bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Pregabalin in Treatment of Polyneuropathy in Multiple Myeloma Patients: A Retrospective Study
Authors: Maschio Marta , Mengarelli Andrea , Zarabla Alessia , Giannarelli Diana , Maialetti Andrea , Gumenyuk Svetlana , Renzi Daniela , Palombi Francesca , Pisani Francesco , Romano Atelda , Spadea Antonio , Galiè Edvina , Marchesi Francesco 
Published: July 2019

Objectives
Polyneuropathy (PN) is a frequent and significant clinical manifestation of multiple myeloma that may be observed at onset of disease or induced during treatment as a therapy-related complication. Polyneuropathy may be a relevant issue in myeloma patients owing to its significant impact on the quality of life, considering that it may lead to dose reduction or treatment discontinuation. The present retrospective study intended to evaluate efficacy of pregabalin (PGB) in treatment of PN in multiple myeloma patients.

Materials and Methods
Medical charts of 108 consecutive PN myeloma patients were reviewed. Data regarding the tumor history and therapy as well as the clinical and neurophysiological examinations 6 months before and after initiation of PGB therapy were collected.

Results
Thirty-eight medical charts had all the requested information. All patients (n = 38) underwent bortezomib-based treatment; 19 were previously treated and 19 were treatment naive. At first neurologic visit, all patients had PN symptoms (grade 2 of National Cancer Institute—Common Toxicity Criteria) without relevant pain. Neurophysiological evaluation showed a significant decrease in sensory nerve action potential amplitude (P = 0.006), conduction velocity (P = 0.006), and distal latency (P = 0.03) of sensory nerves between the first and the last neurological examination, in all patient population. Similar results were observed in treatment-naive patients, when the study cohort was stratified according to previous treatment. On the contrary, no significant differences were found between the first and the last neurophysiological follow-up evaluation in previously treated patients. Six months after PGB treatment, all patients reported disappearance of neurological symptoms (grade 0 National Cancer Institute—Common Toxicity Criteria).

Conclusions
In this retrospective study, improvement in neurological symptoms during PGB therapy was observed in the total population, despite the presence of a distal, sensory axonal neuropathy, as evidenced by neurophysiological examination.
FDA oversight of NSIGHT genomic research: the need for an integrated systems approach to regulation
Authors: Milko Laura V. , Chen Flavia , Chan Kee , Brower Amy M. , Agrawal Pankaj B. , Beggs Alan H. , Berg Jonathan S. , Brenner Steven E. , Holm Ingrid A. , Koenig Barbara A. , Parad Richard B. , Powell Cynthia M. , Kingsmore Stephen F. 
Published: July 2019

ABSTRACTThe National Institutes of Health (NIH) funded the Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT) Consortium to investigate the implications, challenges and opportunities associated with the possible use of genomic sequence information in the newborn period. Following announcement of the NSIGHT awardees in 2013, the Food and Drug Administration (FDA) contacted investigators and requested that pre-submissions to investigational device exemptions (IDE) be submitted for the use of genomic sequencing under Title 21 of the Code of Federal Regulations (21 CFR) part 812. IDE regulation permits clinical investigation of medical devices that have not been approved by the FDA. To our knowledge, this marked the first time the FDA determined that NIH-funded clinical genomic research projects are subject to IDE regulation. Here we review the history of and rationale behind FDA oversight of clinical research and the NSIGHT Consortium’s experiences in navigating the IDE process. Overall, NSIGHT investigators found that FDA’s application of existing IDE regulations and medical device definitions aligned imprecisely with the aims of publicly funded exploratory clinical research protocols. IDE risk assessments by the FDA were similar to, but distinct from, protocol risk assessments conducted by local Institutional Review Boards (IRBs), and had the potential to reflect novel oversight of emerging genomic technologies. However, the pre-IDE and IDE process delayed the start of NSIGHT research studies by an average of 10 months, and significantly limited the scope of investigation in two of the four NIH approved projects. Based on the experience of the NSIGHT Consortium, we conclude that policies and practices governing the development and use of novel genomic technologies in clinical research urgently need clarification in order to mitigate potentially conflicting or redundant oversight by IRBs, NIH, FDA, and state authorities.
Association of Kras mutation with tumor deposit status and overall survival of colorectal cancer
Authors: Zhang Meifang , Hu Wenwei , Hu Kun , Lin Yong , Feng Zhaohui , Yun Jing-Ping , Gao Nan , Zhang Lanjing 
Published: July 2019

