bluuebunny/crossref_metadata_2025 huggingface dataset:
The challenge of crafting intelligible intelligence
Authors: Weld Daniel S. , Bansal Gagan
Published: May 2019

To trust the behavior of complex AI algorithms, especially in mission-critical settings, they must be made intelligible.
Programmable solid-state storage in future cloud datacenters
Authors: Do Jaeyoung , Sengupta Sudipta , Swanson Steven
Published: May 2019

Programmable software-defined solid-state drives can move computing functions closer to storage.
How to create a great team culture (and why it matters)
Authors: Matsudaira Kate
Published: May 2019

Build safety, share vulnerability, and establish purpose.
Neural net worth
Authors: Savage Neil
Published: May 2019

Yoshua Bengio, Geoffrey Hinton, and Yann LeCun this month will receive the 2018 ACM A.M. Turing Award for conceptual and engineering breakthroughs that have made deep neural networks a critical component of computing.
High-Performance Nafion Membrane Modified Using a 1,2,4-Triazole Derivative
Authors: Jedeok  , Ohira Akihiro , Nakao Hidenobu
Published: May 2019

Modifying the polymer structure of a Nafion membrane by adding a 1,2,4-triazole derivative and then removing it led to higher performance. The ion cluster size of the modified Nafion membrane was larger than that of the original Nafion membrane. The ion exchange capacity (IEC) was the same as that of the Nafion ionomer, but the conductivity was higher due to the modified membrane structure, which has a higher proton mobility. The cell performance of the modified Nafion membrane was better than that of Nafion 212, and in particular, the performance under low relative humidity (RH) conditions was improved. Our simple method using a 1,2,4-triazole derivative as an additive can be applied to the modification of other perfluorosulfonic acid (PFSA) and hydrocarbon polymer electrolytes and will contribute to the improvement of cell performances under high and low RH conditions.
Leucine coingestion augments the muscle protein synthetic response to the ingestion of 15 g of protein following resistance exercise in older men
Authors: Holwerda Andrew M. , Paulussen Kevin J. M. , Overkamp Maarten , Goessens Joy P. B. , Kramer Irene-Fleur , Wodzig Will K. W. H. , Verdijk Lex B. , de Groot Lisette C. P. G. M. , van Loon Luc J. C.
Published: May 2019

Older adults have shown an attenuated postexercise increase in muscle protein synthesis rates following ingestion of smaller amounts of protein compared with younger adults. Consequently, it has been suggested that older adults require the ingestion of more protein to increase postexercise muscle protein synthesis rates compared with younger adults. We investigated whether coingestion of 1.5 g of free leucine with a single 15-g bolus of protein further augments the postprandial muscle protein synthetic response during recovery from resistance-type exercise in older men. Twenty-four healthy older men (67 ± 1 yr) were randomly assigned to ingest 15 g of milk protein concentrate (MPC80) with (15G+LEU; n = 12) or without (15G; n = 12) 1.5 g of free leucine after performing a single bout of resistance-type exercise. Postprandial protein digestion and amino acid absorption kinetics, whole body protein metabolism, and postprandial myofibrillar protein synthesis rates were assessed using primed, continuous infusions with l-[ ring-2H5]phenylalanine, l-[ ring-2H2]tyrosine, and l-[1-13C]leucine combined with ingestion of intrinsically l-[1-13C]phenylalanine-labeled milk protein. A total of 70 ± 1% (10.5 ±0.2 g) and 75 ± 2% (11.2 ± 0.3 g) of the protein-derived amino acids were released in the circulation during the 6-h postexercise recovery phase in 15G+LEU and 15G, respectively ( P < 0.05). Postexercise myofibrillar protein synthesis rates were 16% (0.058 ± 0.003 vs. 0.049 ± 0.002%/h, P < 0.05; based on l-[ ring-2H5]phenylalanine) and 19% (0.071 ± 0.003 vs. 0.060 ± 0.003%/h, P < 0.05; based on l-[1-13C]leucine) greater in 15G+LEU compared with 15G. Leucine coingestion further augments the postexercise muscle protein synthetic response to the ingestion of a single 15-g bolus of protein in older men.
mTORC1/rpS6 signaling complex modifies BTB transport function: an in vivo study using the adjudin model
Authors: Yan Ming , Li Linxi , Mao Baiping , Li Huitao , Li Stephen Y. T. , Mruk Dolores , Silvestrini Bruno , Lian Qingquan , Ge Renshan , Cheng C. Yan
Published: May 2019

