bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mathematical Modeling Predicts Response to Chemotherapy and Drug Combinations in Ovarian Cancer
Authors: Kozłowska Emilia , Färkkilä Anniina , Vallius Tuulia , Carpén Olli , Kemppainen Jukka , Grénman Seija , Lehtonen Rainer , Hynninen Johanna , Hietanen Sakari , Hautaniemi Sampsa 
Published: May 2018

Abstract
Platinum-based chemotherapy constitutes the backbone of clinical care in advanced solid cancers such as high-grade serous ovarian cancer (HGSOC) and has prolonged survival of millions of patients with cancer. Most of these patients, however, become resistant to chemotherapy, which generally leads to a fatal refractory disease. We present a comprehensive stochastic mathematical model and simulator approach to describe platinum resistance and standard-of-care (SOC) therapy in HGSOC. We used pre- and posttreatment clinical data, including 18F-FDG-PET/CT images, to reliably estimate the model parameters and simulate “virtual patients with HGSOC.” Treatment responses of the virtual patients generated by our mathematical model were indistinguishable from real-life patients with HGSOC. We demonstrated the utility of our approach by evaluating the survival benefit of combination therapies that contain up to six drugs targeting platinum resistance mechanisms. Several resistance mechanisms were already active at diagnosis, but combining SOC with a drug that targets the most dominant resistance subpopulation resulted in a significant survival benefit. This work provides a theoretical basis for a cancer treatment paradigm in which maximizing platinum's killing effect on cancer cells requires overcoming resistance mechanisms with targeted drugs. This freely available mathematical model and simulation framework enable rapid and rigorous evaluation of the benefit of a targeted drug or combination therapy in virtual patients before clinical trials, which facilitates translating preclinical findings into clinical practice.
Significance: These findings present a comprehensive mathematical model for platinum resistance and standard-of-care therapy in a solid cancer, allowing virtual evaluation of novel therapy regimens. Cancer Res; 78(14); 4036–44. ©2018 AACR.
Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells
Authors: Liu Shengzhi , Fan Yao , Chen Andy , Jalali Aydin , Minami Kazumasa , Ogawa Kazuhiko , Nakshatri Harikrishna , Li Bai-Yan , Yokota Hiroki 
Published: May 2018

Abstract
While bone is a frequent target of breast cancer–associated metastasis, little is known about the effects of tumor–bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, fluphenazine and trifluoperazine, on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of fluphenazine and trifluoperazine downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of fluphenazine and trifluoperazine on tumor growth, tumor–osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor–osteocyte interactions strengthen dopamine receptor–mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment.
Significance: These findings provide novel insight into the cellular cross-talk in the bone microevironment and the effects of dopamine modulators on mammary tumor cells and osteocytes. Cancer Res; 78(14); 3865–76. ©2018 AACR.
Chemopreventive Efficacy of the Cyclooxygenase-2 (Cox-2) Inhibitor, Celecoxib, Is Predicted by Adenoma Expression of Cox-2 and 15-PGDH
Authors: Wang Jiping , Cho Nancy L. , Zauber Ann G. , Hsu Meier , Dawson Dawn , Srivastava Amitabh , Mitchell-Richards Kisha A. , Markowitz Sanford D. , Bertagnolli Monica M. 
Published: May 2018

Abstract
Background: The Adenoma Prevention with Celecoxib (APC) Trial showed that cyclooxygenase-2 (Cox-2) inhibitor, celecoxib, decreased adenoma development in patients at high risk for colorectal cancer. A prospectively planned analysis of the APC Trial tested the hypothesis that expression of target enzymes in adenomas removed before beginning study treatment would identify individuals at high risk of adenoma development, and/or predict response to Cox-2 inhibition.
Methods: Pre-treatment adenomas were examined using immunohistochemistry to assess expression of Cox-2 (high vs. low) and 15-prostaglandin dehydrogenase (15-PGDH, presence vs. loss). The Mantel–Cox test evaluated whether these markers predicted benefit from celecoxib for reduction of adenoma detection.
Results: Patients whose pre-treatment adenomas demonstrated elevated Cox-2 achieved the greatest adenoma reduction with celecoxib treatment [RR, 0.37; 95% confidence interval (CI), 0.22–0.61; P = 0.0001]. This reduction was less in the low Cox-2 category (RR, 0.64; 95% CI, 0.56–0.73). Patients whose pre-treatment adenomas showed 15-PGDH loss had a similar treatment-associated reduction in adenoma detection (RR, 0.60; 95% CI, 0.52–0.69; P &lt; 0.0001). In contrast, patients with intact tumor 15-PGDH expression did not significantly benefit from celecoxib (RR, 0.73; 95% CI, 0.47–1.12; P = 0.15). However, subset analysis suggested that this lack of response to celecoxib was confined to those patients with 15-PGDH intact tumors who were also using cardioprotective aspirin.
Conclusions: The expression of Cox-2 and 15-PGDH in pre-treatment adenomas provides predictive information in patients treated with celecoxib for prevention of colorectal adenomas.
Impact: The results of this study show that Cox-2 and 15-PGDH are characteristics of colorectal adenomas that may be used to predict nonsteroidal anti-inflammatory drug chemoprevention efficacy. Cancer Epidemiol Biomarkers Prev; 27(7); 728–36. ©2018 AACR.
Time-to-Event Bayesian Optimal Interval Design to Accelerate Phase I Trials
Authors: Yuan Ying , Lin Ruitao , Li Daniel , Nie Lei , Warren Katherine E. 
Published: May 2018

