bluuebunny/crossref_metadata_2025 huggingface dataset:
Was South Georgia covered by an ice cap during the Last Glacial Maximum?
Authors: White Duanne A. , Bennike Ole , Melles Martin , Berg Sonja , Binnie Steven A.
Published: June 2017

The behaviour of ice caps and glaciers on sub-Antarctic islands during previous periods of warming provide key empirical evidence for understanding the behaviour of marine ice sheets in the future. However, the extent of ice on sub-Antarctic islands during the last 100 kyr is poorly constrained. Here, we investigate the past glacial extents on South Georgia, where previous Last Glacial Maximum (LGM) reconstructions vary between small fjord-terminating glaciers and a large marine-based ice sheet. To help resolve this uncertainty, we apply Schmidt hammer relative-age dating to measure rock hardness and, thus, exposure age of a range of glacial deposits. Applying a hardness–age calibration curve constructed from well-dated Holocene, late-glacial deposits and terminal LGM deposits, we determine that deglaciation of the approximately 600 m-high peaks on the outer Lewin Peninsula occurred during the latter half of the last glacial stage, and probably the end of the LGM. We infer that South Georgia was covered by a marine-based ice cap during the latter part of the last glacial stage.
Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder
Authors: Langdale Christopher L. , Hokanson James A. , Sridhar Arun , Grill Warren M.
Published: June 2017

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2. PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.
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.
Perspectives on classical controversies about the motor cortex
Authors: Omrani Mohsen , Kaufman Matthew T. , Hatsopoulos Nicholas G. , Cheney Paul D.
Published: June 2017

Primary motor cortex has been studied for more than a century, yet a consensus on its functional contribution to movement control is still out of reach. In particular, there remains controversy as to the level of control produced by motor cortex (“low-level” movement dynamics vs. “high-level” movement kinematics) and the role of sensory feedback. In this review, we present different perspectives on the two following questions: What does activity in motor cortex reflect? and How do planned motor commands interact with incoming sensory feedback during movement? The four authors each present their independent views on how they think the primary motor cortex (M1) controls movement. At the end, we present a dialogue in which the authors synthesize their views and suggest possibilities for moving the field forward. While there is not yet a consensus on the role of M1 or sensory feedback in the control of upper limb movements, such dialogues are essential to take us closer to one.
Mitochondria and Reactive Oxygen Species Contribute to Neurogenic Hypertension
Authors: Chan Samuel H.H. , Chan Julie Y.H.
Published: June 2017

Beyond its primary role as fuel generators, mitochondria are engaged in a variety of cellular processes, including redox homeostasis. Mitochondrial dysfunction, therefore, may have a profound impact on high-energy-demanding organs such as the brain. Here, we review the roles of mitochondrial biogenesis and bioenergetics, and their associated signaling in cellular redox homeostasis, and illustrate their contributions to the oxidative stress-related neural mechanism of hypertension, focusing on specific brain areas that are involved in the generation or modulation of sympathetic outflows to the cardiovascular system. We also highlight future challenges of research on mitochondrial physiology and pathophysiology.
Modeling Physiological Events in 2D vs. 3D Cell Culture
Authors: Duval Kayla , Grover Hannah , Han Li-Hsin , Mou Yongchao , Pegoraro Adrian F. , Fredberg Jeffery , Chen Zi
Published: June 2017

Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two-dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research.
Orthogonal Symmetries and Reflections in Banach Spaces
Authors: Jaballah Ali , Saidi Fathi B.
Published: June 2017

Let X be a Banach space. We introduce a concept of orthogonal symmetry and reflection in X. We then establish its relation with the concept of best approximation and investigate its implication on the shape of the unit ball of the Banach space X by considering sections over subspaces. The results are then applied to the space C(I) of continuous functions on a compact set I. We obtain some nontrivial symmetries of the unit ball of C(I). We also show that, under natural symmetry conditions, every odd function is orthogonal to every even function in X. We conclude with some suggestions for further investigations.
Attractors for a Class of Abstract Evolution Equations with Fading Memory
Authors: Wang Xuan , Duan Fenxia , Hu Didi
Published: June 2017