Studies have shown that the mTORC1/rpS6 signaling cascade regulates Sertoli cell blood-testis barrier (BTB) dynamics. For instance, specific inhibition of mTORC1 by treating Sertoli cells with rapamycin promotes the Sertoli cell barrier, making it “tighter.” However, activation of mTORC1 by overexpressing a full-length rpS6 cDNA clone (i.e., rpS6-WT, wild type) in Sertoli cells promotes BTB remodeling, making the barrier “leaky.” Also, there is an increase in rpS6 and p-rpS6 (phosphorylated and activated rpS6) expression at the BTB in testes at stages VIII–IX of the epithelial cycle, and it coincides with BTB remodeling to support the transport of preleptotene spermatocytes across the barrier, illustrating that rpS6 is a BTB-modifying signaling protein. Herein, we used a constitutively active, quadruple phosphomimetic mutant of rpS6, namely p-rpS6-MT of p-rpS6-S235E/S236E/S240E/S244E, wherein Ser (S) was converted to Glu (E) at amino acid residues 235, 236, 240, and 244 from the NH2 terminus by site-directed mutagenesis, for its overexpression in rat testes in vivo using the Polyplus in vivo jet-PEI transfection reagent with high transfection efficiency. Overexpression of this p-rpS6-MT was capable of inducing BTB remodeling, making the barrier “leaky.” This thus promoted the entry of the nonhormonal male contraceptive adjudin into the adluminal compartment in the seminiferous epithelium to induce germ cell exfoliation. Combined overexpression of p-rpS6-MT with a male contraceptive (e.g., adjudin) potentiated the drug bioavailability by modifying the BTB. This approach thus lowers intrinsic drug toxicity due to a reduced drug dose, further characterizing the biology of BTB transport function.
Excessive Neutrophil Extracellular Trap Formation Aggravates Acute Myocardial Infarction Injury in Apolipoprotein E Deficiency Mice via the ROS-Dependent Pathway
Authors: Zhou Zheliang , Zhang Shuning , Ding Suling , Abudupataer Mieradilijiang , Zhang Zhiwei , Zhu Xiaowei , Zhang Weiwei , Zou Yunzeng , Yang Xiangdong , Ge Junbo , Hong Tao
Published: May 2019

Genetically human apolipoprotein E (APOE) ε32 is associated with a decreased risk of ischemic heart disease. ApoE deficiency in mice impairs infarct healing after myocardial infarction (MI). After the ischemic injury, a large number of neutrophils are firstly recruited into the infarct zone and then degrade dead material and promote reparative phase transformation. The role of ApoE in inflammation response in the early stage of MI remains largely unclear. In this study, we investigated the effect of ApoE deficiency on neutrophils’ function and myocardial injury after myocardial infarction. By left coronary artery ligation in ApoE-/- and wild-type (WT) mice, we observed increased infarct size and neutrophil infiltration in ApoE-/- mice. Within the infarct zone, more neutrophil extracellular traps (NETs) were observed in ApoE-/- mice, while increased ex vivo NET formation was detected in ApoE-/- mouse-derived neutrophils through the NADPH oxidase-ROS-dependent pathway. Suppressing overproduced NETs reduced myocardial injury in ApoE-/- mice after ligation. In general, our findings reveal a critical role of apolipoprotein E in regulating Ly6G+ neutrophil activation and NET formation, resulting in limiting myocardial injury after myocardial infarction. In such a process, apolipoprotein E regulates NET formation via the ROS-MAPK-MSK1 pathway.
Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β-cells
Authors: Plecitá-Hlavatá Lydie , Engstová Hana , Ježek Jan , Holendová Blanka , Tauber Jan , Petrásková Lucie , Křen Vladimír , Ježek Petr
Published: May 2019

Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion- pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.
Effect of Ocular Hypertension on D-β-Aspartic Acid-Containing Proteins in the Retinas of Rats
Authors: Kanamoto Takashi , Tachibana Takashi , Kitaoka Yasushi , Hisatomi Toshio , Ikeda Yasuhiro , Murakami Yusuke , Tobiume Kei , Asaoka Ryo , Kiuchi Yoshiaki
Published: May 2019

Purpose. To investigate the effect of ocular hypertension-induced isomerization of aspartic acid in retinal proteins.Methods. Adult Wistar rats with ocular hypertension were used as an experimental model. D-β-aspartic acid-containing proteins were isolated by SDS-PAGE and western blot with an anti-D-β-aspartic acid antibody and identified by liquid chromatography-mass spectrometry analysis. The concentration of ATP was measured by ELISA.Results. D-β-aspartic acid was expressed in a protein band at around 44.5 kDa at much higher quantities in the retinas of rats with ocular hypertension than in those of normotensive rats. The 44.5 kDa protein band was mainly composed ofα-enolase, S-arrestin, and ATP synthase subunitsαandβ, in both the ocular hypertensive and normotensive retinas. Moreover, increasing intraocular pressure was correlated with increasing ATP concentrations in the retinas of rats.Conclusion. Ocular hypertension affected the expression of proteins containing D-β-aspartic acid, including ATP synthase subunits, and up-regulation of ATP in the retinas of rats.
Enhanced Biocompatibility and Antibacterial Activity of Selective Laser Melting Titanium with Zinc-Doped Micro-Nano Topography
Authors: Wu Fan , Xu Ruogu , Yu Xiaolin , Yang Jiamin , Liu Yun , Ouyang Jianglin , Zhang Chunyu , Deng Feilong
Published: May 2019

