bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-Cell Profiles and Clinically Useful Properties of Human Mesenchymal Stem Cells of Adipose and Bone Marrow Origin
Authors: Zhou Wenyan , Lin Junxin , Zhao Kun , Jin Kaixiu , He Qiulin , Hu Yejun , Feng Gang , Cai Youzhi , Xia Chen , Liu Hua , Shen Weiliang , Hu Xueqing , Ouyang Hongwei 
Published: May 2019

Background: Mesenchymal stem cells (MSCs) can be isolated from various tissues and can present themselves as a promising cell source for cell-based therapies. Although adipose- and bone marrow–derived mesenchymal stem cells have already been used in a considerable number of clinical trials for osteoarthritis treatment, systematic analyses from single- to bulk-cell resolution as well as clinical outcomes of these 2 MSCs are still insufficient. Purpose: To explore the characteristics and differences of adipose-derived stem cells (ADSCs) and bone marrow MSCs (BMSCs) at single- and bulk-cell levels, to study the clinical outcomes of these 2 cells on the treatment of osteoarthritis, and to provide potential guidance on the more precise clinical application of these MSCs. Study Design: Controlled laboratory study and meta-analysis. Methods: Same donor–derived ADSCs and BMSCs were isolated and cultured. Single- and bulk-cell assays were used to identify the characteristics of these 2 cells. Meta-analysis of clinical trials was done to compare the clinical therapeutic effects in osteoarthritis treatment with ADSCs and BMSCs. Results: Single-cell RNA sequencing analysis showed that the population of ADSCs showed lower transcriptomic heterogeneity when compared with BMSCs. Additionally, as compared with BMSCs, ADSCs were less dependent on mitochondrial respiration for energy production. Furthermore, ADSCs had a lower expression level of human leukocyte antigen class I antigen and higher immunosuppression capacity when compared with the BMSC population. Meta-analysis of current clinical trials of osteoarthritis treatment with MSCs consistently showed that ADSCs are more stable than BMSCs in their therapeutic effect. Conclusion: These results provide basic biological insights into human ADSCs and BMSCs at the single-cell resolution. Findings indicated that ADSCs may be a more controllable stem cell source, may be more adaptable to surviving in the hypoxic articular cavity niche, and may exhibit superiority in regulating inflammation. Based on the meta-analysis results of the different characteristics of ADSCs and BMSCs, ADSCs were implicated as being a better cell source for osteoarthritis treatment. Clinical Relevance: These results guide a more precise clinical application of adipose and bone marrow mesenchymal stem cells.
Cementless Arthroprostheses: Case Result
Authors: Caniggia M. , Ferrata P. , Maniscalco P. , Bocchi L. 
Published: May 2019

The Authors analyse the cases treated with cementless hip endo- and arthroprostheses from 1983 to the present at the Orthopaedic and Traumatology Department of the University of Siena, Italy. They review, in chronological order, the cases treated with three different types of cementless hip prosthesis: the GCO, the PCA and the Omnifit prosthesis.
Congenital Hip Dislocation Relationship between Echography and Treatment: Our Experience
Authors: Albisetti W. , Carbone B. , Facchini R. , Rossetti F. , Serantoni S. 
Published: May 2019

The Authors consider that hip echography plays a fundamental role in the diagnosis of congenital hip dislocation in the perinatal age group and that this methodic provides accurate information. The absence of risk to the patient allows its utilization in the screening protocol. The aim of the research was not only to confirm echography utility in diagnosis, but also to plan and to promote its uniform use as a prognostic instrument in predicting and guiding a more accurate therapeutic approach.
Minimally Invasive Lobectomy Modality and Other Predictors of Conversion to Thoracotomy
Authors: Hendriksen Brandon S. , Hollenbeak Christopher S. , Taylor Matthew D. , Reed Michael F. 
Published: May 2019

