bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of somatic mutations identifies signs of selection during in vitro aging of primary dermal fibroblasts
Authors: Narisu Narisu , Rothwell Rebecca , Vrtačnik Peter , Rodríguez Sofía , Didion John , Zöllner Sebastian , Erdos Michael R. , Collins Francis S. , Eriksson Maria 
Published: August 2019

AbstractSomatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson–Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre‐ and post‐expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging‐related genes. Allele frequencies of 58 somatic mutations differed between the pre‐ and post‐cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
Long‐term repopulation of aged bone marrow stem cells using young Sca‐1 cells promotes aged heart rejuvenation
Authors: Li Jiao , Li Shu‐Hong , Dong Jun , Alibhai Faisal J. , Zhang Chongyu , Shao Zheng‐Bo , Song Hui‐Fang , He Sheng , Yin Wen‐Juan , Wu Jun , Weisel Richard D. , Liu Shi‐Ming , Li Ren‐Ke 
Published: August 2019

AbstractReduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca‐1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca‐1+ or Sca‐1− cells from young (2–3 months) or aged (18–19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca‐1+, young Sca‐1−, old Sca‐1+, and old Sca‐1−. Four months later, expression of rejuvenation‐related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase‐related protein (DNA‐PKcs, TRF‐2) expression, whereas expression of senescence‐related genes (p16INK4a, P19ARF, p27Kip1) and proteins (p16INK4a, p27Kip1) was decreased in Sca‐1+ chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP−CD31+) but not cardiomyocytes were the primary cell type rejuvenated by young Sca‐1+ cells as shown by improved proliferation, migration, and tubular formation abilities. C‐X‐C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP+) cells isolated from young Sca‐1+ chimeric hearts. Protein expression of Cxcr4, phospho‐Akt, and phospho‐FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca‐1+ group. Reconstitution of aged BM with young Sca‐1+ cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells.
Effects of Alcohol and Acetate on Cerebral Blood Flow: A Pilot Study
Authors: Tanabe Jody , Yamamoto Dorothy J. , Sutton Brianne , Brown Mark S. , Hoffman Paula L. , Burnham Ellen L. , Glueck Deborah H. , Tabakoff Boris 
Published: August 2019

BackgroundAcute alcohol produces effects on cerebral metabolism and blood flow. Alcohol is converted to acetate, which serves as a source of energy for the brain and is an agonist at G protein‐coupled receptors distributed in different cell types in the body including neurons. Acetate has been hypothesized to play a role in the cerebral blood flow (CBF) response after alcohol ingestion. We tested whether administration of acetate would alter CBF in a pattern similar to or different from that of alcohol ingestion in healthy individuals.MethodsTwenty‐four healthy participants were assigned by convenience to receive either 0.6 g/kg alcohol orally (n = 12) or acetate intravenously (n = 12). For each participant, CBF maps were acquired using an arterial spin labeling sequence on a 3T magnetic resonance scanner after placebo and after drug administration. Whole‐brain CBF maps were compared between placebo and drug using a paired t‐test, and set at a threshold of p < 0.05 corrected for multiple comparisons (k ≥ 142 voxels, ≥3.78 cm3), voxel‐level p < 0.005. Intoxication was measured after placebo and drug administration with a Subjective High Assessment Scale (SHAS‐7).ResultsCompared to placebo, alcohol and acetate were associated with increased CBF in the medial thalamus. Alcohol, but not acetate, was associated with increased CBF in the right orbitofrontal, medial prefrontal and cingulate cortex, and hippocampus. Plasma acetate levels increased following administration of alcohol and acetate and did not differ between the 2 arms. Alcohol, but not acetate, was associated with an increase in SHAS‐7 scores (p < 0.001).ConclusionsIncreased thalamic CBF associated with either alcohol or acetate administration suggests that the thalamic CBF response after alcohol could be mediated by acetate. Compared to other brain regions, thalamus may differ in its ability to metabolize acetate or expression of receptors responsive to acetate. Increased prefrontal and limbic CBF associated with alcohol may be linked to alcohol's behavioral effects.
Human airway epithelial extracellular vesicle miRNA signature is altered upon asthma development
Authors: Bartel Sabine , La Grutta Stefania , Cilluffo Giovanna , Perconti Giovanni , Bongiovanni Antonella , Giallongo Agata , Behrends Jochen , Kruppa Jochen , Hermann Stefanie , Chiang Dapi , Pfaffl Michael W. , Krauss‐Etschmann Susanne 
Published: August 2019