Selective laser melting (SLM) titanium is a suitable material for use in customized implants. However, long-term implant survival requires both successful osseointegration and promising antibacterial characteristics. Native SLM titanium thus requires proper modifications to improve its bioactivity and antibacterial efficacy. Micro-arc oxidation (MAO) was conducted on sandblasted SLM substrate to form a microporous TiO2 coating. Subsequently, hydrothermal treatment was applied to fabricate micro-nano zinc-incorporated coatings with different Zn content (1 mM-Zn and 100 μM-Zn). Surface characterization was performed using scanning electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, a three-dimensional profilometer, and a contact angle measuring device. The osteoblast-like cell line MC3T3-E1, Subclone 14, was used in cell viability assays to evaluate adhesion, proliferation, and ALP activity. An antibacterial assay was conducted using Streptococcus sanguinis and Fusobacterium nucleatum. Zn-incorporated samples exhibited higher adhesion, proliferation, and differentiation than did SLM and MAO samples. 100 μM Zn samples exhibited the highest proliferation, and 1 mM-Zn samples manifested the highest ALP activity. In addition, Zn-incorporated samples exerted inhibitory effects on both Streptococcus sanguinis and Fusobacterium nucleatum. Combining micro-arc oxidation and hydrothermal treatment, we successfully fabricated a novel Zn-incorporated coating on a microporous SLM surface which possesses both outstanding bioactivity and antibacterial efficacy.
A Smart Glove to Track Fitness Exercises by Reading Hand Palm
Authors: Akpa A. H. Elder , Fujiwara Masashi , Suwa Hirohiko , Arakawa Yutaka , Yasumoto Keiichi
Published: May 2019

Medical studies have intensively demonstrated that sports activity can enhance both the mental and the physical health of practitioners. In recent years, fitness activity became the most common way to motivate and engage people in sports activity. Recently, there have been multiple attempts to elaborate on the “ideal” IoT-based solution to track and assess these fitness activities. Most fitness activities (except aerobic activities like running) involve one or multiple interactions between the athlete’s hand palms and body or between the hand palms and the workout materials. In this work, we present our idea to exploit these biomechanical interactions of the hand palms to track fitness activities via a smart glove. Our smart glove-based system integrates force-sensitive resistor (FSR) sensors into wearable fitness gloves to identify and count fitness activity, by analyzing the time series of the pressure distribution in the hand palms observed during fitness sessions. To assess the performance of our proposed system, we conducted an experimental study with 10 participants over 10 common fitness activities. For the user-dependent activity recognition case, the experimental results showed 88.90% of the F score for overall activity recognition. The result of leave-one-participant-out cross-validation showed an F score ranging from 58.30% to 100%, with an average of 82.00%. For the exercise repetition count, the system achieved an average counting error of 9.85%, with a standard deviation of 1.38.
Roles of Chinese Medicine and Gut Microbiota in Chronic Constipation
Authors: Xu Zhenyuan , Liu Tianhao , Zhou Qingli , Chen Jing , Yuan Jiali , Yang Zhongshan
Published: May 2019

Chronic constipation is a common gastrointestinal dysfunction, but its aetiology and pathogenesis are still unclear. Interestingly, the compositions of the gut microbiota in constipation patients and healthy controls are different. Various studies reported the different gut microbiota alterations in constipation patients, but most studies indicated that constipation patients showed the decreased beneficial bacteria and the reduced species richness of gut bacteria. Besides, the alterations in the gut microbiota may lead to constipation and constipation-related symptoms and the regulation of gut microbiota has a positive effect on gut functional diseases such as constipation. Microbial treatment methods, such as probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, can be used to regulate gut microbiota. Increasing evidences have suggested that Chinese medicine (CM) has a good therapeutic effect on chronic constipation. Chinese medicine is well known for its multitarget and multimode effects on diseases as well as less side effects. In previous studies, after the treatment of constipation with CM, the gut microbiota was restored, indicating that the gut microbiota might be the target or important way for CM to exert its efficacy. In this review, we summarized the effects of microbial treatment and CM on the gut microbiota of constipation patients and discussed the relationship between CM and gut microbiota.
Steady-State Motion Visual Evoked Potential (SSMVEP) Enhancement Method Based on Time-Frequency Image Fusion
Authors: Yan Wenqiang , Xu Guanghua , Chen Longting , Zheng Xiaowei
Published: May 2019