AbstractBackgroundThe recent staging manual upstages Node-negative tumor-deposit positive colorectal cancer (CRC) from N0 to N1c category, while the development of tumor-deposit presence is poorly understood. Meanwhile, Kras mutation is associated with progression of CRC, but its link to tumor-deposit status is unclear.MethodThis retrospective cohort study included the patients with incidental CRC diagnosed during 2010-2014 in the National Cancer Database and recorded statuses of Kras and tumor deposit. We conducted multivariable logistic regression and Cox regression analyses to investigate the factors associated with tumor-deposit status and overall-survival, respectively.ResultsA total of 48,200 CRC patients with Kras status were included in the study (25,407 [52.7%] men, 25,648[46.8%] <65 years old, 18 381 [38.1%] with Kras mutation). Adjusted for microsatellite instability, age, pathologic stage and tumor grade, Kras mutation (versus wild-type) was associated with tumor-deposit presence (n=15,229, odds ratio=1.11, 95% CI 1.02 to 1.20). Kras mutation was also independently linked to a worse overall survival of CRC patients regardless of tumor-deposit status (n=8,110, adjusted Hazard ratio=1.40, 95% CI 1.09 to 1.79 for CRC with tumor deposits, and n=2,618, adjusted HR=1.63, 95% CI 1.16 to 2.28 for CRC without), but a better survival in CRC with no known/applicable tumor-deposit status (n=457, adjusted Hazard ratio =0.32, 95% CI 0.11 to 0.95).ConclusionKras mutation is independently associated with tumor-deposit presence, and a worse overall survival of CRC with or without tumor-deposit. Therefore, it may play a role in the development of tumor deposits and serve as a target for CRC treatment.
HeveaDB: a genetic resource database for rubber tree genomic study
Authors: Cheng Han , Xia Yanhua , Zhou Jiannan , Tang Chaorong , Huang Huasun 
Published: July 2019

AbstractWith the proceedings in the genome study in rubber tree, more and more data were produced. However, these data are still deposited in public databases as raw format, and the utilization of these NGS data is hindered for the researchers in rubber tree community. HeveaDB was therefore constructed and maintained under the organization of International Rubber Research and Development Board. The HeveaDB 1.0 (http://hevea.catas.cn) mainly stores 4 versions of Hevea draft genome, 99 NGS transcriptomes, 18451annotated EST sequences, 12 curated gene families, 30200 gene annotations, 5049 wild germplasm phenotype data, and 18328 Wickham rubber clonal information. Several bioinformatic tools are integrated in the database to facilitate the utilization of the data for the users who are not skilled in bioinformatics. With the periodical update and functional improvement, the HeveaDB will serve as a potential platform for genomic studies and breeding technology in rubber tree.
Unexpected plasticity in the life cycle ofTrypanosoma brucei
Authors: Schuster Sarah , Subota Ines , Lisack Jaime , Zimmermann Henriette , Reuter Christian , Morriswood Brooke , Engstler Markus 
Published: July 2019

