bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses
Authors: Lamothe Betty , Wierda William G. , Keating Michael J. , Gandhi Varsha 
Published: March 2016

Abstract
Purpose: Carfilzomib, while active in B-cell neoplasms, displayed heterogeneous response in chronic lymphocytic leukemia (CLL) samples from patients and showed interpatient variability to carfilzomib-induced cell death. To understand this variability and predict patients who would respond to carfilzomib, we investigated the mechanism by which carfilzomib induces CLL cell death.
Experimental Design: Using CLL patient samples and cell lines, complementary knockdown and knockout cells, and carfilzomib-resistant cell lines, we evaluated changes in intracellular networks to identify molecules responsible for carfilzomib's cytotoxic activity. Lysates from carfilzomib-treated cells were immunoblotted for molecules involved in ubiquitin, apoptotic, and endoplasmic reticulum (ER) stress response pathways and results correlated with carfilzomib cytotoxic activity. Coimmunoprecipitation and pull-down assays were performed to identify complex interactions among MCL-1, Noxa, and Bak.
Results: Carfilzomib triggered ER stress and activation of both the intrinsic and extrinsic apoptotic pathways through alteration of the ubiquitin proteasome pathway. Consequently, the transcription factor CCAAT/enhancer-binding protein homology protein (CHOP) accumulated in response to carfilzomib, and CHOP depletion conferred protection against cytotoxicity. Carfilzomib also induced accumulation of MCL-1 and Noxa, whereby MCL-1 preferentially formed a complex with Noxa and consequently relieved MCL-1′s protective effect on sequestering Bak. Accordingly, depletion of Noxa or both Bak and Bax conferred protection against carfilzomib-induced cell death.
Conclusions: Collectively, carfilzomib induced ER stress culminating in activation of intrinsic and extrinsic caspase pathways, and we identified the CHOP protein level as a biomarker that could predict sensitivity to carfilzomib in CLL. Clin Cancer Res; 22(18); 4712–26. ©2016 AACR.
DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1
Authors: Ogitani Yusuke , Aida Tetsuo , Hagihara Katsunobu , Yamaguchi Junko , Ishii Chiaki , Harada Naoya , Soma Masako , Okamoto Hiromi , Oitate Masataka , Arakawa Shingo , Hirai Takehiro , Atsumi Ryo , Nakada Takashi , Hayakawa Ichiro , Abe Yuki , Agatsuma Toshinori 
Published: March 2016

Abstract
Purpose: An anti-HER2 antibody–drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.
Experimental Design: In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.
Results: DS-8201a exhibited a HER2 expression-dependent cell growth–inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a as being well tolerated in humans. DS-8201a was effective in a T-DM1–insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.
Conclusions: DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1–insensitive HER2-positive cancers and low HER2–expressing cancers. Clin Cancer Res; 22(20); 5097–108. ©2016 AACR.
Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms
Authors: Wardill Hannah R. , Gibson Rachel J. , Van Sebille Ysabella Z.A. , Secombe Kate R. , Coller Janet K. , White Imogen A. , Manavis Jim , Hutchinson Mark R. , Staikopoulos Vasiliki , Logan Richard M. , Bowen Joanne M. 
Published: March 2016

Abstract
Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P &lt; 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P &lt; 0.0001), correlating with lower mucosal injury scores (P &lt; 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P &lt; 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.
A New Triglycyl Peptide Linker for Antibody–Drug Conjugates (ADCs) with Improved Targeted Killing of Cancer Cells
Authors: Singh Rajeeva , Setiady Yulius Y. , Ponte Jose , Kovtun Yelena V. , Lai Katharine C. , Hong E. Erica , Fishkin Nathan , Dong Ling , Jones Gregory E. , Coccia Jennifer A. , Lanieri Leanne , Veale Karen , Costoplus Juliet A. , Skaletskaya Anna , Gabriel Rabih , Salomon Paulin , Wu Rui , Qiu Qifeng , Erickson Hans K. , Lambert John M. , Chari Ravi V.J. , Widdison Wayne C. 
Published: March 2016

