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Summary Incidence of hip fracture increased in Korean populations over age 50 between 2008 and 2012, and the number of fractures was predicted to increase by 1.4 times by 2025. This is important information for public health planning. Introduction The purposes of this study were to evaluate the trends in the incidence and mortality of hip fracture between 2008 and 2012 and predict the number of hip fractures in Korea through 2025 using nationwide claims data. Methods The data managed by the National Health Insurance Service were used to identify the hip fractures in patients aged >50 years between 2008 and 2012. Projections of hip fractures were conducted using the Poisson distribution from 2016 to 2025 in Korea. Results The incidence of hip fractures (per 100,000) increased by 14.1 % over the 5 years of the study, by 15.8 % in women and 10.9 % in men; the older age group showed a steep rise and shift in the incidence from 2008 to 2012. The cumulative mortality rates at 1 year after hip fractures were 17.2 % (3575/20,849) in 2008 and 16.0 % (4547/28,426) in 2012. Overall standardized mortality ratios (SMRs) for hip fracture were higher in men (11.93) than in women (11.22) and were higher than those in the general population in all age groups. In 2016, the total number of hip fractures was estimated to increase an overall of 1.4 times by 2025. Conclusions The incidence of hip fracture continues to increase, and the related mortality is still high, although it has decreased over time. The socioeconomic burden of hip fracture is expected to increase in Korea along with the increased estimated number of fractures. Nationwide strategies should include attempts to reduce the future socioeconomic burdens of hip fractures.

Separating structure and electrons in VO2Above 341 kelvin—not far from room temperature—bulk vanadium dioxide (VO2) is a metal. But as soon as the material is cooled below 341 kelvin, VO2 turns into an insulator and, at the same time, changes its crystal structure from rutile to monoclinic. Lee et al. studied the peculiar behavior of a heterostructure consisting of a layer of VO2 placed underneath a layer of the same material that has a bit less oxygen. In the VO2 layer, the structural transition occurred at a higher temperature than the metal-insulator transition. In between those two temperatures, VO2 was a metal with a monoclinic structure—a combination that does not occur in the absence of the adjoining oxygen-poor layer.Science, this issue p. 1037The metal-insulator transition in correlated materials is usually coupled to a symmetry-lowering structural phase transition. This coupling not only complicates the understanding of the basic mechanism of this phenomenon but also limits the speed and endurance of prospective electronic devices. We demonstrate an isostructural, purely electronically driven metal-insulator transition in epitaxial heterostructures of an archetypal correlated material, vanadium dioxide. A combination of thin-film synthesis, structural and electrical characterizations, and theoretical modeling reveals that an interface interaction suppresses the electronic correlations without changing the crystal structure in this otherwise correlated insulator. This interaction stabilizes a nonequilibrium metallic phase and leads to an isostructural metal-insulator transition. This discovery will provide insights into phase transitions of correlated materials and may aid the design of device functionalities.

A major advance in understanding learning behavior stems from experiments showing that reward learning requires dopamine inputs to striatal neurons and arises from synaptic plasticity of cortico-striatal synapses. Numerous reinforcement learning models mimic this dopamine-dependent synaptic plasticity by using the reward prediction error, which resembles dopamine neuron firing, to learn the best action in response to a set of cues. Though these models can explain many facets of behavior, reproducing some types of goal-directed behavior, such as renewal and reversal, require additional model components. Here we present a reinforcement learning model, TD2Q, which better corresponds to the basal ganglia with two Q matrices, one representing direct pathway neurons (G) and another representing indirect pathway neurons (N). Unlike previous two-Q architectures, a novel and critical aspect of TD2Q is to update the G and N matrices utilizing the temporal difference reward prediction error. A best action is selected for N and G using a softmax with a reward-dependent adaptive exploration parameter, and then differences are resolved using a second selection step applied to the two action probabilities. The model is tested on a range of multi-step tasks including extinction, renewal, discrimination; switching reward probability learning; and sequence learning. Simulations show that TD2Q produces behaviors similar to rodents in choice and sequence learning tasks, and that use of the temporal difference reward prediction error is required to learn multi-step tasks. Blocking the update rule on the N matrix blocks discrimination learning, as observed experimentally. Performance in the sequence learning task is dramatically improved with two matrices. These results suggest that including additional aspects of basal ganglia physiology can improve the performance of reinforcement learning models, better reproduce animal behaviors, and provide insight as to the role of direct- and indirect-pathway striatal neurons.

Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro , but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.

Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial–mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.

Background: In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy. Methods: In total, 2158 patients with pathologically proven stage IB–IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis. Results: Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ⩾3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence. Conclusion: This study identified a ‘four-factor model’ in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.

