•Surgical resection is associated with survival benefit.•Adjuvant treatment is not associated with improved overall survival.•Patients with low grade spinal cord tumors have superior overall ...survival.
Primary spinal cord tumors are rare, particularly in the adult population, and national guidelines remain ambiguous with regard to management approaches. To address this knowledge gap, we evaluated management, outcomes, and prognostic factors of these neoplasms.
The National Cancer Database was queried (2004–2016) for newly-diagnosed, histologically-confirmed WHO grades I-III astrocytomas and glioblastoma. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling.
Of 1,033 subjects, 196 (19%) were pilocytic astrocytomas (PAs), 539 (52%) were grade II/III astrocytomas, and 298 (29%) were glioblastomas (GBMs). Respectively, 11%, 30%, and 27% did not undergo resection (biopsy only). RT was delivered to 27%, 54%, and 73%; chemotherapy was given to 5%, 21%, and 37%, respectively. The median OS was not reached for PAs, but was 101.2 months for grade II/III astrocytomas, and 23.9 months for GBMs (p < 0.001). Neither chemotherapy nor RT (or dose thereof) was associated with increased OS for grade II/III astrocytomas (p > 0.05 for all), though there was a trend toward improved OS with the use of chemotherapy for patients with GBM. Surgical resection was associated with improved OS for grade II/III astrocytomas and GBM (p < 0.05). Independent prognostic factors for survival in this cohort included histologic classification and resection (compared to biopsy only) (p < 0.05 for both).
This study sheds light onto the management of these rare tumors; surgery was associated with OS benefit for patients with GBM and Grade II/III astrocytomas. Neither RT nor chemotherapy were associated with OS benefit. Although not implying causation, these data can be used to guide patient counseling and therapeutic approaches.
Purpose
This is the largest study to date evaluating response rates and pathologic complete response (pCR) and predictors thereof, based on molecular subtype, in women with breast cancer having ...undergone neoadjuvant chemotherapy (NC).
Methods
The National Cancer Database was queried for women with cT1-4N1-3M0 breast cancer having received NC. Patients were divided into four subtypes: luminal A, luminal B, Her2, or triple negative (TN). Multivariable logistic regression ascertained factors associated with developing pCR. Kaplan–Meier analysis evaluated overall survival (OS) between patients by degree of response to NC when stratifying patients by subtype.
Results
Of a total of 13,939 women, 322 (2%) were luminal A, 5941 (43%) luminal B, 2274 (16%) Her2, and 5402 (39%) TN. Overall, 19% of all patients achieved pCR, the lowest in luminal A (0.3%) and the highest in Her2 (38.7%). Molecular subtype was an independent predictor of both pCR and OS in this population. Clinical downstaging was associated with improved survival, mostly in women with luminal B, Her2, and TN subtypes. Subgroup analysis of the pCR population demonstrated 5-year OS in the luminal B, Her2, and TN cohorts of 93.0, 94.2, and 90.6%, respectively (Her2 vs. TN,
p
= 0.016).
Conclusions
Assessing nearly 14,000 women from a contemporary United States database, this is the largest known study examining the relationship between response to NC and molecular subtype. Women with luminal A disease are the least likely to undergo pCR, with the highest rates in Her2 disease. Degree of response is associated with OS, especially in luminal B, Her2, and TN patients. Despite the comparatively higher likelihood of achieving pCR in TN cases, this subgroup may still experience a survival detriment, which has implications for an ongoing national randomized trial.
Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due ...to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes and metabolic syndrome, impairments in insulin signaling disrupting entry of glucose into the adipocytes, and skeletal muscle cells. Although the exact underlying cause of IR has not been fully elucidated, a number of major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. In this review, we consider the role these cellular mechanisms play in the development of IR.
Autophagy is a lysosomal degradation process and protective housekeeping mechanism to eliminate damaged organelles, long-lived misfolded proteins and invading pathogens. Autophagy functions to ...recycle building blocks and energy for cellular renovation and homeostasis, allowing cells to adapt to stress. Modulation of autophagy is a potential therapeutic target for a diverse range of diseases, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. Traditionally, food deprivation and calorie restriction (CR) have been considered to slow aging and increase longevity. Since autophagy inhibition attenuates the anti-aging effects of CR, it has been proposed that autophagy plays a substantive role in CR-mediated longevity. Among several stress stimuli inducers of autophagy, fasting and CR are the most potent non-genetic autophagy stimulators, and lack the undesirable side effects associated with alternative interventions. Despite the importance of autophagy, the evidence connecting fasting or CR with autophagy promotion has not previously been reviewed. Therefore, our objective was to weigh the evidence relating the effect of CR or fasting on autophagy promotion. We conclude that both fasting and CR have a role in the upregulation of autophagy, the evidence overwhelmingly suggesting that autophagy is induced in a wide variety of tissues and organs in response to food deprivation.
Aims/hypothesis We sought to establish the extent and basis for adaptive changes in beta cell numbers in human pregnancy. Methods Pancreas was obtained at autopsy from women who had died while ...pregnant (n = 18), post-partum (n = 6) or were not pregnant at or shortly before death (controls; n = 20). Pancreases were evaluated for fractional pancreatic beta cell area, islet size and islet fraction of beta cells, beta cell replication (Ki67) and apoptosis (TUNEL), and indirect markers of beta cell neogenesis (insulin-positive cells in ducts and scattered beta cells in pancreas). Results The pancreatic fractional beta cell area was increased by ∼1.4-fold in human pregnancy, with no change in mean beta cell size. In pregnancy there were more small islets rather than an increase in islet size or beta cells per islet. No increase in beta cell replication or change in beta cell apoptosis was detected, but duct cells positive for insulin and scattered beta cells were increased with pregnancy. Conclusions/interpretation The adaptive increase in beta cell numbers in human pregnancy is not as great as in most reports in rodents. This increase in humans is achieved by increased numbers of beta cells in apparently new small islets, rather than duplication of beta cells in existing islets, which is characteristic of pregnancy in rodents.
