RhoA-ROCK competes with YAP to regulate amoeboid breast cancer cell migration in response to lymphatic-like flow.

Lymphatic drainage generates force that induces prostate cancer cell motility via activation of Yes-associated protein (YAP), but whether this response to fluid force is conserved across cancer types is unclear. Here, we show that shear stress corresponding to fluid flow in the initial lymphatics modifies taxis in breast cancer, whereas some cell lines use rapid amoeboid migration behavior in response to fluid flow, a separate subset decrease movement. Positive responders displayed transcriptional profiles characteristic of an amoeboid cell state, which is typical of cells advancing at the edges of neoplastic tumors. Regulation of the HIPPO tumor suppressor pathway and YAP activity also differed between breast subsets and prostate cancer. Although subcellular localization of YAP to the nucleus positively correlated with overall velocity of locomotion, YAP gain- and loss-of-function demonstrates that YAP inhibits breast cancer motility but is outcompeted by other pro-taxis mediators in the context of flow. Specifically, we show that RhoA dictates response to flow. GTPase activity of RhoA, but not Rac1 or Cdc42 Rho family GTPases, is elevated in cells that positively respond to flow and is unchanged in cells that decelerate under flow. Disruption of RhoA or the RhoA effector, Rho-associated kinase (ROCK), blocked shear stress-induced motility. Collectively, these findings identify biomechanical force as a regulator amoeboid cell migration and demonstrate stratification of breast cancer subsets by flow-sensing mechanotransduction pathways.

Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats / Losartán previene las alteraciones del lecho vascular mesentérico en ratas alimentadas con dieta alta en grasas

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model

La disfunción del tejido adiposo perivascular del lecho mesentérico posee una participación en la fisiopatología de la hipertensión arterial relacionada con el síndrome metabólico. Por lo tanto, podría considerarse como un nuevo blanco terapéutico en las enfermedades cardiovasculares y metabólicas. Además de su efecto antihipertensivo, existe un interés creciente en las acciones pleiotrópicas de losartán, antagonista del receptor de angiotensina II. El objetivo del estudio fue analizar las acciones de losartán sobre el índice de adiposidad y la liberación de prostanoides del lecho vascular mesentérico y su relación con la presión arterial, así como en el índice HOMA-IR (modelo de evaluación homeostático de la resistencia a la insulina) en ratas con dieta alta en grasas. Observamos que la dieta alta en grasas incrementó la adiposidad del lecho vascular mesentérico y la liberación de prostanoides vasoconstrictores como tromboxano (TX) B2 y prostaglandina (PG) F2α, así como la PGE2, un prostanoide inflamatorio en el contexto de resistencia a la insulina e hipertensión. También encontramos una correlación positiva entre el índice de adiposidad y la presión arterial sistólica y ambos parámetros se correlacionan positivamente con el índice HOMA IR. Adicionalmente observamos que la liberación de estos prostanoides se correlaciona con la presión arterial sistólica, así como con el índice de adiposidad del lecho vascular mesentérico. El tratamiento con losartán previno todas estas alteraciones y normalizó la relación PGI2/TXA2 en ratas alimentadas con una dieta alta en grasa. Concluimos entonces que losartán puede ejercer acciones beneficiosas sobre las alteraciones del tejido adiposo perivascular y la disfunción endotelial a través de la restauración del equilibrio normal de sustancias vasoactivas en este modelo experimental

Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats.

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model.

PD-L1 expression and infiltration by CD4+ and FoxP3+ T cells are increased in Xp11 translocation renal cell carcinoma and indicate poor prognosis.

