Rapid telomere movement in meiotic prophase is promoted by NDJ1, MPS3, and CSM4 and is modulated by recombination.

Haploidization of the genome in meiosis requires that chromosomes be sorted exclusively into pairs stabilized by synaptonemal complexes (SCs) and crossovers. This sorting and pairing is accompanied by active chromosome positioning in meiotic prophase in which telomeres cluster near the spindle pole to form the bouquet before dispersing around the nuclear envelope. We now describe telomere-led rapid prophase movements (RPMs) that frequently exceed 1 microm/s and persist throughout meiotic prophase. Bouquet formation and RPMs depend on NDJ1, MPS3, and a new member of this pathway, CSM4, which encodes a meiosis-specific nuclear envelope protein required specifically for telomere mobility. RPMs initiate independently of recombination but differ quantitatively in mutants that fail to complete recombination, suggesting that RPMs respond to recombination status. Together with recombination defects described for ndj1, our observations suggest that RPMs and SCs balance the disruption and stabilization of recombinational interactions, respectively, to regulate crossing over.

Species-differences in the in vitro biotransformation of trifluoroethene (HFO-1123).

1,1,2-Trifluoroethene (HFO-1123) is anticipated for use as a refrigerant with low global warming potential. Inhalation studies on HFO-1123 in rats indicated a low potential for toxicity (NOAELs ≥ 20,000 ppm). In contrast, single inhalation exposure of Goettingen® minipigs (≥ 500 ppm) and New Zealand white rabbits (≥ 1250 ppm) resulted in severe toxicity. It has been suggested that these pronounced species-differences in toxicity may be attributable to species-differences in biotransformation of HFO-1123 via the mercapturic acid pathway. Therefore, the overall objective of this study was to evaluate species-differences in glutathione (GSH) dependent in vitro metabolism of HFO-1123 in susceptible versus less susceptible species and humans as a basis for human risk assessment. Biotransformation of HFO-1123 to S-(1,1,2-trifluoroethyl)-L-glutathione (1123-GSH) and subsequent cysteine S-conjugate ß-lyase-mediated cleavage of the corresponding cysteine conjugate (1123-CYS) was monitored in hepatic and renal subcellular fractions of mice, rats, minipigs, rabbits, and humans. While 1123-GSH formation occurred at higher rates in rat and rabbit liver S9 compared to minipig and human S9, increased ß-lyase cleavage of 1123-CYS was observed in minipig kidney cytosol as compared to cytosolic fractions of other species. Increased ß-lyase activity in minipig cytosol was accompanied by time-dependent formation of monofluoroacetic acid (MFA), a highly toxic compound that interferes with cellular energy production via inhibition of aconitase. Consistent with the significantly lower ß-lyase activity in human cytosols, the intensity of the MFA signal in human cytosols was only a fraction of the signal obtained in minipig subcellular fractions. Even though the inconsistencies between GSH and ß-lyase-dependent metabolism do not allow to draw a firm conclusion on the overall contribution of the mercapturic acid pathway to HFO-1123 biotransformation and toxicity in vivo, the ß-lyase data suggest that humans may be less susceptible to HFO-1123 toxicity compared to minipigs.

In Vivo reflectance confocal microscopy of cutaneous acute graft-versus-host disease: concordance with histopathology and interobserver reproducibility of a glossary with representative images.