AbstractA triglycyl peptide linker (CX) was designed for use in antibody–drug conjugates (ADC), aiming to provide efficient release and lysosomal efflux of cytotoxic catabolites within targeted cancer cells. ADCs comprising anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-EGFR antibodies with maytansinoid payloads were prepared using CX or a noncleavable SMCC linker (CX and SMCC ADCs). The in vitro cytotoxic activities of CX and SMCC ADCs were similar for several cancer cell lines; however, the CX ADC was more active (5–100-fold lower IC50) than the SMCC ADC in other cell lines, including a multidrug-resistant line. Both CX and SMCC ADCs showed comparable MTDs and pharmacokinetics in CD-1 mice. In Calu-3 tumor xenografts, antitumor efficacy was observed with the anti-EpCAM CX ADC at a 5-fold lower dose than the corresponding SMCC ADC in vivo. Similarly, the anti-EGFR CX ADC showed improved antitumor activity over the respective SMCC conjugate in HSC-2 and H1975 tumor models; however, both exhibited similar activity against FaDu xenografts. Mechanistically, in contrast with the charged lysine-linked catabolite of SMCC ADC, a significant fraction of the carboxylic acid catabolite of CX ADC could be uncharged in the acidic lysosomes, and thus diffuse out readily into the cytosol. Upon release from tumor cells, CX catabolites are charged at extracellular pH and do not penetrate and kill neighboring cells, similar to the SMCC catabolite. Overall, these data suggest that CX represents a promising linker option for the development of ADCs with improved therapeutic properties. Mol Cancer Ther; 15(6); 1311–20. ©2016 AACR.
Metformin for Reducing Racial/Ethnic Difference in Prostate Cancer Incidence for Men with Type II Diabetes
Authors: Wang Chen-Pin , Lehman Donna M. , Lam Yui-Wing F. , Kuhn John G. , Mahalingam Devalingam , Weitman Steven , Lorenzo Carlos , Downs John R. , Stuart Elizabeth A. , Hernandez Javier , Thompson Ian M. , Ramirez Amelie G. 
Published: March 2016

Abstract
Racial/ethnic disparity in prostate cancer is under studied in men with diabetes who are at a higher risk of aggressive prostate cancer. This study assessed the race/ethnic disparity in prostate cancer incidence for men with type II diabetes (T2D) and whether the impact of metformin on prostate cancer incidence varied by race/ethnicity. We conducted a retrospective study in 76,733 male veterans with T2D during 2003 to 2012. Cox proportional hazards model adjusting for covariates and propensity scores of metformin use and race/ethnic group membership was utilized to compute the HR of prostate cancer incidence associated with race/ethnicity and compare HR associated with metformin use between race/ethnic groups. Mean follow-up was 6.4 ± 2.8 years; 7% were Hispanics; 17% were African Americans (AA); mean age was 67.8 ± 9.8 years; 5.2% developed prostate cancer; and 38.9% used metformin. Among these diabetic men without metformin use, prostate cancer incidence was higher in Hispanics and AA than in non-Hispanic White (NHW). Use of metformin alone or metformin + statins was associated with a greater prostate cancer incidence reduction in Hispanics compared with NHW, but not between AA and NHW. Use of metformin + finasteride was associated with a greater prostate cancer incidence reduction in Hispanics and AA compared with NHW. Our results suggested that metformin treatment could be a potential strategy to reduce prostate cancer incidence in the minority populations who are at high risk for fatal prostate cancer. It will be important to further examine the pleiotropic effects of metformin in multi-race/ethnic prospective studies to better inform clinical management and potentially reduce racial/ethnic disparity in prostate cancer incidence among diabetic men. Cancer Prev Res; 9(10); 779–87. ©2016 AACR.
Sensory, Cognitive, and Sensorimotor Learning Effects in Recognition Memory for Music
Authors: Mathias Brian , Tillmann Barbara , Palmer Caroline 
Published: March 2016

AbstractRecent research suggests that perception and action are strongly interrelated and that motor experience may aid memory recognition. We investigated the role of motor experience in auditory memory recognition processes by musicians using behavioral, ERP, and neural source current density measures. Skilled pianists learned one set of novel melodies by producing them and another set by perception only. Pianists then completed an auditory memory recognition test during which the previously learned melodies were presented with or without an out-of-key pitch alteration while the EEG was recorded. Pianists indicated whether each melody was altered from or identical to one of the original melodies. Altered pitches elicited a larger N2 ERP component than original pitches, and pitches within previously produced melodies elicited a larger N2 than pitches in previously perceived melodies. Cortical motor planning regions were more strongly activated within the time frame of the N2 following altered pitches in previously produced melodies compared with previously perceived melodies, and larger N2 amplitudes were associated with greater detection accuracy following production learning than perception learning. Early sensory (N1) and later cognitive (P3a) components elicited by pitch alterations correlated with predictions of sensory echoic and schematic tonality models, respectively, but only for the perception learning condition, suggesting that production experience alters the extent to which performers rely on sensory and tonal recognition cues. These findings provide evidence for distinct time courses of sensory, schematic, and motoric influences within the same recognition task and suggest that learned auditory–motor associations influence responses to out-of-key pitches.
Beat that Word: How Listeners Integrate Beat Gesture and Focus in Multimodal Speech Discourse
Authors: Dimitrova Diana , Chu Mingyuan , Wang Lin , Özyürek Asli , Hagoort Peter 
Published: March 2016