In this paper, we study the dynamics of an abstract evolution equation with fading memory with a critical growing nonlinearity. By use of some new methods and asymptotic estimate techniques, we first verify the asymptotic compact of solution semigroup and then prove the existence of global attractors in weak topological space and strong topological space, while the forcing term only belongs to H−1(Ω) or L2(Ω), respectively. The results are new and appear to be optimal.
Design of 0.8–2.7 GHz High Power Class-F Harmonic-Tuned Power Amplifier with Parasitic Compensation Circuit
Authors: Cheng Zhiqun , Xuan Xuefei , Ke Huajie , Liu Guohua , Dong Zhihua , Gao Steven
Published: June 2017

The design, implementation, and measurements of a high efficiency and high power wideband GaN HEMT power amplifier are presented. Package parasitic effect is reduced significantly by a novel compensation circuit design to improve the accuracy of impedance matching. An improved structure is proposed based on the traditional Class-F structure with all even harmonics and the third harmonic effectively controlled, respectively. Also the stepped-impedance matching method is applied to the third harmonic control network, which has a positive effect on the expansion bandwidth. CGH40025F power transistor is utilized to build the power amplifier working at 0.8 to 2.7 GHz, with the measured saturated output power 20–50 W, drain efficiency 52%–76%, and gain level above 10 dB. The second and the third harmonic suppression levels are maintained at −16 to −36 dBc and −16 to −33 dBc, respectively. The simulation and the measurement results of the proposed power amplifier show good consistency.
Geometric Mappings under the Perturbed Extension Operators in Complex Systems Analysis
Authors: Wang Chaojun , Cui Yanyan , Liu Hao
Published: June 2017

In this paper, we mainly seek conditions on which the geometric properties of subclasses of biholomorphic mappings remain unchanged under the perturbed Roper-Suffridge extension operators. Firstly we generalize the Roper-Suffridge operator on Bergman-Hartogs domains. Secondly, applying the analytical characteristics and growth results of subclasses of biholomorphic mappings, we conclude that the generalized Roper-Suffridge operators preserve the geometric properties of strong and almost spiral-like mappings of typeβand orderα,SΩ⁎(β,A,B)as well as almost spiral-like mappings of typeβand orderαunder different conditions on Bergman-Hartogs domains. Sequentially we obtain the conclusions on the unit ballBnand for some special cases. The conclusions include and promote some known results and provide new approaches to construct biholomorphic mappings which have special geometric characteristics in several complex variables.
P-Rex1 Expression in Invasive Breast Cancer in relation to Receptor Status and Distant Metastatic Site
Authors: Marotti Jonathan D. , Muller Kristen E. , Tafe Laura J. , Demidenko Eugene , Miller Todd W.
Published: June 2017

Background. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) has been implicated in cancer growth, metastasis, and response to phosphatidylinositol 3-kinase (PI3K) inhibitor therapy. The aim of this study was to determine whether P-Rex1 expression differs between primary and metastatic human breast tumors and between breast cancer subtypes. Design. P-Rex1 expression was measured in 133 specimens by immunohistochemistry: 40 and 42 primary breast tumors from patients who did versus did not develop metastasis, respectively, and 51 breast-derived tumors from metastatic sites (36 of which had matching primary tumors available for analysis). Results. Primary breast tumors showed significant differences in P-Rex1 expression based on receptor subtype. ER+ and HER2+ primary tumors showed higher P-Rex1 expression than primary triple-negative tumors. HER2+ metastases from all sites showed significantly higher P-Rex1 expression compared to other metastatic receptor subtypes. Solid organ (i.e., brain, lung, and liver) metastases showed higher P-Rex1 expression compared to bone metastases. Conclusions. P-Rex1 expression is increased in ER+ and HER2+ breast cancers compared to triple-negative tumors. P-Rex1 may be differentially expressed in metastatic tumors based on site and receptor status. The role of P-Rex1 in the development of breast cancer metastases and as a predictive biomarker of therapeutic response warrants further investigation.
Thermodynamics of Lithium Intercalation in Randomly Oriented High Graphene Carbon
Authors: Kadam Rahul S. , Gadkaree Kishor P.
Published: June 2017

