Search

Preclinical studies using genetically engineered mouse models (GEMM) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here, we describe a multicenter cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008, participating laboratories have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation–academic–industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development. Cancer Res; 77(21); 5706–11. ©2017 AACR.

Background On May 19, 2017, the cluster of 6 acute respiratory infections due to adenovirus in the swimming department of a physical education school (School J) was reported to Korea Centers for Disease Control and Prevention. An epidemiological investigation was conducted to identify the transmission route of the infection and to control the outbreak. Materials and methods A retrospective cohort study (Study 1) was conducted on students and teachers of the athletic departments using the swimming pool, and a prospective surveillance (Study 2) was conducted on all students and teachers of the School J. A case was defined as any student and school personnel who developed more than two of the following symptoms from April 10 to July 2, 2017: fever, sore throat, cough, rhinorrhea, or headache. Relative risks (RRs) were calculated to compare the attack rates according to potential risk factors. Multivariable logistic regression was performed to identify the risk factors for infection in the outbreak. Results 47 cases were identified: 33 (55.9%) cases occurred among 59 students and teachers in Study 1 and 14 (3.9%) among 362 students and school personnel in Study 2. There were 18 laboratory confirmed adenovirus infection cases. The common symptoms were headache (71.7%), fever (69.6%), rhinorrhea (63.0%), sputum (56.5%), and sore throat (54.3%). 23.9% of the cases were accompanied with diarrhea and 19.6% with eye congestion. None of the cases developed pneumonia. 32.6% of the cases were hospitalized. In Study 1, attack rate in the swimming department was higher than that in others (RR: 1.90; 95% confidence interval [CI]: 1.01-3.60). In Study 2, being a member of the shooting department (RR: 20.70; 95% CI: 4.90-87.47) and being a first year high school student (RR: 10.95; 95% CI: 2.90-41.33) were identified as risk factors for the infections. Genetic analyses of the adenoviruses showed 100% identical sequence in homology and confirmed the human adenovirus B55 (HAdV-B55). No adenovirus was detected at examining the water and environment of the swimming pool and dormitory. Conclusion The outbreak is inferred to be occurred via propagated transmission among the students in the same athletic department, while the students with symptoms of respiratory infection continued performing school activities without any restrictions. Infection control measures such as early detection of symptoms of respiratory infection and restriction of group activity are necessary to prevent respiratory infection outbreak in the communal living setting.

Background In November 2015, reuse of needles and syringes in conjunction with an increase in cases of HCV at a clinic in Korea was reported and investigated by public health authorities. Patients who received injections at the clinic from the first time this infection control breach may have occurred in 2008 through 2015 when the practice was stopped were offered screening for HCV and other blood-borne pathogens such as HIV, HTLV, HBV, syphilis, and malaria. Objectives The aim of this study was to assess whether an outbreak of hepatitis C had occurred among the potentially exposed clinic patients due to this infection control breach. Study Design We performed hepatitis C viral RNA load tests and genotyping using plasma from hepatitis C antibody-positive individuals who had visited the clinic between May 2008 and November 2015. We analyzed the core-E2 and NS5B regions of the virus from RNA-positive samples by constructing a phylogenetic tree based on maximum likelihood analysis. To identify transmission risk factors and epidemiological relationships among the patients, we reviewed their medical records, assessed staff infection control practices and performed environmental inspection of the clinic. Environmental samples from medication room surfaces and medication vial contents were tested for HCV RNA. Results and Conclusions Among the 1721 patients tested, 96 were IgG-positive and 70 were viral RNA-positive. Among the 61 patients whose viral loads were greater than the detection limit, 41 (67.2%) were classified as genotype 1a, 1 (1.6%) as genotype 1b, 18 (29.5%) as genotype 1, and one (1.6%) as genotype 2. After sequencing, 12 genotype 1 cases were further classified as genotype 1a (11) or 1b (1). The sequences of the core-E2 and NS5B regions of 45 patients formed a monophyletic cluster distinct from genotype 1a. The hepatitis C virus sequences from patients and environmental specimens were well-matched in the partial E1 gene region. We detected genotype 1a RNA in environmental specimens, indicating a healthcare-associated outbreak caused by reuse of syringes and contaminated multi-dose vials. Our molecular epidemiological investigation of hepatitis C genotype 1a, rare in Korea, will aid investigations of infection sources during future pathogen outbreaks.