AIMS: Interaction between programmed death-1 ligand (PD-L1) and its receptor programmed death 1 (PD-1) on T cells inactivates antitumour immune responses. PD-L1 expression has been associated with poor prognosis in renal cell carcinoma (RCC) and predicts adverse outcome. This study was designed to evaluate the impact of PD-L1 expression and the immune microenvironment on the clinical outcome in Xp11 translocation renal cell carcinoma (TRCC) and, therefore, their potential relevance as prognostic biomarkers. METHODS AND RESULTS: The present retrospective analysis investigated expression of PD-L1 and immune cells CD8, CD4, CD3, forkhead box protein 3 (FoxP3) and PD-1 in TRCC compared to other types of RCC. FFPE specimens were collected between 2011 and 2017 from 311 patients who underwent nephrectomy at our institution for RCC. Specimens were immunostained for PD-L1, CD8, CD4, CD3, FoxP3 and PD-1, and an outcome analysis was conducted. PD-L1 expression rate was highest in TRCC (68%, 16 of 25), followed by mucinous tubular and spindle cell RCC and collecting duct carcinoma (33%, one of three), papillary RCC (27%, seven of 26), clear cell RCC (16%, 29 of 233), chromophobe RCC (11%, two of 18) and multilocular cystic RCC (0%, none of three). In TRCC, PD-L1 expression was associated with poor recurrence-free survival (RFS) (P = 0.041). The CD4high and FoxP3high groups showed a significantly shorter RFS (P = 0.05 and P = 0.031, respectively) compared to CD4low and FOXPlow groups. CONCLUSION: PD-L1 expression was higher in TRCC than in other types of RCC. High PD-L1 tumour cell expression and tumour infiltration by CD4+ and FoxP3+ immune cells were associated with poor RFS in TRCC.

Development of circulating CD4+ T-cell memory.

The ability of circulating CD4+ T cells to retain memories of previous antigenic encounters is a cardinal feature of the adaptive immune system. Over the past two decades, since the first description of central and effector memory T cells, many studies have examined molecular mechanisms controlling CD8+ T-cell memory, with comparatively less research into CD4+ T-cell memory. Here, we review a number of seminal studies showing that circulating memory CD4+ T cells develop directly from effector cells; and in so doing, preserve features of their effector precursors. We examine mechanisms controlling the development and phenotypes of memory CD4+ T cells, and provide an updated model that accommodates both the central and effector memory paradigm and the diverse T helper cell classification system.

Clinicopathologic characteristics of double primary endometrial and colorectal cancers in a single institution.

AIM: To investigate the clinicopathologic and genetic correlations between double primary endometrial and colorectal cancer related to Lynch syndrome and to analyze germline mutations in mismatch repair genes in endometrial cancer patients in Korea. METHODS: Thirteen patients diagnosed with pathologically endometrial and colorectal cancer between January 2005 and November 2016 in a single institution were enrolled in the study. The medical records were retrospectively analyzed. The genetic mutational information of endometrial cancer in Korea was retrieved from the literature review. RESULTS: Endometrial cancer was diagnosed first in eight (62%) patients, and one patient was diagnosed with colorectal cancer first. Endometrioid adenocarcinoma was reported in 10 of 13 (77%) endometrial cancer patients. Endometrial cancer was found at the low uterine segment in three patients. Three of four patients had high microsatellite instability. The loss of mismatch repair proteins was confirmed in 7 of 11 cases using immunohistochemistry. Four patients fulfilled clinical criteria based on a family history of cancer. Overall, the incidence of suspected Lynch syndrome was 77% (10/13). Four of them underwent genetic testing and three were found to have a pathogenic germline mutation. A possible founder mutation, c.1757_1758insC in MLH1, was observed in 21 germline mutation information from literature review. CONCLUSION: The present study describes the clinicopathologic data of double primary endometrial and colorectal cancer patients and supports that these patients should undergo closed approach for Lynch syndrome. Moreover, a possible founder mutation in Korean endometrial cancer patients was identified.

Sarcomatoid carcinoma in the trachea: A case report and literature review.

Tracheal sarcomatoid carcinoma is an extremely infrequent neoplasm with unclear pathogenesis and clinical outcomes. To date, only two cases have been described in English literature. We report a case of a 37-year-old patient complaining of hemoptysis, dyspnea, and cough. An intraluminal polypoid mass in the trachea was found and ultimately diagnosed as tracheal sarcomatoid carcinoma in the cervical trachea with both carcinomatous and sarcomatoid morphology. The patient is alive without recurrence after segmental resection of the trachea. We also present a comparative analysis of our case with a prior tracheal sarcomatoid carcinoma case.