Objective Minimally invasive approaches to lobectomy are increasing. Rates of conversion to thoracotomy are well reported but risk factors are poorly understood. This study aimed to determine the impact of surgical modality (video-assisted thoracoscopic surgery [VATS] and robotic) on conversion as well as to identify other risk factors for conversion. Methods The National Cancer Database (NCDB) was used to identify patients who underwent minimally invasive lobectomy between 2010 and 2015. Patient characteristics were compared between VATS and robotic approaches using chi-squared tests and t-tests. Logistic regression models were used to control for covariates and identify factors associated with all minimally invasive conversion, VATS conversion, and robotic conversion. Propensity score matching was used to compare conversion rates of VATS and robotic lobectomy. Results The study included 51,723 patients with lung cancer who underwent minimally invasive lobectomy (VATS or robotic). Conversion was identified in 7,109 (7.3%) operations. The odds of VATS conversions were nearly twice that of robotic conversions (OR 1.94 P < 0.0001). After controlling for VATS and robotic patient imbalances with propensity score matching, there was a 5% difference in conversion rates (14% vs. 9%, P < 0.0001). Other predictors of minimally invasive conversion included community hospitals, tumor size 4.5 cm or greater, and an increasing Charlson comorbidity index ( P < 0.03 for all). Conclusions VATS is associated with nearly twice the odds of conversion as robotic lobectomy. Identifying specific risk factors for both VATS and robotic conversions may aid in appropriate modality selection and reduction of conversions.
Choroid plexus volume after stroke
Authors: Egorova Natalia , Gottlieb Elie , Khlif Mohamed Salah , Spratt Neil J , Brodtmann Amy 
Published: May 2019

Background Cerebrospinal fluid circulation is crucial for the functioning of the brain. Aging and brain pathologies such as Alzheimer’s disease have been associated with a change in the morphology of the ventricles and the choroid plexus. Despite the evidence from animal models that the cerebrospinal fluid system plays an important role in neuroinflammation and the restoration of the brain after ischemic brain injury, little is known about changes to the choroid plexus after stroke in humans. Aims Our goal was to characterize structural choroid plexus changes poststroke. Methods We used an automatic segmentation tool to estimate the volumes of choroid plexus and lateral ventricles in stroke and control participants at three time points (at baseline, 3 and 12 months) over the first year after stroke. We assessed group differences cross-sectionally at each time point and longitudinally. For stroke participants, we specifically differentiated between ipsi- and contra-lesional volumes. Statistical analyses were conducted for each region separately and included covariates such as age, sex, total intracranial volume, and years of education. Results We observed significantly larger choroid plexus volumes in stroke participants compared to controls in both cross-sectional and longitudinal analyses. Choroid plexus volumes did not exhibit any change over the first year after stroke, with no difference between ipsi- and contra-lesional volumes. This was in contrast to the volume of lateral ventricles that we found to enlarge over time in all participants, with more accelerated expansion in stroke survivors ipsi-lesionally. Conclusions Our results suggest that chronic stages of stroke are characterized by larger choroid plexus volumes, but the enlargement likely takes place prior to or very early after the stroke incident.
Syndactyly release: a comparison of skin graft versus graftless techniques in the same patient
Authors: Wang Angela A. , Hutchinson Douglas T. 
Published: May 2019

Syndactyly release may be done by skin graft or graftless techniques. We prospectively examined bilateral syndactyly releases in the same patient at one operation. The grafted side was randomized and the contralateral side was done graftless. Fourteen patients had surgery at a mean age of 27 months (range 7–166). The mean follow-up was 52 months (range 6–111). The mean tourniquet time was 97 minutes (range 66–135) for graft and 84 minutes (55–120) for graftless. The mean finger abduction was 57° (32°–80°) for graft and 54° (38°–80°) for graftless. The mean web creep score was 1.2 (0–3) for graft and 2.1 (0–3) for graftless. The mean scar score was 1.9 (1–3) bilaterally. The mean parents’ visual analogue scale for graft cosmesis was 7.1 (5–9) and 6.2 (4.3–8) for graftless. The surgeon’s visual analogue scale for graft was 7.9 (6.4–9.5) and 6.2 (4–8.7) for graftless. The therapist’s visual analogue scale was 7.9 (6.5–10) and 6.4 (4.7–8) for graftless. Although there is a longer tourniquet time with grafting, there may be advantages in appearance and web creep. Level of evidence: II
Simple Post-Processing of Continuous Glucose Monitoring Measurements Improves Endpoints in Clinical Trials
Authors: Jensen Morten Hasselstrøm , Dethlefsen Claus , Hejlesen Ole , Vestergaard Peter 
Published: May 2019

