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This study aimed at evaluating the predictive ability of the Physical Resilience Instrument for Older Adults (PRIFOR) for the recovery of frailty, activity of daily living (ADL), and quality of life in older adults suffering from acute health stressors. The longitudinal study was adopted and patients aged 65 and older with Clinical Frailty Scale (CFS) scores between 4 and 6 were included. The PRIFOR was used to assess physical resilience at baseline. Katz ADL, CFS and EuroQoL 5-dimension Questionnaire (EQ5D) scores were all assessed at baseline and one month after discharge. The mean age of the 192 participants was 76.29 ± 6.53 years, and 50.5% were female. After adjusting for the baseline condition, the PRIFOR was only significantly associated with the CFS (β=-0.183, p

Metabolic syndrome (MS) was conceptualized to identify people at risk for cardiovascular disease and type 2 diabetes; however, the epidemiology of MS and its combinations of components in older adults remains unclear. Data from the Senior Health Examination Program of the New Taipei City Government in Taiwan in 2014 were obtained for this study. All participants aged 65 years or older and those with a prior history of cardiovascular disease, cerebrovascular disease, or diabetes mellitus were excluded. 29,164 senior citizens were retrieved for this study, and 12,331 (41.28%) of the participants were male. Female participants were more likely to have MS (42.7% vs.31.3%, p

Summary Introduction It is believed that Rhodiola rosea is able to reduce various stressors caused by chemical and biological factors. Studies have demonstrated that Rhodiola rosea is able to retard muscle damage caused by intense exercise; however, whether this effect is related to inflammatory cytokines remains unknown. The purpose of this study is to examine the impact of Rhodiola rosea administration after continuous endurance exercise on the inflammatory responses. Summary of facts and results Twelve healthy subjects were recruited. The study was a randomized, double-blind, crossover study, composed of two 8-day trials, each separated by a 2-week washout phase. Each trial included a 3-day exercise period consisting of a 30-min run at 75% VO2max per day followed by a 5-day recovery period. The subjects were given two orally administered capsules of placebo (P) or Rhodiola rosea (Rh) per day during the recovery period and immediately after continuous exercise. At 24 and 48 h after the exercise, the blood creatine kinase (CK) levels were higher than those before exercise in both groups. The blood variables had returned to the baseline level at 24 h after exercise except the CK level. The CK levels were lower in the Rh group than that in the P group 72 h after continuous exercise (208.2 ± 32.7 vs 136.7 ± 13.8 U/L, P Conclusion The main finding of this study is that supplementation of Rhodiola rosea after continuous endurance exercise has a trend to decrease blood CK levels moderately, but it is unable to reduce inflammatory reactions.

Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.

Background Whether there is a difference in survival after neoadjuvant chemoradiotherapy plus surgery (CRT-S) compared with definitive chemoradiotherapy (dCRT) in patients with locally advanced oesophageal squamous cell carcinoma (SCC) remains controversial. Methods Patients with SCC who underwent curative treatment from 2008 to 2014 were identified from the Taiwan Cancer Registry. Propensity score matching was undertaken to balance pretreatment clinical variables. Overall survival was compared between patients undergoing CRT-S or dCRT. Univariable and multivariable analyses were performed to identify prognostic factors for overall survival. Results A total of 5832 patients with clinical stage II and III oesophageal SCC receiving CRT-S (1754) or dCRT (4078) were included. After propensity score matching, each group included 1661 patients. The 3-year overall survival rate for patients treated with CRT-S was 41·1 per cent compared with 17·9 per cent for those who had dCRT (P < 0·001). In multivariable analysis, treatment modality was an independent prognostic factor in the overall cohort before propensity score matching: hazard ratio 0·45 (95 per cent c.i. 0·40 to 0·51) for CRT-S versus dCRT (P < 0·001). In separate analyses of patients with clinical stage II and those with stage III disease, CRT-S was associated with significantly better overall survival than dCRT. Conclusion Neoadjuvant chemoradiotherapy and oesophagectomy is associated with better overall survival than dCRT in patients with stage II and III oesophageal SCC.

Hormonal changes, in either men or women experiencing chronic kidney disease, cause decreased libido, erectile dysfunction, dysmenorrhea, and ovarian dysfunction, all of which may contribute to infertility. Patients' endocrinal and sexual function could be rapidly restored after successful renal transplantation (RTx), which may assist in achieving a successful pregnancy. However, fetuses will be exposed to the immunosuppressive agents passed on from the female recipients, which may be another potential factor leading to a poor fetal outcome. This nationwide study examined the perinatal status of offspring from RTx recipients in Taiwan.The National Health Insurance (NHI) program is a mandatory universal health insurance program in Taiwan which provides coverage for 99.6% of its population. Nationwide, births totaled 2,562,253 between 2001 and 2012. Of that total, 97 births were from mothers who had had a RTx prior to delivery. A total of 2,561,973 births from the general population was then determined by combining the NHI database with the National Birth Registry database. Offspring from the RTx recipients and the general population was at a ratio of 1:10 matched by both birth year and birth month, where 77 offspring were from RTx recipients, while 770 served as a control.The offspring from the RTx group displayed significant statistical differences from the general population regarding low birth weight ( 2500 g) (53.3% vs 9.9%, P .001), premature delivery ( 37 weeks) (46.8% vs 10.7%, P .001), and high cesarean section delivery rate (50.7% vs 38.2%, P = .033). Regarding the Apgar score, which was assessed 1 minute and 5 minutes after each birth, fewer than 7 disclosed rates of 21.3% and 6.7% respectively in offspring of the RTx group; the corresponding numbers were 5.1% (P .001) and 2.3% (P = .028) respectively in the other group.Upon restoration of fertility after RTx, most female recipients wish to have their own child; therefore, we as doctors have the responsibility to provide the necessary information we possess regarding the outcomes of offspring of female surgery recipients of childbearing age. Consequently, as the outcomes may not be satisfactory, we will continue to require more studies on the long-term outcome of offspring from RTx recipients in order to provide a more rational conclusion.