AbstractBackgroundmiRNAs are master regulators of signaling pathways critically involved in asthma and are transferred between cells in extracellular vesicles (EV). We aimed to investigate whether the miRNA content of EV secreted by primary normal human bronchial epithelial cells (NHBE) is altered upon asthma development.MethodsNHBE cells were cultured at air‐liquid interface and treated with interleukin (IL)‐13 to induce an asthma‐like phenotype. EV isolations by precipitation from basal culture medium or apical surface wash were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blot, and EV‐associated miRNAs were identified by a RT‐qPCR‐based profiling. Significant candidates were confirmed in EVs isolated by size‐exclusion chromatography from nasal lavages of children with mild‐to‐moderate (n = 8) or severe asthma (n = 9), and healthy controls (n = 9).ResultsNHBE cells secrete EVs to the apical and basal side. 47 miRNAs were expressed in EVs and 16 thereof were significantly altered in basal EV upon IL‐13 treatment. Expression of miRNAs could be confirmed in EVs from human nasal lavages. Of note, levels of miR‐92b, miR‐210, and miR‐34a significantly correlated with lung function parameters in children (FEV1FVC%pred and FEF25‐75%pred), thus lower sEV‐miRNA levels in nasal lavages associated with airway obstruction. Subsequent ingenuity pathway analysis predicted the miRNAs to regulate Th2 polarization and dendritic cell maturation.ConclusionOur data indicate that secretion of miRNAs in EVs from the airway epithelium, in particular miR‐34a, miR‐92b, and miR‐210, might be involved in the early development of a Th2 response in the airways and asthma.
Preoperative intraocular pressure as a strong predictive factor for intraocular pressure rise during vacuum application in femtosecond laser‐assisted cataract surgery
Authors: Mariacher Siegfried , Laubichler Peter , Wendelstein Jascha , Mariacher Martina , Bolz Matthias 
Published: August 2019

AbstractPurposeTo evaluate the effect of preoperative intraocular pressure (IOP) and the vacuum level on IOP during femtosecond laser‐assisted cataract surgery.MethodsIntraocular pressure was measured in 40 enucleated porcine eyes by intracameral manometry prior, during and after vacuum application using the VICTUS femtosecond laser platform (Bausch&Lomb, Technolas Perfect Vision GmbH, Germany). Twenty combinations of different preoperative IOP levels (12, 16, 20 and 24 mmHg) and different vacuum levels (350–550 mbar) were investigated.ResultsMultivariate regression analysis indicated that both the vacuum level (beta = 0.138; p < 0.001) but much stronger the preoperative IOP (beta = 0.861; p < 0.001) were predictive factors for IOP rise during vacuum application. Mean IOP was 28.23 ± 3.86, 34.23 ± 3.92, 40.35 ± 4.41 and 46.82 ± 4.11 mmHg in groups with baseline IOP of 12, 16, 20 and 24 mmHg, respectively. In the 350, 450 and 550 mbar group, and mean IOP was 35.85 ± 7.85, 37.33 ± 7.90 and 39.00 ± 8.04 mmHg, respectively. Lowering the preoperative IOP by 2 mmHg and reducing the vacuum from maximum to minimum resulted in a similar reduction in IOP during vacuum application (−3.10 ± 0.79 mmHg versus −3.15 ± 0.88 mmHg; p = 0.015). Furthermore, decreasing the baseline IOP from 20 to 12 mmHg resulted in a 30.0% reduction in intraoperative IOP.ConclusionPreoperative IOP was a stronger predictive factor for intraoperative IOP rise than the applied vacuum level. Measurements and critical interpretation of preoperative IOP in a preliminary examination could help estimating the individual risk of significant IOP rise during femtosecond laser‐assisted cataract surgery and could help taking early countermeasures in selected cases. Due to the porcine ex vivo model, further studies are needed to verify these findings.
Cyclodialysis: an updated approach to surgical strategies
Authors: Selvan Harathy , Gupta Viney , Gupta Shikha 
Published: August 2019