Biomechanical Forces Promote Immune Regulatory Function of Bone Marrow Mesenchymal Stromal Cells.

Mesenchymal stromal cells (MSCs) are believed to mobilize from the bone marrow in response to inflammation and injury, yet the effects of egress into the vasculature on MSC function are largely unknown. Here we show that wall shear stress (WSS) typical of fluid frictional forces present on the vascular lumen stimulates antioxidant and anti-inflammatory mediators, as well as chemokines capable of immune cell recruitment. WSS specifically promotes signaling through NFκB-COX2-prostaglandin E2 (PGE2 ) to suppress tumor necrosis factor-α (TNF-α) production by activated immune cells. Ex vivo conditioning of MSCs by WSS improved therapeutic efficacy in a rat model of traumatic brain injury, as evidenced by decreased apoptotic and M1-type activated microglia in the hippocampus. These results demonstrate that force provides critical cues to MSCs residing at the vascular interface which influence immunomodulatory and paracrine activity, and suggest the potential therapeutic use of force for MSC functional enhancement. Stem Cells 2017;35:1259-1272.

Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma.

Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.

Predictive Mortality Index for Community-Dwelling Elderly Koreans.

There are very few predictive indexes for long-term mortality among community-dwelling elderly Asian individuals, despite its importance, given the rapid and continuous increase in this population. We aimed to develop 10-year predictive mortality indexes for community-dwelling elderly Korean men and women based on routinely collected clinical data.We used data from 2244 elderly individuals (older than 60 years of age) from the southwest Seoul Study, a prospective cohort study, for the development of a prognostic index. An independent longitudinal cohort of 679 elderly participants was selected from the Korean Genome Epidemiology Study in Ansan City for validation.During a 10-year follow-up, 393 participants (17.5%) from the development cohort died. Nine risk factors were identified and weighed in the Cox proportional regression model to create a point scoring system: age, male sex, smoking, diabetes, systolic blood pressure, triglyceride, total cholesterol, white blood cell count, and hemoglobin. In the development cohort, the 10-year mortality risk was 6.6%, 14.8%, 18.2%, and 38.4% among subjects with 1 to 4, 5 to 7, 8 to 9, and ≥10 points, respectively. In the validation cohort, the 10-year mortality risk was 5.2%, 12.0%, 16.0%, and 16.0% according to these categories. The C-statistic for the point system was 0.73 and 0.67 in the development and validation cohorts, respectively.The present study provides valuable information for prognosis among elderly Koreans and may guide individualized approaches for appropriate care in a rapidly aging society.

A Cell Biologist's Field Guide to Aurora Kinase Inhibitors.

Aurora kinases are essential for cell division and are frequently misregulated in human cancers. Based on their potential as cancer therapeutics, a plethora of small molecule Aurora kinase inhibitors have been developed, with a subset having been adopted as tools in cell biology. Here, we fill a gap in the characterization of Aurora kinase inhibitors by using biochemical and cell-based assays to systematically profile a panel of 10 commercially available compounds with reported selectivity for Aurora A (MLN8054, MLN8237, MK-5108, MK-8745, Genentech Aurora Inhibitor 1), Aurora B (Hesperadin, ZM447439, AZD1152-HQPA, GSK1070916), or Aurora A/B (VX-680). We quantify the in vitro effect of each inhibitor on the activity of Aurora A alone, as well as Aurora A and Aurora B bound to fragments of their activators, TPX2 and INCENP, respectively. We also report kinome profiling results for a subset of these compounds to highlight potential off-target effects. In a cellular context, we demonstrate that immunofluorescence-based detection of LATS2 and histone H3 phospho-epitopes provides a facile and reliable means to assess potency and specificity of Aurora A versus Aurora B inhibition, and that G2 duration measured in a live imaging assay is a specific readout of Aurora A activity. Our analysis also highlights variation between HeLa, U2OS, and hTERT-RPE1 cells that impacts selective Aurora A inhibition. For Aurora B, all four tested compounds exhibit excellent selectivity and do not significantly inhibit Aurora A at effective doses. For Aurora A, MK-5108 and MK-8745 are significantly more selective than the commonly used inhibitors MLN8054 and MLN8237. A crystal structure of an Aurora A/MK-5108 complex that we determined suggests the chemical basis for this higher specificity. Taken together, our quantitative biochemical and cell-based analyses indicate that AZD1152-HQPA and MK-8745 are the best current tools for selectively inhibiting Aurora B and Aurora A, respectively. However, MK-8745 is not nearly as ideal as AZD1152-HQPA in that it requires high concentrations to achieve full inhibition in a cellular context, indicating a need for more potent Aurora A-selective inhibitors. We conclude with a set of "good practice" guidelines for the use of Aurora inhibitors in cell biology experiments.