Background: Triple Negative Breast Cancer (TNBC) accounts for 15-20% of breast cancers, and has a poor prognosis compared with hormone receptor-positive or HER2-amplified disease. There is currently no targeted therapy to salvage chemotherapy resistant TNBC confirming a need for predictive biomarkers of sensitivity to therapy. This study aimed to evaluate the impact of TP53 mutations, common in TNBC, on sensitivity to therapy and patient outcomes. Methods: TNBC samples (pretreatment biopsies and surgical specimens, n=106) had annotated response to standardized anthracycline/taxane based neoadjuvant chemotherapy (NACT) and 3-year survival data, by which time most recurrences occur in TNBC. RNAseq was performed using Illumina HiSeq with mRNA library preparation protocol to identify TP53 mutations, which were then scored using the Evolutionary Action Score (EAS), a novel computational model shown to be successful at identifying deleterious mutations. This work was supported by an ASCO Conquer Cancer Foundation Young Investigator Award grant. Results: 106 TNBC patients were enrolled on this study, 14 had stage I, 65 stage II, and 24 had stage III disease. 64 patient samples have been analyzed to date, of which 39 (61%) harbored a TP53 mutation, and 24 (38%) were TP53 wildtype. Pathologic complete response (pCR) and survival Of 47 patients who received NACT, 14 (30%) achieved a pCR, and 33 (70%) had residual disease (RD). Patients who achieved a pCR had a significantly better 3-year recurrence free survival (RFS) (100% vs 59%, p=0.011) and overall survival (OS) (100% vs 62%, p-0.01) compared to patients who had residual disease. TP53 status and pCR The rate of pCR was significantly higher in the TP53 mutant group (11/29, 38%) compared to TP53 wildtype (2/17, 12%) TNBC (OR = 4.6, (0.9, 24), p = 0.046). Patients with wild-type and mutant TP53 TNBC who achieved a pCR had excellent 3-year RFS and OS at 100%. Among patients with RD, TP53 wild-type TNBC exhibited a non-significant trend towards higher 3-year RFS (72% vs 49%,HR = 2.5 (0.8, 8.0) p = 0.12) and OS (79% vs 48%,HR = 2.6 (0.8, 8.4) p = 0.11) compared to TP53 mutant TNBC. TP53 status and survival The 3-year OS for TP53 mutant TNBC was 72%, compared to 86% for TP53 wildtype TNBC (HR = 1.5 (0.5, 4.3), p = 0.48). There was no difference in 3-year RFS between the two groups. TP53 EAS and survival Among 39 non-silent TP53 mutant cases, EAS ranged from 42.3 to 100 with a median score of 87.6. The 3-year OS for patients with EAS ≥86.7 was 73%, compared to 74% for patients with EAS Conclusion: TP53 mutations were associated with a higher chance of achieving a pCR; NACT Patients who achieved a pCR to NACT had excellent outcomes, regardless of TP53 mutation status. In patients with RD following NACT, TP53 mutant TNBC had a trend towards worse outcomes compared to TP53 wild-type TNBC. Larger cohorts are required to further evaluate the impact of TP53 mutations and TP53 EAS on survival outcomes in TNBC. Citation Format: Mitri Z, Lin C-H, Hess KR, Thompson A, Lichtarge O, Hubbard R, Fu C, Symmans WF, Moulder-Thompson SL. The impact of TP53 mutation and pathological response to neoadjuvant chemotherapy on triple negative breast cancer outcomes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-05.

This study was to investigate the effect of oxidized wheat gluten (OG) on growth performance, gut morphology and its oxidative states of broilers. One hundred and eighty-day-old male broilers (10 chicks/pen) were randomly allocated into three dietary treatments: control diet (CON), diet with 8% wheat gluten (WG) and diet with 8% OG with six pens/treatment. Body weight (BW) (21 and 35 days) and average daily gain (ADG) (1-21 days and 22-35 days) decreased (p .05) and feed conversion ratio (FCR) (1-21 days and 22-35 days) increased (p .05) in OG treatment. Feed intake (FI) decreased (p .05) in WG and OG treatments during 22-35 days. However, FI was not influenced by dietary treatments during 1-21 days (p .05). The OG-fed broilers had a lower faecal pH value (p .05) and higher faecal moisture content (p 05) at 14, 21, 28 and 35 days. Villus height, crypt depth and V/C value were not different (p .05) among treatments at 21 and 35 days. Lipid peroxidation (LPO) (21 and 35 days) and malondialdehyde (MDA) (35 days) content in crop of OG treatment increased (p .05). Oxidized glutathione (GSSG) (21 days), LPO (21 and 35 days) and MDA (21 and 35 days) content in ileum of OG treatment increased (p .05). The reduced glutathione/oxidized glutathione (GSH/GSSG) (21 days) and (GSH) (35 days) in ileum of OG treatment decreased (p .05). The present findings indicate that OG might be a stressor for broiler gut, which could induce oxidative stress both in crop and in ileum, and the diarrhoea as well. The growth performance of broiler was consequently depressed.

Background For breast cancer (BC) patients with brain metastases (BM) who are not suitable for surgery/radiosurgery, whole brain radiotherapy (WBRT) remained the only standard treatment. Recently, we have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for BM of BC progressing from WBRT (Clin Cancer Res. 2015;21(8):1851). The CNS objective response rate is 77.1% according to volumetric criteria, and 60% according to RECIST 1.1. It has been demonstrated that enlarged brain tumor size is a predictor of WBRT failure. We hypothesized that, for BC with BM, induction BEEP treatment could decrease the size of brain metastases and thereby enhance effectiveness of WBRT. Methods This is a Phase II, randomized, open-labelled study (NCT02185352). Key inclusion criteria: BC with measurable brain metastatic tumor who had not received WBRT and not suitable for surgery or radiosurgery; KPS ≥30%. Key exclusion criteria: patients who had leptomeningeal metastases; history of disease progression during prior cisplatin treatment. In the experimental arm, patients will be treated by induction BEEP for three cycles followed by WBRT. In the control arm, patients will receive upfront WBRT for brain metastases. The BEEP regimen consist of bevacizumab (15 mg/kg) on Day 1 and, with a 1 day window period, followed by etoposide (70 mg/m2/day, Day 2 to Day 4) and cisplatin (70 mg/m2, Day 2), in a 21-day cycle. Stratification is based on the Graded Prognostic Assessment (GPA) score. Primary endpoint: brain-specific progression free survival (PFS) according to RECIST 1.1; key secondary endpoint: the 2-month brain-specific objective response rate (BS-ORR) of BEEP alone and WBRT alone. Other secondary endpoints include overall survival, extra-CNS tumor PFS, safety, time-to-improvement of neurological function,brain-specific PFS according to volumetric criteria, and BS-ORR. Approximately 126 patients will be 2:1 randomized. Multi-center recruitment is ongoing. To our knowledge this is the first randomized trial investigating a targeted therapy plus chemotherapy as induction regimen followed by WBRT as first line treatment for BC with BM. Citation Format: Lu Y-S, Tseng L-M, Yu J-C, Rau K-M, Chao T-Y, Chen S-C, Chiu C-F, Chang Y-C, Chen TW-W, Lin C-H, Chang D-Y, Chao T-C, Huang S-M, Huang C-S, Cheng A-L. Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-03.

