bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uptake of peer-led venue-based HIV testing sites in Sweden aimed at men who have sex with men (MSM) and trans persons: a cross-sectional survey
Authors: Strömdahl Susanne , Hoijer Jonas , Eriksen Jaran 
Published: May 2019

ObjectivesHIV testing among high-risk groups is a key intervention to diagnose persons living unknowingly with HIV to enable linkage to care and effective antiretroviral treatment. This study aimed to evaluate the uptake of Testpoint, the first large-scale HIV testing programme in Sweden where peer, non-healthcare personnel offered venue-based testing. Testing was performed by staff from the Swedish Foundation for Lesbian, Gay, Bisexual and Transgender Rights (RFSL Sweden) and testing was performed at the RFSL offices, gay clubs and gay cruising areas, as well as at various gay festivals. The test was a rapid test using capillary blood from a finger prick.MethodsA cross-sectional survey of all persons aged>18 years who came for HIV testing at one of Testpoint’s locations in Sweden between 1 February and 31 December 2016.Results595 respondents (96% response rate) were included. Five persons were diagnosed with HIV and referred for treatment and care. A fifth of participants had never tested for HIV before. More than half of the participants were foreign born and the median age was 31 years. About one-fifth of participants stated they would not have tested through the healthcare system if Testpoint was not available.ConclusionsTestpoint reached their target population of young, foreign-born men who have sex with men (MSM) as well as first time testers and persons who stated that they would not have tested within the healthcare system. Such peer HIV testing outside the healthcare setting is a possible way of increasing uptake of testing in high-risk groups.
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

AbstractThe 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

Abstract

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

Abstract

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

Abstract

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 &lt;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 &lt;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

AbstractBackground: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

Abstract

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

Abstract

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 (&lt;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

Abstract

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

Abstract

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

Abstract
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.