Silicon stripixel sensors utilizing a novel design of comb-type pixels intertwining with one other are capable of two-dimensional position detection of charged particles. We have designed and fabricated the stripixel sensors with 128 X and 128 Y strips in an active area of about 6 cm × 6 cm. Each strip in our design, in turn, consists of 128 comb-type basic units. X and Y basic units are intertwined in such a fashion that a pair of X and Y units forms a pixel in a stripixel sensor, and the pixel is sensitive to a charged particle passing through it. We present the design, device simulation, and fabrication of the silicon stripixel sensors. We also present the electrical characteristics of the sensors.

Non-saponin gingseng fraction components (NSRG) have been known to have a variety of biological activity. However, the effects of these components on the function of brain cell have not been characterized in detail. In this study, we investigated the preventive effect of non-saponin red ginseng components on acrylamide (ACR)-induced suppression of neural cell adhesion molecule (NCAM), which is highly expressed in neuronal cells. The data showed that NSRG blocked the suppression of NCAM expression by ACR in neuroblastoma cells (SK-N-SH). In addition, NSRG significantly increased NCAM expression in ACR-nontreated neuroblastoma cells. NSRG treatment resulted in the increase of cell proliferation in a concentration-dependent manner. We also examined whether NSRG could modulate the NO production of astrocytes. When glioma cells (C6) were treated with various concentrations of NSRG (100-300 ㎍/ml) in the presence or absence of IFN-γ for 24 hours, NO production was suppressed in IFN-γ-stimulated C6 cells. Taken together, these results demonstrate that treatment of brain cells with NSRG results in the enhancement of proliferation, the suppression of NO production and the protective effect on NCAM expression impaired by ACR. Thus, the present data suggest that NSRG has proliferative and neuroprotective effects and these effects could be useful in neuronal diseases.

The neurofibromatoses (NF) are a group of rare genetic disorders that can affect all races equally at an incidence from 1:3000 (NF1) to a log unit lower for NF2 and schwannomatosis. Since the research community is reporting an increasing number of malignant cancers that carry mutations in the NF genes, the general interest of both the research and pharma community is increasing and the authors saw an opportunity to present a novel, fresh approach to drug discovery in NF. The aim of the paper is to challenge the current drug discovery approach to NF, whereby existing targeted therapies that are either in the clinic or on the market for other disease indications are repurposed for NF. We offer a suggestion for an alternative drug discovery approach. In the new approach, selective and tolerable targeted therapies would be developed for NF and later expanded to patients with more complex diseases such as malignant cancer in which the NF downstream pathways are deregulated. The Children's Tumor Foundation, together with some other major NF funders, is playing a key role in funding critical initiatives that will accelerate the development of better targeted therapies for NF patients, while these novel, innovative treatments could potentially be beneficial to molecularly characterized cancer patients in which NF mutations have been identified.

We present a numerical model using the phase-field method (PFM) for stress-induced-voiding (SIV) in a metal line. The model was verified by comparison with the typical stress-migration (SM) analytical model. We investigated the effects of flaw location and density on time-to-failure (TTF). The model was applied to the failure analysis of the BEOL process of a 0.13um device for automobiles.