Abstract
Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose-escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients’ toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose-escalation/deescalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target dose-limiting toxicity (DLT) rate and has higher accuracy to identify the MTD. Compared with the more complicated model-based time-to-event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD but is simpler to implement with substantially better overdose control. As the TITE-CRM is more aggressive in dose escalation, it is less likely to underdose patients. When there are no pending data, the TITE-BOIN seamlessly reduces to the BOIN design. Numerical studies show that the TITE-BOIN design supports continuous accrual without sacrificing patient safety or the accuracy of identifying the MTD, and therefore has great potential to accelerate early-phase drug development. Clin Cancer Res; 24(20); 4921–30. ©2018 AACR.
Spindle Assembly Disruption and Cancer Cell Apoptosis with a CLTC-Binding Compound
Authors: Bond Michael J. , Bleiler Marina , Harrison Lauren E. , Scocchera Eric W. , Nakanishi Masako , G-Dayanan Narendran , Keshipeddy Santosh , Rosenberg Daniel W. , Wright Dennis L. , Giardina Charles 
Published: May 2018

Abstract
AK3 compounds are mitotic arrest agents that induce high levels of γH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC50 of approximately 50 nmol/L. AK306 was active on a broad spectrum of cancer cell lines with total growth inhibition values ranging from approximately 25 nmol/L to 25 μmol/L. Using biotin and BODIPY-linked derivatives of AK306, binding to clathrin heavy chain (CLTC/CHC) was observed, a protein with roles in endocytosis and mitosis. AK306 inhibited mitosis and endocytosis, while disrupting CHC cellular localization. Cells arrested in mitosis by AK306 showed the formation of multiple microtubule-organizing centers consisting of pericentrin, γ-tubulin, and Aurora A foci, without apparent centrosome amplification. Cells released from AK306 arrest were unable to form bipolar spindles, unlike nocodazole-released cells that reformed spindles and completed division. Like AK306, CHC siRNA knockdown disrupted spindle formation and activated p53. A short-term (3-day) treatment of tumor-bearing APC-mutant mice with AK306 increased apoptosis in tumors, but not normal mucosa. These findings indicate that targeting the mitotic CHC complex can selectively induce apoptosis and may have therapeutic value.
Implication: Disruption of clathrin with a small-molecule inhibitor, AK306, selectively induces apoptosis in cancer cells by disrupting bipolar spindle formation. Mol Cancer Res; 16(9); 1361–72. ©2018 AACR.
A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma
Authors: Chan Wing Keung , Kang Siwen , Youssef Youssef , Glankler Erin N. , Barrett Emma R. , Carter Alex M. , Ahmed Elshafa H. , Prasad Aman , Chen Luxi , Zhang Jianying , Benson Don M. , Caligiuri Michael A. , Yu Jianhua 
Published: May 2018

Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy of plasma cells, with an estimated 30,000 new cases diagnosed each year in the United States, signifying the need for new therapeutic approaches. We hypothesized that targeting MM using a bispecific antibody (biAb) to simultaneously engage both innate and adaptive cytolytic immune cells could present potent antitumor activity. We engineered a biAb by fusing an anti-CS1 single-chain variable fragment (scFv) and an anti-NKG2D scFv (CS1-NKG2D biAb). Although NKG2D is a potent activation receptor ubiquitously expressed on mostly cytolytic immune cells including NK cells, CD8+ T cells, γδ T cells, and NKT cells, the CS1 tumor-associated antigen on MM represents a promising target. CS1-NKG2D biAb engaged human MM cell lines and NKG2D+ immune cells, forming immune synapses. In effector cells, CS1-NKG2D biAb triggered the phosphorylation of AKT, a downstream protein kinase of the activated NKG2D–DAP10 complex. The EC50 values of CS1-NKG2D biAb for CS1high and for CS1low MM cell lines with effector PBMCs were 10−12 and 10−9 mol/L, respectively. CS1-NKG2D biAb acted through multiple types of immune cells, and this induced cytotoxicity was both CS1- and NKG2D-specific. In vivo, survival was significantly prolonged using CS1-NKG2D biAb in a xenograft NOD-SCIDIL2γc−/− (NSG) mouse model engrafted with both human PBMCs and MM cell lines. Collectively, we demonstrated that the CS1-NKG2D biAb facilitated an enhanced immune synapse between CS1+ MM cells and NKG2D+ cytolytic innate and antigen-specific effector cells, which, in turn, activated these immune cells for improved clearance of MM. Cancer Immunol Res; 6(7); 776–87. ©2018 AACR.
Multivessel Occlusion in Patients Subjected to Thrombectomy
Authors: Kaesmacher Johannes , Mosimann Pascal J. , Giarrusso Mattia , El-Koussy Marwan , Zibold Felix , Piechowiak Eike , Dobrocky Tomas , Meier Raphael , Jung Simon , Bellwald Sebastian , Arnold Marcel , Mordasini Pasquale , Fischer Urs , Gralla Jan 
Published: May 2018

Background and Purpose—
Patients with embolic large-vessel occlusion may present with additional coincidental acute occlusions within or distant from the involved territory, referred to as multivessel occlusion (MVO). Purpose of this study was to assess prevalence of MVO, associated factors, and clinical relevance in patients undergoing endovascular stroke treatment.

Methods—

Image data of consecutive endovascular candidates (n=720) with direct access to angiography were extracted from a prospective registry. Prevalence of MVO was assessed with multimodal magnetic resonance imaging/computed tomography and confirmed by intra-arterial angiography. Explorative analysis of associated factors and clinical relevance was evaluated using multivariable logistic regression including variables with
P
<0.15 in univariate comparison. Good functional outcome was defined as modified Rankin Scale score ≤2 at day 90.

Results—
MVO was present in 10.7% of patients (95% confidence interval [CI], 6.4%–13.0%). Two, 3, and 4 concomitant occlusions were found in 80.5%, 16.9%, and 2.6% of MVO cases, respectively. Detection rate on initial radiological report was 54.5%. Downstream MVO was present in around one third of MVO (n=27/77, 35.1%), whereas all other MVO (n=50/77, 64.9%) occurred in different territories. Independent factors related to MVO were statin treatment (adjusted odds ratio [aOR], 0.477; 95% CI, 0.276–0.827), higher systolic blood pressure (aOR per mm Hg increase, 1.014; 95% CI, 1.005–1.023), and primary occlusion site M2 (aOR, 1.870; 95% CI, 1.103–3.170). MVO was related to lower rates of successful reperfusion (aOR, 0.549; 95% CI, 0.316–0.953) and lower rates of good functional outcome (aOR, 0.437; 95% CI, 0.207–0.923).

Conclusions—
Every tenth patient subjected to angiography for endovascular stroke treatment experienced MVO in our series, and only half were prospectively identified on preinterventional diagnostic imaging. Patients with MVO had higher baseline systolic blood pressure and were less often medicated with statins, an observation that warrants external validation and evaluation regarding causality. Occurrence of MVO has implication for treatment decisions, negatively affects endovascular treatment success, and is predictive of worse clinical outcome.
Haptic Foot Pedal: Influence of Shoe Type, Age, and Gender on Subjective Pulse Perception
Authors: Geitner Claudia , Birrell Stewart , Krehl Claudia , Jennings Paul 
Published: May 2018

