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      • Clinico-Pathologic Subtypes of Breast Cancer Primary Tumors Are Related to Prognosis after Recurrence

        Sanchez, Cesar,Camus, Mauricio,Medina, Lidia,Oddo, David,Artigas, Rocio,Sepulveda, Alejandra Perez,Domainguez, Francisco,Razmilic, Dravna,Navarro, Maria Elena,Galindo, Hector,Acevedo, Francisco Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.12

        Background: Pathological factors, based mainly on immunohistochemistry (IHC) and histological differentiation, are mostly used to differentiate breast cancer (BC) subtypes. Our present aim was to describe the characteristics and survival of a relapsing BC patient cohort based on clinico-pathologic subtypes determined for the primary tumors. Methods: We used a clinico- pathological definition of BC subtypes based on histological grade (HG), estrogen receptor (ER), progesterone receptor (PgR),and epidermal growth factor receptor type 2 (HER2) expression assessed by IHC. We determined variables associated with loco-regional recurrence (LRR), second primaries (SP), systemic recurrence (SR) and post-recurrence survival (PRS). Results: Out of 1,702 patients, 240 (14%) had an event defined as recurrence. Those with recurrent disease were significantly younger than those without,and were initially diagnosed at more advanced stages, with larger tumors, greater lymph nodal involvement and higher HG. With a median follow up of 61 months (1-250), 4.6% of patients without recurrence and 56.6% of patients with an event defined as recurrence had died. The median PRS for the LRR group was 77 months; 75 months for those who developed a SP and 22 months for patients with an SR (p <0.0001). In SR cases, the median PRS was shorter for ER- tumors than for ER+ tumors (15 vs. 26 months, respectively; p = 0.0019, HR 0.44; CI: 0.25-0.44). Conclusions: Subtype, defined through classic histopathologic parameters determined for primary tumors, was found to eb related to type of recurrence and also to prognosis after relapse.

      • Breast Cancer at Extreme Ages - a Comparative Analysis in Chile

        Acevedo, Francisco,Camus, Mauricio,Sanchez, Cesar Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.4

        Background: Young onset breast cancer (BC) has a worse outcome as compared to in the elderly. However, some studies have shown that BC in the elderly, despite indolent features, does also cause increase in mortality. In an attempt to compare clinic-pathological characteristics, BC subtypes and survival in patients with BC presenting at extremes of age, we performed a retrospective study. Materials and Methods: Patients were either ${\leq}40$ or ${\geq}70$ years old. Subtypes were defined using immunohistochemistry and histological grade. Chi-Square test was used for evaluation of categorical variables, and Kaplan-meier and log-rank for disease-specific survival (DSS) and disease free survival (DFS). Results: We analyzed 256 patients ${\leq}40$ and 366 patients ${\geq}70$. Younger patients presented with more aggressive disease, with less luminal A but more luminal B and triple negative (TN) subtype. With a median follow-up of 57.5 months, DFS at 5 years in younger patients was 72.3% vs 84.6% in the elderly (p=0.007). Luminal A and B disease presented with worse DFS in younger patients. The opposite was seen in the TN subgroup. Although we found no significant differences in DSS, older patients with TN tumors died of BC more frequently. This group also received less chemotherapy. Conclusions: Young patients present with more aggressive disease, this translating into worse DFS. However, elderly patients with TN disease represent a particular subpopulation with worse DFS and DSS, suggesting that chemotherapy should not be withheld only because of age.

      • SCISCIESCOPUS

        Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis.

        Lee, Eun-Woo,Lee, Min-Sik,Camus, Suzanne,Ghim, Jaewang,Yang, Mi-Ran,Oh, Wonkyung,Ha, Nam-Chul,Lane, David P,Song, Jaewhan Published for the European Molecular Biology Organ 2009 The EMBO journal Vol.28 No.14

        <P>Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. Interestingly, MKRN1 used earlier unknown sites, K291 and K292, for p53 ubiquitination and subsequent degradation. Under severe stress conditions, however, MKRN1 primarily induced the efficient degradation of p21. This regulatory process contributed to the acceleration of DNA damage-induced apoptosis by eliminating p21. MKRN1 depletion diminished adriamycin or ultraviolet-induced cell death, whereas ectopic expression of MKRN1 facilitated apoptosis. Furthermore, MKRN1 stable cell lines that constantly produced low levels of p53 and p21 exhibited stabilization of p53, but not p21, with increased cell death on DNA damage. Our results indicate that MKRN1 exhibits dual functions of keeping cells alive by suppressing p53 under normal conditions and stimulating cell death by repressing p21 under stress conditions.</P>