AbstractCyclodialysis is a rare occurrence and is difficult to treat, it being concealed behind the iris. In view of the varied success outcomes of the different available surgical repair techniques, there is at present no clear consensus regarding their management strategies. Through this article, we intend to appraise the established surgical methods, update the novel techniques in vogue, discuss their outcomes and propose a uniform system to codify these corrective techniques. They have been reclassified under the terms ‘exocyclopexy’, ‘endocyclopexy’, ‘exocyclotamponade’ and ‘endocyclotamponade’ based on the approach used and their mode of action. The ab‐interno techniques (endocyclopexy and endocyclotamponade) are easier to perform, offer good success rates and better safety profiles such that they may be considered as a viable alternative to the standard exocyclopexy in either cataractous or pseudophakic and aphakic eyes.
Unsupervised breastfeeding was related to sudden unexpected postnatal collapse during early skin‐to‐skin contact in cerebral palsy cases
Authors: Miyazawa Tokuo , Itabashi Kazuo , Tamura Masanori , Suzuki Hideaki , Ikenoue Tsuyomu ,   Prevention Recurrence Committee, Japan Obstetric Compensation System for Cerebral Palsy
Published: August 2019

AbstractAimThis study aimed to identify the clinical features of infants who were healthy at birth, but developed sudden unexpected collapse and were then diagnosed with cerebral palsy before 5 years of age.MethodsWe retrospectively analysed 1182 records from the no‐fault Japan Obstetric Compensation System for Cerebral Palsy database up to 2016. This identified 45 subjects (3.8%) who were subsequently diagnosed with severe cerebral palsy due to sudden unexpected postnatal collapse (SUPC). They were all healthy at birth, based on the criteria of five‐minute Apgar scores of seven or more, with normal umbilical cord blood gases and no need for neonatal resuscitation within five minutes of birth.ResultsThe median birth weight of the 45 subjects (26 males) was 2770 g (range 2006‐3695 g). Of these, 10 developed SUPC during early skin‐to‐skin contact (SSC). Medical personnel were not present in all 10 cases: nine were being breastfed at the time and eight of the mothers did not notice their infant's abnormal condition until medical staff alerted them.ConclusionThis national study of children with cerebral palsy who appeared healthy at birth found that unsupervised breastfeeding was a common factor in cases of SUPC during early SSC.
Minimal residual disease monitoring in early stage follicular lymphoma can predict prognosis and drive treatment with rituximab after radiotherapy
Authors: Pulsoni Alessandro , Della Starza Irene , Cappelli Luca V. , Tosti Maria E. , Annechini Giorgia , Cavalli Marzia , De Novi Lucia A. , D’Elia Gianna M. , Grapulin Lavinia , Guarini Anna , Del Giudice Ilaria , Foà Robin 
Published: August 2019