Periodic array of polyelectrolyte-gated organic transistors from electrospun poly(3-hexylthiophene) nanofibers.

High-performance organic field-effect transistors (OFETs) based on polyelectrolyte gate dielectric and electrospun poly(3-hexylthiophene) (P3HT) nanofibers were fabricated on a flexible polymer substrate. The use of UV-crosslinked hydrogel including ionic liquids for the insulating layer enabled fast and large-area fabrication of transistor arrays. The P3HT nanofibers were directly deposited on the methacrylated polymer substrate. During UV irradiation through a patterned mask, the methacrylate groups formed covalent bonds with the patterned polyelectrolyte dielectric layer, which provides mechanical stability to the devices. The OFETs operate at voltages of less than 2 V. The average field-effect mobility and on/off ratio were approximately 2 cm(2)/(Vs) and 10(5), respectively.

Laparoscopic management of uterine prolapse with cystocele and rectocele using "Gynemesh PS".

OBJECTIVE: Our department performed laparoscopic correction of uterine or vault prolapse with cystocele and rectocele using the "Gynemesh PS." The aim of this study was to evaluate the surgical outcomes and perioperative morbidity after a laparoscopic operation. MATERIALS AND METHODS: From August 2004 to September 2005, we performed laparoscopic pelvic floor repairs in 6 cases of vault prolapse and 15 cases of uterine prolapse at the Department of Obstetrics and Gynecology at the Kyungpook National University Hospital (Daegu, Korea). Uterine and vault prolapse were repaired by laparoscopic rectocele and cystocele repair using the Gynemesh PS, uterosacral ligament suspension, paravaginal repair, and Burch colposuspension. In uterine prolapse, we also carried out a subtotal hysterectomy. The stage of prolapse was classified by means of the pelvic organ prolapse quantification (POPQ) system. RESULTS: The mean age, Q-index, and parity were 64 years (range, 47-79), 24.6 (range, 18.7 approximately 27.8), and 5 (range, 3 approximately 10), respectively. Mean operation time was 141 minutes (range, 90 approximately 211). Mean estimated blood loss was 53 mL (range, 20 approximately 80). Mean hospital stay was 5 days (range, 3 approximately 9 days). There were no major complications, but postoperative voiding difficulty developed in 1 case. Mean preoperative POPQ stage was 3 and immediate, 6-week, 3-month, 6-month, and 1-year postoperative POPQ score was 0. Mean follow-up period was 7.5 months (range, 3 approximately 13). The objective success rate was 100%. CONCLUSIONS: Laparoscopic pelvic floor repair is an effective procedure and enables us to combine the advantages of laparotomy with the low morbidity of the vaginal route. In Europe, the sacrocolpopexy was more popular, but uterosacral ligament suspension is the most natural anatomic repair of defects and, hence, the least likely to be predisposed to future defects in the anterior or posterior vaginal wall or to compromise vaginal function. However, further studies are required on the long-term efficiency and reliability in order to evaluate the value of this technique.

Relationship between glycemic status and progression of carotid intima-media thickness during treatment with combined statin and extended-release niacin in ARBITER 2.