AbstractCommunication is facilitated when listeners allocate their attention to important information (focus) in the message, a process called “information structure.” Linguistic cues like the preceding context and pitch accent help listeners to identify focused information. In multimodal communication, relevant information can be emphasized by nonverbal cues like beat gestures, which represent rhythmic nonmeaningful hand movements. Recent studies have found that linguistic and nonverbal attention cues are integrated independently in single sentences. However, it is possible that these two cues interact when information is embedded in context, because context allows listeners to predict what information is important. In an ERP study, we tested this hypothesis and asked listeners to view videos capturing a dialogue. In the critical sentence, focused and nonfocused words were accompanied by beat gestures, grooming hand movements, or no gestures. ERP results showed that focused words are processed more attentively than nonfocused words as reflected in an N1 and P300 component. Hand movements also captured attention and elicited a P300 component. Importantly, beat gesture and focus interacted in a late time window of 600–900 msec relative to target word onset, giving rise to a late positivity when nonfocused words were accompanied by beat gestures. Our results show that listeners integrate beat gesture with the focus of the message and that integration costs arise when beat gesture falls on nonfocused information. This suggests that beat gestures fulfill a unique focusing function in multimodal discourse processing and that they have to be integrated with the information structure of the message.
Forest Degradation Associated with Logging Frontier Expansion in the Amazon: The BR-163 Region in Southwestern Pará, Brazil
Authors: Pinheiro T. F. , Escada M. I. S. , Valeriano D. M. , Hostert P. , Gollnow F. , Müller H. 
Published: March 2016

Abstract
Forest degradation is the long-term and gradual reduction of canopy cover due to forest fire and unsustainable logging. A critical consequence of this process is increased atmospheric carbon emissions. Although this issue is gaining attention, forest degradation in the Brazilian Amazon has not yet been properly addressed. The claim here is that this process is not constant throughout Amazonia and varies according to colonization frontiers. Moreover, the accurate characterization of degradation requires lengthy observation periods to track gradual forest changes. The forest degradation process, the associated timeframe, spatial patterns, trajectories, and extent were characterized in the context of the Amazon frontiers of the 1990s using 28 years (1984–2011) of annual Landsat images. Given the large database and the characteristic of logging and burning, this study used data mining techniques and cell approach classification to analyze the spatial patterns and to construct associated trajectories. Multitemporal analysis indicated that forest degradation in the last two decades has caused as many interannual landscape changes as have clear-cuts. In addition, selective logging, as a major aspect of forest degradation, affected a larger amount of forest land than did forest fire. Although a large proportion of logged forest was deforested in the following years, selective logging did not always precede complete deforestation. Instead, the results indicate that logged forests were abandoned for approximately 4 years before clearance. Throughout the forest degradation process, there were no recurrent forest fires, and loggers did not revisit the forest. Forest degradation mostly occurred as a result of a single selective logging event and was associated with low-intensity forest damage.
On the Impacts of Different Definitions of Maximum Dimension for Nonspherical Particles Recorded by 2D Imaging Probes
Authors: Wu Wei , McFarquhar Greg M. 
Published: March 2016

AbstractKnowledge of ice crystal particle size distributions (PSDs) is critical for parameterization schemes for atmospheric models and remote sensing retrieval schemes. Two-dimensional in situ images captured by cloud imaging probes are widely used to derive PSDs in term of maximum particle dimension (). In this study, different definitions of for nonspherical particles recorded by 2D probes are compared. It is shown that the derived PSDs can differ by up to a factor of 6 for μm and mm. The large differences for μm are caused by the strong dependence of sample volume on particle size, whereas differences for mm are caused by the small number of particles detected. Derived bulk properties can also vary depending on the definitions of because of discrepancies in the definition of used to characterize the PSDs and that used to describe the properties of individual ice crystals. For example, the mass-weighted mean diameter can vary by 2 times, the ice water content (IWC) by 3 times, and the mass-weighted terminal velocity by 6 times. Therefore, a consistent definition of should be used for all data and single-particle properties. As an invariant measure with respect to the orientation of particles in the imaging plane for 2D probes, the diameter of the smallest circle enclosing the particle () is recommended as the optimal definition of . If the 3D structure of a particle is observed, then the technique can be extended to determine the minimum enclosing sphere.
Mapping access to community-developed healthy food baskets including cost and availability
Authors: Ginn Alison , Majumdar Anne , Carr Marimba , Eastwood Ginny , Menger Beth 
Published: March 2016