The steady-state motion visual evoked potential (SSMVEP) collected from the scalp suffers from strong noise and is contaminated by artifacts such as the electrooculogram (EOG) and the electromyogram (EMG). Spatial filtering methods can fuse the information of different brain regions, which is beneficial for the enhancement of the active components of the SSMVEP. Traditional spatial filtering methods fuse electroencephalogram (EEG) in the time domain. Based on the idea of image fusion, this study proposed an SSMVEP enhancement method based on time-frequency (T-F) image fusion. The purpose is to fuse SSMVEP in the T-F domain and improve the enhancement effect of the traditional spatial filtering method on SSMVEP active components. Firstly, two electrode signals were transformed from the time domain to the T-F domain via short-time Fourier transform (STFT). The transformed T-F signals can be regarded as T-F images. Then, two T-F images were decomposed via two-dimensional multiscale wavelet decomposition, and both the high-frequency coefficients and low-frequency coefficients of the wavelet were fused by specific fusion rules. The two images were fused into one image via two-dimensional wavelet reconstruction. The fused image was subjected to mean filtering, and finally, the fused time-domain signal was obtained by inverse STFT (ISTFT). The experimental results show that the proposed method has better enhancement effect on SSMVEP active components than the traditional spatial filtering methods. This study indicates that it is feasible to fuse SSMVEP in the T-F domain, which provides a new idea for SSMVEP analysis.
Patient-Specific Tumor Growth Trajectories Determine Persistent and Resistant Cancer Cell Populations during Treatment with Targeted Therapies
Authors: Grassberger Clemens , McClatchy David , Geng Changran , Kamran Sophia C. , Fintelmann Florian , Maruvka Yosef E. , Piotrowska Zofia , Willers Henning , Sequist Lecia V. , Hata Aaron N. , Paganetti Harald
Published: May 2019

The importance of preexisting versus acquired drug resistance in patients with cancer treated with small-molecule tyrosine kinase inhibitors (TKI) remains controversial. The goal of this study is to provide a general estimate of the size and dynamics of a preexisting, drug-resistant tumor cell population versus a slow-growing persister population that is the precursor of acquired TKI resistance. We describe a general model of resistance development, including persister evolution and preexisting resistance, solely based on the macroscopic trajectory of tumor burden during treatment. We applied the model to 20 tumor volume trajectories of EGFR-mutant lung cancer patients treated with the TKI erlotinib. Under the assumption of only preexisting resistant cells or only persister evolution, it is not possible to explain the observed tumor trajectories with realistic parameter values. Assuming only persister evolution would require very high mutation induction rates, while only preexisting resistance would lead to very large preexisting populations of resistant cells at the initiation of treatment. However, combining preexisting resistance with persister populations can explain the observed tumor volume trajectories and yields an estimated preexisting resistant fraction varying from 10−4 to 10−1 at the time of treatment initiation for this study cohort. Our results also demonstrate that the growth rate of the resistant population is highly correlated to the time to tumor progression. These estimates of the size of the resistant and persistent tumor cell population during TKI treatment can inform combination treatment strategies such as multi-agent schedules or a combination of targeted agents and radiotherapy.

Significance:

These findings quantify pre-existing resistance and persister cell populations, which are essential for the integration of targeted agents into the management of locally advanced disease and the timing of radiotherapy in metastatic patients.
Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project
Authors: Jackson Sarah S. , Van Dyke Alison L. , Zhu Bin , Pfeiffer Ruth M. , Petrick Jessica L. , Adami Hans-Olov , Albanes Demetrius , Andreotti Gabriella , Beane Freeman Laura E. , Berrington de González Amy , Buring Julie E. , Chan Andrew T. , Chen Yu , Fraser Gary E. , Freedman Neal D. , Gao Yu-Tang , Gapstur Susan M. , Gaziano J. Michael , Giles Graham G. , Grant Eric J. , Grodstein Francine , Hartge Patricia , Jenab Mazda , Kitahara Cari M. , Knutsen Synnove F. , Koh Woon-Puay , Larsson Susanna C. , Lee I-Min , Liao Linda M. , Luo Juhua , McGee Emma E. , Milne Roger L. , Monroe Kristine R. , Neuhouser Marian L. , O’Brien Katie M. , Peters Ulrike , Poynter Jenny N. , Purdue Mark P. , Robien Kim , Sandler Dale P. , Sawada Norie , Schairer Catherine , Sesso Howard D. , Simon Tracey G. , Sinha Rashmi , Stolzenberg-Solomon Rachael Z. , Tsugane Shoichiro , Wang Renwei , Weiderpass Elisabete , Weinstein Stephanie J. , White Emily , Wolk Alicja , Yuan Jian-Min , Zeleniuch-Jacquotte Anne , Zhang Xuehong , McGlynn Katherine A. , Campbell Peter T. , Koshiol Jill
Published: May 2019

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.