Background: Continuous glucose monitoring (CGM) is a powerful tool to be considered both in clinical practice and clinical trials. However, CGM has been criticized for being inaccurate for many reasons including a physiological delay. This study sought to investigate the current delay issue and propose a simple post-processing procedure. Method: More than a million hours of the Dexcom G4 CGM from 472 subjects investigated in a state-of-the-art clinical trial were analyzed by time shifting the CGM measurements and comparing them to plasma glucose (PG) measurements. The resultant CGM measurements were then assessed in relation to real-world clinical research endpoints. Results: A CGM time shift of −9 minutes was optimal and reduced mean absolute relative difference (MARD) statistically significantly with 1.0% point. The MARD reduction resulted in better clinical research endpoints of hypoglycemia and postprandial glucose increments. Conclusions: The delay in CGM is still an issue. The delay in this study was identified to be 9 minutes compared to PG. With a simple post-processing approach of time shifting the CGM measurements with −9 minutes, it was possible to obtain a statistically significantly lower MARD and subsequently obtain clinical research endpoints of improved validity.
Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma
Authors: Wu Xiaosheng , Stenson Mary , Abeykoon Jithma , Nowakowski Kevin , Zhang Lianwen , Lawson Joshua , Wellik Linda , Li Ying , Krull Jordan , Wenzl Kerstin , Novak Anne J. , Ansell Stephen M. , Bishop Gail A. , Billadeau Daniel D. , Peng Kah Whye , Giles Francis , Schmitt Daniel M. , Witzig Thomas E. 
Published: May 2019

Abstract
Targeting the B-cell receptor and phosphatidylinositol 3-kinase/mTOR signaling pathways has shown meaningful, but incomplete, antitumor activity in lymphoma. Glycogen synthase kinase 3 (GSK3) α and β are 2 homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several key signaling pathways. To date, no agent targeting GSK3 has been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3β compared with normal B and T lymphocytes at the messenger RNA and protein levels. Utilizing a new GSK3 inhibitor 9-ING-41 and by genetic deletion of GSK3α and GSK3β genes using CRISPR/CAS9 knockout, GSK3 was demonstrated to be functionally important to lymphoma cell growth and proliferation. GSK3β binds to centrosomes and microtubules, and lymphoma cells treated with 9-ING-41 become arrested in mitotic prophase, supporting the notion that GSK3β is necessary for the progression of mitosis. By analyzing recently published RNA sequencing data on 234 diffuse large B-cell lymphoma patients, we found that higher expression of GSK3α or GSK3β correlates well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.
Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II
Authors: Jones Courtney L. , Stevens Brett M. , D’Alessandro Angelo , Culp-Hill Rachel , Reisz Julie A. , Pei Shanshan , Gustafson Annika , Khan Nabilah , DeGregori James , Pollyea Daniel A. , Jordan Craig T. 
Published: May 2019

Abstract
We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.
Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies
Authors: Bodelon Clara , Ambatipudi Srikant , Dugué Pierre-Antoine , Johansson Annelie , Sampson Joshua N. , Hicks Belynda , Karlins Eric , Hutchinson Amy , Cuenin Cyrille , Chajès Veronique , Southey Melissa C. , Romieu Isabelle , Giles Graham G. , English Dallas , Polidoro Silvia , Assumma Manuela , Baglietto Laura , Vineis Paolo , Severi Gianluca , Herceg Zdenko , Flanagan James M. , Milne Roger L. , Garcia-Closas Montserrat 
Published: May 2019

Abstract

Background
Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.

Methods
We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/−), and time since blood collection (< 5, 5–10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.

