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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.

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.

Multiferroic BiFeO 3 nanopowders are synthesized through a sol–gel route using the environment-friendly and non-toxic maltose as the complexing and reducing agent. A high content of hydroxyl groups is found to be critical in the preparation of phase-pure BiFeO 3 materials. Fourier transform infrared spectroscopy, thermogravimetric analysis and differential scanning calorimetry reveal that the optimal calcination temperature of BiFeO 3 precursor is about 450 °C in the synthesis, leading to the formation of phase-pure and well-crystallized BiFeO 3 nanopowders with sizes being about 40 nm. Magnetic measurements illustrate the ferromagnetic behavior of BiFeO 3 nanopowders at room temperature. The maximum and remanent magnetizations of the nanopowders are about 0.657 and 0.048 emu/g, respectively, under the magnetic field of 50 kOe. Moreover, the energy band gap of the nanopowders is approximately 2.27 eV, confirming their strong absorbance of the visible light. Graphical Abstract

SummaryIn Korean, atypical subtrochanteric fractures (ASF) were rare. Higher BMI and use of bisphosphonate were significant risk factors of ASF.IntroductionRecently, ASF have been reported to increase among patients on bisphosphonate. However, the incidence of ASF and the association between ASF and bisphosphonate use have not been well defined in Asian population. Our purposes are (1) to estimate the proportion of ASF among Korean patients with proximal femur fracture and (2) to determine the associated risk factors of ASF in the Korean patients.MethodsWe conducted a multicenter (16 academic hospitals), prospective Korean hip fracture study on hip fracture in a cohort of patients aged 50 years or older from South Korea between July 2014 and May 2016. As a part of Korean hip fracture study, primary analysis examined the proportion of ASF among proximal femur fracture. To identify ASF, according to the definition by ASBMR task force, all radiographs of subtrochanteric fracture were reviewed. Associated risk factors for occurrence of ASF were also evaluated by using multivariable logistic regression analysis.ResultsAmong 1361 patients with proximal femoral fractures due to low-energy trauma, 17 fractures (1.2%) were identified as ASF. Higher BMI and use of bisphosphonate before injury were independent risk factors of ASF.ConclusionIn Korean, ASF were rare. Higher BMI and use of bisphosphonate were significant risk factors of ASF.

The tumor-suppressor RUNX3 has a critical role in a lineage determination, cell cycle arrest and apoptosis. Lozenge ( Lz ), a Drosophila homolog of mammalian RUNX family members, has integral roles in these processes and specifically in eye cell fate determination. To elucidate the genetic modifiers of Lz/RUNX3 , we performed a large-scale functional screen in a fly mutant library. The screen revealed genetic interactions between the Lz , Rac and Hippo pathways. Analysis of interactions among these genes revealed that the defective phenotype resulting from activation of Yki , an end point effector of the Hippo pathway, was suppressed by Lz and enhanced by Rac-Trio . Molecular biological analysis using mammalian homologs reveled that LATS1/2-mediated YAP phosphorylation-facilitated dissociation of the YAP-TEAD4 complex and association of the YAP-RUNX3 complex. When cells were stimulated to proliferate, activated RAC-TRIO signaling inhibited LATS1/2-mediated YAP phosphorylation; consequently, YAP dissociated from RUNX3 and associated with TEAD, thereby replacing the YAP-RUNX3 complex with YAP-TEAD. RUNX3 contributed to both association and dissociation of YAP-TEAD complex, most likely through the formation of the YAP-TEAD-RUNX3 ternary complex. Ectopic expression of RUNX3 in MKN28 gastric cancer cells reduced tumorigenicity, and the tumor-suppressive activity of RUNX3 was associated with its ability to interact with YAP. These results identify a novel regulatory mechanism, mediated by the Hippo and RAC-TRIO pathways, that changes the binding partner of YAP.

Summary Objective Little is known about the burden of severe retinal disease between young‐onset type 2 (T2D) and type 1 diabetes (T1D). This study assessed the prevalence of significant retinopathy in young‐onset T2D vs. T1D and its predictive factors. Methods This was a cross‐sectional study. Subjects with T1D and T2D diagnosed below age 40 were identified from diabetes eye screening register. Preproliferative, proliferative, maculopathy changes and/or previous laser photocoagulation treatment were considered to have significant retinopathy (SigDR). Results A total of 1306 subjects were identified, of whom 842 and 464 had T1D and T2D, respectively. The mean age of diagnosis was significantly lower in T1D subjects (T1D vs. T2D; 20.1 ± 10.3 vs. 32.1 ± 6.0 years, p < 0.0005). Although the T2D cohort had shorter diabetes duration (T1D vs. T2D; 20.8 ± 13.0 vs. 13.7 ± 9.0 years, p < 0.0005), the overall prevalence of SigDR was similar to T1D (T1D vs. T2D; 21.6 vs. 20.9%, p = NS). After adjusting for diabetes duration, the T2D cohort experienced significantly higher prevalence of this complication than T1D after 10 years duration. The age threshold beyond which the T2D cohort began to experience greater burden of SigDR was approximately 50 years. The prevalence of any retinopathy after 15 years duration was 75–80% for both young‐onset cohort. Risk factors for SigDR (older age, diabetes duration, systolic BP, HbA1c and creatinine) were similar in both young‐onset diabetes cohort with poor glycaemic control being the strongest variable. Lower age of T2D diagnosis was not a predictive factor. Conclusions Irrespective of diabetes type, subjects with young‐onset diabetes possessed high lifetime risk for retinopathy. However, young‐onset T2D cohort was more susceptible to severe retinal disease with substantial burden of this complication by the fifth decade of life.