Background: The administration of oral pregabalin preoperatively has been reported to reduce acute postoperative pain. However, no clinical study to date has yet fully investigated whether or not pregabalin premedication affects sensory and motor blocks using spinal anesthesia and its effect upon early postoperative pain management. This prospective, randomized, and double-blind clinical study was designed to evaluate the efficacy of a single dose of pregabalin in terms of spinal blockade duration and its potential opioid-sparing effect during the first 24 hours subsequent to urogenital surgery. Methods: Forty-four patients scheduled for urogenital surgery under spinal anesthesia were randomly allocated to 2 groups: group C (no premedication; orally administered placebo 2 hours before surgery) and group P (orally administered 150 mg pregabalin 2 hours before surgery). Results: The duration of sensory and motor blockade was significantly prolonged in group P patients when compared with that in group C patients, and the pain scores at postoperative 6 and 24 hours were significantly lower in group P patients. Requests for analgesics during the first postoperative 24 hours were lower among group P patients. Conclusion: Premedication with a single dose of 150 mg pregabalin before surgery promoted the efficacy of intrathecal bupivacaine and improved postoperative analgesia in patients undergoing urogenital surgery under spinal anesthesia.

Purpose This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations. Patients and Methods Patients with invasive breast cancer ≥ 3 cm were eligible. Ixabepilone 40 mg/m2 was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles. Results One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) –negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in ≤ 3% of patients. Reversible peripheral neuropathy was experienced by 3% of patients. Conclusion ER, microtubule-associated protein tau, and a 10-gene PLR model that included ER were identified as predictors of ixabepilone-induced pCR. Results indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.

Herpes zoster most commonly occurs in elderly patients, and usually affects sensory neurons. Therefore, its characteristic symptoms are segmental pain, itching, and sensory changes in the affected areas. A 71-yr-old woman experienced painful herpetic rash on the right cervical 2–4 dermatomes for 16 days. Two days after the onset of the rash, she was diagnosed with herpes zoster, and prescribed 250 mg famciclovir three times a day for 7 days, pregabalin 150 mg twice a day, and tramadol 150 mg once a day for 14 days, by a dermatologist. Despite medication, her pain was rated at an intensity of 6/10 on the numeric rating scale. In addition, she complained of severe itching sensation on the affected dermatomes. Superficial cervical plexus block (SCPB) was performed at the right C4 level with 15 ml 0.5% lidocaine plus triamcinolone 30 mg. Five days after the procedure, pain and itching completely disappeared. SCPB may be an effective option for the treatment of acute pain and itching arising from herpes zoster, and for the prevention of postherpetic neuralgia.

Breast cancer susceptibility proteins 1 and 2 (BRCA-1 and BRCA-2) are two key tumor suppressor genes that play important roles in tumorigenesis. Functional loss or reduction of BRCA-1 and/or BRCA-2 protein expression often leads to poor clinical outcomes in breast and ovarian cancer patients. To explore the utility of BRCA-1 and -2 as potential predictive biomarkers for targeted therapeutic approaches, we optimized and used an immunohistochemistry procedure to determine the expression profiles of BRCA-1 and BRCA-2 proteins on a large number of human breast and ovarian tumors and corresponding normal tissues. We found the expression of BRCA-1 and BRCA-2 proteins was down-regulated in breast and ovarian tumors when compared with corresponding normal tissues. BRCA-1 expression was detected in 100% of normal breast tissues whereas it was expressed in 91% and 71% of primary and metastatic tumors, respectively. Furthermore, the expression levels of BRCA-1 were lower in the majority of primary and metas...