Significance:

These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
Gaussian Mixture Models for Probabilistic Classification of Breast Cancer
Authors: Prabakaran Indira , Wu Zhengdong , Lee Changgun , Tong Brian , Steeman Samantha , Koo Gabriel , Zhang Paul J. , Guvakova Marina A.
Published: May 2019

In the era of omics-driven research, it remains a common dilemma to stratify individual patients based on the molecular characteristics of their tumors. To improve molecular stratification of patients with breast cancer, we developed the Gaussian mixture model (GMM)–based classifier. This probabilistic classifier was built on mRNA expression data from more than 300 clinical samples of breast cancer and healthy tissue and was validated on datasets of ESR1, PGR, and ERBB2, which encode standard clinical markers and therapeutic targets. To demonstrate how a GMM approach could be exploited for multiclass classification using data from a candidate marker, we analyzed the insulin-like growth factor I receptor (IGF1R), a promising target, but a marker of uncertain importance in breast cancer. The GMM defined subclasses with downregulated (40%), unchanged (39%), upregulated (19%), and overexpressed (2%) IGF1R levels; inter- and intrapatient analyses of IGF1R transcript and protein levels supported these predictions. Overexpressed IGF1R was observed in a small percentage of tumors. Samples with unchanged and upregulated IGF1R were differentiated tumors, and downregulation of IGF1R correlated with poorly differentiated, high-risk hormone receptor–negative and HER2-positive tumors. A similar correlation was found in the independent cohort of carcinoma in situ, suggesting that loss or low expression of IGF1R is a marker of aggressiveness in subsets of preinvasive and invasive breast cancer. These results demonstrate the importance of probabilistic modeling that delves deeper into molecular data and aims to improve diagnostic classification, prognostic assessment, and treatment selection.

Significance:

A GMM classifier demonstrates potential use for clinical validation of markers and determination of target populations, particularly when availability of specimens for marker development is low.
Global Increasing Incidence of Young-Onset Colorectal Cancer Across 5 Continents: A Joinpoint Regression Analysis of 1,922,167 Cases
Authors: Lui Rashid N. , Tsoi Kelvin K.F. , Ho Jason M.W. , Lo C.M. , Chan Felix C.H. , Kyaw Moe H. , Sung Joseph J.Y.
Published: May 2019

Background:

Colorectal cancer incidence among young adults in the United States is on the rise, but whether this phenomenon is present in other parts of the world is not well documented. This study aims to explore the temporal change of incidence rates for colorectal cancer in various countries across the globe.

Methods:

We extracted colorectal cancer incidence and population data from 1988 to 2007 based on data from the International Agency for Research on Cancer and compared incidence between age groups. Twelve representative jurisdictions from five continents were selected. Young-onset colorectal cancer cases were defined as those ages <50 years. Joinpoint regression was used to measure the trends of colorectal cancer incidence and to estimate the annual percent change (APC).

Results:

The APC for those ages <50 years was noted to be increasing at a faster rate as compared with those ages ≥50 years in many regions, including Australia (+1.10% vs. −0.35%), Brazil (+9.20% vs. +5.72%), Canada (+2.60% vs. −0.91%), China–Hong Kong (+1.82% vs. −0.10%), China–Shanghai (+1.13% vs. −2.68%), Japan (+2.63% vs. +0.90%), the United Kingdom (+3.33% vs. +0.77%), and the United States (+1.98% vs. −2.88%). These trends were largely driven by rectal cancer, except in Brazil and the United Kingdom.

Conclusions:

Increasing incidence of young-onset colorectal cancer was noted in many regions across the globe.

Impact:

Further studies focusing on young-onset colorectal cancer, particularly with regard to risk factors and establishing the optimal age of screening, are warranted.
Smoking and Pancreatic Cancer Incidence: A Pooled Analysis of 10 Population-Based Cohort Studies in Japan
Authors: Koyanagi Yuriko N. , Ito Hidemi , Matsuo Keitaro , Sugawara Yumi , Hidaka Akihisa , Sawada Norie , Wada Keiko , Nagata Chisato , Tamakoshi Akiko , Lin Yingsong , Takeuchi Taro , Kitamura Yuri , Utada Mai , Sadakane Atsuko , Mizoue Tetsuya , Naito Mariko , Tanaka Keitaro , Shimazu Taichi , Tsugane Shoichiro , Inoue Manami
Published: May 2019

Background:

Detailed prospective evaluation of cigarette smoking associated with pancreatic cancer risk in large Asian populations is limited. The aim of this study was to examine this association in a Japanese population, with a particular focus on evaluating sex differences.

Methods:

We performed a pooled analysis of 10 population-based cohort studies. We calculated study-specific HRs and 95% confidence intervals (CI) using Cox proportional hazards regression, and then estimated summary HRs by pooling these estimates with a random effects model.

Results:

During 4,695,593 person-years of follow-up in 354,154 participants, 1,779 incident pancreatic cancer cases were identified. We observed an increased pancreatic cancer risk for current smoking compared with never smoking in both males [HR (95% CI), 1.59 (1.32–1.91)] and females [HR (95% CI), 1.81 (1.43–2.30)]. Significant risk elevations for former smoking and small cumulative dose of ≤20 pack-years (PY) were observed only among females, regardless of environmental tobacco smoke exposure. Trend analysis indicated significant 6% and nonsignificant 6% increases in pancreatic cancer risk for every 10 PYs in males and females, respectively. Risk became comparable with never smokers after 5 years of smoking cessation in males. In females, however, we observed no risk attenuation by smoking cessation.