This paper covers details of systematic investigation of the thermodynamics (entropy and enthalpy) of intercalation associated with lithium ion in a structurally novel carbon, called Randomly Oriented High Graphene (ROHG) carbon and graphite. Equilibrated OCV (Open Circuit Voltage) versus temperature relationship is investigated to determine the thermodynamic changes with the lithium intercalation. ROHG carbon shows entropy of 9.36 J·mol−1·K−1and shows no dependency on the inserted lithium concentration. Graphite shows initial entropy of 84.27 J·mol−1·K−1and shows a strong dependence on lithium concentration. ROHG carbon (from −90.85 kJ mol−1to −2.88 kJ mol−1) shows gradual change in the slope of enthalpy versus lithium ion concentration plot compared to graphite (−48.98 kJ mol−1to 1.84 kJ mol−1). The study clearly shows that a lower amount of energy is required for the lithium ion intercalation into the ROHG structure compared to graphite structure. Randomly oriented graphene platelet cluster structure of ROHG carbon makes it easier for the intercalation or deintercalation of lithium ion. The ease of intercalation and the small cluster structure of ROHG as opposed to the long linear platelet structure of graphite lead to higher rates of the charge-discharge process for ROHG, when used as an electrode material in electrochemical applications.
Finite Element Model for Linear Elastic Thick Shells Using Gradient Recovery Method
Authors: Feumo Achille Germain , Nzengwa Robert , Nkongho Anyi Joseph
Published: June 2017

This research purposed a new family of finite elements for spherical thick shell based on Nzengwa‐Tagne’s model proposed in 1999. The model referred to hereafter as N‐T model contains the classical Kirchhoff‐Love (K‐L) kinematic with additional terms related to the third fundamental form governing strain energy. Transverse shear stresses are computed and C0 finite element is proposed for numerical implementation. However, using straight line triangular elements does not guarantee a correct computation of stress across common edges of adjacent elements because of gradient jumps. The gradient recovery method known as Polynomial Preserving Recovery (PPR) is used for local interpolation and applied on a hemisphere under diametrically opposite charges. A good agreement of convergence results is observed; numerical results are compared to other results obtained with the classical K‐L thin shell theory. Moreover, simulation on increasing values of the ratio of the shell shows impact of the N‐T model especially on transverse stresses because of the significant energy contribution due to the third fundamental form tensor present in the kinematics of this model. The analysis of the thickness ratio shows difference between the classical K‐L theory and N‐T model when the ratio is greater than 0.099.
Molecular Identification ofMycobacteriumSpecies of Public Health and Veterinary Importance from Cattle in the South State of México
Authors: Zaragoza Bastida Adrian , Rivero Pérez Nallely , Valladares Carranza Benjamín , Isaac-Olivé Keila , Moreno Pérez Pablo , Sandoval Trujillo Horacio , Ramírez Durán Ninfa
Published: June 2017

Mycobacteriumgenus causes a variety of zoonotic diseases. The best known example is the zoonotic tuberculosis due toM. bovis. Much less is known about “nontuberculous mycobacteria (NTM),” which are also associated with infections in humans. The Mexican standard NOM-ZOO-031-1995 regulates the presence ofM. bovisin cattle; however, no regulation exists for the NTM species. The objective of this study was to isolate and identify nontuberculous mycobacteria species from cattle of local herds in the south region of the State of Mexico through the identification and detection of the 100 bp molecular marker in the 23S rRNA gene with subsequent sequencing of the 16S rRNA gene. Milk samples (35) and nasal exudate samples (68) were collected. From the 108 strains isolated, 39 were selected for identification. Thirteen strains isolated from nasal exudates amplified the 100 bp molecular marker and were identified asM. neoaurum(six strains),M. parafortuitum(four strains),M. moriokaense(two strains), andM. confluentis(one strain). ExceptM. parafortuitum, the other species identified are of public health and veterinary concern because they are pathogenic to humans, especially those with underlying medical conditions.
Finite Element Solution of an Unsteady MHD Flow through Porous Medium between Two Parallel Flat Plates
Authors: Sa’adAldin AbdelLatif , Qatanani Naji
Published: June 2017