BACKGROUND: We previously reported in a placebo-controlled study that extended-release niacin slowed the progression of carotid atherosclerosis when added to statin monotherapy. This analysis examines the relationship between glycemic status and the effects of niacin on common carotid intima-media thickness (CIMT) and HDL cholesterol. METHODS: Post-hoc, subgroup analysis of ARBITER 2, a randomized, placebo-controlled trial of once-daily extended-release niacin (1000 mg) added to background statin therapy in 167 patients (mean age 67 years) with known coronary heart disease. The primary analysis was a comparison of the primary endpoint, the change in CIMT, between participants with either normal glycemic status, diabetes mellitus (DM) or the metabolic syndrome (MS). RESULTS: Baseline cardiovascular risk variables were significantly worse in those with abnormal glycemic status, particularly among subjects with MS. Niacin increased HDL-C to a similar degree (approximately 20%) across normals, DM and MS. Placebo-treated patients had the greatest CIMT progression, regardless of glycemic status. The lowest progression rate was observed in niacin treated patients with normal glycemic status. Among all niacin treated subjects, there was a significant linear relationship between change in CIMT and change in HDL-C (r = -0.16; p = 0.05), which was of similar magnitude in subgroups with normal glycemic status (r = -0.23; p = 0.08) and DM (r = -0.22; p = 0.17). In those with MS, there was no relationship between changes in HDL and CIMT, (r = 0.11; p = 0.44), whereas blood glucose was positive correlated to change in CIMT (r = 0.30; p = 0.04). In multivariable linear models controlling for MS characteristics and blood glucose changes, only the change in HDL independently predicted change in CIMT. CONCLUSIONS: During niacin treatment, increases in HDL-C are related to changes in CIMT in the setting of both normal glycemic status and diabetes mellitus.

Normalization of intestinal metaplasia in the esophagus and esophagogastric junction: incidence and clinical data.

BACKGROUND: Attention has focused on whether normalization, regression, and development of dysplasia and cancer in specialized intestinal metaplasia (SIM) differ among long-segment Barrett's esophagus (LSBE), short-segment BE (SSBE), and esophagogastric junction SIM (EGJSIM). We prospectively followed a cohort of SIM patients receiving long-term antisecretory medications to determine: (a) histologic normalization (no evidence of SIM on biopsy), (b) change in SIM length, (c) incidence of dysplasia and cancer, and (d) factors associated with normalization. METHODS: One hundred forty-eight patients with SIM were identified in our original cohort. Of these, 60.5% (23/38) LSBE, 69.8% (44/63) SSBE, and 72.3% (34/47) EGJSIM patients underwent repeat surveillance over a mean 44.4 +/- 9.7 months. Demographic, clinical, and endoscopic data were obtained. RESULTS: (a) With long-term, antisecretory therapy, normalization occurred in 0/23 LSBE, 30% (13/44) of SSBE, and 68% (23/34) of EGJSIM (P < 0.001). (b) Normalization was more likely with EGJSIM (odds ratio [OR] 6.7, CI 2.3-19.3, P= 0.005), female gender (OR 7.3, CI 2.3-23.1, P= 0.001), or absence of hiatal hernia (OR 2.9, CI 1.02-8.06, P= 0.002). (c) A significant decrease in mean SIM length was noted for the entire population (2.5 +/- 0.3 to 2.13 +/- 0.3 cm, P= 0.004). (d) Follow-up incidence of dysplasia and cancer was 26.1% (3 indefinite, 2 low-grade dysplasia [LGD], 1 cancer) for LSBE, 6.8% (2 indefinite, 1 LGD) for SSBE, and none for EGJSIM (P < 0.004). CONCLUSIONS: (a) Normalization of SIM occurs most frequently in EGJSIM>SSBE>LSBE. (b) Factors associated with normalization favor less severe GER and shorter segments of SIM. (c) Surveillance of LSBE results in the greatest yield for identifying dysplasia and cancer.

The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3.

