between NON and RAC (P = 0.43). Retention of Cu and Fe was unaffected by strategies (P ≥ 0.49). Urine output and urine N excretion were greater in NON vs. RAC (P ≤ 0.05). Nitrogen retention (as percent of N intake) was lesser (P = 0.05) in CON (40.0%) vs. SUPZN (44.3%) and lesser (P = 0.02) in NON (39.5%) vs. RAC (44.8%). Zinc and N retention were found to be positively correlated (r = 0.46, P < 0.01). Average daily gain and G:F across the 86-d trial were lesser in NON vs. RAC (P < 0.03). Overall, SUPZN appears to improve N retention, suggesting that increasing dietary Zn may be important for cattle growth beyond that induced by ractopamine hydrochloride.

The objective of this study was to assess whether supplemental Zn source or concentration would affect ruminant Zn retention and nutrient digestibility. Thirty-six weaned crossbred Polypay wethers, were sorted by BW to 3 periods and stagger started on a common diet (22 mg Zn/kg DM) for a 52-d depletion period. Day 52 BW was used to assign Zn treatments (3 lambs/treatment/ period): no supplemental Zn (CON), or supplemental Zn (40 mg Zn/d) from Zn sulfate (ING; Zinc Nacional, Monterrey, SA, Mexico), Zn methionine (ORG; Zinpro 120; Zinpro, Eden Prairie, MN), or Zn hydroxychloride (HYD; IntelliBond Z; Micronutrients USA LLC, Indianapolis, IN). On day 53 (day 1 of Zn treatments), lambs were moved to metabolism crates for 10 d of adaptation and 5 d of total fecal and urine collection. Blood for plasma Zn analysis was collected on day 52 and day 68. Data were analyzed as a randomized complete design with fixed effects of treatment, period and the interaction, which was significant (P ≥ 0.19) for day 68 plasma Zn but was removed for all other variables. Contrast statements were used to separate treatment means: CON vs. ZINC (ING, ORG, HYD), ING vs. HYD, and ORG vs. HYD. Day 52 plasma Zn concentrations were similar when CON was compared with ZINC (P = 0.84),

RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of b-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on b-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC 50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G 2 -M cellcycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear b-catenin. RX-5902 exhibited doseproportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFb, and Wnt/b-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear b-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.