SummarySince 2000, we have investigated 67 consecutive patients with stage I/II follicular lymphoma (FL) for the presence of BCL2/IGH rearrangements by polymerase chain reaction (PCR), real time quantitative PCR (RQ‐PCR) and digital droplet PCR (ddPCR). All patients were treated with involved‐field radiotherapy (IF‐RT) (24–30 Gy). From 2005, patients with minimal residual disease (MRD) after IF‐RT received rituximab (R) (375 mg/m2, 4 weekly administrations). The median follow‐up is 82 months (17–196). At diagnosis, 72% of patients were BCL2/IGH+. Progression‐free survival (PFS) was significantly better in patients with undetectable/low levels (<10−5) of circulating BCL2/IGH+ cells at diagnosis and in those who were persistently MRD− during follow‐up (P = 0·0038). IF‐RT induced an MRD− status in 50% of cases; 16/19 (84%) MRD+ patients after IF‐RT became MRD− after R treatment. A significantly longer PFS was observed in MRD+ patients treated with R compared to untreated MRD+ patients (P = 0·049). In early stage FL, both circulating levels of BCL2/IGH+ cells at diagnosis and MRD status during follow‐up bear prognostic implications. Standard IF‐RT fails to induce an MRD‐negative status in half of patients. Most patients become MRD− following treatment with R and this is associated with a significantly better PFS.
Development of a prognostic model for overall survival in multiple myeloma using the Connect® MM Patient Registry
Authors: Terebelo Howard R. , Abonour Rafat , Gasparetto Cristina J. , Toomey Kathleen , Durie Brian G. M. , Hardin James W. , Jagannath Sundar , Wagner Lynne , Narang Mohit , Flick E. Dawn , Srinivasan Shankar , Yue Lihua , Kitali Amani , Agarwal Amit , Rifkin Robert M. ,   on behalf of the CONNECT MM Registry Investigators
Published: August 2019

SummaryMedian overall survival (OS) has improved for patients with newly diagnosed multiple myeloma (NDMM), but prognosis varies depending on baseline patient characteristics. Current models use data from selected clinical trial populations, which prevent application to patients in an unselected community setting that reflects routine clinical practice. Using data from the Connect® MM Registry, a large, US, multicentre, prospective observational cohort study (Cohort 1: 2009–2011; Cohort 2: 2012–2016) of 3011 patients with NDMM, we identified prognostic variables for OS via the multivariable analysis of baseline patient characteristics in Cohort 1 (n = 1493) and developed a tool to examine individual outcomes. Factors associated with OS (n = 1450 treated patients; P < 0·05) were age, del(17p), triplet therapy use, EQ‐5D mobility, International Staging System stage, solitary plasmacytoma, history of diabetes, platelet count, Eastern Cooperative Oncology Group performance status and serum creatinine, which were used to create survival matrices for 3‐ and 5‐year OS. The model was internally and externally validated using Connect MM Cohort 2 (Harrell's concordance index, 0·698), MM‐015 (0·649), and the phase 3 FIRST (0·647) clinical trials. This novel prognostic tool may help inform outcomes for NDMM in the era of triplet therapy use with novel agents.
Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer
Authors: Miyake Makito , Hori Shunta , Ohnishi Sayuri , Toritsuka Michihiro , Fujii Tomomi , Shimizu Takuto , Owari Takuya , Morizawa Yosuke , Gotoh Daisuke , Itami Yoshitaka , Nakai Yasushi , Anai Satoshi , Torimoto Kazumasa , Tanaka Nobumichi , Fujimoto Kiyohide 
Published: August 2019

