Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis

Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The phase III IKEMA study (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03275285","term_id":"NCT03275285"}}NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) versus Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Addition of Isa prolonged progression-free survival (PFS) in patients with RI (hazard ratio: 0.27; 95% confidence interval [CI]: 0.11–0.66; median PFS not reached for Isa-Kd versus 13.4 months for Kd [20.8-month follow-up]). Complete renal responses occurred more frequently with Isa-Kd (52.0%) versus Kd (30.8%) and were durable in 32.0% versus 7.7% of patients, respectively. Treatment exposure was longer with Isa-Kd, with median number of started cycles and median duration of exposure of 20 versus 9 cycles and 81.0 versus 35.7 weeks for Isa-Kd versus Kd, respectively. Among patients with RI, the incidence of patients with grade ≥3 treatment-emergent adverse events was similar between the two arms (79.1% in Isa-Kd vs. 77.8% in Kd). In summary, the addition of Isa to Kd improved clinical outcomes with a manageable safety profile in patients with RI, consistent with the benefit observed in the overall IKEMA study population.     

The Complex Role of Lactic Acid Bacteria in Food Detoxification

Toxic ingredients in food can lead to serious food-related diseases. Such compounds are bacterial toxins (Shiga-toxin, listeriolysin, Botulinum toxin), mycotoxins (aflatoxin, ochratoxin, zearalenone, fumonisin), pesticides of different classes (organochlorine, organophosphate, synthetic pyrethroids), heavy metals, and natural antinutrients such as phytates, oxalates, and cyanide-generating glycosides. The generally regarded safe (GRAS) status and long history of lactic acid bacteria (LAB) as essential ingredients of fermented foods and probiotics make them a major biological tool against a great variety of food-related toxins. This state-of-the-art review aims to summarize and discuss the data revealing the involvement of LAB in the detoxification of foods from hazardous agents of microbial and chemical nature. It is focused on the specific properties that allow LAB to counteract toxins and destroy them, as well as on the mechanisms of microbial antagonism toward toxigenic producers. Toxins of microbial origin are either adsorbed or degraded, toxic chemicals are hydrolyzed and then used as a carbon source, while heavy metals are bound and accumulated. Based on these comprehensive data, the prospects for developing new combinations of probiotic starters for food detoxification are considered.     

Can a pragmatic responsive feeding scale be developed and applied globally?

Responsive feeding (RF) has been recognized as necessary to prevent all forms of malnutrition including stunting and childhood obesity. Specific RF guidelines have been developed, but it is unclear how RF behaviours can be monitored systematically. Therefore, developing valid and reliable abbreviated and pragmatic RF scales is an important global priority. This is challenging, as RF is a construct with multiple dimensions including recognizing and responding to hunger and satiety cues, providing a nurturing environment during feeding episodes, and understanding how feeding needs evolve as a function of the developmental stage of the young child. Further, RF is embedded within the responsive parenting framework that in addition to RF includes sleep, soothing and play routines and the interconnections between them. A recent pioneer study conducted in a rural area of Cambodia validated an 8‐item RF scale through direct feeding observations of 6‐ to 23‐month‐old infants at home, as part of two cross‐sectional surveys conducted before and after a complementary feeding intervention. It is important for similar research to be conducted elsewhere to find out if it is possible or not to develop a core RF scale that is valid and reliable and that has adequate specificity and sensitivity for application in community studies and population surveys globally. As highlighted in this article, different definitions of RF have been used in the field; thus, it is important to reach consensus on a single definition to help move this research area forward.     

Development and characterization of poly(lactic-co-glycolic) acid nanoparticles loaded with copaiba oleoresin

Abstract

Copaiba oleoresin (CPO), obtained from Copaifera landgroffii, is described as active to a large number of diseases and more recently in the endometriosis treatment. In this work, poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing CPO were obtained using the design of experiments (DOE) as a tool to optimize the production process. The nanoparticles optimized by means of DOE presented an activity in relation to the cellular viability of endometrial cells. The DOE showed that higher amounts of CPO combined with higher surfactant concentrations resulted in better encapsulation efficiency and size distribution along with good stability after freeze drying. The encapsulation efficiency was over 80% for all produced nanoparticles, which also presented sizes below 300?nm and spherical shape. A decrease in viability of endometrial stromal cells from ectopic endometrium of patients with endometriosis and from eutopic endometriotic lesions was demonstrated after 48?h of incubation with the CPO nanoparticles. The nanoparticles without CPO were not able to alter the cell viability of the same cells, indicating that this material was not cytotoxic to the tested cells and suggesting that the effect was specific to CPO. The results indicate that the use of CPO nanoparticles may represent a promising alternative for the treatment of endometriosis.     