SummaryThe prognostic impact of circumferential resection margin (CRM) in surgically resected esophageal squamous cell carcinoma (ESCC) has been controversial. This investigation assessed the prognostic impact of CRM in surgically resected pathologic T3 ESCC patients with or without neoadjuvant chemoradiotherapy (nCRT). We reviewed consecutive p/yp T3 ESCC patients undergoing esophagectomy from two medical centers between January 2009 and December 2016. The cohort was divided into two groups: upfront esophagectomy (upfront surgery) and nCRT followed by esophagectomy (nCRT + surgery). CRM status was assessed and divided into CRM > 1 mm, 0 1 mm (log-rank P = 0.817) and significantly outlived those with tumor at CRM (log-rank P 1 mm failed to show survival superiority to CRM between 0 and 1 mm or involved by cancer (log-rank P = 0.390). In conclusion, a negative CRM, even though being

Background Hypoglycemic episode (HE) increases the risk of cardiovascular mortality. The impact of HE on the risk of sudden death remains unclear. We hypothesized that HE increases the risks of ventricular arrhythmia (VA) and sudden cardiac arrest (SCA), and that anti-diabetic agents (ADAs) causing hypoglycemia also increase the risks of VA and SCA. Methods Patients aged ≥20 years with newly diagnosed diabetes were identified from the Taiwan National Insurance Database. HE was defined as the presentation of hypoglycemic coma or specified/unspecified hypoglycemia. For control group, we included diabetic patients without HE, and they were frequency-matched to the HE group at a 4:1 ratio. The primary outcome was the occurrence of any event of VA (including ventricular tachycardia and fibrillation) and SCA during the defined follow-up periods. Multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for VA or SCA. Results A total of 54,303 diabetic patients were screened with 1,037 of them in the HE group, and 4,148 in the control group. During a mean follow-up period of 3.3±2.5 years, 29 VA/SCA events had occurred. Compared to the control group, the HE group had a higher incidence of VA/SCA (adjusted HR: 2.42, p=0.04). Diabetic patients medicated with insulin for glycemic control increased the risk of VA/SCA compared to those without insulin (adjusted HR: 3.05, p=0.01). Kaplan-Meier survival curves Conclusions HEs in patients with diabetes increased the risks of VA and SCA compared to those without. Their use of insulin also independently increased the risk of VA/SCA.

Hereditary gingival fibromatosis (HGF) is a rare genetic disorder featured by nonsyndromic pathological overgrowth of gingiva. The excessive gingival tissues can cause dental, masticatory, and phonetic problems, which impose severe functional and esthetic burdens on affected individuals. Due to its high recurrent rate, patients with HGF have to undergo repeated surgical procedures of gingival resection, from childhood to adulthood, which significantly compromises their quality of life. Unraveling the genetic etiology and molecular pathogenesis of HGF not only gains insight into gingival physiology and homeostasis but also opens avenues for developing potential therapeutic strategies for this disorder. Recently, mutations in REST (OMIM *600571), encoding a transcription repressor, were reported to cause HGF (GINGF5; OMIM #617626) in 3 Turkish families. However, the functions of REST in gingival homeostasis and pathogenesis of REST-associated HGF remain largely unknown. In this study, we characterized 2 HGF families and identified 2 novel REST mutations, c.2449C>T (p.Arg817*) and c.2771_2793dup (p.Glu932Lysfs*3). All 5 mutations reported to date are nonsenses or frameshifts in the last exon of REST and would presumably truncate the protein. In vitro reporter gene assays demonstrated a partial or complete loss of repressor activity for these truncated RESTs. When coexpressed with the full-length protein, the truncated RESTs impaired the repressive ability of wild-type REST, suggesting a dominant negative effect. Immunofluorescent studies showed nuclear localization of overexpressed wild-type and truncated RESTs in vitro, indicating preservation of the nuclear localization signal in shortened proteins. Immunohistochemistry demonstrated a comparable pattern of ubiquitous REST expression in both epithelium and lamina propria of normal and HGF gingival tissues despite a reduced reactivity in HGF gingiva. Results of this study confirm the pathogenicity of REST truncation mutations occurring in the last exon causing HGF and suggest the pathosis is caused by an antimorphic (dominant negative) disease mechanism.

Background The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is appealing due to the convenience of oral combinations, but the overlapping toxicities may be of concern. A phase I/II study was designed to understand the tolerability and efficacy of this combination treatment. Methods Female MBC patients (pts) with HER2 positive, but regardless of ER status, were eligible. In the phase I part, pts refractory to HER2-targeted treatment or chemotherapy were eligible. In the phase II part, only pts who had not exposed to HER2-targted treatment in the metastatic setting were eligible. Hormonal treatments were not allowed during the study for ER positive pts. Lapatinib was given once daily and oral vinorelbine was given on days 1 and 8 of a 21-day cycle. A 3+3 standard dose escalation rule was applied in phase I part (Table 1). The maximum tolerated dose (MTD) was the highest dose level with less than 33% of pts experiencing dose limiting toxicity (DLT) and will used as starting dose for phase II part. The primary endpoint of the phase II part was progression-free survival (PFS). Tumor response was assessed according to RECIST 1.1. Pt number estimation in the phase II part was based on Simon 2 stage design. Results From 2009 Jun to 2013 Feb, a total of 46 pts were enrolled in phase I (n=15) and II (n=31) parts. The median age was 52.8 (range 34.3-84.0) and the median follow-up time was 39.2 months (range 6.1-62.2). Twenty-eight (60.9%) pts were ER positive. In the phase I part, 2 pts in dose level III had DLTs (Grade 3 neutropenia and grade 3 diarrhea (n=1), prolonged neutropenia delaying next cycle treatment (n=1)). Other common ≥40% grade 1/2 adverse events (AE) in the first-cycle include diarrhea (80.0%), skin rash (66.7%), fatigue (60.0%), and vomiting (40.0%). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the phase II part, 11 pts had intra-patient dose escalation of vinorelbine from 50 to 60 mg/m2 after first-cycle if no major toxicities were noted. Grade 3/4 AEs in the first-cycle include neutropenia, diarrhea, and infection in 12.9%, 3.2% and 3.2%, respectively. Grade 1/2 AEs were similar to the phase I results. Persistent treatment (in 8 cycles) increased the rate of grade 3/4 neutropenia (22.6%) and ALT/AST elevation (6.5%).The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) pts had PR, and the clinical benefit rate (CBR) was 38.7%. A higher dose (level III vs. level II) of vinorelbine was not associated with a better CBR (p=0.71), PFS (p=0.73), or OS (p=0.11). Among pts who had disease progression records, 13.2% (5/38) had brain metastasis progression. Long-term disease control (under treatment for more than 2 years) were achieved in 13.0% (6/46, 2 ER positive, 4 ER negative) pts. Conclusion The combination of lapatinib 1000 mg and oral vinorelbine 60 mg/m2 was general tolerable with manageable toxicities. Clinical efficacy was demonstrated with long-term responders observed. Table 1 Vinorelbine D1 & D8/21-day cycleLapatinib Daily/21-day cycleNo. of pt recruitedNo. of pt with grade 3/4 toxicities in first-cycle mg/m2mgN=15(I)+31(II)NLevel 030100030Level I40100030Level II5010006+206(II)Level III6010003+112(I)Level IV60125000 Citation Format: Chen TW-W, Yeh D-C, Chao T-Y, Lin C-H, Chow LW-C, Hsieh Y-Y, Huang S-M, Cheng A-L, Huang C-S, Lu Y-S. A phase I/II study of the combination of lapatinib and oral vinorelbine in HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-23.

