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.