Spin-orbit coupling results in technologically-crucial phenomena underlying magnetic devices like magnetic memories and energy-efficient motors. In heavy element materials, the strength of spin-orbit ...coupling becomes large to affect the overall electronic nature and induces novel states such as topological insulators and spin-orbit-integrated Mott states. Here we report an unprecedented charge-ordering cascade in IrTe2 without the loss of metallicity, which involves localized spin-orbit Mott states with diamagnetic Ir(4+)-Ir(4+) dimers. The cascade in cooling, uncompensated in heating, consists of first order-type consecutive transitions from a pure Ir(3+) phase to Ir(3+)-Ir(4+) charge-ordered phases, which originate from Ir 5d to Te 5p charge transfer involving anionic polymeric bond breaking. Considering that the system exhibits superconductivity with suppression of the charge order by doping, analogously to cuprates, these results provide a new electronic paradigm of localized charge-ordered states interacting with itinerant electrons through large spin-orbit coupling.
Aging is a biological process characterized by time-dependent functional declines that are influenced by changes in redox status and by oxidative stress-induced inflammatory reactions. An organism’s ...pro-inflammatory status may underlie the aging process and age-related diseases. In this review, we explore the molecular basis of low-grade, unresolved, subclinical inflammation as a major risk factor for exacerbating the aging process and age-related diseases. We focus on the redox-sensitive transcription factors, NF-κB and FOXO, which play essential roles in the expression of pro-inflammatory mediators and anti-oxidant enzymes, respectively. Major players in molecular inflammation are discussed with respect to the age-related up-regulation of pro-inflammatory cytokines and adhesion molecules, cyclo-oxygenase-2, lipoxygenase, and inducible nitric oxide synthase. The molecular inflammation hypothesis proposed by our laboratory is briefly described to give further molecular insights into the intricate interplay among redox balance, pro-inflammatory gene activation, and chronic age-related inflammatory diseases. The final section discusses calorie restriction as an aging-retarding intervention that also exhibits extraordinarily effective anti-inflammatory activity by modulating GSH redox, NF-κB, SIRT1, PPARs, and FOXOs.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
Gastric ultrasound is a valid tool for non-invasive assessment of the nature and volume of gastric contents in adults and children. Perioperative fasting guidelines recommend oral carbohydrates up to ...2 h before elective surgery. We evaluated gastric volume in children using ultrasound before and after drinking carbohydrate fluids before surgery.
Paediatric patients younger than 18 yr old undergoing elective surgery were enrolled. Initial ultrasound assessment of gastric volume was performed after fasting for 8 h. Two hours before surgery, patients were given carbohydrate drinks: 15 ml kg−1 for patients younger than 3 yr old and 10 ml kg−1 for those more than 3 yr old. Before induction of general anaesthesia, the gastric volume was reassessed. Parental satisfaction scores (0+totally satisfied, 10+totally dissatisfied) and complications were recorded.
Of the 86 enrolled patients, 79 completed the study; three refused to ingest the requested volume, and surgery was delayed for more than 2 h in four patients. The mean (sd) of the initial and second ultrasound measurements were 2.09 (0.97) and 1.85 (0.94) cm2, respectively (P+0.01; mean difference 0.24 cm2, 95% confidence interval 0.06–0.43). The median (interquartile range) satisfaction score was 2.4 (0–6). Two instances of postoperative vomiting and one instance of postoperative nausea occurred.
Carbohydrate fluids ingested 2 h before surgery reduced the gastric volume and did not cause serious complications in paediatric patients. Parents were satisfied with the preoperative carbohydrate drink. Children may benefit from drinking carbohydrate fluids up to 2 h before elective surgery.
cris.nih.go.kr (KCT0001546).
Aims/hypothesis
The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the ...susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.
Methods
Rat insulin promoter (RIP)-
Cre
+
;autophagy-related 7 (
Atg7
)
F/W
mice were bred with
ob/w
mice to derive RIP-
Cre
+
;
Atg7
F/F
-
ob/ob
mice and to induce ER stress in vivo.
GFP-LC3
+
-
ob/ob
mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.
Results
Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with
ob/ob
mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.
Conclusions/interpretation
These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
Changes in the carrier mobility of tensile strained Si and SiGe nanowires (NWs) were examined using an electrical push-to-pull device (E-PTP, Hysitron). The changes were found to be closely related ...to the chemical structure at the surface, likely defect states. As tensile strain is increased, the resistivity of SiGe NWs deceases in a linear manner. However, the corresponding values for Si NWs increased with increasing tensile strain, which is closely related to broken bonds induced by defects at the NW surface. Broken bonds at the surface, which communicate with the defect state of Si are critically altered when Ge is incorporated in Si NW. In addition, the number of defects could be significantly decreased in Si NWs by incorporating a surface passivated Al2O3 layer, which removes broken bonds, resulting in a proportional decrease in the resistivity of Si NWs with increasing strain. Moreover, the presence of a passivation layer dramatically increases the extent of fracture strain in NWs, and a significant enhancement in mobility of about 2.6 times was observed for a tensile strain of 5.7%.
To assess the outcome of Staphylococcus aureus bacteraemia (SAB) according to factors associated with necessity for longer treatment in conjunction with the duration of treatment.
We prospectively ...collected the data of patients with SAB consecutively during 12 to 39 months from 11 hospitals. If multiple episodes of SAB occurred in one patient, only the first episode was enrolled. Factors associated with necessity for longer treatment were defined as follows: persistent bacteraemia, metastatic infection, prosthesis and endocarditis. If any of the factors were present, then the case was defined as longer antibiotic treatment warranted (LW) group; those without any factors were defined as shorter antibiotic treatment sufficient (SS) group. Poor outcome was defined as a composite of 90-day mortality or 30-day recurrence. Duration of antibiotic administration was classified as <14 or ≥14 days in the SS group and <28 or ≥28 days in the LW group.
Among 2098 cases, the outcome was analysed in 1866 cases, of which 591 showed poor outcome. The SS group accounted for 964 cases and the LW group for 852. On multivariate analysis, age over 65 years, pneumonia, higher Sequential Organ Failure Assessment (SOFA) score and chronic liver diseases were risk factors for poor outcome. Administration of antibiotics less than the recommendation was associated with poor outcome, but this significance was observed only in the LW group (adjusted odds ratio = 1.68; 95% confidence interval, 1.00–2.83; p 0.05).
Inappropriately short antibiotic treatment was associated with poor outcome in the LW group. Vigilant evaluation for risk factors to determine the duration of treatment may improve the outcome among patients with SAB.
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