Background: Food security is a topical issue but one that can be difficult to measure. Objective: To develop a community-approved food basket tool and use this to investigate the availability and affordability of a healthy diet in a multicultural urban setting. Design: A 7-day healthy food basket (HFB) containing 96 foods for six household types was developed through focus groups ( n = 6) with local residents recruited via the local health service and community organisations. A total of 41 stores were surveyed against the recommendations of the HFB. The availability and price of core food groups and energy dense discretionary foods were analysed. Setting: A multicultural area in Central London with a high concentration of socially and economically deprived households. Results: Healthy food for a variety of minority ethnic diets was available in the study area, although only one supermarket and three online stores stocked the full basket. Discretionary foods were readily available and often cheaper than healthier options. The largest proportions of cost were attributed to protein foods (30%–38%) and fruit and vegetables (20%–27%). Most foods in the HFB were cheaper at larger supermarkets, although fruit and vegetables cost less at markets and local stores. Total basket price varied greatly between stores, with cost savings achieved when buying from at least three stores. Conclusion: Economically disadvantaged members of the community may be excluded from accessing a healthy diet rather than cheaper foods that are energy dense and low in nutrients, particularly if they are unable to shop around. These findings provide insight for the development of voluntary sector partnership programmes, community education and local policy planning.
Survival Impact of Initial Therapy in Patients with T1‐T2 Glottic Squamous Cell Carcinoma
Authors: Brady Jacob S. , Marchiano Emily , Kam David , Baredes Soly , Eloy Jean Anderson , Park Richard Chan Woo 
Published: March 2016

ObjectiveLaryngeal cancer most commonly arises from the glottis. Comparable outcomes in survival have been shown in patients with early glottic squamous cell carcinoma treated with either surgery or radiotherapy.Study Design and SettingAdministrative database study.Subjects and MethodsThe US National Cancer Institute’s SEER database (Surveillance, Epidemiology, and End Results) was queried for cases of early glottic cancer (T1‐T2N0M0, 1988‐2012). We identified 13,312 qualifying cases. Patient demographics, therapeutic measures, and survival outcomes were examined with appropriate univariate and multivariate analyses.ResultsEarly glottic cancer has a mean age at diagnosis of 64.8 ± 11.6 years and a male:female ratio of 6.9:1. The most common treatment modality was radiotherapy alone (51.6%), followed by combination therapy with surgery first (31.5%). Overall, the 5‐year disease‐specific survival (DSS) rate was 88.4%. When stratified by treatment modality and stage, 5‐year DSS for T1 tumors was 93.2% with surgery alone and 89.0% with radiation alone (P <. 0001). With combination therapy, the 5‐year DSS was 91.3% for surgery first and 84.9% for radiation first (P =. 0239). In T2 tumors, 5‐year DSS was improved with single‐modality therapy versus multimodality therapy (81.1% vs 76.4; P =. 0255).ConclusionIn T1 disease, surgery alone shows improved 5‐year DSS versus radiation alone, but this difference was not observed in T2 tumors. Additionally, surgery, rather than radiation, shows improved 5‐year DSS when implemented as a first‐line therapy. Combination therapy does not show improved 5‐year DSS for early glottic cancer.
Olfactory and Gustatory Functions after Anterior Palatoplasty in Patients with Primary Snoring
Authors: Saglam Omer , Altundag Aytug , Cayonu Melih , Salihoglu Murat , Azizli Elad , Dursun Engin , Cetin Bilal 
Published: March 2016

ObjectiveIn this study, we investigated the chemical senses (namely, olfaction), the 4 basic tastes, and umami taste in patients who underwent anterior palatoplasty (AP) for primary snoring.Study DesignProspective clinical study.SettingMulticenter, tertiary care hospitals.Subjects and MethodsThe age range of the 28 participants was 22 to 47 years, and all had been diagnosed with primary snoring by polysomnography. Orthonasal and retronasal olfactory testing was performed using the respective “Sniffin’ Sticks.” Tests for the 4 basic tastes (sweet, sour, salty, and bitter) and umami were performed before and 6 months after AP.ResultsThe changes between the preoperative and postoperative results for the 4 basic tastes, which were applied to the anterior tongue region, were not significant. Retronasal olfactory function improved significantly 6 months after AP (P =. 007). After AP, umami scores for the soft palate but not those of the anterior and posterior tongue decreased significantly (P =. 001).ConclusionPatients scheduled for AP should be properly informed about potential postoperative taste and flavor changes. They should also be warned of a possible loss of appetite due to a postoperative decrease in the umami taste sensation of the soft palate.