Formation and Thermal Stability of the ω-Phase in Ti–Nb and Ti–Mo Alloys Subjected to HPT

This paper discusses the features of ω-phase formation and its thermal stability depending on the phase composition, alloying element and the grain size of the initial microstructure of Ti–Nb and Ti–Mo alloys subjected to high-pressure torsion (HPT) deformation. In the case of two-phase Ti–3wt.% Nb and Ti–20wt.% Nb alloys with different volume fractions of α- and β-phases, a complete β→ω phase transformation and partial α→ω transformation were found. The dependence of the α→ω transformation on the concentration of the alloying element was determined: the greater content of Nb in the α-phase, the lower the amount of ω-phase that was formed from it. In the case of single-phase Ti–Mo alloys, it was found that the amount of ω-phase formed from the coarse-grained β-phase of the Ti–18wt.% Mo alloy was less than the amount of the ω-phase formed from the fine α′-martensite of the Ti–2wt.% Mo alloy. This was despite the fact that the ω-phase is easier to form from the β-phase than from the α- or α′-phase. It is possible that the grain size of the microstructure also affected the phase transformation, namely, the fine martensitic plates more easily gain deformation and overcome the critical shear stresses necessary for the phase transformation. It was also found that the thermal stability of the ω-phase in the Ti–Nb and Ti–Mo alloys increased with the increasing concentration of Nb or Mo.     

Mechanism of voltage sensing in Ca2+- and voltage-activated K+ (BK) channels

In neurosecretion, allosteric communication between voltage sensors and Ca²⁺ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.

Excitable tissues accomplish their signaling functions thanks in part to the interplay of several voltage-sensitive ion channels (1–6). Hence, to understand these processes, it is crucial to establish how voltage-sensitive ion channels sense changes in the electric field across the membrane, an issue that has been a matter of extensive study and intense debate for decades. The most widely accepted mechanism proposes the existence of voltage-sensor domains (VSDs), modules that undergo two or more discrete conformational states in response to changes in the membrane voltage. The simplest model considers two states: active (A), which promotes pore opening, and resting (R), which promotes channel closing. To accomplish its function, VSDs contain voltage-sensitive particles, which move in response to changes in the electric field. This movement triggers the interconversion between the two discrete conformational states. These voltage-sensing particles are typically the guanidine groups of arginine residues within the S4 transmembrane segment, which undergo a combination of rotational, translational, and tilting movement in response to changes in membrane voltage (7–14).The large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels have a wide distribution in mammalian tissues (15–18), where they participate in a diversity of physiological processes. Their malfunction is often related to diverse pathological conditions (19, 20). BK channel open probability is independently regulated by membrane depolarization and intracellular Ca²⁺ concentration (21, 22), each stimulus being detected by specialized modules. Like other voltage-sensitive K⁺ (Kv) channels, BK is an homotetramer in which each of its α subunits consists of a pore domain (PD; S5-S6 transmembrane segments), a voltage-sensing domain (VSD; S1–S4 transmembrane segments) containing a positively charged S4, and a cytosolic C-terminal regulatory domain, which contains the Ca²⁺-binding sites (23, 24). Also, like some members of other K⁺ channel families (25, 26), the VSD and PD of BK are non–domain swapped (23, 24). BK channels display some distinctive structural and functional features: Despite sharing the selectivity filter sequence with Kv channels, BK unitary conductance and selectivity are exquisitely high (27–30). The BK α subunit has an additional transmembrane segment S0 [therefore, its N terminus faces the extracellular medium (31)], and the voltage sensitivity in BK channels is significantly lower than that of Kv channels, presumably because of their lower number of gating charges (32).Although thoroughly studied, research into BK VSD and its voltage dependence has faced several technical obstacles. The relatively small gating charge per channel (32) and the large conductance of the BK pore makes isolating of the gating currents from the ionic currents a tough experimental challenge. In addition, because mutations of VSD residues can produce very large shifts in both the gating charge-voltage (Q(V)) and the conductance-voltage G(V)) relationships (33), it is necessary to use extreme voltages to accurately measure the voltage dependence of some mutants. Consequently, the identification of BK gating charges has been addressed by using indirect approaches (33, 34). The combination of electrophysiology measurements and kinetic modeling suggests a decentralized VSD in the BK channel, where four charged residues (D153 and R167 in S2, D186 in S3, and R213 in S4) act as voltage sensor particles (33). A recent report of the atomistic cryo-electron microscopy (cryo-EM) structures of the human BK channel and its homolog in Aplysia californica (AcSlo) revealed minor structural differences between the VSD in both the Ca²⁺-bound (open pore) and the Ca²⁺-unbound (closed pore) conformations (23, 24, 35). This result can be explained if the conformational changes of the BK VSD upon activation are small compared to those that occur during the activation of other channels, such as HCN channels (12–14).In this study, we identified voltage-sensing particles in the BK channel by using a direct functional approach, involving gating of current measurements and analysis of the Q(V) curves spanning 800 mV in the voltage axis. Systematic neutralization of the individual charged residues in the VSD (S1–S4) revealed that only the neutralization of two arginines in S4 (R210 and R213) changed the voltage dependence of the Q(V) curves. Neutralization of other VSD charges point to roles in tuning of the half-activation voltage of the VSD and its allosteric coupling with the PD. Molecular dynamics (MD) simulations based on the cryo-EM structures of the human BK channel (35) as templates suggested that R210 and R213 lie in a very narrow septum separating intra- and extracellular water-filled vestibules. This interpretation is consistent with the robust hyperpolarization-activated proton currents generated when R210 is mutated to the protonable amino acid histidine. Overall, our results point to a unique and distinctive mode of activation in BK: In contrast to Kv channels, where positive charges move one by one through a charge transfer center (absent in BK channels) that spans the entire electric field (36, 37), charge movement in BK channels is limited to the small displacement of R210 and R213, which itself constitutes a narrow septum where the electric field drops.     