Background The long-term outcomes of minimally invasive lateral pelvic lymph node dissection (LPND) are not completely known. The aim of this study was to compare long-term outcomes between robotic and laparoscopic LPND in low rectal cancer patients with suspected lymph node metastasis in the pelvic sidewall. Methods We retrospectively reviewed the records of all rectal cancer patients who had laparoscopic or robotic total mesorectal excision (TME) with LPND between March 2006 and June 2016. Stage IV patients were excluded. The outcomes of patients who had laparoscopic and robotic TME with LPND were compared. Results Twenty-nine patients had laparoscopic LPND and 70 had robotic LPND. No significant differences in patient characteristics were observed between the two groups. The urinary retention rate was lower in the robotic group than in the laparoscopic group (7.1% vs. 24.1%; p  = 0.043). During a median follow-up of 44.3 months, the overall recurrence rates were 48.3% and 31.4% in the laparoscopic and robotic groups, respectively ( p  = 0.175). The 5-year disease-free survival rates were 50.4% and 67.0% in the laparoscopic and robotic groups, respectively ( p  = 0.227). The 5-year overall survival rates were 65.0% and 92.2% in the laparoscopic and robotic groups, respectively ( p  = 0.017). Conclusions Robotic TME with LPND is safe and feasible. In particular, it is associated with lower urinary retention. Robotic TME with LPND might yield a similar local recurrence rate and 5-year disease-free survival, but favorable long-term overall survival as compared to the laparoscopic approach. However, considering the retrospective nature and both major variables of TME and LPND involved together, this should be cautiously interpreted.

Mammalian target of rapamycin complex (mTORC) regulates a variety of cellular responses including proliferation, growth, differentiation and cell migration. In this study, we show that mammalian target of rapamycin complex 2 (mTORC2) regulates invasive cancer cell migration through selective activation of Akt1. Insulin-like growth factor-1 (IGF-1)-induced SKOV-3 cell migration was completely abolished by phosphatidylinositol 3-kinase (PI3K) (LY294002, 10 μ M ) or Akt inhibitors (SH-5, 50 μ M ), whereas inhibition of extracellular-regulated kinase by an ERK inhibitor (PD98059, 10 μ M ) or inhibition of mammalian target of rapamycin complex 1 (mTORC1) by an mTORC1 inhibitor (Rapamycin, 100 n M ) did not affect IGF-1-induced SKOV-3 cell migration. Inactivation of mTORC2 by silencing Rapamycin-insensitive companion of mTOR (Rictor), abolished IGF-1-induced SKOV-3 cell migration as well as activation of Akt. However, inactivation of mTORC1 by silencing of Raptor had no effect. Silencing of Akt1 but not Akt2 attenuated IGF-1-induced SKOV-3 cell migration. Rictor was preferentially associated with Akt1 rather than Akt2, and over-expression of Rictor facilitated IGF-1-induced Akt1 activation. Expression of PIP3-dependent Rac exchanger1 (P-Rex1), a Rac guanosine exchange factor and a component of the mTOR complex, strongly stimulated activation of Akt1. Furthermore, knockdown of P-Rex1 attenuated Akt activation as well as IGF-1-induced SKOV-3 cell migration. Silencing of Akt1 or P-Rex1 abolished IGF-1-induced SKOV-3 cell invasion. Finally, silencing of Akt1 blocked in vivo metastasis, whereas silencing of Akt2 did not. Given these results, we suggest that selective activation of Akt1 through mTORC2 and P-Rex1 regulates cancer cell migration, invasion and metastasis.

Summary Recent meta‐analysis by the Cochrane collaboration concluded that treatment of varicocele may improve an infertile couple's chance of pregnancy. However, there has been no consensus on the management of subclinical varicocele. Therefore, we determine the impact of varicocele treatment on semen parameters and pregnancy rate in men with subclinical varicocele. The randomised controlled trials that assessed the presence and/or treatment of subclinical varicocele were included for systematic review and meta‐analysis. Random effect model was used to calculate the weighted mean difference of semen parameters and odds ratio of pregnancy rates. Seven trials with 548 participants, 276 in subclinical varicocelectomy and 272 in no‐treatment or clomiphene citrate subjects, were included. Although there was also no statistically significant difference in pregnancy rate (OR 1.29, 95% CI 0.99–1.67), surgical treatment resulted in statistically significant improvements on forward progressive sperm motility (MD 3.94, 95% CI 1.24–6.65). However, the evidence is not enough to allow final conclusions because the quality of included studies is very low and further research is needed.

Substitution-induced modifications in structural, magnetic and optical properties of Nb doped and Sm–Nb co-doped BiFeO 3 nanoparticles are reported. X-ray diffraction and Raman analyses indicate that the phase transforms from a rhombohedral to orthorhombic one due to Nb doping and Sm–Nb co-doping. The Nb doping and Sm–Nb co-doping both can lead to a decrease in particle size and an enhancement in magnetic properties, but there is a much stronger effect for the Sm–Nb co-doping than for the Nb doping. With increasing doping concentration of Nb and Sm, the maximum and remanent magnetizations first increase and then drop down, i.e., there is a maximum value in both maximum and remanent magnetizations. The optimal maximum and remanent magnetizations are obtained as 0.601 and 0.155 emu/g, respectively, at y  = 0.05 for BiFe 1 -  y Nb y O 3 nanoparticles, while they are 0.954 and 0.206 emu/g at x  = 0.15 for Bi 1 -  x Sm x Fe 0.95 Nb 0.05 O 3 nanoparticles. Meanwhile, the corresponding optical energy band gap of these samples decreases from 2.16 to 2.02 eV with increasing Sm–Nb co-doping concentration, indicating a strong absorption of visible light. Consequently, the magnetic and optical properties of BiFeO 3 nanoparticles can be improved considerably by doping high-valence transition and rare earth elements. Graphical Abstract