Conclusions:

This study supports the well-known association between smoking and pancreatic cancer and indicates potential sex differences in a Japanese population. Quitting smoking would be beneficial for pancreatic cancer prevention, especially in males.

Impact:

Pancreatic cancer risk is increased with cumulative smoking exposure and decreased with smoking cessation, with potential sex differences.
Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer
Authors: Slovin Susan , Hussain Syed , Saad Fred , Garcia Jorge , Picus Joel , Ferraldeschi Roberta , Crespo Mateus , Flohr Penelope , Riisnaes Ruth , Lin Chihche , Keer Harold , Oganesian Aram , Workman Paul , de Bono Johann
Published: May 2019

Purpose:

Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P.

Patients and Methods:

Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (regimen 1); or at 120 mg/m2 on day 1 and day 2 weekly for 3 of 4 weeks (regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTC) and in fresh tumor tissue biopsies.

Results:

Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose limiting at 260 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients showed an objective or PSA response.

Conclusions:

Onalespib in combination with AA/P showed mild evidence of some biological effect; however, this effect did not translate into clinical activity, hence further exploration of this combination was not justified.
Inferring the Evolution and Progression of Small-Cell Lung Cancer by Single-Cell Sequencing of Circulating Tumor Cells
Authors: Su Zhe , Wang Zhijie , Ni Xiaohui , Duan Jianchun , Gao Yan , Zhuo Minglei , Li Ruoyan , Zhao Jun , Ma Qi , Bai Hua , Chen Hengyu , Wang Shuhang , Chen Xixi , An Tongtong , Wang Yuyan , Tian Yanhua , Yu Jiangyong , Wang Di , Xie Xiaoliang Sunney , Bai Fan , Wang Jie
Published: May 2019

Purpose:

Genomic analyses of small-cell lung cancer (SCLC) are limited by the availability of tumor specimens. This study aimed to investigate the suitability of single-cell sequencing of circulating tumor cells (CTC) as a method of inferring the evolution and progression of SCLCs.

Experimental Design:

Between July 1, 2011, and July 28, 2014, 48 consecutively diagnosed patients with SCLC were recruited for this study. CTCs were captured from each patient with CellSearch system. Somatic mutations and copy number alterations (CNA) were monitored by single-cell sequencing of CTCs during chemotherapy.

Results:

Single-cell sequencing of CTCs can provide a mutational atlas for SCLC. A 10-CNA score based on single CTCs was established as a classifier for outcomes of initial chemotherapy in patients with SCLC. The survival analyses demonstrated that patients with low CNA scores (<0) had significantly prolonged progression-free survival (PFS) and overall survival (OS) after first-line chemotherapy in comparison with those with high scores (≥0; PFS: 212 days vs. 110.5 days, P = 0.0042; and OS: 223.5 days vs. 424 days, P = 0.0006). The positive predictive value and negative predictive value of the CNA score for clinical subtype (refractory vs. sensitive) were 80.0% and 93.7%, respectively. By tracing allele-specific CNAs in CTCs isolated at different time points during chemotherapy, we showed that CNA heterogeneity might result from allelic losses of initially consistent CNAs.

Conclusions:

Single CTC-based sequencing can be utilized to depict the genomic profiles and evolutionary history of SCLC, thus offering the potential for clinical stratification of patients with SCLC.
Mitotic DNA Synthesis Is Differentially Regulated between Cancer and Noncancerous Cells
Authors: Graber-Feesl Cari L. , Pederson Kayla D. , Aney Katherine J. , Shima Naoko
Published: May 2019

Mitotic DNA synthesis is a recently discovered mechanism that resolves late replication intermediates, thereby supporting cell proliferation under replication stress. This unusual form of DNA synthesis occurs in the absence of RAD51 or BRCA2, which led to the identification of RAD52 as a key player in this process. Notably, mitotic DNA synthesis is predominantly observed at chromosome loci that colocalize with FANCD2 foci. However, the role of this protein in mitotic DNA synthesis remains largely unknown. In this study, we investigated the role of FANCD2 and its interplay with RAD52 in mitotic DNA synthesis using aphidicolin as a universal inducer of this process. After examining eight human cell lines, we provide evidence for FANCD2 rather than RAD52 as a fundamental supporter of mitotic DNA synthesis. In cancer cell lines, FANCD2 exerts this role independently of RAD52. Surprisingly, RAD52 is dispensable for mitotic DNA synthesis in noncancerous cell lines, but these cells strongly depend on FANCD2 for this process. Therefore, RAD52 functions selectively in cancer cells as a secondary regulator in addition to FANCD2 to facilitate mitotic DNA synthesis. As an alternative to aphidicolin, we found partial inhibition of origin licensing as an effective way to induce mitotic DNA synthesis preferentially in cancer cells. Importantly, cancer cells still perform mitotic DNA synthesis by dual regulation of FANCD2 and RAD52 under such conditions.

