bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interhemispheric interactions between trunk muscle representations of the primary motor cortex
Authors: Jean-Charles Loyda , Nepveu Jean-Francois , Deffeyes Joan E. , Elgbeili Guillaume , Dancause Numa , Barthélemy Dorothy 
Published: June 2017

Unilateral arm movements require trunk stabilization through bilateral contraction of axial muscles. Interhemispheric interactions between primary motor cortices (M1) could enable such coordinated contractions, but these mechanisms are largely unknown. Using transcranial magnetic stimulation (TMS), we characterized interhemispheric interactions between M1 representations of the trunk-stabilizing muscles erector spinae at the first lumbar vertebra (ES L1) during a right isometric shoulder flexion. These interactions were compared with those of the anterior deltoid (AD), the main agonist in this task, and the first dorsal interosseous (FDI). TMS over the right M1 elicited ipsilateral silent periods (iSP) in all three muscles on the right side. In ES L1, but not in AD or FDI, ipsilateral motor evoked potential (iMEP) could precede the iSP or replace it. iMEP amplitude was not significantly different whether ES L1 was used to stabilize the trunk or was voluntarily contracted. TMS at the cervicomedullary junction showed that the size of cervicomedullary evoked potential was unchanged during the iSP but increased during iMEP, suggesting that the iSP, but not the iMEP, is due to intracortical mechanisms. Using a dual-coil paradigm with two coils over the left and right M1, interhemispheric inhibition could be evoked at interstimulus intervals of 6 ms in ES L1 and 8 ms in AD and FDI. Together, these results suggest that interhemispheric inhibition is dominant when axial muscles are involved in a stabilizing task. The ipsilateral facilitation could be evoked by ipsilateral or subcortical pathways and could be used depending on the role axial muscles play in the task. NEW & NOTEWORTHY The mechanisms involved in the bilateral coordination of axial muscles during unilateral arm movement are poorly understood. We thus investigated the nature of interhemispheric interactions in axial muscles during arm motor tasks in healthy subjects. By combining different methodologies, we showed that trunk muscles receive both inhibitory and facilitatory cortical outputs during activation of arm muscles. We propose that inhibition may be conveyed mainly through interhemispheric mechanisms and facilitation by subcortical mechanisms or ipsilateral pathways.
Risk of Second Malignancies in Solid Organ Transplant Recipients Who Develop Keratinocyte Cancers
Authors: Zamoiski Rachel D. , Yanik Elizabeth , Gibson Todd M. , Cahoon Elizabeth K. , Madeleine Margaret M. , Lynch Charles F. , Gustafson Sally , Goodman Marc T. , Skeans Melissa , Israni Ajay K. , Engels Eric A. , Morton Lindsay M. 
Published: June 2017

AbstractSolid organ transplant recipients have increased risk for developing keratinocyte cancers, including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, keratinocyte cancers are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on keratinocyte cancer occurrence, with 15 state cancer registries. Risk of developing malignancies after keratinocyte cancer was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n = 6,169) was associated with 1.44-fold increased risk [95% confidence interval (CI), 1.31–1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx (HR, 5.60; 95% CI, 4.18–7.50) and lung (HR, 1.66; 95% CI, 1.16–2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR, 2.77; 95% CI, 1.29–5.96) and female genital cancers (HR, 3.43; 95% CI, 1.44–8.19). In contrast, BCC (n = 3,669) was not associated with overall risk of later malignancy (HR, 0.98; 95% CI, 0.87–1.12), including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk. Cancer Res; 77(15); 4196–203. ©2017 AACR.
RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression
Authors: Wang Yongquan , Wang Jianghua , Zhang Li , Karatas Omer Faruk , Shao Longjiang , Zhang Yiqun , Castro Patricia , Creighton Chad J. , Ittmann Michael 
Published: June 2017

