JNK-dependent release of mitochondrial protein,Smac, during apoptosis in multiple myeloma (MM) cells

Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Previous studies have shown that c-Jun NH(2)-terminal kinase (JNK) is involved in regulating another mitochondrial protein, cytochrome c during apoptosis; however, the role of JNK in the release of mitochondrial Smac is unknown. Here we show that induction of apoptosis in multiple myeloma (MM) cells is associated with activation of JNK, translocation of JNK from cytosol to mitochondria, and release of Smac from mitochondria to cytosol. Blocking JNK either by dominant-negative mutant (DN-JNK) or cotreatment with a specific JNK inhibitor, SP600125, abrogates both stress-induced release of Smac and induction of apoptosis. These findings demonstrate that activation of JNK is an obligatory event for the release of Smac during stress-induced apoptosis in MM cells.     

Trisomy 18q

Summary A 2-month-old male infant with partial trisomy 18, 46,XY,der(4),t(4;18)(q35;q21.1)mat, was presented. Except for atypical facies, he had many of the significant signs of full trisomy 18. Phenotype-karyotype correlations based on the data of our case and those from the literature were discussed. Major features of trisomy 18, such as congenital heart disease, early death, and external malformations, appear to be consistently related to the trisomic state of 18q21. Characteristic congenital heart diseases in trisomy 18 were polyvalvular disease in 100%, membranous ventricular septal defect, patent ductus arteriosus, and high take-off of the right coronary ostium. Pathology of the heart did not differ between full and partial 18-trisomy cases.     

Design and synthesis of novel Cdc25A-inhibitors having phosphate group as a hydrophilic residue

Compounds (6a-e) were synthesized by phosphorylation of hydrophobic perhydroindan derivatives derived from vitamin D(3), and were found to show strong inhibitory activity towards dual-specificity phosphatase Cdc25A (IC(50)=0.7-24.5 microM).     

Ku86 variant expression and function in multiple myeloma cells is associated with increased sensitivity to DNA damage

Ku is a heterodimer of Ku70 and Ku86 that binds to double-stranded DNA breaks (DSBs), activates the catalytic subunit (DNA-PKcs) when DNA is bound, and is essential in DSB repair and V(D)J recombination. Given that abnormalities in Ig gene rearrangement and DNA damage repair are hallmarks of multiple myeloma (MM) cells, we have characterized Ku expression and function in human MM cells. Tumor cells (CD38(+)CD45RA(-)) from 12 of 14 (86%) patients preferentially express a 69-kDa variant of Ku86 (Ku86v). Immunoblotting of whole cell extracts (WCE) from MM patients shows reactivity with Abs targeting Ku86 N terminus (S10B1) but no reactivity with Abs targeting Ku86 C terminus (111), suggesting that Ku86v has a truncated C terminus. EMSA confirmed a truncated C terminus in Ku86v and further demonstrated that Ku86v in MM cells had decreased Ku-DNA end binding activity. Ku86 forms complexes with DNA-PKcs and activates kinase activity, but Ku86v neither binds DNA-PKcs nor activates kinase activity. Furthermore, MM cells with Ku86v have increased sensitivity to irradiation, mitomycin C, and bleomycin compared with patient MM cells or normal bone marrow donor cells with Ku86. Therefore, this study suggests that Ku86v in MM cells may account for decreased DNA repair and increased sensitivity to radiation and chemotherapeutic agents, whereas Ku86 in MM cells confers resistance to DNA damaging agents. Coupled with a recent report that Ku86 activity correlates with resistance to radiation and chemotherapy, these results have implications for the potential role of Ku86 as a novel therapeutic target.     

Risk Factors and Prevalence of Helicobacter pylori in Five Largest Islands of Indonesia: A Preliminary Study

The prevalence of Helicobacter pylori infection in Indonesia is still controversial and mainly investigated in the largest ethnic group, Javanese. We examined the prevalence of H. pylori infection using four different tests including culture, histology confirmed by immunohistochemistry and rapid urease test. We also analyzed risk factors associated with H. pylori infection in five largest islands in Indonesia. From January 2014–February 2015 we consecutively recruited a total of 267 patients with dyspeptic symptoms in Java, Papua, Sulawesi, Borneo and Sumatera Island. Overall, the prevalence of H. pylori infection was 22.1% (59/267). Papuan, Batak and Buginese ethnics had higher risk for H. pylori infection than Javanese, Dayak and Chinese ethnics (OR = 30.57, 6.31, 4.95; OR = 28.39, 5.81, 4.61 and OR = 23.23, 4.76, 3.77, respectively, P <0.05). The sensitivity and specificity for RUT and culture were 90.2%, 92.9% and 80.5%, 98.2%, respectively. The patients aged 50–59 years group had significantly higher H. pylori infection than 30–39 years group (OR 2.98, P = 0.05). Protestant had significantly higher H. pylori infection rate than that among Catholic (OR 4.42, P = 0.008). It was also significantly lower among peoples who used tap water as source of drinking water than from Wells/river (OR 9.67, P = 0.03). However only ethnics as become independent risk factors for H. pylori infection. Although we confirmed low prevalence of H. pylori in Javanese; predominant ethnic in Indonesia, several ethnic groups had higher risk of H. pylori infection. The age, religion and water source may implicate as a risk factor for H. pylori infection in Indonesia.     