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.

Background Metaplastic breast cancer (MBC) is a rare but aggressive subtype of invasive breast cancer, which is generally resistance to conventional chemotherapy. The majority of MBCs do not express the estrogen receptor, progesterone receptor and negative for HER-2/neu over expression. Thus, targeted treatment options to treat MBCs are also limited. Cancer cell lines are important tools used for us to test the therapeutic efficacy of anticancer agents. However, few in vitro systems for studying MBC are developed. Here we report a newly established novel MBC cell line using the recently developed conditionally reprogrammed cell method and search for effective therapeutic regiments to treat MBCs. Methodology The tumor tissue used for cell line establishment was obtained from a 40 year-old Taiwanese female, who was diagnosed with T2N2aM1 metaplastic carcinoma of breast cancer (with squamous metaplasia). The MBC tumor tissue was first digested by collagenase/ dispase mixture. After digestion, the MBC tumor cells were cultured in F medium with irradiated 3T3-J2 fibroblasts supplemented by 5 uM ROCK inhibitor (Liu et al., Am. J. Pathol. 2012). Subsequently, the MBC tumor tissue cells were passaged and propagated in these conditions until the majority of culture is tumor cells. The MBC tumor cell line was further passaged in DMEM/F12 medium without feeder cells and ROCK inhibitor. Finally, the MBC cell line (MBC-1) was characterized using DNA sequencing, immunofluorescence, Western blotting and viability assays. Results The genomic DNA of MBC1 was examined using DNA sequencing, and the MBC-1 maintained known patient's tumor mutation at the TP53 locus (p.V73fs*76). The MBC cell line also harbored EGFR gene amplification as the patient's tumor, according to quantitative PCR assays. To evaluate tumorigenicity, the MBC cell line was injected subcutaneously into immunocompromised mice, and the MBC tumors formed four weeks after injection. The MBC-1 stained positively using pan-cytokeratin antibody and negative of vimentin, confirming the epithelial origin of the cell line. To explore the possible effective treatment options, the cell line was incubated with different targeted therapy and chemotherapy agents, and the MBC cell line was relatively resistant to most of targeted therapy and chemotherapeutic agents. However, EGFR inhibitors (gefitinib and afatinib) could partially inhibit growth of the MBC cell line. We hypothesis that the inhibitory effect could act through inhibiting the amplified EGFR receptors. To further enhance the effect of EGFR inhibitors in the MBC-1, we combine the EGFR inhibitors with chemotherapy agents, and discovered that EGFR inhibitor and paclitaxel were synergistic across the range of concentration tested. The study on downstream mechanism of the synergism is ongoing. Conclusions We have successfully established a novel metaplastic carcinoma cell line with EGFR amplification from a patient using the conditionally reprogrammed cell method. Based on the preclinical study in the cell line, we found that combining EGFR inhibitor and paclitaxel could be a promising strategy to treat MBC with EGFR amplification. Citation Format: Chung P-H, Chen TW-W, Chang D-Y, Lin C-H, Huang S-M, Lu Y-S. Synergistic effect of EGFR1 inhibitor and paclitaxel in newly patient derived metaplastic carcinoma cell line which harbored EGFR gene amplification [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-09.

[Image: see text] GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure–activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

Consider a double aerodynamic pendulum that represents a double pendulum, the second link of which carries a thin wing with symmetrical airfoil. The entire system is placed in flow with the constant speed V and mounted in such a way that both axes of the pendulum are vertical. We assume that both joints of the pendulum are equipped with linear spiral springs. Systems of rigid bodies that move under the combined action of elastic forces and aerodynamic (or hydrodynamic) load are called aeroelastic systems and are of great interest from the point of view of basic research and applications (especially in the areas of aerospace and civil engineering). An elastically mounted double-link aerodynamic pendulum is considered. It is assumed that the flow acts only upon the second link of the system. Conditions of asymptotic stability of the trivial equilibrium “along the flow” (when both links are stretched along the flow) are obtained. Influence of position of the wing and of coefficients of structural stiffness upon the stability is discussed. Limit cycles are studied that arise in the system for a certain range of values of parameters. Dependence of their amplitude on coefficients of stiffness is analyzed.

Objective A four-fold increase of suicide mortality has been demonstrated in systemic lupus erythematosus (SLE) patients. Prior studies showed that the most common method of suicide attempts in SLE patients involves drug overdose. Therefore, we conducted a nationwide population-based case-control study to elucidate factors associated with drug overdose as suicide attempt in SLE patients. Methods This study was based on the National Health Insurance Research Database in Taiwan. We identified all SLE patients from January 1, 2000 to December 31, 2010. Patients who had suicidal drug overdose (SDO) were selected as cases while age- and gender-matched patients who did not have SDO were selected as controls. Results The incidence rate of SDO in SLE patients was 291 cases per 100,000 person-years, higher than that in the general population (160 cases per 100,000 person-years). In a multivariate logistic regression analysis, we observed that SDO was associated with psychiatric disorders such as depressive disorders (odds ratio: 8.36, 95% confidence interval (CI): 5.60–12.48) and insomnia (odds ratio: 2.71, 95% CI: 1.73–4.25), and lower monthly income (odds ratios: 2.74 to 3.50) in SLE patients. Conclusion SDO is associated with psychiatric disorders such as depressive disorders and insomnia, and lower monthly income in SLE patients.