AbstractAfrican trypanosomes cause sleeping sickness in humans and nagana in cattle. These unicellular parasites are transmitted by the bloodsucking tsetse fly. In the mammalian host’s circulation, tissues, and interstitium, at least two main life cycle stages exist: slender and stumpy bloodstream stages. Proliferating slender stage cells differentiate into cell cycle-arrested stumpy stage cells at high population densities. This developmental stage transition occurs in response to the quorum sensing factor SIF (stumpy induction factor), and is thought to fulfil two main functions. First, it auto-regulates the parasite load in the host. Second, the stumpy stage is regarded as pre-adapted for tsetse fly infection and the only stage capable of successful vector transmission. Here, we show that proliferating slender stage trypanosomes are able to complete the complex life cycle in the fly as successfully as the stumpy stage, and that a single parasite is sufficient for productive infection. Our findings not only propose a revision to the traditional rigid view of the trypanosome life cycle, but also suggest a solution to a long-acknowledged paradox in the transmission event: parasitaemia in chronic infections is characteristically low, and so the probability of a tsetse ingesting a stumpy cell during a bloodmeal is also low. The finding that proliferating slender parasites are infective to tsetse flies helps shed light on this enigma.
Optical interrogation of sympathetic neuronal effects on macroscopic cardiac monolayer dynamics
Authors: Burton R.A.B. , Tomek J. , Ambrosi C.M. , Larsen H.E. , Sharkey A.R. , Capel R.A. , Bilton S. , Klimas A. , Stephens G. , Li D. , Gallone G. , Herring N. , Mann E. , Kumar A. , Kramer H. , Entcheva E. , Paterson D.J. , Bub G. 
Published: July 2019

ABSTRACTAlterations in autonomic function are known to occur in cardiac conditions including sudden cardiac death. Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias. Dissecting direct neural-cardiac interactions at the cellular level is technically challenging and understudied due to the lack of experimental model systems and methodologies. Here we demonstrate the utility of optical interrogation of sympathetic neurons and their effects on macroscopic cardiac monolayer dynamics to address research targets such as the effects of adrenergic stimulation via the release of neurotransmitters, the effect of neuronal numbers on cardiac wave behaviour and the applicability of optogenetics in mechanisticin vitrostudies. We combine photo-uncaging or optogenetic neural stimulation with imaging of cardiac monolayers to measure electrical activity in an automated fashion, illustrating the power and high throughput capability of such interrogations. The methods described highlight the challenges and benefits of co-cultures as experimental model systems.
Metabolic control of immune-competency by odors inDrosophila
Authors: Madhwal Sukanya , Shin Mingyu , Joshi Manish K , Kapoor Ankita , Ur Rehman Pirzada Mujeeb , Gor Kavan , Shim Jiwon , Mukherjee Tina 
Published: July 2019

SUMMARYDrosophilablood-progenitor cells generate an inflammatory cell-type termed lamellocyte, in response to parasitic wasp-infections. In this study we show that olfaction primes lamellocyte potential. Specifically, larval odor-detection mediated release of systemic γ-aminobutyric acid (GABA) from neurosecretory cells, is detected and internalized by blood progenitor-cells. GABA catabolism through the GABA-shunt pathway prevents Sima (HIFα) protein degradation. Sima is necessary and sufficient for lamellocyte induction. However, limited systemic GABA availability during development restricts blood-progenitor Sima levels and consequently their lamellocyte potential. PreconditioningDrosophilalarvae in odor environments mimicking parasitoid-threatened conditions raises systemic GABA and blood-progenitor Sima levels. As a result, infection responses in these animals are rapid and efficient. Overall, this study explores the importance of sensory control of myeloid-immunity and unravels the adaptive influence of environmental odor-experience on myeloid-metabolism and priming innate-immune potential.
Metal-organic framework (MOF) nanomedicine preparations of sildenafil designed for the future treatment of pulmonary arterial hypertension
Authors: Mohamed Nura A. , Saleh Haissam Abou , Kameno Yu , Marei Isra , de Nucci Gilberto , Ahmetaj-Shala Blerina , Shala Fisnik , Kirkby Nicholas S. , Jennings Lewis , Davies Robert P. , Lickiss Paul D. , Mitchell Jane A. 
Published: July 2019