Finite element solution of unsteady magnetohydrodynamics (MHD) flow of an electrically conducting, incompressible viscous fluid past through porous medium between two parallel plates is presented in the presence of a transverse magnetic field and Hall effect. The results obtained from some test cases are then compared with previous published work using the finite difference method (FDM). Numerical examples show that the finite element method (FEM) gives more accurate results in comparison with the finite difference method (FDM).
Environmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies
Authors: Mandolesi Laura , Gelfo Francesca , Serra Laura , Montuori Simone , Polverino Arianna , Curcio Giuseppe , Sorrentino Giuseppe
Published: June 2017

We do not all grow older in the same way. Some individuals have a cognitive decline earlier and faster than others who are older in years but cerebrally younger. This is particularly easy to verify in people who have maintained regular physical activity and healthy and cognitively stimulating lifestyle and even in the clinical field. There are patients with advanced neurodegeneration, such as Alzheimer’s disease (AD), that, despite this, have mild cognitive impairment. What determines this interindividual difference? Certainly, it cannot be the result of only genetic factors. We are made in a certain manner and what we do acts on our brain. In fact, our genetic basis can be modulated, modified, and changed by our experiences such as education and life events; daily, by sleep schedules and habits; or also by dietary elements. And this can be seen as true even if our experiences are indirectly driven by our genetic basis. In this paper, we will review some current scientific research on how our experiences are able to modulate the structural organization of the brain and how a healthy lifestyle (regular physical activity, correct sleep hygiene, and healthy diet) appears to positively affect cognitive reserve.
Huanglian‐Jie‐Du‐Tang Extract Ameliorates Depression‐Like Behaviors through BDNF‐TrkB‐CREB Pathway in Rats with Chronic Unpredictable Stress
Authors: Ye Yi-Lu , Zhong Kai , Liu Dan-Dan , Xu Jing , Pan Bei-Bei , Li Xiang , Yu Yue-Ping , Zhang Qi
Published: June 2017

Neuroinflammation is considered as one of the common pathogeneses of depression. Huanglian‐Jie‐Du‐Tang (HJDT) is a traditional Chinese herbal formula. The present study investigates the antidepressant‐like effect of HJDT and its possible mechanism in rats. Rats were given HJDT (2, 4, and 8 g/kg, intragastrically), paroxetine (1.8 mg/kg, intragastrically), or an equivalent volume of saline for 42 days. The depression‐related behaviors, including sucrose preference test (SPT), open field test (OFT), novel objective recognition task (NORT), and forced swimming test (FST), were detected. 5‐Hydroxytryptamine (5‐HT) and dopamine (DA) contents, microglial activation, proinflammatory cytokines, and brain derived neurotrophic factor (BDNF), tropomyosin receptor kinases B (TrkB), and cAMP‐responsive element binding protein (CREB) expression were investigated. The results indicated HJDT (2 and 4 g/kg) dramatically ameliorated the depression‐like behaviors. Also HJDT decreased the number of microglia and the proinflammatory cytokines in hippocampus. Western‐blotting analysis displayed HJDT upregulated BDNF, TrkB, and pCREB/CREB expression in hippocampus. Particularly, pCREB DNA activity enhanced with HJDT treatment in hippocampus. But there was no difference in the 5‐HT and DA contents with HJDT treatment. In conclusion, it was supposed that HJDT might be a potential Chinese medicine decoction for treating or alleviating complex symptoms of depression through BDNF‐TrkB‐CREB pathway.
The Controversial C5a Receptor C5aR2: Its Role in Health and Disease
Authors: Zhang Ting , Garstka Malgorzata A. , Li Ke
Published: June 2017

After the discovery of the C5a receptor C5aR1, C5aR2 is the second receptor found to bind C5a and its des-arginine form. As a heptahelical G protein-coupled receptor but devoid of the intracellular Gαsignal, C5aR2 is special and confusing. Ramifications and controversies about C5aR2 are under debate since its identification, from putative ligands and cellular localization to intracellular signals and pathological roles in inflammation and immunity. The ruleless and even conflicting pro- or anti-inflammatory role of C5aR2 in animal models of diverse diseases makes one bewildered. This review summarizes reports on C5aR2, tries to clear up available evidence on these four controversial aspects, and delineates C5aR2 function(s). It also summarizes available toolboxes for C5aR2 study.
Economic Burden Analysis of Parkinson’s Disease Patients in China
Authors: Yang Jun-Xiu , Chen Lei
Published: June 2017