BACKGROUND: The reliability to non-invasively identify features of inflammatory dermatoses by reflectance confocal microscopy (RCM) remains unknown. Lack of formal training among RCM readers can result in inconsistent assessments, limiting clinical utility. Specific consensus terminology with representative images is necessary to ensure consistent feature-level interpretation among RCM readers. OBJECTIVES: (1) Develop a glossary with representative images of RCM features of cutaneous acute graft-versus-host disease (aGVHD) for consistent interpretation among observers, (2) assess the interobserver reproducibility among RCM readers using the glossary, and (3) determine the concordance between RCM and histopathology for aGVHD features. METHODS: Through an iterative process of refinement and discussion among five international RCM experts, we developed a glossary with representative images of RCM features of aGVHD. From April to November 2018, patients suspected of aGVHD were imaged with RCM and subsequently biopsied. 17 lesions from 12 patients had clinically and pathologically confirmed cutaneous aGVHD. For each of these lesions, four dermatopathologists and four RCM readers independently evaluated the presence of aGVHD features in scanned histopathology slides and 1.5 × 1.5 mm RCM submosaics at 4 depths (blockstacks) respectively. RCM cases were adjudicated by a fifth RCM expert. Interobserver reproducibility was calculated by mean pairwise difference (U statistic). Concordance between modalities was determined by fraction of assignments with agreement. RESULTS: We present a glossary with representative images of 18 aGVHD features by RCM. The average interobserver reproducibility among RCM readers (75%, confidence interval, CI: 71-79%) did not differ significantly from dermatopathologists (80%, 76-85%). The concordance between RCM and histopathology was 59%. CONCLUSIONS: By using the glossary, the interobserver reproducibility among RCM readers was similar to the interobserver reproducibility among dermatopathologists. There was reasonable concordance between RCM and histopathology to visualize aGVHD features. The implementation of RCM can now be advanced in a variety of inflammatory conditions with a validated glossary and representative image set.

Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

High somatostatin receptor expression and efficacy of somatostatin analogues in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive, high-grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastatic MCC (mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low- and moderate-grade NETs that express somatostatin receptors (SSTRs). OBJECTIVES: To assess SSTR expression and the efficacy of SSAs in mMCC, a high-grade NET. Methods In this retrospective study of 40 patients with mMCC, SSTR expression was assessed radiologically by somatostatin receptor scintigraphy (SRS; n = 39) and/or immunohistochemically when feasible (n = 9). Nineteen patients (18 had SRS uptake in MCC tumours) were treated with SSA. Disease control was defined as progression-free survival (PFS) of ≥ 120 days after initiation of SSA. RESULTS: Thirty-three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) of SRS uptake. Of 19 patients treated with SSA, seven had a response-evaluable target lesion; three of these seven patients (43%) experienced disease control, with a median PFS of 237 days (range 152-358). Twelve of 19 patients did not have a response-evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (median PFS of 429 days, range 143-1757). The degree of SSTR expression (determined by SRS and/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. CONCLUSIONS: In contrast to other high-grade NETs, mMCC tumours appear frequently to express SSTRs. SSAs can lead to clinically meaningful disease control with minimal side-effects. Targeting of SSTRs using SSA or other novel approaches should be explored further for mMCC.

Acute decrease in the stiffness of resting muscle belly due to static stretching.

The purpose of the study was to examine the acute effect of static stretching exercise on the resting stiffness of gastrocnemius muscle belly. Ten healthy young adults performed standing wall stretching in dorsiflexion for 1 min at a time and repeated five times. Before and after stretching, the shear modulus was measured in medial and lateral heads of the resting gastrocnemius muscle with ultrasound shear-wave elastography. After the stretching, dorsiflexion range of motion (ROM) of the ankle joint increased (P < 0.01) by 3.9° and returned in 20 min. Immediately after stretching, shear modulus decreased (P < 0.01) by 14%, compared with before stretching across muscle heads. The decrease in shear modulus returned in 20 min after stretching. In the comparison group of 10 additional subjects, the standing intervention without stretching had no influence on these measures. There was a negative correlation between dorsiflexion ROM and shear modulus in either head before and after stretching. The results demonstrate the transient decreases in the stiffness of the resting gastrocnemius muscle belly and indicate that joint flexibility is greater in individuals with lower resting stiffness of the muscle belly.

Genetic analyses of GII.17 norovirus strains in diarrheal disease outbreaks from December 2014 to March 2015 in Japan reveal a novel polymerase sequence and amino acid substitutions in the capsid region.

A novel GII.P17-GII.17 variant norovirus emerged as a major cause of norovirus outbreaks from December 2014 to March 2015 in Japan. Named Hu/GII/JP/2014/GII.P17-GII.17, this variant has a newly identified GII.P17 type RNA-dependent RNA polymerase, while the capsid sequence displays amino acid substitutions around histo-blood group antigen (HBGA) binding sites. Several variants caused by mutations in the capsid region have previously been observed in the GII.4 genotype. Monitoring the GII.17 variant's geographical spread and evolution is important.