Summary There is a significant learning curve for endoscopic submucosal dissection of esophageal neoplasms that has not been fully characterized. This retrospective study included 33 consecutive superficial esophageal neoplasms for analysis of the learning curve for esophageal endoscopic submucosal dissection based on a single, novice endoscopist's experience. The study was divided into three periods (T1, T2, and T3) of 10 endoscopic submucosal dissection procedures in chronological order, with 13 procedures in the last period. Patient factors (age, sex, coexistent esophageal varices, or submucosal fibrosis) and tumor factors (location at upper esophagus, involving >3/4 esophageal circumference) for endoscopic submucosal dissection were not statistically different between the periods. The mean procedure time was 74.6 min/cm2, 23.4 min/cm2, and 10.5 min/cm2 for T1, T2, and T3, respectively. The procedure time decreased over time (P = 0.02) and post hoc test revealed significant difference was only between T3 and T1 (P = 0.019). The en bloc resection rate was 50%, 100%, and 92.3% for T1, T2, and T3, respectively (P for trend = 0.015). R0 resection rate was 40%, 100%, and 84.6% for T1, T2, and T3, respectively (P for trend = 0.023). Two patients had complications: each one patient in T1 and T3 period experienced major bleeding during the procedure (P for trend = 0.875). None of the patients had esophageal perforation. The results of the study concluded that at least 30 cases of endoscopic submucosal dissection of esophageal neoplasms are needed for a novice endoscopist to gain early proficiency in this technique.

Background An increased risk of tuberculosis (TB) has been found in subjects with Sjogren9s syndrome (SS); however, whether TB or nontuberculous mycobacteria (NTM) infection is associated with the risk of SS is still unknown. Objectives To explore the association between a history of mycobacterial infection and the risk of newly diagnosed SS. Methods After excluding those who had rheumatoid arthritis and systemic lupus erythematosus, we identified 5,751 newly diagnosed SS cases and 86,265 non-SS patients matched (1:15) for age, sex, and the year of first diagnosis date as controls using nationwide, population-based, claims data. The association between the risk of incident SS and a history of treated mycobacterial infection, including TB and NTM, was quantified by odds ratios (ORs) with 95% confidence intervals (CIs) using conditional logistic regression analysis after adjusting for Charlson comorbidity index (CCI) and bronchiectasis. Results The mean ± SD age was 55±14 years and the proportion of female gender was 87.8% in newly diagnosed SS cases and non-SS controls. An association was observed between NTM infection (OR, 11.24; 95% CI, 2.37–53.24) and incident SS, but not between TB infection and incident SS (OR, 1.29; 95% CI, 0.97–1.71) after adjustment for CCI and bronchiectasis. The magnitude of the association between NTM and SS risk was greatest among those aged between 45 and 65 years (OR, 39.24; 95% CI, 3.97–387.75). Conclusions The present study demonstrates a statistically significant association of newly-diagnosed SS with a history of NTM, but not TB infection. References Peri Y, Agmon-Levin N, Theodor E, et al. Sjogren9s syndrome, the old and the new. Best practice & research Clinical rheumatology 2012;26(1):105–17. Mavragani CP, Moutsopoulos HM. The geoepidemiology of Sjogren9s syndrome. Autoimmunity reviews 2010;9(5):A305–10. Elkington P, Tebruegge M, Mansour S. Tuberculosis: An Infection-Initiated Autoimmune Disease? Trends in immunology 2016. Acknowledgements The authors would like to thank the Biostatistics Task Force of Taichung Veterans General Hospital, Taichung, Taiwan, ROC for statistical support. Disclosure of Interest None declared

Objective: Over the past 15 years, Yuli Veterans Hospital (YVH) in Taiwan has developed the Yuli model to reform long-stay care for psychiatric patients. The development of the Yuli model could be divided into pre-early (1998–1999), early (2000–2006) and late (2007–2008) periods according to the setting-up of the community facilities. In the pre-early period, a vocational rehabilitation program was established for psychiatric patients in YVH. In the later periods, the independent living skills training and the program for social reintegration were instituted in the community facilities. This study aimed to evaluate mortality among the long-stay patients with schizophrenia during the three periods. Methods: In all, 2457 patients with schizophrenia who had been hospitalized for at least one year initially were retrospectively followed from 1 January 1998 to 31 December 2008. Compared with the general population in Taiwan, we calculated the age- and sex-specific standardized mortality ratios (SMRs) of those patients by cause of death during the three periods. Results: Most of the patients were male (81.3%). The mean ± SD age of the patients was 57.83 ± 16.95 years. The all-, natural- and unnatural-cause mortalities of the patients were nearly two times greater than those of the general population during the whole study period. Compared with those in the pre-early and early periods, all patients in the late period had the lowest mortality gaps. In the pre-early, early and late periods, the all-cause SMR were 5.40 (95% confidence interval (CI) = 4.27–6.81), 2.90 (95% CI = 2.20–3.79) and 1.17 (95% CI = 0.54–2.22), respectively, for the 50–69-year-old male patients. Nearly half of all the patients who participated the whole comprehensive rehabilitation program belonged to this sex and age group (N = 156, 46.6%). Conclusions: With the setting-up of community facilities for the comprehensive rehabilitation program, the mortality gaps among the 50–69-year-old male patients apparently decreased using the Yuli model.