The power of proteasome inhibition in multiple myeloma

ABSTRACT

Introduction: Proteasome inhibitors (PIs) are therapeutic backbones of multiple myeloma treatment, with PI-based therapies being standards of care throughout the treatment algorithm. Proteasome inhibition affects multiple critical signaling pathways in myeloma cells and interacts synergistically with mechanisms of action of other conventional and novel agents, resulting in substantial anti-myeloma activity and at least additive effects.

Areas covered: This review summarizes the biologic effects of proteasome inhibition in myeloma and provides an overview of the importance of proteasome inhibition to the current treatment algorithm. It reviews key clinical data on three PIs, specifically bortezomib, carfilzomib, and ixazomib; assesses ongoing phase 3 trials with these agents; and looks ahead to the increasingly broad role of both approved PIs and PIs under investigation in the frontline and relapsed settings.

Expert commentary: Progress to date with PIs in multiple myeloma has been impressive, but there remain unmet needs and challenges, as well as increasing opportunities to optimize the use of these agents. Understanding discrepancies between PIs in terms of efficacy and safety profile is a key goal of ongoing research, along with proteomics-based efforts to identify potential biomarkers of sensitivity and resistance, thereby enabling increasingly personalized treatment approaches in the future.     

A comparison of head-out mist bathing,with or without facial fanning,with head-out half-body low-water level bathing in humans—a pilot study

To reduce the risks of Japanese-style bathing, half-body bathing (HBLB) has been recommended in Japan, but discomfort due to the cold environment in winter prevents its widespread adoption. The development of the mist sauna, which causes a gradual core temperature rise with sufficient thermal comfort, has reduced the demerits of HBLB. We examined head-out 42 °C mist bathing with 38 °C HBLB up to the navel to see if it could improve thermal comfort without detracting from the merits of HBLB, with and without the effects of facial fanning (FF). The subjects were seven healthy males aged 22–25 years. The following bathing styles were provided: (1) HBLB—head-out half-body low bathing of 38 °C up to the navel (20 min); (2) HOMB—head-out mist bathing of 42 °C and HBLB of 38 °C (20 min); and (3) HOMBFF—HOMB with FF (20 min). HOMB raised the core temperature gradually. HOMBFF suppressed the core temperature rise in a similar fashion to HOMB. Increases in blood pressure and heart rate usually observed in Japanese traditional-style bathing were less marked in HOMBs with no significant difference with and without FF. The greatest body weight loss was observed after Japanese traditional-style bathing, with only one-third of this amount lost after mist bathing, and one-sixth after HBLB. HOMB increased thermal sensation, and FF also enhanced post-bathing invigoration. We conclude that HOMB reduces the risks of Japanese traditional style bathing by mitigating marked changes in the core temperature and hemodynamics, and FF provides thermal comfort and invigoration.     

Effects of isotonic and isometric exercises with mist sauna bathing on cardiovascular,thermoregulatory, and metabolic functions

To clarify the effects of isometric and isotonic exercise during mist sauna bathing on the cardiovascular function, thermoregulatory function, and metabolism, six healthy young men (22?±?1 years old, height 173?±?4 cm, weight 65.0?±?5.0 kg) were exposed to a mist sauna for 10 min at a temperature of 40 °C, and relative humidity of 100 % while performing or not performing ～30 W of isometric or isotonic exercise. The effect of the exercise was assessed by measuring tympanic temperature, heart rate, systolic and diastolic blood pressure, chest sweat rate, chest skin blood flow, and plasma catecholamine and cortisol, glucose, lactate, and free fatty acid levels. Repeated measures ANOVA showed no significant differences in blood pressure, skin blood flow, sweat rate, and total amount of sweating. Tympanic temperature increased more during isotonic exercise, and heart rate increase was more marked during isotonic exercise. The changes in lactate indicated that fatigue was not very great during isometric exercise. The glucose level indicated greater energy expenditure during isometric exercise. The free fatty acid and catecholamine levels indicated that isometric exercise did not result in very great energy expenditure and stress, respectively. The results for isotonic exercise of a decrease in lactate level and an increase in plasma free fatty acid level indicated that fatigue and energy expenditure were rather large while the perceived stress was comparatively low. We concluded that isotonic exercise may be a more desirable form of exercise during mist sauna bathing given the changes in glucose and free fatty acid levels.