STUDY DESIGN.Retrospective chart analysis of 199 individuals aged 18–80 years scheduled for lumbar spine surgery.
OBJECTIVE.The purpose of this study was to quantify changes in muscle cross sectional ...area (CSA) and fat signal fraction (FSF) with age in men and women with lumbar spine pathology and compare them to published normative data.
SUMMARY OF BACKGROUND DATA.Pathological changes in lumbar paraspinal muscle are often confounded by age-related decline in muscle size (CSA) and quality (fatty infiltration). Individuals with pathology have been shown to have decreased CSA and fatty infiltration of both the multifidus and erector spinae muscles, but the magnitude of these changes in the context of normal aging is unknown.
METHODS.Individuals aged 18–80 years who were scheduled for lumbar surgery for diagnoses associated with lumbar spine pain or pathology were included. Muscle CSA and FSF of the multifidus and erector spinae were measured from preoperative T2-weighted magnetic resonance images at the L4 level. Univariate and multiple linear regression analyses were performed for each outcome using age and gender as predictor variables. Statistical comparisons of univariate regression parameters (slope and intercept) to published normative data were also performed.
RESULTS.There was no change in CSA with age in either gender (p > 0.05), but women had lower CSAʼs than men in both muscles (p < 0.0001). There was an increase in FSF with age in erector spinae and multifidus muscles in both genders (p < 0.0001). Multifidus FSF values were higher in women with lumbar spine pathology than published values for healthy controls (p = 0.03), and slopes tended to be steeper with pathology for both muscles in women (p < 0.08) but not in men (p > 0.31).
CONCLUSIONS.Lumbar muscle fat content, but not CSA changes with age in individuals with pathology. In women, this increase is more profound than age-related increases in healthy individuals.Level of Evidence3
Genome-scale CRISPR-Cas9 viability screens performed in cancer cell lines provide a systematic approach to identify cancer dependencies and new therapeutic targets. As multiple large-scale screens ...become available, a formal assessment of the reproducibility of these experiments becomes necessary. We analyze data from recently published pan-cancer CRISPR-Cas9 screens performed at the Broad and Sanger Institutes. Despite significant differences in experimental protocols and reagents, we find that the screen results are highly concordant across multiple metrics with both common and specific dependencies jointly identified across the two studies. Furthermore, robust biomarkers of gene dependency found in one data set are recovered in the other. Through further analysis and replication experiments at each institute, we show that batch effects are driven principally by two key experimental parameters: the reagent library and the assay length. These results indicate that the Broad and Sanger CRISPR-Cas9 viability screens yield robust and reproducible findings.
During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient
. Previous case reports and small case ...series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance
. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.
Corrosion tests were performed in steam and supercritical water at 500°C for two ferritic–martensitic alloys: HCM12A and NF616. The corrosion kinetics for the two alloys are similar in both ...environments showing near cubic behavior, but the corrosion rate was significantly higher in supercritical water than in steam. Examinations of the oxide layers using scanning electron microscopy and microbeam synchrotron diffraction and fluorescence show that both alloys form two-layer oxide structures in either environment. The outer layer contains only Fe3O4, while the inner layer contains a mixture of Fe3O4 and FeCr2O4. Additionally, marker experiments using a novel photolithographic deposition process show that the original water–metal interface corresponds with the outer–inner layer interface as expected. The results are discussed in light of known corrosion mechanisms.
1 Department of Cardiology, Children's Hospital Boston, and Department of Genetics, Harvard Medical School, Boston;
2 Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical ...School, Boston, and the Broad Institute of Harvard and MIT, Cambridge, Massachusetts;
3 Department of Cardiology and Pneumology, Georg August University, Göttingen, Germany;
4 Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
5 Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, and Howard Hughes Medical Institute, Chevy Chase, Maryland
ABSTRACT
MicroRNAs are recently discovered regulators of gene expression and are becoming increasingly recognized as important regulators of heart function. Genome-wide profiling of microRNAs in human heart failure has not been reported previously. We measured expression of 428 microRNAs in 67 human left ventricular samples belonging to control ( n = 10), ischemic cardiomyopathy (ICM, n = 19), dilated cardiomyopathy (DCM, n = 25), or aortic stenosis (AS, n = 13) diagnostic groups. miRNA expression between disease and control groups was compared by ANOVA with Dunnett's post hoc test. We controlled for multiple testing by estimating the false discovery rate. Out of 428 microRNAs measured, 87 were confidently detected; 43 were differentially expressed in at least one disease group. In supervised clustering, microRNA expression profiles correctly grouped samples by their clinical diagnosis, indicating that microRNA expression profiles are distinct between diagnostic groups. This was further supported by class prediction approaches, in which the class (control, ICM, DCM, AS) predicted by a microRNA-based classifier matched the clinical diagnosis 69% of the time ( P < 0.001). These data show that expression of many microRNAs is altered in heart disease and that different types of heart disease are associated with distinct changes in microRNA expression. These data will guide further studies of the contribution of microRNAs to heart disease pathogenesis.
heart failure; gene expression; expression profiling
Review of the literature.
To summarize current cost and clinical efficacy data in minimally invasive spine (MIS) surgery.
Cost effectiveness (CE), using cost per quality-adjusted life-years gained, ...has been shown for lumbar discectomy, decompressive laminectomy, and for instrumented and noninstrumented lumbar fusions in several high-quality studies using conventional, open surgical procedures. Currently, comparisons of costs and clinical outcomes of MIS surgery to open (or nonoperative) approaches are rare and of lesser quality, but suggest that a potential for cost benefits exist using less-invasive surgical approaches.
A literature review was performed using the database of the National Center for Biotechnology Information (NCBI), PUBMED/Medline.