Background and Objective. Parkinson’s Disease (PD) is a progressive neurodegenerative disorder, which is prevalent in people over 65 years old. PD reduces patients’ quality of life and exerts a heavy economic burden on patients and their families. The purpose of this research is to identify the costs of PD and to evaluate the economic distribution of medical care for PD patients in China. Methods. A professional survey was administered to 116 patients with PD. Records of medical cost were reviewed. Direct and indirect costs were analyzed. The main cost-driving factors of PD were identified using multivariate regression analysis. Results. The average annual cost per PD patient in China is $3,225.94, with direct and indirect costs accounting for $2,503.46 and $722.48, respectively. Direct costs consist of $556.27 for surgery, $44.67 for appointment fees, $605.67 for prescription medication, $460.29 for hospitalization, $71.03 for auxiliary examination, $35.64 for transportation, $10.39 for special equipment, and $719.50 for formal care. The total cost is closely related to surgical treatment, dopamine agonist, and levodopa costs. Conclusion. The cost of PD patients in China is considerable and exceeds average economic capacity, especially antiparkinson medication and caring costs. This study may provide a reference for PD healthcare optimization in the future.
Coexpression Analysis of Transcriptome on AIDS and Other Human Disease Pathways by Canonical Correlation Analysis
Authors: Chen Yahong , Yuan Jinjin , Han Xianlin , Liu Xiaolong , Han Xiao , Ye Hanhui
Published: June 2017

Acquired immune deficiency syndrome is a severe disease in humans caused by human immunodeficiency virus. Several human genes were characterized as host genetic factors that impact the processes of AIDS disease. Recent studies on AIDS patients revealed a series disease is complicating with AIDS. To resolve gene interaction between AIDS and complicating diseases, a canonical correlation analysis was used to identify the global correlation between AIDS and other disease pathway genes expression. The results showed that HLA-B, HLA-A, MH9, ZNED1, IRF1, TLR8, TSG101, NCOR2, and GML are the key AIDS-restricted genes highly correlated with other disease pathway genes. Furthermore, pathway genes in several diseases such as asthma, autoimmune thyroid disease, and malaria were globally correlated with ARGs. It suggests that these diseases are a high risk in AIDS patients as complicating diseases.
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

Solid 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

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

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

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

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 < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 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 < 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

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 < 0.05) or fluorescence imaging of 2-NBDG (P < 0.05) and proflavine (P < 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

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

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.
Androgen Receptor Expression in an Indian Breast Cancer Cohort with Relation to Molecular Subtypes and Response to Neoadjuvant Chemotherapy - a Prospective Clinical Study
Authors: Anand Akshay , Singh Kul R. , Kumar Surender , Husain Nuzhat , Kushwaha Jitendra K. , Sonkar Abhinav A.
Published: June 2017

Background: Breast cancer (BC) is associated with advanced presentation in developing countries like India due to various socio-economic factors. The presence of BC molecular subtypes such as the triple-negative (TN) subtype adds to this menace. Androgen receptor (AR) is emerging as a new biological marker. The aim of this study was to examine the prevalence of AR with relation to different BC subtypes, and its role in predicting response to neoadjuvant chemotherapy. Methods: 116 cases of invasive BC (infiltrating ductal carcinoma, not otherwise specified) were evaluated. AR expression was correlated with clinicopathological factors, established prognostic markers, BC subtypes and it ability for predicting response to neoadjuvant chemotherapy. Results: AR was expressed in 56% of the cases. AR expression was significantly associated with early stage (p < 0.03), low axillary burden (p < 0.04), estrogen receptor (p = 0.002), progesterone receptor (p = 0.001) expression and luminal A molecular subtype. No significant association was observed with age, tumor size and HER2/neu status. One-third of TNBC cases expressed AR. Higher AR expression corelated to good clinical response to neoadjuvant chemotherapy. Conclusion: AR can be utilized as a predictor of response to neoadjuvant chemotherapy especially in developing countries such as India where the load of advanced disease is high.
Pregnant and Breastfeeding Women: Drinking for Two?
Authors: Bardosono Saptawati , Morin Clémentine , Guelinckx Isabelle , Pohan Rizki
Published: June 2017