Accurate predictions of crop yield are critical for developing effective agricultural and food policies at the regional and global scales. We evaluated a machine-learning method, Random Forests (RF), ...for its ability to predict crop yield responses to climate and biophysical variables at global and regional scales in wheat, maize, and potato in comparison with multiple linear regressions (MLR) serving as a benchmark. We used crop yield data from various sources and regions for model training and testing: 1) gridded global wheat grain yield, 2) maize grain yield from US counties over thirty years, and 3) potato tuber and maize silage yield from the northeastern seaboard region. RF was found highly capable of predicting crop yields and outperformed MLR benchmarks in all performance statistics that were compared. For example, the root mean square errors (RMSE) ranged between 6 and 14% of the average observed yield with RF models in all test cases whereas these values ranged from 14% to 49% for MLR models. Our results show that RF is an effective and versatile machine-learning method for crop yield predictions at regional and global scales for its high accuracy and precision, ease of use, and utility in data analysis. RF may result in a loss of accuracy when predicting the extreme ends or responses beyond the boundaries of the training data.
The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the ...dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.
Exosomes are nano-sized membranous vesicles that are secreted by cells. They have an important role in transferring proteins, mRNA, miRNA and other bioactive molecules between cells and regulate gene ...expression in recipient cells. Therefore, exosomes are a mechanism by which communication between cells is achieved and they are involved in a wide range of physiological processes, especially those requiring cell–cell communication. In the cardiovascular system, exosomes are associated with endothelial cells, cardiac myocytes, vascular cells, stem and progenitor cells, and play an essential role in development, injury and disease of the cardiovascular system. In recent years, accumulating evidence implicates exosomes in the development and progression of cardiovascular disease. Additionally, exosomal microRNAs are considered to be key players in cardiac regeneration and confer cardioprotective and regenerative properties on both cardiac and non-cardiac cells and, additionally, stem and progenitor cells. Notably, miRNAs may be isolated from blood and offer a potential source of novel diagnostic and prognostic biomarkers for cardiovascular disease. In this review, we summarize and assess the functional roles of exosomes in cardiovascular physiology, cell-to-cell communication and cardio-protective effects in cardiovascular disease.
The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory cell population called the neural ...crest, a complete enteric nervous system is necessary for proper gut function. Disorders that arise as a consequence of defective neural crest cell development are termed neurocristopathies. One such disorder is Hirschsprung disease (HSCR), also known as congenital megacolon or intestinal aganglionosis. HSCR occurs in 1/5000 live births and typically presents with the inability to pass meconium, along with abdominal distension and discomfort that usually requires surgical resection of the aganglionic bowel. This disorder is characterized by a congenital absence of neurons in a portion of the intestinal tract, usually the distal colon, because of a disruption of normal neural crest cell migration, proliferation, differentiation, survival, and/or apoptosis. The inheritance of HSCR disease is complex, often non-Mendelian, and characterized by variable penetrance. Extensive research has identified a number of key genes that regulate neural crest cell development in the pathogenesis of HSCR including RET , GDNF , GFRα1 , NRTN , EDNRB , ET3 , ZFHX1B , PHOX2b , SOX10 , and SHH . However, mutations in these genes account for only ∼50% of the known cases of HSCR. Thus, other genetic mutations and combinations of genetic mutations and modifiers likely contribute to the etiology and pathogenesis of HSCR. The aims of this review are to summarize the HSCR phenotype, diagnosis, and treatment options; to discuss the major genetic causes and the mechanisms by which they disrupt normal enteric neural crest cell development; and to explore new pathways that may contribute to HSCR pathogenesis.
Abstract The Milky Way dust extinction curve in the near-infrared (NIR) follows a power-law form, but the value of the slope, β NIR , is debated. Systematic variations in the slope of the Milky Way ...UV extinction curve are known to be correlated with variations in the optical slope (through R V ), but whether such a dependence extends to the NIR is unclear. Finally, because of low dust column densities, the NIR extinction law is poorly understood at high Galactic latitudes where most extragalactic work takes place. In this paper, we construct extinction curves from 56,649 stars with Sloan Digital Sky Survey (SDSS) and Two Micron All Sky Survey photometry, based on stellar parameters from SDSS spectra. We use dust maps to identify dust-free stars, from which we calibrate the relation between stellar parameters and intrinsic colors. Furthermore, to probe the low-dust regime at high latitudes, we use aggregate curves based on many stars. We find no systematic variation of β NIR across low-to-moderate dust columns (0.02 < E ( B − V ) ≲ 1), and report average β NIR = 1.85 ± 0.01, in agreement with the law in the 2019 Fitzpatrick et al. study, but steeper than the Cardelli et al. and 1999 Fitzpatrick laws. Star-to-star scatter in β NIR is relatively small (σ( β NIR ) = 0.13). We also find no intrinsic correlation between β NIR and R V (there is an apparent correlation that is the result of the correlated uncertainties in the two values). These results hold for typical sightlines; we do not probe very dusty regions near the Galactic Center, nor rare sightlines with R V > 4. Finally, we find R H = 0.345 ± 0.007 and comment on its bearing on Cepheid calibrations and the determination of H 0 .
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