Abstract
African American (AA) men exhibit a relatively high incidence and mortality due to prostate cancer even after adjustment for socioeconomic factors, but the biological basis for this disparity is unclear. Here, we identify a novel region on chromosome 4p16.3 that is lost selectively in AA prostate cancer. The negative regulator of G-protein signaling RGS12 was defined as the target of 4p16.3 deletions, although it has not been implicated previously as a tumor-suppressor gene. RGS12 transcript levels were relatively reduced in AA prostate cancer, and prostate cancer cell lines showed decreased RGS12 expression relative to benign prostate epithelial cells. Notably, RGS12 exhibited potent tumor-suppressor activity in prostate cancer and prostate epithelial cell lines in vitro and in vivo. We found that RGS12 expression correlated negatively with the oncogene MNX1 and regulated its expression in vitro and in vivo. Further, MNX1 was regulated by AKT activity, and RGS12 expression decreased total and activated AKT levels. Our findings identify RGS12 as a candidate tumor-suppressor gene in AA prostate cancer, which acts by decreasing expression of AKT and MNX1, establishing a novel oncogenic axis in this disparate disease setting. Cancer Res; 77(16); 4247–57. ©2017 AACR.
Clinical Development of PD-1/PD-L1 Immunotherapy for Gastrointestinal Cancers: Facts and Hopes
Authors: Chau Ian 
Published: June 2017

Abstract
Gastrointestinal (GI) cancers are among the most deadly malignancies. Although serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumors of each primary anatomical site but also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success. Molecular characteristics of tumors and their interaction with the tumor microenvironment would further affect development of combination therapy, including immunotherapy. Currently, immune checkpoint blockade attracts the most intense research, and the successful integration of these novel agents in GI cancers in the treatment paradigm requires an in-depth understanding of the diverse immune environment of these cancers. Clin Cancer Res; 23(20); 6002–11. ©2017 AACR.
Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk
Authors: Villani Anita , Greer Mary-Louise C. , Kalish Jennifer M. , Nakagawara Akira , Nathanson Katherine L. , Pajtler Kristian W. , Pfister Stefan M. , Walsh Michael F. , Wasserman Jonathan D. , Zelley Kristin , Kratz Christian P. 
Published: June 2017

Abstract
In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features
Authors: Hendry Shona , Pang Jia-Min B. , Byrne David J. , Lakhani Sunil R. , Cummings Margaret C. , Campbell Ian G. , Mann G. Bruce , Gorringe Kylie L. , Fox Stephen B. 
Published: June 2017

Abstract
Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.
Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n = 55) and mutation data (n = 20).
Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%–90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P = 0.002/0.035), ER-negative (P = 0.02/0.02), and ERBB2-amplified tumors (P &lt; 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P &lt; 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P = 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P &lt; 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.
Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210–7. ©2017 AACR.
Detection of Head and Neck Cancer in Surgical Specimens Using Quantitative Hyperspectral Imaging
Authors: Lu Guolan , Little James V. , Wang Xu , Zhang Hongzheng , Patel Mihir R. , Griffith Christopher C. , El-Deiry Mark W. , Chen Amy Y. , Fei Baowei 
Published: June 2017

Abstract
Purpose: This study intends to investigate the feasibility of using hyperspectral imaging (HSI) to detect and delineate cancers in fresh, surgical specimens of patients with head and neck cancers.
Experimental Design: A clinical study was conducted in order to collect and image fresh, surgical specimens from patients (N = 36) with head and neck cancers undergoing surgical resection. A set of machine-learning tools were developed to quantify hyperspectral images of the resected tissue in order to detect and delineate cancerous regions which were validated by histopathologic diagnosis. More than two million reflectance spectral signatures were obtained by HSI and analyzed using machine-learning methods. The detection results of HSI were compared with autofluorescence imaging and fluorescence imaging of two vital-dyes of the same specimens.
Results: Quantitative HSI differentiated cancerous tissue from normal tissue in ex vivo surgical specimens with a sensitivity and specificity of 91% and 91%, respectively, and which was more accurate than autofluorescence imaging (P &lt; 0.05) or fluorescence imaging of 2-NBDG (P &lt; 0.05) and proflavine (P &lt; 0.05). The proposed quantification tools also generated cancer probability maps with the tumor border demarcated and which could provide real-time guidance for surgeons regarding optimal tumor resection.
Conclusions: This study highlights the feasibility of using quantitative HSI as a diagnostic tool to delineate the cancer boundaries in surgical specimens, and which could be translated into the clinic application with the hope of improving clinical outcomes in the future. Clin Cancer Res; 23(18); 5426–36. ©2017 AACR.
A Novel Combination Treatment Targeting BCL-XL and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified Colorectal Cancers
Authors: Cho Sung-Yup , Han Jee Yun , Na Deukchae , Kang Wonyoung , Lee Ahra , Kim Jooyoung , Lee Jieun , Min Seoyeon , Kang Jinjoo , Chae Jeesoo , Kim Jong-Il , Park Hansoo , Lee Won-Suk , Lee Charles 
Published: June 2017