AbstractPulmonary Arterial Hypertension (PAH) is an aggressive disease with poor prognosis, no available cure, and low survival rates. Currently, there are several classes of vasodilator drugs that are widely used as treatment strategies for PAH. These include (i) endothelin-1 receptor antagonists, (ii) phosphodiesterase type 5 inhibitors, (iii) prostacyclin analogues, and (iv) soluble guanylate cyclase activators. Despite their clinical benefits, these therapies are hindered by their systemic side effects. This limitation could be overcome by controlled drug release, with future modifications for targeted drug delivery, using a nanomedicine approach. In the current study, we have evaluated one particular nanomedicine platform (the highly porous iron-based metal-organic framework (MOF) commonly referred to as MIL-89) as a carrier of the PAH drug sildenafil. We have previously shown that MIL-89 is relatively non-toxic in a range of human cell types and well tolerated in vivo. Here we prepared a nano-formulation of MIL-89 (nanoMIL-89) and then successfully charged it with a payload of sildenafil (sil@nanoMIL-891). sil@nanoMIL-89 was then shown to release sildenafil in a biphasic manner with an initial rapid release over 6 hours followed by a more sustained release over 72 hours. Both nanoMIL-89 and sil@nanoMIL-89 were relatively non-toxic when incubated with human endothelial cells for 24 hours. Finally, the vasodilator effect of sil@nanoMIL-89 was measured over 8 hours using isolated mouse aorta. Consistent with drug release kinetics, sil@nanoMIL-89 induced vasodilation after a lag phase of >4 hours. Thus, in sil@nanoMIL-89, we have produced a nano-formulation of sildenafil displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of sil@nanoMIL-89, including in PAH models, is now required and constitutes the subject of ongoing investigation.
Elevated intracellular cAMP concentration mediates growth suppression in glioma cells
Authors: Safitri Dewi , Potter Harriet , Harris Matthew , Winfield Ian , Kopanitsa Liliya , Yeung Ho Yan , Svensson Fredrik , Rahman Taufiq , Harper Matthew T , Bailey David , Ladds Graham 
Published: July 2019

SUMMARYSupressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a protein kinase A (PKA)-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.
The functional organization of excitation and inhibition in the dendritic arbors of retinal direction-selective ganglion cells
Authors: Jain Varsha , Murphy-Baum Benjamin L. , deRosenroll Geoff , Sethuramanujam Santhosh , Delsey Mike , Delaney Kerry , Awatramani Gautam B. 
Published: July 2019

SUMMARYRecent studies indicate that the precise timing and location of excitation and inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How excitatory and inhibitory inputs are functionally organized at the subcellular level in intact circuits remains unclear. To address this issue, we took advantage of the retinal direction-selective ganglion cell circuit, in which directionally tuned inhibitory GABAergic input arising from starburst amacrine cells shape direction-selective dendritic responses. We combined two-photon Ca2+ imaging with genetic, pharmacological, and single-cell ablation methods to examine local E/I. We demonstrate that when active dendritic conductances are blocked, direction selectivity emerges semi-independently within unusually small dendritic segments (<10 µm). Impressively, the direction encoded by each segment is relatively homogenous throughout the ganglion cell’s dendritic tree. Together the results demonstrate a precise subcellular functional organization of excitatory and inhibitory input, which suggests that the parallel processing scheme proposed for direction encoding could be more fine-grained than previously envisioned.
Coexpression enables multi-study cellular trajectories of development and disease
Authors: Hie Brian , Cho Hyunghoon , Bryson Bryan , Berger Bonnie 
Published: July 2019

