Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a ...fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; 33, 51, 9, 28, 17, 41, respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.
Dementia currently affects 50 million people globally with this expected to triple by 2050. Even though hearing loss is associated with cognitive decline, the underlying mechanisms are not fully ...understood. Considering hearing loss is the largest modifiable risk factor for developing dementia, it is essential to study the effect of hearing aids on cognitive function.
To systematically review the existing literature to examine the evidence for using hearing aids intervention as a treatment for deteriorating cognitive function.
A search of PubMed, Cochrane Library, Embase and grey literature was conducted revealing 3060 unique records between 1990-2020. Two reviewers independently selected longitudinal studies observing the effects of hearing aids on cognitive function in persons without dementia at onset of the study. Due to the heterogeneity of the data, a meta-analysis could not be performed. Outcomes are described in a summary of findings table and portrayed diagrammatically.
We identified 17 unique studies, spanning 30 years of research and 3526 participants. The included studies made use of 50 different cognitive function tests. These tests were grouped into separate cognitive domains according to the DSM-V classification for further analysis. The most beneficial impact of hearing aids seems to be in the cognitive domain of executive function, with six studies showing improvement, two studies being inconclusive and three studies not demonstrating a significant effect. Three of five studies demonstrated significant improvement when screening for brief mental status. The least beneficial impact is seen in domain of complex attention, with eight studies showing no significant effects, compared with one demonstrating improvement with intervention.
Based on this systematic review, we conclude that there is controversy about the effects of hearing aids on cognition. Additional research through randomized clinical trials with standardized cognitive assessment and longer follow-up is warranted to further elucidate this relationship.
Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) ...profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
Background The inability of surgeons to identify parathyroid glands accurately during cervical endocrine surgery hinders patients from achieving postoperative normocalcemia. An intrinsic, ...near-infrared fluorescence method was developed for real-time parathyroid identification with high accuracy. This study assesses the clinical utility of this approach. Methods Autofluorescence measurements were obtained from 137 patients (264 parathyroid glands) undergoing parathyroidectomy and/or thyroidectomy. Measurements were correlated to disease state, calcium levels, parathyroid hormone, vitamin D levels, age, sex, ethnicity, and body mass index. Statistical analysis identified which factors affect parathyroid detection. Results High parathyroid fluorescence was detected consistently and showed wide variability across patients. Near-infrared fluorescence was used to identify 256 of 264 (97%) of glands correctly. The technique showed high accuracy over a wide variety of disease states, although patients with secondary hyperparathyroidism demonstrated confounding results. Analysis revealed body mass index ( P < .01), disease state ( P < .01), vitamin D ( P < .05), and calcium levels ( P < .05) account greatly for variability in signal intensity. Age, sex, parathyroid hormone, and ethnicity had no effect. Conclusion This intrinsic fluorescence-based intraoperative technique can detect nearly all parathyroid glands accurately in real time. Its discrimination capacity is largely unlimited by patient variables, but several factors affect signal intensity. These results demonstrate potential clinical utility of optical guidance for parathyroid detection.
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we ...demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.
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•MYC and MCL1 increase cancer stem cells in chemotherapy-resistant TNBC•MYC and MCL1 cooperatively promote mtOXPHOS, which in turn induces HIF-1α•MCL1 induces CSCs independent of its BH3-dependent, anti-apoptotic function•Inhibition of HIF1-α abolishes CSC enrichment in chemotherapy-resistant TNBC
MYC and MCL1 are co-amplified in drug-resistant breast cancer. Lee et al. reveal that MYC and MCL1 cooperate to maintain cancer stem cells (CSCs) resistant to chemotherapy by increasing mitochondrial OXPHOS, ROS production, and HIF-1α expression. Inhibition of HIF-1α blocks CSC expansion and restores chemotherapy sensitivity.
The 2019 coronavirus disease (COVID-19) has not appeared to affect children as severely as adults. However, approximately 1 month after the COVID-19 peak in New York City in April 2020, cases of ...children with prolonged fevers abruptly developing inflammatory shock-like states have been reported in Western Europe and the United States.
This case series describes four previously healthy children with COVID-19 infection confirmed by serologic antibody testing, but negative by nasopharyngeal RT-PCR swab, presenting to the Pediatric Emergency Department (PED) with prolonged fever (5 or more days) and abrupt onset of hemodynamic instability with elevated serologic inflammatory markers and cytokine levels (IL-6, IL-8 and TNF-α).