Background: The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison with non-EAOC. Methods: After we searched an electronic search to identify relevant studies published online between January 1990 and December 2012, we found 20 case–control and 15 cohort studies including 444 255 patients from 1 625 potentially relevant studies. In the meta-analysis, ovarian cancer risk by endometriosis and clinicopathologic characteristics were evaluated using risk ratio (RR) or standard incidence ratio (SIR), and prognosis was investigated using hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity was evaluated using Higgins I 2 to select fixed-effect ( I 2 ⩽50%) or random effects models ( I 2 >50%), and found no publication bias using funnel plots with Egger’s test ( P >0.05). Furthermore, we performed subgroup analyses based on study design, assessment of endometriosis, histology, disease status, quality of study and adjustment for potential confounding factors to minimise bias. Results: Endometriosis increased ovarian cancer risk in case–control or two-arm cohort studies (RR, 1.265; 95% CI, 1.214–1.318) and single-arm cohort studies (SIR, 1.797; 95% CI, 1.276–2.531), which were similar in subgroup analyses. Although progression-free survival was not different between EAOC and non-EAOC (HR, 1.023; 95% CI, 0.712–1.470), EAOC was associated with better overall survival than non-EAOC in crude analyses (HR, 0.778; 95% CI, 0.655–0.925). However, progression-free survival and overall survival were not different between the two groups in subgroup analyses. Stage I–II disease, grade 1 disease and nulliparity were more common in EAOC (RRs, 1.959, 1.319 and 1.327; 95% CIs, 1.367–2.807, 1.149–1.514 and 1.245–1.415), whereas probability of optimal debulking surgery was not different between the two groups (RR, 1.403; 95% CI, 0.915–2.152). Furthermore, endometrioid and clear cell carcinomas were more common in EAOC (RRs, 1.759 and 2.606; 95% CIs, 1.551–1.995 and 2.225–3.053), whereas serous carcinoma was less frequent in EAOC than in non-EAOC (RR, 0.733; 95% CI, 0.617–0.871), and there was no difference in the risk of mucinous carcinoma between the two groups (RR, 0.805; 95% CI, 0.584–1.109). These clinicopathologic characteristics were also similar in subgroup analyses. Conclusions: Endometriosis is strongly associated with the increased risk of ovarian cancer, and EAOC shows favourable characteristics including early-stage disease, low-grade disease and a specific histology such as endometrioid or clear cell carcinoma. However, endometriosis may not affect disease progression after the onset of ovarian cancer.

Gene fusion is involved in the development of various types of malignancies. Recent advances in sequencing technology have facilitated identification of gene fusions and have stimulated the research of this field in cancer. In the present study, we performed next-generation transcriptome sequencing in order to discover novel gene fusions in gastric cancer. A total of 282 fusion transcript candidates were detected from 12 gastric cancer cell lines by bioinformatic filtering. Among the candidates, we have validated 19 fusion transcripts, which are 7 inter-chromosomal and 12 intra-chromosomal fusions. A novel DUS4L – BCAP29 fusion transcript was found in 2 out of 12 cell lines and 10 out of 13 gastric cancer tissues. Knockdown of DUS4L – BCAP29 transcript using siRNA inhibited cell proliferation. Soft agar assay further confirmed that this novel fusion transcript has tumorigenic potential. We also identified that microRNA-coding gene PVT1, which is amplified in double minute chromosomes in SNU-16 cells, is recurrently involved in gene fusion. PVT1 produced six different fusion transcripts involving four different genes as fusion partners. Our findings provide better insight into transcriptional and genetic alterations of gastric cancer: namely, the tumorigenic effects of transcriptional read-through and a candidate region for genetic instability.

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 IrTe 2 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 5 d to Te 5 p 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. The influence of spin–orbit coupling on itinerant electrons underlies the formation of spin–orbit Mott states. Here, the authors demonstrate a temperature-hysteretic cascade between charge-ordered phases stabilized by localized 5 d spin–orbit Mott dimer states in metallic iridium ditelluride.

Weyl semimetals are crystalline solids that host emergent relativistic Weyl fermions and have characteristic surface Fermi-arcs in their electronic structure. Weyl semimetals with broken time reversal symmetry are difficult to identify unambiguously. In this work, using angle-resolved photoemission spectroscopy, we visualized the electronic structure of the ferromagnetic crystal Co₃Sn₂S₂ and discovered its characteristic surface Fermi-arcs and linear bulk band dispersions across the Weyl points. These results establish Co₃Sn₂S₂ as a magnetic Weyl semimetal that may serve as a platform for realizing phenomena such as chiral magnetic effects, unusually large anomalous Hall effect and quantum anomalous Hall effect.