Overexpression of nucleostemin contributes to an advanced malignant phenotype and a poor prognosis in oral squamous cell carcinoma.

BACKGROUND: Nucleostemin (NS) is essential for the maintenance of stem cell properties, the functions of which remain poorly understood in cancer cells. The purpose of this study was to explore the impact of NS on malignancy and its clinical significance in oral squamous cell carcinoma (OSCC) patients. METHODS: We investigated the effects of NS on the proliferation and invasion of OSCC using NS-overexpressing or -knockdown OSCC cells. We assessed the activation of the STAT3 (signal transducer and activator of transcription 3) signalling pathway and the downstream targets in the cells with different expression levels of NS. An immunohistochemical analysis of NS was also performed in 54 OSCC patients who were treated with preoperative chemoradiotherapy and surgery. RESULTS: The overexpression of NS significantly enhanced the proliferation and invasive potential of OSCC cells. On the other hand, downregulation of NS suppressed the invasiveness of the cells. The alterations of these malignant phenotypes were associated with the activation of STAT3 signalling and its downstream targets. An immunohistochemical analysis demonstrated that a high NS tumour expression level significantly correlated with an advanced T-stage and N-stage. Furthermore, a Cox regression analysis revealed that the NS status (hazard ratio, 9.09; P=0.002) was a significant progression factor for OSCC patients. CONCLUSIONS: Our results suggest that targeting NS may provide a promising treatment for highly malignant OSCC.

Overexpression of cIAP2 contributes to 5-FU resistance and a poor prognosis in oral squamous cell carcinoma.

BACKGROUND: Resistance to 5-fluorouracil (5-FU) is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about apoptosis resistance, which contributes to 5-FU resistance in OSCC. METHODS: We focussed on the cellular inhibitor of apoptosis protein 2 (cIAP2) on the basis of a DNA microarray data using parental and 5-FU-resistant OSCC cell lines. The effects of cIAP2 downregulation on 5-FU sensitivity and apoptosis were evaluated. An immunohistochemical analysis of cIAP2 and related proteins, cIAP1 and X-linked IAP, was performed in 54 OSCC patients who were treated with 5-FU-based chemoradiotherapy and surgery. RESULTS: The downregulation of cIAP2 significantly enhanced the sensitivity of the 5-FU-resistant cells to 5-FU, with a significant increase in apoptosis. The immunohistochemical analysis demonstrated a high cIAP2 tumour expression to significantly correlate with the pathological response to chemoradiotherapy. Furthermore, a Cox regression analysis revealed the cIAP2 expression status (hazard ratio, 4.91; P=0.037) and the pathological response to chemoradiotherapy (hazard ratio, 0.418; P=0.016) to be significant prognostic factors for OSCC patients. CONCLUSION: These novel findings demonstrate that cIAP2 may represent a potentially useful therapeutic target for improving the treatment and survival of OSCC patients, particularly in the setting of 5-FU resistance.

Health-related quality of life in cutaneous T-cell lymphoma: A cross-sectional survey study.

Background: Patients with cutaneous T-cell lymphoma (CTCL) often have indolent but symptomatic disease. Objective: Assessment of the health-related quality of life (HRQoL) of patients with CTCL. Methods: Cross-sectional survey study. HRQoL was measured by Skindex-16 and FACT-G. Results: A total of 372 responses were received; 80 incomplete/ineligible responses were excluded. A majority of respondents identified as white (87%; 250/288) and female (67%; 193/286) with a mean age of 57 ± 14 years. Most patients had early-stage (IA-IIA) (74%; 162/203) mycosis fungoides (87%; 241/279). There were 33 (12%; 33/279) patients with Sézary syndrome. Mean itch score (visual analogue scale; VAS) was 3.2 ± 2.8, overall; 2.7 ± 2.6 for early, and 4.2 ± 2.9 for advanced disease (p = 0.008). Thirty-eight percent (108/284) and 24% (69/284) reported head/neck and groin/genital involvement, respectively.Overall HRQoL was 46 ± 27 (Skindex-16) and 71 ± 19 (FACT-G), with worse HRQoL for patients with advanced versus early disease (Skindex-16: 67 vs. 40; p=<0.001, FACT-G: 62 vs. 76; p = 0.001). Predictors of worse HRQoL included head/neck, hand/foot or groin/genital involvement, younger age and spending >15 min daily treating CTCL. Limitations: Include anonymous survey methodology, underrepresentation of certain CTCL subtypes and non-white respondents. Conclusions: Patients with CTCL, particularly those with advanced disease or involvement of the head/neck, acral or groin/genital sites, experience significant impact on HRQoL.