Emergency physicians must maintain a high clinical suspicion for this COVID-19 associated post-infectious cytokine release syndrome, with features that overlap with Kawasaki Disease (KD) and Toxic Shock Syndrome (TSS) in children with recent or current COVID-19 infection, as patients can decompensate quickly.
•COVID-19 post-infectious cytokine release syndrome is a novel disease in children.•This syndrome has similar features as Kawasaki Disease and Toxic Shock Syndrome.•Features include prolonged fever, gastrointestinal symptoms with or without rash..•These patients decompensate quickly and require admission to monitor for stability
Growth hormone (GH) and insulin-like growth factor (IGF)-1 regulate the development and function of cells throughout the body. Several clinical diseases that result in a decline in physical and ...mental functions are marked by mutations that disrupt GH or IGF-1 signaling. During the lifespan there is a robust decrease in both GH and IGF-1. Because GH and IGF-1 are master regulators of cellular function, impaired GH and IGF-1 signaling in aging/disease states leads to significant alterations in tissue structure and function, especially within the brain. This review is intended to highlight the effects of the GH and IGF-1 on neuronal structure, function, and plasticity. Furthermore, we address several potential mechanisms through which the age-related reductions in GH and IGF-1 affect cognition. Together, the studies reviewed here highlight the importance of maintaining GH and IGF-1 signaling in order to sustain proper brain function throughout the lifespan.
•Levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) decrease with age.•Several aspects of neuronal development, structure, and function are regulated by GH/IGF-1.•Age-related reductions in GH/IGF-1 negatively affect cognition.•Maintaining GH and IGF-1 signaling may be beneficial for maintaining brain function in aging.
We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow ...cytometry, and immunohistochemistry data.quanTIseq analysis of 8000 tumor samples revealed that cytotoxic T cell infiltration is more strongly associated with the activation of the CXCR3/CXCL9 axis than with mutational load and that deconvolution-based cell scores have prognostic value in several solid cancers. Finally, we used quanTIseq to show how kinase inhibitors modulate the immune contexture and to reveal immune-cell types that underlie differential patients' responses to checkpoint blockers.Availability: quanTIseq is available at http://icbi.at/quantiseq .
Many people have claimed that sleep has helped them solve a difficult problem, but empirical support for this assertion remains tentative. The current experiment tested whether manipulating ...information processing during sleep impacts problem incubation and solving. In memory studies, delivering learning-associated sound cues during sleep can reactivate memories. We therefore predicted that reactivating previously unsolved problems could help people solve them. In the evening, we presented 57 participants with puzzles, each arbitrarily associated with a different sound. While participants slept overnight, half of the sounds associated with the puzzles they had not solved were surreptitiously presented. The next morning, participants solved 31.7% of cued puzzles, compared with 20.5% of uncued puzzles (a 55% improvement). Moreover, cued-puzzle solving correlated with cued-puzzle memory. Overall, these results demonstrate that cuing puzzle information during sleep can facilitate solving, thus supporting sleep’s role in problem incubation and establishing a new technique to advance understanding of problem solving and sleep cognition.
The oxygen abundance gradients among nebular emission line regions in spiral galaxies have been used as important constraints for models of chemical evolution. We present the largest-ever ...full-wavelength optical spectroscopic sample of emission line nebulae in a spiral galaxy (M31). We have collected spectra of 253 H II regions and 407 planetary nebulae (PNe) with the Hectospec multi-fiber spectrograph of the MMT. We measure the line-of-sight extinction for 199 H II regions and 333 PNe; we derive oxygen abundance directly, based on the electron temperature, for 51 PNe; and we use strong-line methods to estimate oxygen abundance for 192 H II regions and nitrogen abundance for 52 H II regions. The relatively shallow oxygen abundance gradient of the more extended H II regions in our sample is generally in agreement with the result of Zaritsky et al., based on only 19 M31 H II regions, but varies with the strong-line diagnostic employed. Our large sample size demonstrates that there is significant intrinsic scatter around this abundance gradient, as much as ~3 times the systematic uncertainty in the strong-line diagnostics. The intrinsic scatter is similar in the nitrogen abundances, although the gradient is significantly steeper. On small scales (deprojected distance <0.5 kpc), H II regions exhibit local variations in oxygen abundance that are larger than 0.3 dex in 33% of neighboring pairs. We do not identify a significant oxygen abundance gradient among PNe, but we do find a significant gradient in the NII ratio that varies systematically with surface brightness. Our results underscore the complex and inhomogeneous nature of the interstellar medium of M31, and our data set illustrates systematic effects relevant to future studies of the metallicity gradients in nearby spiral galaxies.
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