Objective: This study investigates the influence of shoe type (sneakers and safety boots), age, and gender on the perception of haptic pulse feedback provided by a prototype accelerator pedal in a running stationary vehicle. Background: Haptic feedback can be a less distracting alternative to traditionally visual and auditory in-vehicle feedback. However, to be effective, the device delivering the haptic feedback needs to be in contact with the person. Factors such as shoe type vary naturally over the season and could render feedback that is perceived well in one situation, unnoticeable in another. In this study, we evaluate factors that can influence the subjective perception of haptic feedback in a stationary but running car: shoe type, age, and gender. Method: Thirty-six drivers within three age groups (≤39, 40–59, and ≥60) took part. For each haptic feedback, participants rated intensity, urgency, and comfort via a questionnaire. Results: The perception of the haptic feedback is significantly influenced by the interaction between the pulse’s duration and force amplitude and the participant’s age and gender but not shoe type. Conclusion: The results indicate that it is important to consider different age groups and gender in the evaluation of haptic feedback. Future research might also look into approaches to adapt haptic feedback to the individual driver’s preferences. Application: Findings from this study can be applied to the design of an accelerator pedal in a car, for example, for a nonvisual in-vehicle warning, but also to plan user studies with a haptic pedal in general.
Temporal bone contrast-enhanced high-resolution CT evaluation of pulsatile tinnitus after sigmoid sinus wall reconstruction
Authors: Ding Heyu , Zhao Pengfei , Lv Han , Liu Xuehuan , Zeng Rong , Wang Guopeng , Gong Shusheng , Wang Zhenchang 
Published: May 2018

Background Sigmoid sinus wall reconstruction (SSWR) is a proven effective treatment for pulsatile tinnitus (PT) caused by sigmoid sinus wall dehiscence (SSWD) with or without sigmoid sinus diverticulum (SSD); however, comprehensive analysis of the postoperative imaging manifestations has not yet been reported. Purpose To analyze temporal bone computed tomography (CT) imaging features following SSWR in patients with PT. Material and Methods Following SSWR, temporal bone contrast-enhanced high-resolution CT (HRCT) images from 33 PT cases were retrospectively analyzed. Patients were divided into two groups based on follow-up interval: a short-interval group (≤18 months, 12 cases) and a long-interval group (>18 months, 21 cases). The mending material density and morphology was analyzed. Postoperative changes of the venous sinus were evaluated. Imaging manifestations of the normal temporal bone and mastoid air cells adjacent to the operative field were observed. Results The order of CT values of mending materials was significantly lower in the short-interval group than in the long-interval group (Z = −4.716, P < 0.001); the incidence of complete newly remodeled cortical bone on the rim of the mending materials was significantly higher in the long-interval group than in the short-interval group ( P < 0.001). Eleven patients (33.3%) showed varying degrees of remnant SSWD. The mending materials and normal mastoid bone structure showed complete fusion (n = 12, 36.4%), partial fusion (n = 16, 48.5%), or complete separation (n = 5, 15.2%). Conclusion Temporal bone contrast-enhanced HRCT can be used to observe imaging features of the mending materials, venous sinus, adjacent normal temporal bone and mastoid air cells following SSWR.
Interleukin‐6 trans‐signaling contributes to chronic hypoxia‐induced pulmonary hypertension
Authors: Maston Levi D. , Jones David T. , Giermakowska Wieslawa , Resta Thomas C. , Ramiro‐Diaz Juan , Howard Tamara A. , Jernigan Nikki L. , Herbert Lindsay , Maurice Anna A. , Gonzalez Bosc Laura V. 
Published: May 2018

Interleukin‐6 (IL‐6) is a pleotropic cytokine that signals through the membrane‐bound IL‐6 receptor (mIL‐6R) to induce anti‐inflammatory (“classic‐signaling”) responses. This cytokine also binds to the soluble IL‐6R (sIL‐6R) to promote inflammation (“trans‐signaling”). mIL‐6R expression is restricted to hepatocytes and immune cells. Activated T cells release sIL‐6R into adjacent tissues to induce trans‐signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. Reports show that IL‐6 is produced by pulmonary arterial smooth muscle cells (PASMCs) exposed to hypoxia in culture as well as the medial layer of the pulmonary arteries in mice exposed to chronic hypoxia (CH), and IL‐6 knockout mice are protected from CH‐induced pulmonary hypertension (PH). IL‐6 has the potential to contribute to a broad array of downstream effects, such as cell growth and migration. CH‐induced PH is associated with increased proliferation and migration of PASMCs to previously non‐muscularized vessels of the lung. We tested the hypothesis that IL‐6 trans‐signaling contributes to CH‐induced PH and arterial remodeling. Plasma levels of sgp130 were significantly decreased in mice exposed to CH (380 mmHg) for five days compared to normoxic control mice (630 mmHg), while sIL‐6R levels were unchanged. Consistent with our hypothesis, mice that received the IL‐6 trans‐signaling‐specific inhibitor sgp130Fc, a fusion protein of the soluble extracellular portion of gp130 with the constant portion of the mouse IgG1 antibody, showed attenuation of CH‐induced increases in right ventricular systolic pressure, right ventricular and pulmonary arterial remodeling as compared to vehicle (saline)‐treated control mice. In addition, PASMCs cultured in the presence of IL‐6 and sIL‐6R showed enhanced migration but not proliferation compared to those treated with IL‐6 or sIL‐6R alone or in the presence of sgp130Fc. These results indicate that IL‐6 trans‐signaling contributes to pulmonary arterial cell migration and CH‐induced PH.
The Effect of Comorbidities and Age on Functional Outcomes After Total Knee Arthroplasty in the Octogenarian: A Matched Cohort Study
Authors: Cher Eric Wei Liang , Tay Kae Sian , Zhang Karen , Tan Seang Beng , Howe Tet Sen , Koh Joyce Suang Bee 
Published: May 2018