Implications:

These key differences in mitotic DNA synthesis between cancer and noncancerous cells advance our understanding of this mechanism and can be exploited for cancer therapies.
Perceptual Consequences of Variability in Native and Non-Native Speech
Authors: Baese-Berk Melissa M. , Morrill Tuuli H.
Published: May 2019

Background/Aims:
Native speakers often have a difficult time understanding non-native speech, and this challenge is frequently attributed to a more variable signal. While theories and models of general speech perception are grounded in issues of variability, they rarely consider non-native speech. Here, we ask how a specific type of variability (speaking rate) impacts two measures of perception for both native and non-native speech.
Methods:
In the present study, one group of listeners transcribed speech, providing a measure of intelligibility. A second group of listeners rated how fluent the speaker was, providing a measure of fluency.
Results:
The results show that variability in speaking rate correlates with a non-native speaker’s intelligibility. However, perceived fluency measures are not predicted by this variability measure.
Conclusions:
These results, taken with studies of the range of variability in non-native speech, suggest that variability in non-native speech is not a monolithic construct. Current theories and models of perception can be enhanced by examining non-native speech and how variability in that speech impacts perception.
Effects of Language Background on the Development of Sociolinguistic Awareness: The Perception of Accent Variation in Monolingual and Multilingual 5- to 7-Year-Old Children
Authors: Evans Bronwen G. , Tomé-Lourido Gisela
Published: May 2019

As a result of complex international migration patterns, listeners in large urban centres such as London, UK, likely encounter large amounts of variation in spoken language. However, although dealing with variation is crucial to communication, relatively little is known about how the ability to do this develops. Still less is known about how this might be affected by language background. The current study investigates whether early experience with variation, specifically growing up bilingually in London, affects accent categorization. Sixty children (30 monolingual, 30 bilingual) aged 5–7 years, were tested in their ability to comprehend and categorize talkers in 2 out of 3 accents: a home, unfamiliar regional and unfamiliar foreign-accented variety. All children demonstrated high, above-chance performance in the comprehension task, but language background significantly affected the children’s ability to categorize talkers. Bilinguals were able to categorize talkers in all accent conditions, but although all children were able to understand the talkers, monolingual children were only able to categorize talkers in the home-foreign accent condition. Overall, the results are consistent with an approach in which gradient representations of accent variation emerge alongside an understanding of how variation is used meaningfully within a child’s environment.
Bronchopulmonary Dysplasia Is Associated with Altered Brain Volumes and White Matter Microstructure in Preterm Infants
Authors: Lee Jong-Min , Choi Yong-Ho , Hong Jinwoo , Kim Na Young , Kim Eun bee , Lim Jung-sun , Kim Jong Deok , Park Hyun-Kyung , Lee Hyun Ju
Published: May 2019

Background: Bronchopulmonary dysplasia (BPD), an inflammatory disease involving disrupted lung development, is associated with neurodevelopmental outcome in preterm infants. Objective: This study examined the brain volume and white matter (WM) microstructure in preterm infants at term-equivalent age and explored the effects of BPD on brain development. Method: We studied 56 preterm infants (33 with BPD and 23 without BPD) with no evidence of focal abnormalities on conventional magnetic resonance imaging (MRI) at term-equivalent age. Regional brain volumes and diffusion tensor images were examined using advanced segmentation techniques to acquire quantitative volume measurements, and the JHU neonatal template was used for the atlas-based analysis. We compared these infants with 22 healthy term infants of a similar postmenstrual age. Results: The preterm infants with BPD had smaller cerebral WM (p = 0.005) volumes than the preterm infants without BPD, independent of sex, gestational age, age at MRI scan, and total intracranial volume. Independent of sex, gestational age, and age at MRI scan, the preterm infants with BPD exhibited marked reductions in fractional anisotropy in the corpus callosum (p = 0.006), corticospinal tract (p = 0.003), and superior cerebellar peduncle (p = 0.002) compared with the infants with no BPD, with a significance level of p ≤ 0.008 as a Bonferroni correction for multiple comparisons. Conclusion: Our study highlights the potential impairing influence of BPD on WM and cerebellar development in preterm infants compared with those without BPD at term-equivalent age, suggesting its clinical significance for neurodevelopment in BPD infants.
Fluoride Dentifrice Overcomes the Lower Resistance of Fluorotic Enamel to Demineralization
Authors: Almeida Luma Fabiane , Marín Lina María , Martínez-Mier Esperanza Angeles , Cury Jaime Aparecido
Published: May 2019