The primary aim of this cross-sectional survey was to assess the total fluid intake (TFI; sum of drinking water and all other fluids) and the intake of water and all other types of beverages in a sample of pregnant and breastfeeding women representative of Java-Island, Indonesia. Therefore, 299 pregnant and 296 breastfeeding women completed a 7-day fluid-specific record. A secondary aim was to estimate the total water intake (TWI; sum of water from fluids and food moisture), and one 24-h recall was performed to determine water intake from food moisture. The median TFI of pregnant and breastfeeding women were 2,250 (1,800-2,800) and 2,360 (1,954-2,968) mL/day, respectively. The largest contributor to TFI was water (72 and 77% for pregnant/breastfeeding women, respectively). Pregnant women to the extent of 42% and 54% of breastfeeding women did not reach the adequate intake (AI) of water from fluids. In pregnant and breastfeeding women, the median water intake from foods was 592 and 613 mL/day, representing 21 and 20% of TWI. Concluding that a high proportion of the pregnant and breastfeeding subjects did not reach the AI of water from fluid, it seems important to put in place actions such as providing education materials and ensuring access to safe water. Moreover, future surveys should dedicate attention to the assessment of fluid intake and hydration status among pregnant and breastfeeding women in other countries.
The Discovery of Water Channels (Aquaporins)
Authors: Brown Dennis
Published: June 2017

The movement of water into and out of cells is a fundamental biological process that is essential for life. Such water movement not only regulates the activity of individual cells but also is responsible for the functioning of many organ systems and for maintaining whole body water balance. It had long been suspected that water movement across biological cell membranes was in some way enhanced or facilitated by pores or channels, but the search to identify these channels was long and tedious. As is often the case in science, the secret of the water channel was eventually discovered by chance in 1992 by Peter Agre and his colleagues at the Johns Hopkins University in Baltimore, who were working on red blood cell membrane proteins. This “first” water channel was originally named CHIP28 and is now known as aquaporin 1. Agre received the Nobel Prize in Chemistry in 2003 for this discovery. There are currently 13 known aquaporins in mammals, distributed in most tissues, but many more have been identified in lower organisms and in the plant kingdom. The involvement of aquaporins in processes such as urinary concentration and body fluid homeostasis, brain function, glandular secretion, skin hydration, male fertility, hearing, vision, and most important body functions that can be imagined are now all under intense scientific scrutiny. Moreover, defects in aquaporin function have been related to various disease conditions and pathological states. This brief review will discuss their background, discovery, and function in selected bodily processes, especially focusing on hydration.
Preventive and Therapeutic Proximal Sealing: A 3.5-Year Randomized Controlled Clinical Trial Follow-Up
Authors: Basili Cristian P. , Emilson Claes Göran , Corvalan Gonzalo C. , Moran Maria Paz , Torres Carlos , Quiroz Mariela D. , Gomez Santiago Sergio
Published: June 2017

Objective: The aim of this split-mouth, randomized controlled clinical trial was to evaluate the efficacy of proximal sealing for avoiding the development of new caries lesions or arresting incipient caries lesions on the mesial surface of first permanent molars (6m) abutting lesions on the distal surface of second primary molars (05d) in children at high caries risk. Methods: A total of 61 children 8-10 years old were selected based on the caries status of the proximal sites of 05d and 6m. Children with caries on 05d and caries-free 6m were placed in the preventive sealing group and children with caries on both 05d and 6m in the therapeutic group. The children in each group had one 6m surface pair and in each pair one 6m surface was randomly allocated to receive a preventive or therapeutic sealing. Using a split-mouth design, the other 6m surface in the pair served as control. Results: After 3.5 years, standardized follow-up radiographs were obtained for the 45 children who remained. In the preventive sealing group, 4 out of 30 (13.3%) sealed and 16 out of 30 (53.3%) unsealed sound 6m surfaces had developed new caries lesions (p = 0.004, McNemar test). In the therapeutic sealing group, the progression of the carious lesions on 6m was observed in 3 out of 15 sealed (20.0%) and 8 out of 15 (53.3%) unsealed caries control surfaces (p = 0.06). Conclusions: Preventive sealing on sound 6m surfaces abutting 05d lesions in children at high caries risk efficaciously prevents the development of caries lesions. Therapeutically sealing active non-cavitated caries lesions reduces the progression.