Abstract
Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited. KRAS and BRAF mutations are prevalent genetic alterations in colorectal cancers, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments. In this study, we have found that a subgroup of colorectal cancers, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 (encoding BCL-XL) amplification, can be effectively targeted by simultaneous inhibition of BCL-XL (with ABT-263) and MCL1 (with YM-155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL-XL and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup. Mol Cancer Ther; 16(10); 2178–90. ©2017 AACR.
Inhibition of Ciliogenesis Promotes Hedgehog Signaling, Tumorigenesis, and Metastasis in Breast Cancer
Authors: Hassounah Nadia B. , Nunez Martha , Fordyce Colleen , Roe Denise , Nagle Ray , Bunch Thomas , McDermott Kimberly M. 
Published: June 2017

Abstract
Primary cilia are chemosensors that play a dual role to either activate or repress Hedgehog signaling, depending on presence or absence of ligand, respectively. While inhibition of ciliogenesis has been shown to be characteristic of breast cancers, the functional consequence is unknown. Here, for the first time, inhibition of ciliogenesis led to earlier tumor formation, faster tumor growth rate, higher grade tumor formation, and increased metastasis in the polyoma middle T (PyMT) mouse model of breast cancer. In in vitro model systems, inhibition of ciliogenesis resulted in increased expression of Hedgehog-target genes through a mechanism involving loss of the repressor form of the GLI transcription factor (GLIR) and activation of Hedgehog target gene expression through cross-talk with TGF-alpha (TGFA) signaling. Bioinformatics analysis revealed that increased Hedgehog signaling is frequently associated with increased TGFA; signaling in patients with triple-negative breast cancers (TNBC), a particularly aggressive breast cancer subtype. These results identify a previously unrecognized role for inhibition of ciliogenesis in breast cancer progression. This study identifies inhibition of ciliogenesis as an important event for activation of Hedgehog signaling and progression of breast cancer to a more aggressive, metastatic disease.
Implications: These findings change the way we understand how cancer cells turn on a critical signaling pathways and a provide rationale for developing novel therapeutic approaches to target noncanonical Hedgehog signaling for the treatment of breast cancer. Mol Cancer Res; 15(10); 1421–30. ©2017 AACR.
Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin–NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways
Authors: Liu Wenjuan , Deng Jianxin , Ding Wenwen , Wang Gang , Shen Yuanyuan , Zheng Junmeng , Zhang Xiaoming , Luo Yizhi , Lv Chifei , Wang Yonghui , Chen Liqing , Yan Dewen , Boudreau Ryan L. , Song Long-Sheng , Liu Jie 
Published: June 2017

Background—

KCNE2 is a promiscuous auxiliary subunit of voltage-gated cation channels. A recent work demonstrated that KCNE2 regulates L-type Ca
2+
channels. Given the important roles of altered Ca
2+
signaling in structural and functional remodeling in diseased hearts, this study investigated whether KCNE2 participates in the development of pathological hypertrophy.

Methods and Results—

We found that cardiac KCNE2 expression was significantly decreased in phenylephrine-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes and in transverse aortic constriction–induced cardiac hypertrophy in mice, as well as in dilated cardiomyopathy in human. Knockdown of KCNE2 in neonatal rat ventricular myocytes reproduced hypertrophy by increasing the expression of ANP (atrial natriuretic peptide) and β-MHC (β-myosin heavy chain), and cell surface area, whereas overexpression of KCNE2 attenuated phenylephrine-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased intracellular Ca
2+
transient, calcineurin activity, and nuclear NFAT (nuclear factor of activated T cells) protein levels, and pretreatment with inhibitor of L-type Ca
2+
channel (nifedipine) or calcineurin (FK506) attenuated the activation of calcineurin–NFAT pathway and cardiomyocyte hypertrophy. Meanwhile, the phosphorylation levels of p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were increased, and inhibiting the 3 cascades of mitogen-activated protein kinase reduced cardiomyocyte hypertrophy induced by KCNE2 knockdown. Overexpression of KCNE2 in heart by ultrasound-microbubble–mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin–NFAT and mitogen-activated protein kinase pathways in transverse aortic constriction mice.