2525 Background: Ixabepilone (BMS-247550) is a microtubule stabilizing agent with demonstrable therapeutic value in taxane- refractory breast cancer (BC) patients. Biomarkers to predict either ixabepilone or paclitaxel activity in BC patients have previously been reported. However, markers that differentiate response to the two agents have yet to be identified. This study sought to discover predictive markers that will enable patient selection to differentially enhance response to ixabepilone or paclitaxel in ER-negative (ER-) patients. Materials and Methodologies: Pre-treatment gene expression profiles were generated for 62 ER- patients treated with ixabepilone in clinical study CA163080, and 51 ER- patients treated with T/FAC (paclitaxel and fluorouracil-doxorubicin-cyclophosphamide) in clinical study MDA133. Biomarkers differentially predictive of complete pathological response in breast were identified through gene set enrichment analysis (GSEA) or classification by threshold gradient descent (TGD). Gene knockdown by siRNA was used to study some of these candidate markers. Results: Four candidate models that differentiate response to ixabepilone treatment and taxane-containing therapy were identified. Two of the models, found by GSEA, are based on expression levels for single microtubule-related genes: transforming, acidic coiled-coil containing protein 3 (TACC3) and chromosome condensation protein G (HCAP-G). The potential of HCAP-G as a differential marker was supported by siRNA studies. Two of the models, found by TGD, are based on expression levels for 26 and 20 genes. Areas under the ROC curves for the models applied to each study separately are given in the table . Conclusions: We have identified four predictive models that differentiate response in a clinical trial of ixabepilone from that in a trial of T/FAC. A clinical trial is under way to further evaluate their utility for differentiating response to ixabepilone- and taxane-containing regimens. [Table: see text] [Table: see text]

3011 Background: Ixabepilone is a microtubule stabilizing agent with significant therapeutic value in breast cancer (BC) patients. To identify predictive biomarkers capable of identifying patients likely to receive optimal benefit from ixabepilone treatment, preclinical and clinical studies were carried out. Several biomarkers discovered using preclinical models were validated in a neoadjuvant BC clinical study ( CA163080 ) and one, estrogen receptor 1 (ER), was shown to double the pathological complete response (pCR) rate in patients treated with ixabepilone. To identify candidate sets of biomarkers that could further increase the pCR rate we have performed post-hoc analyses of the preclinical and clinical data. Methods: Eighteen BC cell lines were classified as sensitive or resistant (S/R) based on the IC50 values for ixabepilone treatment. Gene expression profiling of the BC cell lines was conducted and genes correlated with the S/R classification were identified using a k-Nearest Neighbors algorithm. Patients in clinical study CA163080 underwent a pretreatment core needle biopsy from which RNA was isolated and gene expression profiles generated (data available on 134 patients). Analyses using the preclinical and clinical markers were conducted using various statistical tools. Results: Several markers used in combination with ER were found to be capable of tripling the pCR to ixabepilone in CA163080. In addition to ER other predictive markers were identified that were as predictive as ER, including several genes whose expression is anti-correlated with ER and are part of the ER pathway. Finally, various sub-group analyses were performed and manifested the importance of clinical sample variation that needs to be considered for the analysis. Conclusions: Several single biomarkers identified from preclinical studies were validated in the clinical study CA163080 , demonstrating the utility of this approach. Such markers can be used in combination to better identify patients likely to respond to ixabepilone in future clinical trials. Furthermore, molecular response markers that can be tied to the mechanism of drug resistance can be used for further developing chemotherapy in drug development. [Table: see text]

586 Background: Previous studies have confirmed the activity of ixabepilone (BMS-247550, a semi-synthetic analog of epothilone) in metastatic BC. The present study was designed to determine the pathological response obtained with ixabepilone as neoadjuvant therapy for BC and to obtain tumor samples for analysis of gene expression and identification of potential predictors of response to ixabepilone. Methods: Women with invasive stage IIA-IIIB breast cancer with tumors ≥3 cm diameter received 40 mg/m2 ixabepilone as a 3-hour infusion on Day 1 for up to four 21-day cycles, followed by surgery within 3–4 weeks of completion of chemotherapy. Biopsies for analysis of mRNA expression were obtained both pre- and post-therapy. Adjuvant chemotherapy with an anthracycline combination regimen followed by radiotherapy and tamoxifen were administered as indicated. Pathological response was assessed using the Sataloff criteria. Results: A total of 164 patients were enrolled. Data were available for 47 patients for this...