Personalized Nutrition and Cardiovascular Disease Prevention: From Framingham to PREDIMED

Diet is considered the cornerstone for the prevention of age-related diseases, and a low-fat diet has been considered for decades as the most suitable alternative to achieve this goal. However, mounting evidence supports the efficacy of other alternatives, such as the Mediterranean diet. Nevertheless, it is well known that people present a dramatic range of responses to similar environmental challenges, and it has been shown that some of this variability is rooted in the genome. In fact, this knowledge is driving the field of nutrigenetics. The finding of interactions between diet and genetic variants has led to intense research and debate about the effectiveness of personalized nutrition as a more suitable tool for the prevention of chronic diseases than the traditional 1-size-fits-all recommendations. Here, we provide some of our own examples that illustrate the progression of nutrigenetics through the years, from the initial studies within the Framingham Heart Study, to the most recent use of large consortia, such as the Cohorts for Heart and Aging Research in Genomic Epidemiology, and ending up with large dietary intervention studies, such as the PREDIMED (Prevención con Dieta Mediterránea) study. These recent approaches are providing more robust and clinically relevant gene–diet interactions. Therefore, although the current evidence level of applying genomic information to tailoring is at its early stages, the prospect of widespread incorporation of nutrigenetics to the clinical practice is encouraging.     

Chile Crece Contigo: Implementation,results, and scaling‐up lessons

Background

Chile Crece Contigo (ChCC) is defined as a comprehensive, intersectoral, and multicomponent policy that aims to help all children reach their full potential for development, regardless of their socio‐economic status.

Methods

This case study was developed on the basis of grey literature review and key informants' interviews.

Results

ChCC behaves as a complex adaptive system that combines universal and targeted benefits for the more vulnerable starting since gestation and until the children are 4 years old. Three key ministries are involved in ChCC management: health, education, and social development. Studies show adequate programme implementation and positive effects of ChCC on child development. In addition, it was found that the more families use ChCC benefits and the longer the subsystem has been operating in the commune, the greater the positive effects.

Conclusions

Strong political support based on principles of equity and child rights combined with strong evidence and funding commitment from government has been central to emergence, scaling up, and sustainability of ChCC. Further sustainability of ChCC will rely on firmly establishing a well‐trained and compensated cadre of early child development professionals and paraprofessionals as well as an improved management and evaluation decentralized system.