Shallow slow earthquakes to decipher future catastrophic earthquakes in the Guerrero seismic gap.

The Guerrero seismic gap is presumed to be a major source of seismic and tsunami hazard along the Mexican subduction zone. Until recently, there were limited observations at the shallow portion of the plate interface offshore Guerrero, so we deployed instruments there to better characterize the extent of the seismogenic zone. Here we report the discovery of episodic shallow tremors and potential slow slip events in Guerrero offshore. Their distribution, together with that of repeating earthquakes, seismicity, residual gravity and bathymetry, suggest that a portion of the shallow plate interface in the gap undergoes stable slip. This mechanical condition may not only explain the long return period of large earthquakes inside the gap, but also reveals why the rupture from past M < 8 earthquakes on adjacent megathrust segments did not propagate into the gap to result in much larger events. However, dynamic rupture effects could drive one of these nearby earthquakes to break through the entire Guerrero seismic gap.

Observation of a large reaction cross section in the drip-line nucleus 22C.

Reaction cross sections (sigma(R)) for 19C, 20C and the drip-line nucleus 22C on a liquid hydrogen target have been measured at around 40A MeV by a transmission method. A large enhancement of sigma(R) for 22C compared to those for neighboring C isotopes was observed. Using a finite-range Glauber calculation under an optical-limit approximation the rms matter radius of 22C was deduced to be 5.4+/-0.9 fm. It does not follow the systematic behavior of radii in carbon isotopes with N < or = 14, suggesting a neutron halo. It was found by an analysis based on a few-body Glauber calculation that the two-valence neutrons in 22C preferentially occupy the 1s(1/2) orbital.

Cerebral glucose utilization: local changes during and after recovery from spreading cortical depression.

Cerebral glucose utilization is markedly increased in most areas of the cerebral cortex and reduced in many subcortical structures during spreading cortical depression. During recovery, cortical glucose utilization is still elevated, but the increased metabolic activity is distributed in columns running perpendicularly through the cortex.

Functional plasticity in the immature striate cortex of the monkey shown by the [14C]deoxyglucose method.

Autoradiographic representation of the local rates of cerebral glucose utilization and local cerebral functional activity by means of the [14C]deoxyglucose technique reveals the existence of the ocular dominance columns in the striate cortex of the monkey in the first day of life. In contrast to the stability of these columns in more mature brain, monocular deprivation for 3 months from the first day of life results in their complete disappearance and a reversion of the autoradiographic pattern to that seen in animals with normal binocular vision. These results are consistent with a reorganization of the representation of the visual fields of the two eyes in the striate cortex and provide additional evidence of the plasticity of the striate cortex of the monkey in early life.

Atomic Control of the SrTiO3 Crystal Surface.

The atomically smooth SrTiO(3) (100) with steps one unit cell in height was obtained by treating the crystal surface with a pH-controlled NH(4)F-HF solution. The homoepitaxy of SrTiO(3) film on the crystal surface proceeds in a perfect layer-by-layer mode as verified by reflection high-energy electron diffraction and atomic force microscopy. Ion scattering spectroscopy revealed that the TiO(2) atomic plane terminated the as-treated clean surface and that the terminating atomic layer could be tuned to the SrO atomic plane by homooepitaxial growth. This technology provides a well-defined substrate surface for atomically regulated epitaxial growth of such perovskite oxide films as YBa(2)Cu(3)O(7-delta).

Mapping the primate visual system with [2-14C]deoxyglucose.

