Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients.

SUMMARY A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous CAPN1 null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knock-out (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1 mediated cleavage of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis, and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

Introduction: Physical capabilities are an important parameter of the functional development of adolescents, not only by chronological age but also by their maturational state, as individuals with the same chronological age can have different performance to their less mature counterparts. Objective: To compare and relate the physical capabilities and hormonal markers according to sex and maturity of adolescents. Method: The sample consisted of adolescents of both sexes, aged 10 to 14 years. We evaluated the maturity achieved by a predictive equation of skeletal age, physical capabilities (explosive power of upper and lower limbs, velocity of upper limbs and agility) and hormonal markers (testosterone and oestradiol) via chemiluminescence. Results: Females showed more advanced maturational status, higher weight, body height and oestradiol levels; males performed better in the explosive force of upper and lower limbs, upper limb speed, agility and testosterone levels. In the normal maturational state males showed greater skeletal age, body weight, body height, explosive strength of upper and lower limbs, and testosterone levels; the females in the normal maturational state had higher skeletal age, body weight, body height, explosive upper limb strength and oestradiol levels. In the male correlation analysis, bone age was related to the explosive strength of upper and lower limbs and testosterone; while bone age in females was related to explosive upper limb strength and oestradiol. Conclusion: It is concluded that maturation, testosterone and oestradiol levels play an important role in the physical aspects and performance of motor skills of adolescents, especially in upper limb force which was more related to the maturation obtained by skeletal age of males and females.

Background: Mechanisms that influence muscle strength can interfere with neuromotor performance and overall health, thus hormone markers and maturation can interact in this process. Objective: The present study aimed to verify the relationship of hormonal markers and biological maturation on neuromotor abilities in young people. Methods: This is a cross-sectional study with 44 female participants (11.5 ± 1.5 years). Hormones were analyzed biochemically. Skeletal and somatic maturation were analyzed using anthropometry. The muscular power of the upper and lower limbs, body speed with change of direction, and speed of the upper limbs were verified. Results: Bone age was correlated with hormonal markers (estradiol: r = 0.58; p = 0.0007), (testosterone: r = 0.51; p = 0.005). Peak growth velocity correlated with estradiol (r = 0.51; p = 0.004). The power of the lower limbs (estradiol: r = 0.52; p = 0.006; testosterone: r = 0.42; p = 0.03) and of the upper limbs (estradiol: r = 0.51; p = 0.007; testosterone: r = 0.42; p = 0.02) had a positive correlation with hormone levels and had similar results with maturation. The analysis by artificial neural networks indicated that the maturation can predict the neuromotor performance between 57.4% and 76%, while the hormonal markers showed a potential of more than 95% for the foreshadowing of the neuromotor performance of the upper limbs. Conclusion: It was possible to conclude that the hormones had a relationship with maturational development and bone age in female subjects.

Background: Endocrine mechanisms can be a determining factor in the neuromuscular performance of young athletes. Objective: The objective of the present study was to relate maturational and hormonal markers to neuromuscular performance, as well as to verify whether young athletes with different testosterone levels show differences in muscle strength. Methods: The sample consisted of 37 young male Brazilian athletes (11.3 ± 0.94 years) who were members of a sports initiation project. Hormonal markers were analyzed biochemically by blood samples, and maturation markers by mathematical models based on anthropometry. Body composition was verified by tetrapolar bioimpedance. The performance of upper and lower limb strength and body speed were analyzed. Results: Hormonal and maturational markers were related to neuromuscular performance (p < 0.05). Young people with higher testosterone levels showed higher muscle strength (p < 0.05). Artificial neural networks showed that testosterone predicted the performance of upper limbs by 49%, and maturation by 60%. Maturation foreshadowed the performance of lower limbs by 30.3%. Conclusion: Biological maturation and hormonal levels can be related to neuromuscular performance, and young people with higher testosterone levels show superior muscle strength in relation to the others.

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Large numbers of well-characterized clinical samples are fundamental to establish relevant associations between the microbiota and disease. Formalin-fixed and paraffin-embedded (FFPE) tissues are routinely used and are widely available clinical materials. Since current approaches to study the microbiota are based on next-generation sequencing (NGS) targeting the bacterial 16S rRNA gene, our aim was to evaluate the feasibility of FFPE gastric tissues for NGS-based microbiota characterization. Analysis of sequencing data revealed the presence of bacteria in the paraffin control. After the subtraction of the operational taxonomic units (OTUs) present in the paraffin control to the FFPE tissue sample dataset, we evaluated the microbiota profiles between paired FFPE and frozen gastric tissues, and between different times of archiving. Compared with frozen gastric tissues, we detected a lower number of OTUs in the microbiota of paired FFPE tissues, regardless of the time of archiving. No major differences in microbial diversity were identified, but taxonomic variation in the relative abundance of phyla and orders was observed between the two preservation methods. This variation was also evident in each case and throughout the times of FFPE archiving. The use of FFPE tissues for NGS-based microbiota characterization should be considered carefully, as biases can be introduced by the embedding process and the time of tissue archiving.

This study aimed to identify the interactional relationships between maturation (biological age (BA)) and lean mass on strength development in young athletes from different sports. Using a cross-sectional study design, a sample of 64 young athletes (rowers, swimmers, jiu-jitsu, volleyball, soccer and tennis players) of both sexes (13.6 ± 1.17 years) were recruited. Body composition was assessed using dual energy bone densitometry with X-ray source (DEXA). Strength of upper limbs (ULS), force hand grip (HG), vertical jump (VJ) and jump against movement (CMJ) were recorded. BA was estimated from anthropometrics. BA relationships were identified with upper limb strength in all athletes, and with the lower limb strength of tennis players, only (p < 0.05). An interaction effect between lean mass and BA was found (η2p = 0.753), as was a local effect within the regression models (ƒ2 ≥ 0.33). Athletes with a higher concentration of lean mass had superior upper and lower limb strength (p < 0.05). Lean mass showed a local effect (ƒ2) greater than that associated with BA. Although maturation is related to strength development, the strength of the relationship is mitigated by the accrual of lean mass. Specifically, the local effect of lean mass on muscle strength is broader than that of maturation, especially for lower limb strength.