Introduction: According to the World Health Organization data repository, the average life expectancy at birth for Singapore in 2015 has risen to 83.4 years, and many octogenarians (OG) remain active socioeconomically. The aim of this study is to compare the improvement and the impact of comorbidities on functional recovery after total knee arthroplasty (TKA) between OG and their younger counterparts. Methods: This is a retrospective study of prospectively collected data from a single institution arthroplasty register. Between January 2006 and December 2011, 209 OG with primary knee osteoarthritis underwent TKA. Each OG (mean age 82 ± 2.1) was then carefully matched to a younger control group (YG, mean age 66 ± 4.5). Their postoperative outcomes measured include Oxford Knee Score (OKS), SF36-Physical Function (SF-PF), and knee society rating score comprising of Knee Score (KS) and Function Score (FS). Their respective degrees of improvement were compared and adjusted for their baseline comorbidities, measured using the Deyo-Charlson Comorbidity Index (D-CCI). Results: There were more comorbidities among the OG ( P < .05). Both groups saw the largest improvement ( P < .05) during the first 6 months. There was no statistical significance between their improvement for OKS, KS, and FS between baseline and 6 months and OKS, FS, and SF-PF between 6 and 24 months. Adjusted for D-CCI using linear regression, the above results remained largely unchanged. Discussion: In our study, both groups showed significant improvement across all functional outcomes, especially during the first 6 months. The improvement observed in OG at 6 and 24 months was comparable to that of YG, despite an overall higher baseline D-CCI. Conclusions: Total knee arthroplasty is a viable treatment option for the OG, offering good functional outcomes and results at 6 and 24 months when compared to their younger counterparts.
Magnesio-hornblende from Lüderitz, Namibia: mineral description and crystal chemistry
Authors: Oberti Roberta , Boiocchi Massimo , Hawthorne Frank C. , Ciriotti Marco E. 
Published: May 2018

ABSTRACTMagnesio-hornblende (IMA2017-059) has been characterized in a specimen collected in the sand dunes of Lüderitz, Karas Region, Namibia. The empirical formula derived from electron microprobe analysis and single-crystal structure refinement is A(□0.73Na0.22K0.05)Σ1.00B(Ca1.79Fe2+0.10Mg0.04Mn2+0.03Na0.04)Σ2.00C(Mg3.48Fe2+0.97Al0.28Fe3+0.23Cr3+0.01Ti0.03)Σ5.00T(Si7.18Al0.82)Σ8.00O22W[(OH)1.93F0.05Cl0.02]Σ2.00. Magnesio-hornblende is biaxial (–), with α = 1.640(2), β = 1.654(2), γ = 1.666(2) (measured with gel-filtered Na light, λ = 589.9 nm), 2V (meas.) = 82(1)° and 2V (calc.) = 84.9°. The unit-cell parameters are a = 9.8308(7), b = 18.0659(11), c = 5.2968(4) Å, β = 104.771(6)° and V = 909.64 (11) Å3 with Z = 2 and space group C2/m. The strongest eight reflections in the X-ray powder pattern [d values (in Å), I, (hkl)] are: 2.709, 100, (151); 8.412, 74, (110); 3.121, 73, (310); 2.541, 58, ($\bar{2}$02); 3.386, 49, (131); 2.596, 45, (061); 2.338, 41, ($\bar{3}$51); and 2.164, 39, (261).