      • Roadmap on optical sensors

        Ferreira, Má,rio F S,Castro-Camus, Enrique,Ottaway, David J,,pez-Higuera, José,Miguel,Feng, Xian,Jin, Wei,Jeong, Yoonchan,Picqué,, Nathalie,Tong, Limin,Reinhard, Bjö,rn M IOP 2017 Journal of optics Vol.19 No.8

        <P>Sensors are devices or systems able to detect, measure and convert magnitudes from any domain to an electrical one. Using light as a probe for optical sensing is one of the most efficient approaches for this purpose. The history of optical sensing using some methods based on absorbance, emissive and florescence properties date back to the 16th century. The field of optical sensors evolved during the following centuries, but it did not achieve maturity until the demonstration of the first laser in 1960. The unique properties of laser light become particularly important in the case of laser-based sensors, whose operation is entirely based upon the direct detection of laser light itself, without relying on any additional mediating device. However, compared with freely propagating light beams, artificially engineered optical fields are in increasing demand for probing samples with very small sizes and/or weak light−matter interaction. Optical fiber sensors constitute a subarea of optical sensors in which fiber technologies are employed. Different types of specialty and photonic crystal fibers provide improved performance and novel sensing concepts. Actually, structurization with wavelength or subwavelength feature size appears as the most efficient way to enhance sensor sensitivity and its detection limit. This leads to the area of micro- and nano-engineered optical sensors. It is expected that the combination of better fabrication techniques and new physical effects may open new and fascinating opportunities in this area. This roadmap on optical sensors addresses different technologies and application areas of the field. Fourteen contributions authored by experts from both industry and academia provide insights into the current state-of-the-art and the challenges faced by researchers currently. Two sections of this paper provide an overview of laser-based and frequency comb-based sensors. Three sections address the area of optical fiber sensors, encompassing both conventional, specialty and photonic crystal fibers. Several other sections are dedicated to micro- and nano-engineered sensors, including whispering-gallery mode and plasmonic sensors. The uses of optical sensors in chemical, biological and biomedical areas are described in other sections. Different approaches required to satisfy applications at visible, infrared and THz spectral regions are also discussed. Advances in science and technology required to meet challenges faced in each of these areas are addressed, together with suggestions on how the field could evolve in the near future.</P>

      • Correlation between Ki67 and Histological Grade in Breast Cancer Patients Treated with Preoperative Chemotherapy

        Petric, Militza,Martinez, Santiago,Acevedo, Francisco,Oddo, David,Artigas, Rocio,Camus, Mauricio,Sanchez, Cesar Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23

        Background and Aim: Breast cancer (BC) is a heterogeneous disease and cell proliferation markers may help to identify subtypes of clinical interest. We here analyzed the correlation between cell proliferation determined by Ki67 and HG in BC patients undergoing preoperative chemotherapy (PCT). Materials and Methods: We obtained clinical/pathological data from patients with invasive BC treated at our institution from 1999 until 2012. Expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor type 2 (HER2) and Ki67 were determined by immuno-histochemistry (IHC). Clinicopathological subtypes were defined as: Luminal A, ER and/or PR positive, HER2 negative, HG 1 or 2; Luminal B, ER and/or PR positive, HER2 negative or positive and/or HG 3; triple negative (TN), ER, PR and HER2 negative independent of HG; HER2 positive, ER, PR negative and HER2 positive, independent of HG. By using Ki67, a value of 14% separated Luminal A and B tumors, independently of the histological grade. We analyzed correlations between Ki67 and HG, to define BC subtypes and their predictive value for response to PCT. Results: 1,560 BC patients were treated in the period, 147 receiving PCT (9.5%). Some 57 had sufficient clinicopathological information to be included in the study. Median age was 52 years (26-72), with 87.7% invasive ductal carcinomas (n=50). We performed IHC for Ki67 in 40 core biopsies and 50 surgical biopsies, 37 paired samples with Ki67 before and after chemotherapy being available. There was no significant correlation between Ki67 and HG (p=0.237), both categorizing patients into different subtypes. In most cases Ki67 decreased after PCT (65.8%). Only 3 patients had pathologic complete response (cPR). Conclusions: In our experience we did not find associations between Ki67 and HG. Determination of clinicopathological luminal subtypes differs by using Ki67 or HG.