Successful renal transplantation (RT) improves quality of life and patient survival. Advances in immunosuppressants for RT have improved the prevention and treatment of acute rejection as well as reduced the risk of chronic graft damage, but immunodeficiency may render patients vulnerable to opportunistic infections. We conducted this study to compare the difference in tuberculosis (TB) infection rates between a single institution and a national database of RT recipients in Taiwan. There were 153 patients with TB (3.2%) among 4,835 RT recipients in the database during the period 2000-2009, with a higher prevalence of men (P = .018) and diabetes patients (P = .029). In our institution's registry, 33 patients (2.7%) developed 35 episodes of TB infection among 1,209 RT recipients, but there were no significant differences in general characteristics among different subgroups. Interestingly, the use of cyclosporine was significantly more frequent in RT recipients with TB than in those without in both the national database and in our institution. In contrast, TB infection was negatively correlated with the use of tacrolimus (TAC) and mycophenolate (MPA). RT recipients with TB infection had poor survival (P = .0013) and low graft survival (P = .0003). Taken together, analyses of the national database and the RT patients in our institution revealed that the use of long-term cyclosporine-based immunosuppressive agents was associated with a greater risk of developing post-transplantation TB compared with that of other immunosuppressive agents, but the chronicity and accumulation effect of TAC and MPA should be observed despite the negative correlation found herein. In conclusion, post-transplantation TB is a serious health threat and one of the major causes of death among RT recipients, and a high index of suspicion to ensure early diagnosis and prompt initiation of treatment for TB is crucial. The use of optimal immunosuppressive agents to minimize acute rejection, monitoring of high-risk recipients, prompt diagnosis, and appropriate treatment are required to manage TB infection in endemic areas such as Taiwan.

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

BACKGROUND AND PURPOSE: Hyperperfusion syndrome is a devastating complication of carotid stent placement. The shortening of cerebral circulation time after stent placement is seen as a good indicator of the development of hyperperfusion syndrome. The purpose of our study was to evaluate whether patients with ipsilateral transverse sinus stenosis are prone to having shortened cerebral circulation time after stent placement, subsequently leading to the possible development of hyperperfusion syndrome. MATERIALS AND METHODS: Forty-nine patients with >70% unilateral carotid stenosis undergoing stent placement were recruited for analysis. Group A consisted of patients with a stenotic ipsilateral transverse sinus >50% greater than the diameter of the contralateral transverse sinus; the remaining patients were in group B. Quantitative DSA was used to calculate cerebral circulation time. Cerebral circulation time was defined as the time difference between the relative time to maximal intensity of ROIs in the proximal internal carotid artery and the internal jugular vein. ΔCCT was defined as cerebral circulation time before stent placement minus cerebral circulation time after stent placement. ΔCCT, white matter hyperintensity signals, and sulcal effacement in MR imaging were compared between the 2 groups. RESULTS: ΔCCT was significantly shorter in group A (0.65 ± 1.3) than in group B (−0.12 ± 1.4). Three patients had white matter hyperintensity signals in group A, and 1 developed hyperperfusion syndrome. Group B showed no MR imaging signs of hyperperfusion syndrome. CONCLUSIONS: Ipsilateral hypoplastic transverse sinus was associated with prolonged cerebral circulation time before stent placement and greatly shortened cerebral circulation time after stent placement. Inadequate venous drainage might play a role in impaired cerebral autoregulation and might influence the development of poststenting hyperperfusion syndrome.

Background: We have recently reported that starting bevacizumab (BE) 1 day before chemotherapy could further induce tumor vascular normalization, thereby significantly enhanced the activity of etoposide (E) and cisplatin (P) in breast cancer patients (pts) with progressing brain metastases after whole brain radiotherapy (WBRT) (ESMO 2013). Lapatinib plus capecitabine is the only proven active regimen for the treatment of brain metastases of HER2 positive breast cancer, with a central nerve system (CNS) objective response rate (ORR) of 18-38% and median time to progression (TTP) of 3.6-5.1 months (mo) in those who had had prior WBRT. Material and methods: Twenty-three HER2 positive breast cancer pts with progressing brain metastases after WBRT were enrolled from Jan 2011 to Jan 2013. Protocol treatment was given in 21 day cycles: BE 15 mg/kg on day 1, E 70 mg/m2/day from day 2 to day 4, and P 70 mg/m2 on day 2 (BEEP regimen), for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS ORR. A CNS objective response was defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. This trial is registered with ClinicalTrials.gov (NCT01281696). Results: Median age was 55.1 (range 33-75); 9 pts were ER+, 14 pts were ER-; 15 pts were ECOG 0-2 (65.2%), and 8 pts were ECOG 3 (34.8%). All of them had previous exposure to trastuzumab, and 20 (87.0%) of them had received trastuzumab containing regimen for the treatment of metastatic disease. Eleven pts (47.8%) received lapatinib treatment before enrollment into this trial. The median lines of chemotherapy for the treatment of metastatic disease were 3 (range 1-8). The median BEEP treatment cycles were 6 (range 1-6). Sixteen of 23 pts (69.6%; 95%CI 47.1-86.8) achieved CNS objective response, including 6 pts (26.1%) with ≥80% and 10 pts (43.5%) with 50-80% CNS volumetric reduction, respectively. Five pts (21.7%) had 20-50% CNS volumetric reduction. Seven of 11 (63.6%) who were refractory to lapatinib treatment had CNS tumor response, and 9 of 12 (75.0%) who were lapatinib naive had CNS ORR. With median follow-up of 12.1 months (mo), the median time to progression was 7.7 mo (95% CI 6.6-8.8), and overall survival was 11.8 mo (95% CI 7.0-16.6) among the 23 pts. Only 3 pts (13.0%) had disease progression during protocol treatment. Grade 3/4 toxicities (≥1%) included neutropenia, leukopenia, thrombocytopenia, infection, anemia, and in 32.7%, 14.0%, 8.4%, 8.4%, and 5.6% per cycles, respectively. Ten pts (43.5%) needed dose reduction of E to 60 mg/m2 and P to 60 mg/m2, and 2 pts discontinued from treatment due to toxicity. Conclusions: BEEP regimen has a significant anti-tumor effect for HER2 positive breast cancer with brain metastasis which progresses after WBRT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-02.

The class A G-protein-coupled receptor GPR40 is predominantly expressed in pancreatic beta cells and plays a major part in fatty acid amplification of glucose-induced insulin secretion. GPR40 agonists are being developed for the treatment of type 2 diabetes. Preclinical studies have shown that GPR40 activation improves glucose control, and recent Phase II trials provided proof-of-concept for this approach. The pharmacology of GPR40 is only partially understood but recent findings suggest that full agonism of the receptor could, in addition to stimulating insulin release, engage the enteroinsular axis. Much remains to be discovered regarding the biology of the receptor to inform the development of GPR40-based drugs.

