Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer

Purpose

Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC.

A paradoxical thrombogenic mutation in factor II at the target site of arthropod bleeding toxin

Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in “exosite I” of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin to downstream substrates. Furthermore, the “exosite I” domain of thrombin was inhibited by the arthropod bleeding toxin Triabin (a protein discovered from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis). Our observation that patients with a p.Tyr434His mutation exhibited recurrent thrombosis provides the first proof-of-concept in humans that a pharmacologic agent targeting “exosite I” could be an effective means of specifically modulating the thrombogenic-side of the coagulation system via the inhibition of factor II.     

Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers

Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down‐slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low‐set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.     

Ultrasonography to Measure Swallowing Muscle Mass and Quality in Older Patients With Sarcopenic Dysphagia

Background

Sarcopenic dysphagia is characterized by difficulty swallowing due to a loss of whole-body skeletal and swallowing muscle mass and function. However, no study has reported on swallowing muscle mass and quality in patients with sarcopenic dysphagia.

Association between craniofacial growth and urinary bone metabolic markers (pyridinoline,deoxypyridinoline) in growing rats

Pyridinoline (Pyr) and deoxypyridinoline (Dpyr) are intermolecular cross-links of mature collagen and reflect the bone turnover. The purpose of this study was to elucidate the association between craniofacial growth and urinary Pyr and Dpyr levels. Lateral cephalograms and 24-hour urine were taken for 7 male rats from 5 to 20 wks old. The urinary Pyr and Dpyr were quantified by high-performance liquid chromatography. The neurocranium and upper viscerocranium exhibited significant increases in size, with the maximum rate at around 6 wks old. The mandible presented more substantial growth, with the maximum change at 8 wks old. The urinary Pyr and Dpyr levels gradually increased and reached the maximum at 8 wks old. No prominent association was found between neurocranial growth and urinary levels of pyridinium cross-links, whereas Pyr and Dpyr levels exhibited similar time-dependent metabolic changes to mandibular growth. In conclusion, it is shown that urinary pyridinium cross-links may be useful for the prediction of mandibular growth.     

The effect of supragingival plaque control on the subgingival microbiota in subjects with periodontal disease

The present investigation was performed to study the effect on the subgingival microbiota, of a plaque control program which included meticulous oral hygiene instruction, supragingival scaling and professional monitoring during a 2 year period. 300 subjects were examined for periodontal disease and monitored for 2 years without treatment. After the 2 year examination, 80 subjects were invited to participate in a treatment program intended to improve the standard of their self-performed plaque control. 40 of the invitees had a gingivitis and only minor attachment loss, while 40 subjects had moderate signs of periodontitis. 62 subjects volunteered for this treatment. 23 of the volunteers (Group AB) had several sites with deep pockets (> 4 mm). 39 of the volunteers had gingivitis but shallow pockets only (Group C). Group AB contributed 31 shallow pocket sites (A-sites) and 40 deep pocket sites (B-sites), while Group C contributed 63 shallow sites (C-sites). After the clinical examination, samples of the subgingival microbiota were harvested from the 134 A, B and C sites. The 62 subjects were enrolled in a supervised oral hygiene program. Supragingival scaling was carried out. Oral hygiene instruction was provided and repeated on an individual need basis so that all subjects reached and maintained a supragingival plaque score which was < 20%. 24 months after the year 2 examination, the 62 subjects were examined again using both clinical and microbiological examination procedures. The findings demonstrated that carefully performed supragingival plaque control changed the quantity and the composition of the supragingival microbiota.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothermia attenuates apoptosis and protects contact between myelin basic protein‐expressing oligodendroglial‐lineage cells and neurons against hypoxia–Ischemia

Periventricular leukomalacia (PVL) is a major form of brain injury among preterm infants, which is characterized by extensive loss and dysfunction of premyelinating oligodendrocytes (pre‐OLs) induced by hypoxia–ischemia (HI). Therapeutic hypothermia, which is a standard treatment for term infants with HI encephalopathy, is not indicated for preterm infants because its safety and effect have not been established. Here we investigate the effectiveness and mechanism of hypothermia for the inhibition of pre‐OLs damage in PVL. For in vivo studies, 6‐day‐old rats underwent left carotid artery ligation, followed by exposure to 6% oxygen for 1 hr under hypothermic or normothermic conditions. The loss of myelin basic protein (MBP) was inhibited by hypothermia. For in vitro studies, primary pre‐OLs cultures were subjected to oxygen–glucose deprivation (OGD) under normothermic or hypothermic conditions, and dorsal root ganglion neurons were subsequently added. Hypothermia inhibited apoptosis of pre‐OLs, and, despite specific downregulation of 21.5‐ and 17‐kDa MBP mRNA expression during hypothermia, recovery of the expression after OGD was superior compared with normothermia. OGD caused disarrangement of MBP distribution, decreased the levels of phosphorylated 21.5‐kDa MBP, and disturbed the capacity to contact with neurons, all of which were restored by hypothermia. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 during and after OGD significantly reduced the protective effects of hypothermia on apoptosis and myelination, respectively. These data suggest that phosphorylated exon 2‐containing (21.5‐ and possibly 17‐kDa) MBP isoforms may play critical roles in myelination and that hypothermia attenuates apoptosis and preserves the contact between OLs and neurons via ERK1/2 phosphorylation. © 2014 Wiley Periodicals, Inc.