The [2-14C]deoxyglucose method was used to identify the cerebral areas related to vision in the rhesus monkey (Macaca mulatta). This was achieved by comparing glucose utilization in a visually stimulated with that in a visually deafferented hemisphere. The cortical areas related to vision included the entire expanse of striate, prestriate, and inferior temporal cortex as far forward as the temporal pole, the posterior part of the inferior parietal lobule, and the prearcuate and inferior prefrontal cortex. Subcortically, in addition to the dorsal lateral geniculate nucleus and superficial layers of the superior colliculus, and structures related to vision included large parts of the pulvinar, caudate, putamen, claustrum, and amygdala. These results, which are consonant with a model of visual function that postulates an occipito-temporo-prefrontal pathway for object vision and an occipito-parieto-prefrontal pathway for spatial vision, reveal the full extent of those pathways and identify their points of contact with limbic, striatal, and diencephalic structures.

Protein kinase C beta inhibitor prevents diabetic peripheral neuropathy, but not histopathological abnormalities of retina in Spontaneously Diabetic Torii rat.

Spontaneously Diabetic Torii (SDT) rat shows severe ocular complications such as tractional retinal detachment. In the present study, effect of protein kinase C beta (PKCbeta) inhibitor JTT-010 was evaluated to clarify the involvement of PKCbeta in complications of SDT rat. SDT rats were administered JTT-010 (10 or 50 mg/kg/day) for 48 weeks. SDT rats showed delayed oscillatory potentials in electroretinogram. Delayed motor nerve conduction velocity, decreased coefficients of variation of R-R intervals in electrocardiogram and thermal hypoalgesia were also observed. These functional disorders were prevented by administration of JTT-010. Abnormal retinal vascular was formed and the optic disc was protruded in SDT rat; however, JTT-010 did not prevent these hyperglycaemia-induced retinal abnormalities. These findings indicate that PKCbeta is intimately involved in diabetic complications; however, it seems that other factor(s) are primary contributors to histopathological abnormalities in retina. Therefore, PKCbeta inhibitors require concurrent administration of antihyperglycaemic drugs to achieve maximum effect on diabetic complications.

Influence of intracoronal bleaching agents on the ultimate strength and ultrastructure morphology of dentine.

OBJECTIVE: To evaluate the effects of intracoronal bleaching on ultimate tensile strength (UTS) of sound and etched dentine and its ultrastructure morphology. METHODOLOGY: Bovine dentine specimens with (e) or without previous etching with 37% phosphoric acid for 15 s were used for the intracoronal bleaching experiments. Teeth were randomly assigned to five treatments (n = 10): (C) control--no bleaching, (SP) sodium perborate, (CP) 35% carbamide peroxide, (25% HP) 25% hydrogen peroxide and (35% HP) 35% hydrogen peroxide. Bleaching was performed four times within a 72 h interval and afterwards, dentine pulp chamber blocks were obtained. The blocks were sectioned in 0.7 mm-thick slices and these were trimmed to reduce the inner dentine to a dumbbell shape with a cross-sectional area of 0.8 mm(2). Specimens were tested with the microtensile method (0.5 mm min(-1)) and data were analysed (two-way ANOVA-Tukey test, P < 0.05). Additional teeth were prepared for transmission electron microscopy (TEM) to evaluate dentine ultramorphology. RESULTS: The mean values of the UTS (SD) in MPa for sound dentine were: C = 48.3(8.5)a, SP = 34.6 (8.2)b, CP = 32.9 (8.9)b, 25% HP = 28.0(4.6)b, 35% HP = 26.4(6.6)b, and pre-etched dentine: Ce = 38.9(13.8)a, SPe = 31.3 (9.3)ab, CPe = 28.4 (6.2)ab, 25% HPe = 30.0 (7.9)ab, 35% HPe = 19.9(4.6)b. Significant differences between the means are indicated by the letters. TEM observations exhibited demineralization areas for all bleaching treatments. CONCLUSION: Bleaching decreased dentine UTS after treatment. Pre-etched not-bleached dentine (Ce) presented UTS similar to pre-etched bleached dentine, except for 35% HPe. The decrease of UTS of bleached dentine could be attributed to ultrastructural alterations such as loss of inorganic components.