Results
The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).

Conclusions
Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.
Interpreting Randomized Clinical Trials in Gynecologic Oncology Surgery: Does One Size Fit All?
Authors: Cantrell Leigh A. , Pfisterer Jacobus , Boggess John , Duska Linda R. 
Published: May 2019

Randomized clinical trials (RCTs) are considered the gold standard of clinical research. They are designed to eliminate bias and to produce objective and generalizable results about new treatment paradigms. Although RCTs have recognized limitations, including long completion time and high cost, they also have transformed clinical research and improved the quality of health care by rigorously evaluating countless new treatment options. Surgical RCTs present their own unique set of limitations including an inability to standardize surgical technique and expertise; an inability to overcome enrollment bias by enrolling surgeons; and a lack of generalizability with respect to institutional resources and abilities. Here, we discuss surgical RCTs in two domains: upfront management of advanced ovarian cancer and surgical management of early-stage cervical cancer. Familiarity with the abundant retrospective data available for both of these clinical scenarios as well as recognition of the strengths and limitations of surgical RCTs are critical to determine the best treatment for an individual patient.
Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results
Authors: Sharma Padmanee , Siefker-Radtke Arlene , de Braud Filippo , Basso Umberto , Calvo Emiliano , Bono Petri , Morse Michael A. , Ascierto Paolo A. , Lopez-Martin Jose , Brossart Peter , Rohrberg Kristoffer , Mellado Begoña , Fischer Bruce S. , Meadows-Shropshire Stephanie , Abdel Saci  , Callahan Margaret K. , Rosenberg Jonathan 
Published: May 2019

PURPOSE CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts. METHODS Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response. RESULTS Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms. CONCLUSION With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.
Prevalence of Isoelectric Electroencephalography Events in Infants and Young Children Undergoing General Anesthesia
Authors: Yuan Ian , Landis William P. , Topjian Alexis A. , Abend Nicholas S. , Lang Shih-Shan , Huh Jimmy W. , Kirschen Matthew P. , Mensinger Janell L. , Zhang Bingqing , Kurth Charles D. 
Published: May 2019

BACKGROUND:In infants and young children, anesthetic dosing is based on population pharmacokinetics and patient hemodynamics not on patient-specific brain activity. Electroencephalography (EEG) provides insight into brain activity during anesthesia. The primary goal of this prospective observational pilot study was to assess the prevalence of isoelectric EEG events—a sign of deep anesthesia—in infants and young children undergoing general anesthesia using sevoflurane or propofol infusion for maintenance.METHODS:Children 0–37 months of age requiring general anesthesia for surgery excluding cardiac, intracranial, and emergency cases were enrolled by age: 0–3, 4–6, 7–12, 13–18, and 19–37 months. Anesthesia was maintained with sevoflurane or propofol infusion. EEG was recorded from induction to extubation. Isoelectric EEG events (amplitude <20 µV, lasting ≥2 seconds) were characterized by occurrence, number, duration, and percent of isoelectric EEG time over anesthetic time. Associations with patient demographics, anesthetic, and surgical factors were determined.RESULTS:Isoelectric events were observed in 63% (32/51) (95% confidence interval [CI], 49–76) of patients. The median (interquartile range [IQR]) number of isoelectric events per patient was 3 (0–31), cumulative isoelectric time per patient was 12 seconds (0–142 seconds), isoelectric time per event was 3 seconds (0–4 seconds), and percent of total isoelectric over anesthetic time was 0.1% (0%–2.2%). The greatest proportion of isoelectric events occurred between induction and incision. Isoelectric events were associated with higher American Society of Anesthesiologists (ASA) physical status, propofol bolus, endotracheal tube use, and lower arterial pressure during surgical phase.CONCLUSIONS:Isoelectric EEG events were common in infants and young children undergoing sevoflurane or propofol anesthesia. Although the clinical significance of these events remains uncertain, they suggest that dosing based on population pharmacokinetics and patient hemodynamics is often associated with unnecessary deep anesthesia during surgical procedures.