Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.     

Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial

BackgroundWomen with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth.Methods and findingsIn this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m²) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (−6.6 ± 5.4% versus −0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful.ConclusionsA preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02432209","term_id":"NCT02432209"}}NCT02432209.

Richard Legro and colleagues investigate the impact of a preconception weight loss intervention on healthy live birth rates in women with obesity and unexplained infertility.     

Factors affecting parasitism by Microctonus aethiopoides (Hymenoptera: Braconidae) and parasitoid development in natural and novel host species

A laboratory study of aspects of parasitoid host acceptance, suitability and physiological regulation in natural and novel host species was carried out to investigate the degree of variability encountered with different hosts and to determine the value of such observations in host range determination. The parasitoid Microctonus aethiopoides Loan was exposed to a natural host, Sitona discoideus Gyllenhal (Coleoptera: Curculionidae) and three novel hosts, the New Zealand native Nicaeana cervina Broun, the introduced weed biological control agent Rhinocyllus conicus (Froehlich), and a congeneric pest species, Sitona lepidus Gyllenhal (all Coleoptera: Curculionidae). Per cent parasitism of these species was 54%, 43%, 39% and 0%, respectively. The results indicated that for both S. discoideus and R. conicus more males than females were parasitized (69% cf. 45%, and 49% cf. 32% respectively) but host size was not a significant factor. Overall, superparasitism was recorded in about 29% of parasitized weevils and there was evidence that host discrimination to avoid superparasitism occurred in the natural host. Conversely, superparasitism occurred more frequently than would be expected in N. cervina (42%) coupled with higher survival of larvae in superparasitized hosts in this species. The frequency distribution of attack of R. conicus by M. aethiopoides was not different from random. Parasitoid development was more rapid in the natural host, S. discoideus, and parasitoid size was positively correlated with host size. There was a strong positive relationship between parasitoid larval survival and the presence of teratocytes in all hosts. Host fecundity and fertility were reduced by parasitism for most species, and in some cases, by exposure to parasitoids in the absence of detectable parasitism. It was concluded that laboratory observations can provide useful information on the compatibility between host and parasitoid which can complement traditional host range tests to predict field host range.     

Characteristics of the interaction between Hsc70 and the transferrin receptor in exosomes released during reticulocyte maturation

The transferrin receptor (TfR) of reticulocytes is released in vesicular form (exosomes) during their maturation to erythrocytes. The heat shock cognate 70-kDa protein (Hsc70) has been demonstrated to interact with the cytosolic domain of the TfR and could thus trigger the receptor toward this secretion pathway. We investigated the characteristics of the interaction between Hsc70 and the TfR in exosomes with an in vitro binding assay using TfR immobilized on Sepharose beads and purified Hsc70. The results show that Hsc70 binds to exosomal TfR with characteristics expected of a chaperone/peptide interaction. We demonstrated that heat-denatured luciferase competed for in vitro binding, dependent on the nucleotide bound to Hsc70, and that this interaction activates the ATPase activity of Hsc70. Moreover, we used immunosuppressive agents that interact with Hsc70, thus decreasing Hsc70 binding to TfR in our in vitro binding assay and enabling us to assess the role of this interaction in vivo during reticulocyte maturation.     

Selenium reduction by a denitrifying consortium

A denitrifying bacterial consortium obtained from the Pullman, Washington wastewater treatment facility was enriched under denitrifying conditions and its ability to reduce selenite and selenate was studied. Replicate experiments at two different experimental conditions were performed. All experiments were performed under electron-acceptor limiting conditions, with acetate as the carbon source and nitrate the electron acceptor. In the first set of experiments, selenite was present, whereas, in the second set, selenate was added. A significant lag period of approximately 150 h was necessary before selenite or selenate reduction was observed. During this lag period, nitrate and nitrite use was observed. Once selenite or selenate reduction had started, nitrate and nitrite reduction was concomitant with selenium species reduction. Trace amounts of selenite were detected during the selenate reduction study. Analysis of the data indicates that, once selenium species reduction was induced, the rate of reduction was proportional to the selenium species concentration and to the biomass concentration. Furthermore, at similar biomass and contaminant concentrations, selenite reduction is approximately four times faster than selenate reduction. Copyright 1999 John Wiley & Sons, Inc.     

Rate and extent of compensatory changes in energy intake and expenditure in response to altered exercise and diet composition in humans

We assessed the effect of no exercise (Nex; control) and high exercise level (Hex; approximately 4 MJ/day) and two dietary manipulations [a high-fat diet (HF; 50% of energy, 700 kJ/100 g) and low-fat diet (LF; 20% of energy, 300 kJ/100 g)] on compensatory changes in energy intake (EI) and energy expenditure (EE) over 7-day periods. Eight lean men were each studied four times in a 2 x 2 randomized design. EI was directly quantified by weight of food consumed. EE was assessed by heart rate (HR) monitoring. Body weight was measured daily. Mean daily EE was 17.6 and 11.5 MJ/day (P < 0.001) on the pooled Hex and Nex treatments, respectively. EI was higher on HF diets (13.4 MJ/day pooled) compared with the LF diets (9.0 MJ/day). Regression analysis showed that these energy imbalances induced significant compensatory changes in EB over time of approximately 0.3-0.4 MJ/day (P < 0.05). These were due to changes in both EI and EE in the opposite direction to the perturbation in energy balance. These changes were significant, small but persistent, amounting to approximately 0.2 and approximately 0.35 MJ/day for EI and EE, respectively.     

Optimal assessment of multiple cues

In a wide range of contexts from mate choice to foraging, animals are required to discriminate between alternative options on the basis of multiple cues. How should they best assess such complex multicomponent stimuli? Here, we construct a model to investigate this problem, focusing on a simple case where a ''chooser'' faces a discrimination task involving two cues. These cues vary in their accuracy and in how costly they are to assess. As an example, we consider a mate-choice situation where females choose between males of differing quality. Our model predicts the following: (i) females should become less choosy as the cost of finding new males increases; (ii) females should prioritize cues differently depending on how choosy they are; (iii) females may sometimes prioritize less accurate cues; and (iv) which cues are most important depends on the abundance of desirable mates. These predictions are testable in mate-choice experiments where the costs of choice can be manipulated. Our findings are applicable to other discrimination tasks besides mate choice, for example a predator''s choice between palatable and unpalatable prey, or an altruist''s choice between kin and non-kin.     

The limits to cost-free signalling of need between relatives

Theoretical models have demonstrated the possibility of stable cost-free signalling of need between relatives. The stability of these cost-free equilibria depends on the indirect fitness cost of cheating and deceiving a donor into giving away resources. We show that this stability is highly sensitive to the distribution of need among signallers and receivers. In particular, cost-free signalling is likely to prove stable only if there is very large variation in need (such that the least-needy individuals stand to gain much less than the most-needy individuals from additional resources). We discuss whether these conditions are likely to be found in altricial avian breeding systems--the most intensively studied instance of signalling of need between relatives. We suggest that cost-free signalling is more likely to prove stable and will provide parents with more information during the earlier phases of chick growth, when parents can more easily meet the demands of a brood (and chicks are more likely to reach satiation). Later, informative yet cost-free signalling is unlikely to persist.