Conclusions—
This study demonstrates that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin–NFAT and mitogen-activated protein kinase pathways. Targeting KCNE2 is a potential therapeutic strategy for the treatment of hypertrophy.
Patient Perceptions on Facilitating Follow-Up After Heart Failure Hospitalization
Authors: Breathett Khadijah , D’Amico Rachel , Adesanya T.M. Ayodele , Hatfield Stefanie , Willis Shannon , Sturdivant Rodney X. , Foraker Randi E. , Smith Sakima , Binkley Philip , Abraham William T. , Peterson Pamela N. 
Published: June 2017

Background—
Timely follow-up after hospitalization for heart failure (HF) is recommended. However, follow-up is suboptimal, especially in lower socioeconomic groups. Patient-centered solutions for facilitating follow-up post-HF hospitalization have not been extensively evaluated.

Methods and Results—

Face-to-face surveys were conducted between 2015 and 2016 among 83 racially diverse adult patients (61% African American, 34% Caucasian, and 5% Other) hospitalized for HF at a university hospital centered in a low-income area of Columbus, Ohio. Patient perceptions of methods to facilitate follow-up post-HF hospitalization and likelihood of using interventions were investigated using a Likert scale: 1=very much to 5=not at all. Results were analyzed by Wilcoxon signed-rank test with Bonferroni correction. The response rate was 82%. The annual household income was <$35 000 for 49% of patients. An appointment near the patient’s home was the most desired intervention (77%), followed by reminder message (73%), transportation to appointment (63%), and elimination of copayment (59%). Interventions most likely to be used if provided were similarly ranked: reminder message (48%), appointment near home (46%), elimination of copay (46%), and transportation to appointment (39%). There were significant differences (
P
=0.001) in high-ranking interventions related to location (appointment near home, transportation, home appointment) and reminder for visit compared with low-ranking interventions related to time (weekend appointment, appointment after 5
pm
) and telemedicine.

Conclusions—
Among this cohort of racially diverse low-income patients hospitalized with HF, an appointment near the patient’s home and a reminder message were the most desired interventions to facilitate follow-up. Further study of similar populations nationwide is warranted.
CCR6 (CC Chemokine Receptor 6) Is Essential for the Migration of Detrimental Natural Interleukin-17–Producing γδ T Cells in Stroke
Authors: Arunachalam Priyadharshini , Ludewig Peter , Melich Patrick , Arumugam Thiruma Valavan , Gerloff Christian , Prinz Immo , Magnus Tim , Gelderblom Mathias 
Published: June 2017

Background and Purpose—
Immune-mediated tissue damage after stroke evolves within the first days, and lymphocytes contribute to the secondary injury. Our goal was to identify T-cell subpopulations, which trigger the immune response.

Methods—
In a model of experimental stroke, we analyzed the immune phenotype of interleukin-17 (IL-17)–producing γδ T cells and explored the therapeutic potential of neutralizing anti-IL-17 antibodies in combination with mild therapeutic hypothermia.

Results—

We show that brain-infiltrating IL-17–positive γδ T cells expressed the Vγ6 segment of the γδ T cells receptor and were largely positive for the chemokine receptor CCR6 (CC chemokine receptor 6), which is a characteristic for natural IL-17–producing γδ T cells. These innate lymphocytes are established as major initial IL-17 producers in acute infections. Genetic deficiency in
Ccr6
was associated with diminished infiltration of natural IL-17–producing γδ T cells and a significantly improved neurological outcome. In the ischemic brain, IL-17 together with tumor necrosis factor-α triggered the expression of CXC chemokines and neutrophil infiltration. Therapeutic targeting of synergistic IL-17 and tumor necrosis factor-α pathways by IL-17 neutralization and therapeutic hypothermia resulted in additional protective effects in comparison to an anti-IL-17 antibody treatment or therapeutic hypothermia alone.

Conclusions—
Brain-infiltrating IL-17–producing γδ T cells belong to the subset of natural IL-17–producing γδ T cells. In stroke, these previously unrecognized innate lymphocytes trigger a highly conserved immune reaction, which is known from host responses toward pathogens. We demonstrate that therapeutic approaches targeting synergistic IL-17 and tumor necrosis factor-α pathways in parallel offer additional neuroprotection in stroke.