AbstractSingle-cell transcriptomic studies of diverse and complex systems are becoming ubiquitous. Algorithms now attempt to integrate patterns across these studies by removing all study-specific information, without distinguishing unwanted technical bias from relevant biological variation. Integration remains difficult when capturing biological variation that is distributed across studies, as when combining disparate temporal snapshots into a panoramic, multi-study trajectory of cellular development. Here, we show that a fundamental analytic shift to gene coexpression within clusters of cells, rather than gene expression within individual cells, balances robustness to bias with preservation of meaningful inter-study differences. We leverage this insight in Trajectorama, an algorithm which we use to unify trajectories of neuronal development and hematopoiesis across studies that each profile separate developmental stages, a highly challenging task for existing methods. Trajectorama also reveals systems-level processes relevant to disease pathogenesis within the microglial response to myelin injury. Trajectorama benefits from efficiency and scalability, processing nearly one million cells in around an hour.
GV1001 prevents ovarian follicle loss triggered by an anti-VEGF monoclonal antibody targeting non-small cell lung carcinoma xenografts in mice
Authors: Jang Dongmin , Min Churl K. , Lee Jisun , Jang Young-Ju , Kim Miran , Hwang Kyungjoo 
Published: July 2019

AbstractPremature ovarian failure (POF) that could result from chemotherapy applied to young female cancer patients is a significant challenge in reproductive biology. It is widely believed that the hyperactivation of dormant primordial follicles following chemotherapy is a leading cause of POF, but it remains unclear how therapeutic cues are generated and transduced into follicular activation. Here, we provide evidence that supports that GV1001, an immunotherapeutic peptide targeting telomerase, plays a role in the deterrence of POF in mice. In vivo non-small cell lung carcinoma (NSCLC) tumor xenografts were produced by inoculating NSCLC cells into the flank of BALB/c female athymic mice and then subjected to cancer chemotherapy with GV1001 and bevacizumab, an anti-cancer antibody drug, humanized anti-VEGF monoclonal antibody. Bevacizumab when administered at the dosage of 5 mg/kg for three weeks was effective in inhibiting growth of NSCLC tumor xenografts, and its anti-cancer efficacy was not interfered by the presence of GV1001. As expected, bevacizumab induced follicular loss by accelerating primordial follicle growth into primary or secondary follicles concomitant with a decline of serum antimullerian hormone (AMH) level and deactivation of Foxo3 signaling as evidenced by immunohistochemical and immunofluorescent assessment. However, bevacizumab-induced follicle stimulating effects were mitigated by GV1001 co-administration as evidenced by the analysis of follicular count, serum AMH level, and Foxo3a expression. From this study, we propose that a combinatorial administration of GV1001 and bevacizumab could deter POF of young female cancer patients without hampering the anti-cancer effectiveness of bevacizumab.
Electrocutaneous stimulation to the face inhibits motor evoked potentials in the hand: face-hand interactions revealed by afferent inhibition
Authors: Ramalho Bia L. , Moly Julien , Raffin Estelle , Harquel Sylvain , Farnè Alessandro , Reilly Karen T. 
Published: July 2019

AbstractReorganization of the sensorimotor cortex following amputation and other interventions has revealed large-scale plastic changes between the hand and face representations. To investigate whether hand-face interactions are also present in the normal state of the system we measured sensorimotor interactions between these two areas using an afferent inhibition transcranial magnetic stimulation (TMS) protocol in which the TMS motor evoked potential (MEP) is inhibited when it is preceded by an afferent stimulus. We hypothesized that if hand-face interactions exist in the normal state of the system then stimulation of the face would inhibit hand MEPs. In two separate experiments we delivered an electrocutaneous stimulus to either the right upper lip (Experiment 1) or right cheek (Experiment 2) and recorded muscular activity from the right first dorsal interosseous (FDI). Both lip and cheek stimulation inhibited FDI MEPs. To investigate the specificity of this effect we conducted two additional experiments in which cutaneous stimulation was applied to either the right forearm (Experiment 3) or right arm (Experiment 4). Neither forearm nor arm stimulation inhibited FDI MEPs. These data provide the first evidence for face-to-hand afferent inhibition and we suggest that the mechanisms underlying these sensorimotor interactions could contribute to face/hand interactions observed following sensorimotor reorganisation.