We evaluated if the low resistance of fluorotic enamel to demineralization could be overcome by fluoride dentifrice (FD) treatment. Paired enamel slabs of sound and fluorotic enamel (n = 20/group) from human teeth presenting Thylstrup and Fejerskov index (TF) scores from 0 to 4 were obtained. Half of the anatomic surface of the enamel slabs was isolated and used as a control (baseline) regarding enamel mineralization and fluoride concentration. The slabs were submitted to a pH-cycling model simulating a high cariogenic challenge, and 2×/day they were treated with placebo dentifrice (PD) or FD (1,100 µg F/g, as NaF). After 10 days, the slabs were cut into two halves. Enamel demineralization was evaluated by cross-sectional microhardness in one half, and the fluoride formed (FF) concentration was determined in the other half. For statistical analysis, the data on net demineralization area (ΔΔS) and FF (µg F/g) were grouped into TF0, TF1–2, and TF3–4, and analyzed by two-way ANOVA followed by Tukey’s test (α = 5%). The factors studied were TF (0, 1–2, and 3–4) and dentifrice treatment (PD or FD). The effect of the factors was statistically significant for ΔΔS and FF (p < 0.05). In the PD group, the following pattern for ΔΔS was observed: TF3–4 > TF1–2 > TF0 (p < 0.05); however, the groups did not differ (p > 0.05) when FD was used. Regarding FF, the groups treated with PD did not differ (p > 0.05), but the greatest (p < 0.05) FF concentration was found in group TF3–4 treated with FD. These findings suggest that the higher susceptibility of fluorotic enamel to demineralization lesions is decreased by the use of FD.
Increasing Heme Oxygenase-1-Expressing Macrophages Indicates a Tendency of Poor Prognosis in Advanced Colorectal Cancer
Authors: Kimura Shingo , Aung Naing Ye , Ohe Rintaro , Yano Mitsuhiro , Hashimoto Toshio , Fujishima Tsukasa , Kimura Wataru , Yamakawa Mitsunori
Published: May 2019

Background: Many cancers express heme oxygenase-1 ­(HO-1) at a higher frequency than healthy tissues, and this elevated expression is associated with cancer prognosis. Here, we aim to clarify the correlation between HO-1-expressing macrophage numbers and clinicopathological parameters of advanced colorectal cancer. Materials and Methods: Formalin-fixed and paraffin-embedded tissues of patients with advanced colorectal cancer were used. To detect HO-1 expression in macrophages, immunohistochemistry was performed. The number of positive cells was measured. Furthermore, HO-1 mRNA in colorectal cancer was examined by reverse transcription polymerase chain reaction. Results: Among the HO-1-negative and HO-1-positive groups, 58.02 and 85.00% of cases, respectively, were positive for lymph node metastasis. The disease-free survival (DFS) time was significantly shorter (p < 0.05) in the ­HO-1-positive group (2.44 years) than in the HO-1-negative group (4.09 years). However, according to the Cox proportional-hazards regression model, the HO-1-positive group could not be a risk factor of poor prognosis. HO-1 mRNA expression was confirmed in colorectal normal and cancer tissues. Conclusion: In this study, the correlation between HO-1-expressing macrophages and clinicopathological parameters in the tumor microenvironment of colorectal cancer was studied for the first time, and the expression was associated with lymph node metastasis and shortening of DFS.
Neurosurgical Resident Exposure to Pediatric Neurosurgery: An Analysis of Resident Case Logs
Authors: White Michael D. , Zollman Joshua , McDowell Michael M. , Agarwal Nitin , Abel Taylor J. , Hamilton David K.
Published: May 2019

Introduction: The purpose of this study is to identify the national trends of exposure to pediatric procedures during neurosurgical residency and to subsequently evaluate how neurosurgery residents’ experiences correlate with the minimum requirements set forth by the American College of Graduate Medical Education (ACGME). Methods: ACGME resident case logs from residents graduating between 2013 and 2017 were retrospectively reviewed. These reports were analyzed to determine trends in resident operative experience in pediatric procedures. The number of cases performed by residents was compared to the required minimums set by the ACGME within each pediatric surgical category. A linear regression analysis and t tests were utilized to analyze the change in cases performed over the study period. Results: A mean of 98.8 procedures were performed for each of the 877 residents graduating between 2013 and 2017. The total number of pediatric procedures declined at a rate of 1.7 cases/year (r2 = 0.77, p = 0.05). Spine and cerebrospinal fluid diversion procedures showed decreasing trends at rates of 1.9 (r2 = 0.70, p = 0.08) and 1.2 (r2 = 0.70, p = 0.08) cases/year, respectively. The number of trauma and brain tumor cases were shown to have increasing rates at 1.0 (r2 = 0.86, p = 0.02) and 0.3 (r2 = 0.69, p = 0.08) cases/year, respectively, with trauma cases showing significant increases. There was also a trend of increasing cases logged as the lead resident surgeon by 12.9 cases/year (r2 = 0.99, p < 0.001). The number of cases performed by the average graduating resident was also significantly higher than the minimums required by the ACGME; residents, on average, performed 3 times the required minimum number of pediatric cases. Conclusion: Neurosurgical residents graduating from 2013 to 2017 reported significantly higher volumes of pediatric neurosurgery cases than the standards set for by the ACGME. During this time, there was also a significant trend of increasing cases logged as the lead resident surgeon, suggesting more involvement in the critical portions of pediatric cases. There was also a significant, but not clinically impactful, decrease in pediatric case volumes during this time. However, the overall data indicate that residents are continuing to gain valuable pediatric experience during residency training.