OBJECTIVE: The ARBITER 2 trial showed that extended-release niacin (ERN) when added to statin monotherapy slowed the progression of carotid atherosclerosis over 12 months. Whether longer treatment with ERN would have a greater effect on carotid intima-media thickness (CIMT) is unknown. RESEARCH DESIGN AND METHODS: We examined the long-term effects of ERN on high density lipoprotein (HDL-C) cholesterol and CIMT during 12-24 months treatment with ERN in ARBITER 2 participants who were either continued or were crossed over (from placebo) to ERN 1000 mg daily. MAIN OUTCOME MEASURES: Among 149 subjects completing ARBITER 2, 130 (88%) enrolled in ARBITER 3. The prespecified primary endpoints were the within-group change in CIMT and HDL-C in patients receiving placebo for 12 months (n = 71), ERN for 12 months (comprised of subjects from ERN treatment during ARBITER 2 (n = 78) and those crossed over to ERN from placebo after ARBITER 2 (n = 47)), and ERN for 24 months spanning ARBITER 2 and 3 (n = 57). Five subjects discontinued the study due to flushing side effects. The study was completed by 104 subjects (47 crossed over from placebo; 57 with ERN continued from ARBITER 2). RESULTS: HDL-C increased in the ERN group from 39.5 +/- 6.7 to 48.6 +/- 13.3 mg/dl (p < 0.001) along with modest reductions in LDL-C and TG. Among 125 participants treated with ERN for 12 months, there was a net regression of CIMT of -0.027 +/- 0.011 mm (p < 0.001 vs. placebo). Among 57 participants treated with ERN for 24 months, there was additional significant regression of CIMT of -0.041 +/- 0.021 mm (p = 0.001 vs. placebo). Controlling for changes in LDL and triglycerides, only changes in HDL-C were independently associated with regression of CIMT (beta = -0.25; p = 0.001). CONCLUSION: When added to statin therapy, ERN significantly increases HDL-C and induces atherosclerosis regression measured by CIMT over 24 months. Limitations to this study include its open-label design and the inability to relate CIMT effects to clinical outcomes.

Dispersion and current-voltage characteristics of helical polyacetylene single fibers.

To study the transport properties of individual helical polyacetylene (PA) fibers, we developed a method to extract a single fiber from tightly entangled ropes of helical PA bulk film. After a few minutes of sonication of a piece of helical PA bulk film in an organic solution containing surfactant, a droplet of solution is deposited on the pre-pattened electrode under argon atmosphere. AFM images show that extracted helical PA fibers are typically 10 mum in length and 100-200 nm in diameter. We found that the helicity of bulk materials is conserved. We present the temperature dependencies of current-voltage characteristics of individual helical PA fibers doped with iodine.

Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.

BACKGROUND: Niacin reduces coronary heart disease morbidity and mortality when taken either alone or in combination with statins; however, the incremental impact of adding niacin to background statin therapy is unknown. METHODS AND RESULTS: This was a double-blind randomized placebo-controlled study of once-daily extended-release niacin (1000 mg) added to background statin therapy in 167 patients (mean age 67 years) with known coronary heart disease and low levels of high-density lipoprotein cholesterol (HDL-C; <45 mg/dL). The primary end point was the change in common carotid intima-media thickness (CIMT) after 1 year. Baseline CIMT (0.884+/-0.234 mm), low-density lipoprotein cholesterol (89+/-20 mg/dL), and HDL-C (40+/-7 mg/dL) were comparable in the placebo and niacin groups. Adherence to niacin exceeded 90%, and 149 patients (89.2%) completed the study. HDL-C increased 21% (39 to 47 mg/dL) in the niacin group. After 12 months, mean CIMT increased significantly in the placebo group (0.044+/-0.100 mm; P<0.001) and was unchanged in the niacin group (0.014+/-0.104 mm; P=0.23). Although the overall difference in IMT progression between the niacin and placebo groups was not statistically significant (P=0.08), niacin significantly reduced the rate of IMT progression in subjects without insulin resistance (P=0.026). Clinical cardiovascular events occurred in 3 patients treated with niacin (3.8%) and 7 patients treated with placebo (9.6%; P=0.20). CONCLUSIONS: The addition of extended-release niacin to statin therapy slowed the progression of atherosclerosis among individuals with known coronary heart disease and moderately low HDL-C.