Reports of clinical results of MIS approaches are far more common than economic evaluations. MIS techniques can be classified as endoscopic or nonendoscopic. Although endoscopic approaches decrease some approach morbidities, the high cost of instrumentation, steep learning curves, and new complication profiles introduced have prevented widespread adoption. Additionally, the high costs have not been shown to be justified by superior clinical benefits. Nonendoscopic MIS approaches, such as percutaneous posterior or lateral, and mini-open lateral and anterior approaches, use direct visualization, standard operative techniques, and report lower complication rates, reduced length of stay, and faster recovery time. For newer MIS and mini-open techniques, significantly lower acute and subacute costs were observed compared with open techniques, mainly due to lower rates of complications, shorter length of stay, and less blood loss, as well as fewer discharges to rehab. Although this suggests that certain MIS procedures produce early cost benefits, the quality of the existing data are low.
Although the CE of MIS surgery is yet to be carefully studied, the few economic studies that do exist suggest that MIS has the potential to be a cost-effective intervention, but only if improved clinical outcomes are maintained (durable). Longer follow-up and better outcome and cost data are needed to determine if incremental CE exists with MIS techniques, versus open or nonsurgical interventions.
Infertility and subfertility are important and pervasive reproductive problems in both domestic animals and humans. The majority of embryonic loss occurs during the first three weeks of pregnancy in ...cattle and women due, in part, to inadequate endometrial receptivity for support of embryo implantation. To identify heifers of contrasting fertility, serial rounds of artificial insemination (AI) were conducted in 201 synchronized crossbred beef heifers. The heifers were then fertility classified based on number of pregnancies detected on day 35 in four AI opportunities. Heifers, classified as having high fertility, subfertility or infertility, were selected for further study. The fertility-classified heifers were superovulated and flushed, and the recovered embryos were graded and then transferred to synchronized recipients. Quantity of embryos recovered per flush, embryo quality, and subsequent recipient pregnancy rates did not differ by fertility classification. Two in vivo-produced bovine embryos (stage 4 or 5, grade 1 or 2) were then transferred into each heifer on day 7 post-estrus. Pregnancy rates were greater in high fertility than lower fertility heifers when heifers were used as embryo recipients. The reproductive tracts of the classified heifers were obtained on day 14 of the estrous cycle. No obvious morphological differences in reproductive tract structures and histology of the uterus were observed in the heifers. Microarray analysis revealed differences in the endometrial transcriptome based on fertility classification. A genome-wide association study, based on SNP genotyping, detected 7 moderate associations with fertility across 6 different chromosomes. Collectively, these studies support the idea that innate differences in uterine function underlie fertility and early pregnancy loss in ruminants. Cattle with defined early pregnancy success or loss is useful to elucidate the complex biological and genetic mechanisms governing endometrial receptivity and uterine competency for pregnancy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Lumbar spine pathology is a common feature of lower back and/or lower extremity pain and is associated with observable degenerative changes in the lumbar paraspinal muscles that ...are associated with poor clinical prognosis. Despite the commonly observed phenotype of muscle degeneration in this patient population, its underlying molecular mechanisms are not well understood. The aim of this study was to investigate the relationships between groups of genes within the atrophic, myogenic, fibrogenic, adipogenic, and inflammatory pathways and multifidus muscle health in individuals undergoing surgery for lumbar spine pathology.
Methods
Multifidus muscle biopsies were obtained from patients (
n
= 59) undergoing surgery for lumbar spine pathology to analyze 42 genes from relevant adipogenic/metabolic, atrophic, fibrogenic, inflammatory, and myogenic gene pathways using quantitative polymerase chain reaction. Multifidus muscle morphology was examined preoperatively in these patients at the level and side of biopsy using T2-weighted magnetic resonance imaging to determine whole muscle compartment area, lean muscle area, fat cross-sectional areas, and proportion of fat within the muscle compartment. These measures were used to investigate the relationships between gene expression patterns and muscle size and quality.
Results
Relationships between gene expression and imaging revealed significant associations between decreased expression of adipogenic/metabolic gene (PPARD), increased expression of fibrogenic gene (COL3A1), and lower fat fraction on MRI (
r
= -0.346,
p
= 0.018, and
r
= 0.386,
p
= 0.047 respectively). Decreased expression of myogenic gene (mTOR) was related to greater lean muscle cross-sectional area (
r
= 0.388,
p
= 0.045).
Conclusion
Fibrogenic and adipogenic/metabolic genes were related to pre-operative muscle quality, and myogenic genes were related to pre-operative muscle size. These findings provide insight into molecular pathways associated with muscle health in the presence of lumbar spine pathology, establishing a foundation for future research that addresses how these changes impact outcomes in this patient population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to ...characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Continuous Al2O3 scales were developed at low temperatures and short exposure time.•Intrinsic chemical failure of Al leads to the recession of protective Al2O3 layer.•Carburization leads to the ...deposition of carbon and deterioration of oxide scale.
Microstructure characterization of corrosion behavior of an alumina forming austenitic (AFA) steel exposed to supercritical carbon dioxide was conducted at 450–650°C and 20MPa. At low temperature and short exposure times, the oxidation kinetics were parabolic and the oxide scales were mainly composed of protective and continuous Al2O3 and (Cr, Mn)-rich oxide layers. As the temperature and exposure time increased, the AFA steel gradually suffered breakaway oxidation and its oxide scales showed a multilayer structure mainly composed of Fe3O4, (Cr, Fe)3O4, NiFe/FeCr2O4/Cr2O3/Al2O3, FeCr2O4/Al2O3, and NiFe/Cr2O3/Al2O3, in sequence. The corrosion mechanism based on the microstructure evolution is discussed in detail.
PDF