BACKGROUND AND PURPOSE: Initial results using IR for CT of the head showed satisfactory subjective and objective imaging quality with a 20–40% radiation dose reduction. The aim of our study was to compare the influence of IR and FBP algorithms on perfusion parameters at standard and lowered doses of CTP. MATERIALS AND METHODS: Forty patients with unilateral carotid stenosis post–carotid stent placement referred for follow-up CTP were divided into 2 groups (tube currents were 100 mAs in group A and 80 mAs in group B). Datasets were reconstructed with IR and FBP algorithms; and SNRs of gray matter, white matter, and arterial and venous ROIs were compared. CBF, CBV, and MTT means and SNRs were evaluated by using linear regression, and qualitative imaging scores were compared across the 2 algorithms. RESULTS: The mean effective radiation dose of group B (2.06 mSv) was approximately 20% lower than that of group A (2.56 mSv). SNRs for ROIs in the dynamic contrast-enhanced images were significantly higher than those for the FBP images. Correlations of the SNRs for CBF, CBV, and MTT across the 2 algorithms were moderate (R2 = 0.46, 0.23, and 0.44, respectively). ROIs in gray matter rather than the IR algorithm predicted increasing SNRs in all CBF, CBV, and MTT maps. Two cases of significant restenosis were confirmed in both algorithms. CBV, CBF, and MTT imaging scores did not differ significantly across algorithms or groups. CONCLUSIONS: Lower dose CTP (20% below normal dose) without IR can effectively identify oligemic tissue in poststenting follow-up. IR does not alter the absolute values or increase the SNRs of perfusion parameters. Other methods should be attempted to improve SNRs in settings with low tube currents.

The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability.Literature databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms.Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events.Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success.

Background: Single nucleotide polymorphisms (SNPs) identified from genome-wide association study (GWAS) have been found to be associated with breast cancer risk. We hypothesized that candidate genes and genes derived from GWAS involving in the Estrone/Estradiol (E2)/Tamoxifen biosynthesis may influence the adjuvant hormonal therapy effect and the survival. In this study, we sought to investigate whether these SNPs are associated with prognosis of hormone receptor (HR)-positive breast cancer patients, especially in HER2-negative patients. Patients and methods: We selected breast cancer susceptibility SNPs identified by GWAS, SNPs in tamoxifen metabolizing related genes, and SNPs in estrogen receptor genes and estrogen metabolism genes, and genotyped for variations of above genes, including ALDH3A1, CYP2C19, COMT, CYP19, MAP3K1, FGFR2, TNRC9, HCN1, ERCC4, CYP3A5, UGT1A1, ER, ABCG2, CYP2B6, CYP2D6, 5p12 in 171 hormone receptor-positive, and Her2-negative early breast cancer patients (127 with negative lymph node [LN], and 44 with 1–3 positive LN). All patients received adjuvant hormonal therapy. The associations were examined between SNPs and distance disease-free survival (DDFS), and overall survival (OS) by using the log-rank test and Cox's proportional hazard model. Furthermore, we combined clinicopathologic features and SNPs into the risk score analysis to further validate above identified genetic markers. Results: We found that SNPs of CYP2B6 (rs3211371), FGFR2 (rs2981582), and MAP3K1 (rs889312) were significantly associated with DDFS and OS. Furthermore, in lymph node-negative patients, CYP2B6 (rs3211371), FGFR2 (rs2981582), MAP3K1 (rs889312) and 5p12 (rs10941679 and rs4415084) were significantly associated with DDFS and OS, while CYP3A5 (rs776746) was significantly associated with OS but not DDFS. We further assessed the associations of disease prognosis with the number of high-risk genotypes in CYP3A5, FGFR2, and MAP3K1, and showed significant dose-response relationships between the number of high-risk alleles at these 3 loci and DDFS (P = 0.005 for trend) and OS (P = 0.0008 for trend). When combining the clinicopathologic features and SNPs into the risk score analysis, patients were divided into 3 subgroups (subgroup 1, risk score1.708, n=43 [LN-positive, n=11]). We found that around 20 % of subgroup 3 patients had early development of distant metastases (DM) in the upfront 3 years (the trend of DM appeared to persist at least 10 years), and subgroup 2 patients had higher risk of DM after 5 years, whereas subgroup 1 patients had no development of DM even after 12 years. Conclusion: Our results indicate that in addition to drug metabolic genes, genes related to cell proliferation, anti-apoptosis, and signaling transduction, for example, CYP3A5, CYP2B6, FGFR2, and MAP3K1 genes were associated with DDFS and OS in HR-positive/Her2-negative breast cancer patients. These findings provide additional insight that the genetic variants, or host factors, may affect the prognosis of breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-02.

Objective To evaluate the utility of a proposed cell transfer technique for constructing cytological smear microarrays and its potential applications in multiplex immunocytochemical (ICC) staining. Methods Ninety-six cytology smears, including two pericardial effusions, 22 ascites and 72 pleural effusions, were transferred to a 33-plex cytological microarray. Paired staining of thyroid transcription factor-1 (TTF-1) and calretinin ICC was performed in duplicate slides. Results Most of the smeared cells selected for transfer could be removed from the original slides with a minimal loss of cells and with no change in morphological features or immunoreactivity. Comparison of the staining results with immunohistochemical staining results, clinical history and histopathological reports available for each patient revealed that TTF-1 was positive in 32/33 metastatic pulmonary adenocarcinomas (PACs), 1/15 non-pulmonary adenocarcinomas and 0/45 benign effusions. The ICC results for TTF-1 on a transferred cytological microarray revealed high (97%) sensitivity and high (96.7%) specificity for the detection of metastatic PAC. Conclusion Cytology microarrays can be constructed by transferring cells from serous fluid cytological smears, and cells transferred to the microarray retain their morphological integrity and immunoreactivity. Researchers can use the technique for simultaneous immunostaining of multiple specimens in studies of neoplastic or non-neoplastic diseases when available tissue samples are limited.

Objective:This retrospective post-hoc analysis of observational studies assesses the frequency of painful physical symptoms (PPS) in patients with major depressive disorder (MDD) of varied severity as may be seen in clinical practice.Methods:Observational studies of MDD that collected a clinician-reported measure of depression severity and included assessment of PPS were screened for this individual patient-level analysis. Six observational studies were included that enrolled outpatients with a diagnosis of MDD (assessed using the 17-item Hamilton depression scale, Hospital Anxiety and Depression Scale–Depression, or Inventory of Depressive Symptomatology). Measures of PPS were based on the original study assessment (modified Somatic Symptom Inventory [SSI] and Visual Analogue Scale [VAS]). Patients were divided into analysis cohorts based on the presence or absence of PPS. To model PPS status, odds ratios were calculated from logistic regression for cross-sectional analysis (main analysis) and ge...