AbstractDespite advances and refinements in surgery and perioperative chemotherapy, there are still unmet medical needs with respect to radical cystectomy for muscle‐invasive bladder cancer (MIBC). We investigated the potential benefit of supplementary granulocyte macrophage colony‐stimulating factor (GM‐CSF) to chemoimmunotherapy with programmed cell death protein‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis blockade and standard neoadjuvant chemotherapy in bladder cancer. We inoculated 2 × 105 MBT2 cells s.c. in C3H mice to create a syngeneic animal model of local recurrence (LR). When the tumor diameter reached 12 mm, the mice were allocated randomly as follows: (i) non‐treated control (vehicle only); (ii) anti‐mPD‐L1 monotherapy; (iii) mGM‐CSF monotherapy; (iv) anti‐mPD‐L1 plus mGM‐CSF; (v) gemcitabine and cisplatin (GC); (vi) GC plus anti‐mPD‐L1; (vii) GC plus mGM‐CSF; and (viii) GC plus anti‐mPD‐L1 plus mGM‐CSF. After completing 2‐week neoadjuvant therapy, tumors were resected for resection margin evaluation and immunohistochemical staining and blood was collected for flow cytometry and ELISA. Operative wounds were sutured, and the operative site was monitored to detect LR. Addition of anti‐mPD‐L1 and mGM‐CSF to neoadjuvant GC chemotherapy enhanced the antitumor effect and reduced positive resection margins (50% vs 12.5%). Combination of GC, anti‐mPD‐L1, and mGM‐CSF resulted in longer LR‐free survival and cancer‐specific survival compared to those in other groups. These effects involved an immunotherapy‐related decrease in oncological properties such as tumor invasion capacity and epithelial‐mesenchymal transition. mGM‐CSF significantly decreased the accumulation of myeloid‐derived suppressor cells in both the blood and tumor microenvironment and blood interleukin‐6 levels. Supplementary GM‐CSF to neoadjuvant GC plus PD‐L1 blockade could decrease LR after radical surgery by immune modulation in the blood and tumor microenvironment.
Comprehensive immune characterization and T‐cell receptor repertoire heterogeneity of retroperitoneal liposarcoma
Authors: Yan Liang , Wang Zhen , Cui Can , Guan Xiaoya , Dong Bin , Zhao Min , Wu Jianhui , Tian Xiuyun , Hao Chunyi 
Published: August 2019

AbstractRetroperitoneal liposarcoma (RLPS) is one of the most common subtypes of retroperitoneal soft tissue sarcomas and lacks effective treatment. This study aimed to provide a thorough profile of immune characteristics of RLPS. This study included 56 RLPS patients. Multisite tumor tissues were collected from 16 patients. Immunohistochemistry was carried out to identify CD4+, CD8+, FoxP3+, CD20+, or programmed cell death‐1 (PD‐1)+ tumor infiltrating lymphocytes (TILs) and Programmed cell death ligand‐1 (PD‐L1) expression in tumor tissues. Ultradeep sequencing of T‐cell receptor (TCR) β‐chain gene was carried out in 42 tumor samples as well as peripheral blood samples collected from 6 patients. In RLPS, TILs were distributed in 3 patterns and T cells were more prevalent than B cells. Generally, the proportion of TILs decreased and PD‐L1 expression increased with tumor progression. Patients with higher PD‐1/PD‐L1 expression tended to have poorer prognosis, whereas patients with tertiary lymphoid structure tended to have a favorable disease‐free survival. Although T‐cell clones in tumors were quite different from those in peripheral blood, TCR sequencing showed low TCR repertoire reads as well as polyclonal status within tumors, which indicated limited T cell response in the tumors. Both TILs distribution and TCR repertoires suggested spatial immune heterogeneity in RLPS. Our research described the immune landscape of RLPS, and suggested RLPS might be a kind of tumor with low T cell infiltration as well as great immune heterogeneity. Therefore, strategies that can facilitate lymphocytic infiltration and immune reactivity need to be developed in the future to improve the efficacy of immunotherapy.
In vivo selection reveals autophagy promotes adaptation of metastatic ovarian cancer cells to abdominal microenvironment
Authors: Kuo Chih‐Lin , Jiang Zhe‐Yu , Wang Ying‐Wen , Lin Ting‐Yu , Huang Wei‐Lin , Wu Fang‐Ju , Luo Ching‐Wei 
Published: August 2019

AbstractPeritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV‐3. Microarray and gene profiling analyses indicated that autophagy‐related genes were enriched in selected malignant sublines. Detection of LC3‐II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high‐density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy‐related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti–autophagy cancer drugs.