      • No Impact of RASs on the Efficacy of SOF/VEL/VOX for 12 weeks in DAA-Experienced Patients: Integrated Analysis of the POLARIS-1/POLARIS-4 Studies

        ( Christoph Sarrazin ),( Curtis L. Cooper ),( Michael P. Manns ),( Rajender Reddy ),( Kris Kowdley ),( Sooji Lee ),( Hadas Dvory-Sobol ),( Evguenia Svarovskia ),( Ross Martin ),( Gregory Camus ),( Bri 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

        Aims: The pangenotypic combination of sofosbuvir (SOF) /velpatasvir (VEL)/voxilaprevir(VOX), inhibit distinct HCV targets, the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively. In Phase 3 studies, SOF/VEL/VOX administered for 12weeks demonstrated a 96% SVR12 rate in NS5A inhibitor-experienced patients in POLARIS-1, and a 97% SVR12 rate in DAA-experienced patient who had not previously received an NS5A inhibitor in POLARIS-4. Here, we evaluate the effect of baseline resistance associated substitutions (RASs) on treatment outcome and the emergence of RASs in patients who experienced virologic failure. Methods: NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virologic failure. NS3 and NS5A class RASs as well as VOX or VEL-specific RASs that confer >2.5-fold changes in EC50 were evaluated. Results: In POLARIS-1, 79% of NS5A inhibitor-experienced patients (205/260) had baseline NS3 and/or NS5A class RASs. Of these, 75% (196/260) had baseline NS5A RASs, the most common RASs. The SVR12 rates were similar in subjects with or without NS3 and/or NS5A class RASs, and with or without VOX or VEL-specific RASs(Table 1). RASs at NS5A position Y93 were present in 25% of patients, of whom 63(95%) achieved SVR12; all patients with ≥2 NS5A RASs achieved SVR12 (n=77). 95%(18/19) of patients with NS5B nucleoside inhibitor(NI) RASs achieved SVR12; 2 patients had S282T at baseline and achieved SVR12. In POLARIS-4, the overall prevalence of baseline NS3 and/or NS5A class RASs was 47%(83/178) and all achieved SVR12. All patients with. Conclusions: Baseline RASs had no impact on response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Viral relapse was not associated with emergence of viral resistance.

      • Ledipasvir/Sofosbuvir for 12 Weeks Is Safe and Effective in CHC and CHB Coinfection Patients: A Phase 3 Study in Taiwan

        ( Chun-Jen Liu ),( Wan-Long Chuang ),( I-Shyan Sheen ),( Horng-Yuan Wang ),( Chi-Yi Chen ),( Kuo-Chih Tseng ),( Ting-Tsung Chang ),( Benede tta Massetto ),( Jenny Yang ),( Gregory Camus ),( Fangqiu Zh 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

        Aims: Patients co-infected with HCV and HBV have more rapid progression and worse outcomes than mono-infected patients. Taiwan has among the highest prevalence of chronic HCV/HBV coinfection in Southeast Asia. This study evaluated the safety and efficacy of an all-oral treatment with ledipasvir(LDV)/sofosbuvir(SOF) for 12 weeks in chronic HCV and HBV coinfection. Methods: Patients with or without compensated cirrhosis chronic HCV GT1/GT2 and HBV (HBsAg+) treatment naïve were enrolled into open-label, receiving LDV 90 mg/SOF 400 mg(QD) for 12 weeks. The primary efficacy endpoint is SVR12. HBV DNA was monitored at all study visits and it will be monitored for 2 years post-treatment. Results: A total of 111 patients (68[61%] with GT1 and 43[39%] with GT2) were enrolled and treated. The majority were female(62%), treatment naive(67%), and non-cirrhotic(85%), with a mean age of 55 years and mean BMI of 24.5kg/m2. All but one was HBeAg negative. Mean baseline HBV DNA was 2.1 log10IU/mL. SVR4 was 100%(111/111). The mean change in HBV DNA ranged from -0.06 log10IU/mL at week 1 to +0.49 log10IU/mL at follow-up visit 4; HBV DNA kinetics are shown in Fig 1. 60(54%) patients had an increase in HBV DNA> 10 x BL or became HBV DNA > LLOQ. No patients had ALT ≥ 2 X baseline. No patients discontinued treatment due to adverse events (AEs). Three patients had serious AEs(optic neuritis, post procedural bleeding and duodenal ulcer bleeding; none was considered drug related). Conclusions: In chronic HCV/HBV infection patients, LDV/SOF for 12 weeks resulted in an SVR4 rate of 100%. Although most patients had an increase in HBV DNA during treatment, this was not associated with ALT elevations ≥2 X baseline, and no patients started HBV therapy to date. This all-oral, interferon-free regimen was well tolerated, supporting its potential as a treatment option for HCV/HBV co-infected patients.

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