C.-H. Wen, C.-H. Lin, S.-C. Tsao, Y.-C. Su, M.-H. Tsai and C.-Y. Chai Micronucleus scoring in liver fine needle aspiration cytology Objective: This study evaluated the role of the micronucleus (MN) in liver fine needle aspiration (FNA) cytology. Methods: Histological features of 75 cases of hepatocellular carcinoma (HCC), of which 25 were well differentiated, 37 moderately differentiated and 13 poorly differentiated, and 58 benign hepatic lesions (total, 133 cases) were correlated with MN expression observed in FNA smears reported as benign (n = 40), atypical (n = 14), suspicious (n = 30) and malignant (n = 49). Results: Stepwise increases in the MN score (0.4 ± 0.6, 1.2 ± 1.3, 6.3 ± 4.2 and 14.3 ± 8.8) correlated with the degree of cytological abnormality: benign, atypia, suspicious and malignant, respectively. The mean MN scores for well-, moderately and poorly differentiated HCC were 5.4 ± 2.2, 11.5 ± 4.5 and 24.9 ± 9.1, respectively, which was significantly different between malignant and suspicious (P

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.

Summary What is known and Objective: An ideal Health Care Service is a service system that focuses on patients. Patients in Taiwan have the freedom to fill their prescriptions at any pharmacies contracted with National Health Insurance. Each of these pharmacies uses its own computer system. So far, there are at least ten different systems on the market in Taiwan. To transmit the prescription information from the hospital to the pharmacy accurately and efficiently presents a great issue. Methods: This study consisted of two-dimensional applications using a QR-code to capture Patient’s identification and prescription information from the hospitals as well as using a webcam to read the QR-code and transfer all data to the pharmacy computer system. Two hospitals and 85 community pharmacies participated in the study. Results and Discussion: During the trial, all participant pharmacies appraised highly of the accurate transmission of the prescription information. The contents in QR-code prescriptions from Taipei area were picked up efficiently and accurately in pharmacies at Taichung area (middle Taiwan) without software system limit and area limitation. The QR-code device received a patent (No. M376844, March 2010) from Intellectual Property Office Ministry of Economic Affair, China. What is new and Conclusion: Our trial has proven that QR-code prescription can provide community pharmacists an efficient, accurate and inexpensive device to digitalize the prescription contents. Consequently, pharmacists can offer better quality of pharmacy service to patients.

Please cite this paper as: Lee C, Lin S, Lin C, Shih J, Lin T, Su Y. Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies. BJOG 2012;119:614–625. Objective To evaluate the clinical value of prenatal array comparative genomic hybridisation (CGH) in screening for submicroscopic genomic imbalances. Design Cross-sectional study. Setting Tertiary referral centre. Population From June 2008 to February 2011, 3171 fetuses underwent prenatal array CGH testing and karyotyping at the National Taiwan University Hospital. Indications for invasive prenatal diagnosis included abnormal karyotype, abnormal ultrasound, advanced maternal age and parental anxiety. Methods In all, 2497 fetuses were screened with 1-Mb resolution bacterial artificial chromosome array-based CGH, and 674 fetuses with 60-K oligonucleotide array-based CGH. Multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, or 105-K oligonucleotide array CGH provided further confirmation. Main outcome measure Copy number variations identified by array CGH. Results Array CGH detected numerical chromosome anomalies in 37 (1.2%) fetuses, microdeletion/duplication in 34 (1.1%) fetuses, large deletion/duplication in 13 (0.4%) fetuses, benign copy number changes in 13 (0.4%) fetuses and variation of unknown clinical significance in five (0.2%) fetuses. Array CGH was effective in identifying submicroscopic genomic imbalance in fetuses with de novo balance translocations (2/17, 1.8%), supernumerary marker chromosomes (3/6, 50%), and abnormal prenatal ultrasound findings (33/194, 17.0%). Array CGH detected microdeletions/duplications in 12 fetuses with normal karyotype. Conclusion Prenatal array CGH is effective in screening for submicroscopic genomic imbalance. Array CGH may add 8.2% to the diagnostic field, compared with conventional karyotyping, for fetuses with abnormal ultrasound results, and is particularly useful in fetuses with karyotypic balanced translocation or marker chromosomes. There is a 0.52% baseline risk of submicroscopic genomic imbalance, even in women with an uneventful prenatal examination.

The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.

Measurement of the strain induced by compression can be useful in the diagnosis of breast tumors. Microcalcification (MC) detected by mammography could be the only symptom of early breast cancers. The purpose of this study was to develop a quantitative method for a differential diagnosis of MC lesions based on the strain ratio (SR) obtained by applying different breast compression pressure during mammography. Methods: This prospective study was conducted with institutional review board approval and the written informed consent was obtained. Twenty-five mastectomy specimens (24 for treatment of breast cancer and 1 from contralateral prophylactic mastectomy) with MCs were examined by digital mammography. There were 24 malignant MCs (mean size of 18.8 mm) detected in the 24 separate specimens, including 14 lesions of invasive carcinoma and 10 lesions of carcinoma in situ. Five benign MCs (mean size of 21.6 mm) were detected, including four lesions which coexisted with malignant MCs in the four separate specimens, and one was discovered in the prophylactic mastectomy specimen. Each specimen experienced four different magnitudes of compression force and the corresponding images were acquired for further analysis. Images in Digital Imaging and Communications in Medicine format (DICOM) were exported into custom software, written in Matlab, to contour the region of interest. Stress was defined as the force divided by the whole specimen area, and the square root of MC area was calculated to represent strain deformation. The SR was the slope of the best-fit line through the four points of each lesion. Histology of the MC was correlated with SR. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of SR for discrimination between benign and malignant MC. Results: The SRs were higher in the malignant MC group (139.10 a.u.) than in the benign MC group (34.09 a.u.; p = 0.024). The SR between invasive carcinoma and carcinoma in situ showed no statistic significance (127.03 a.u. vs. 156.00 a.u.; p = 0.642). The area under the ROC curve for the diagnosis of benign and malignant MC was 0.825 (95% CI, 0.667 to 0.982). Conclusion: This study demonstrated that the SR detected by mammography showed potential for distinguishing benign from malignant MCs. Further in vivo investigations of larger cohorts are necessary to validate these results. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-01.