bluuebunny/crossref_metadata_2025_split huggingface dataset:
HSP70 Inhibition Blocks Adaptive Resistance and Synergizes with MEK Inhibition for the Treatment of NRAS-Mutant Melanoma
Authors: Parris Joshua L.D. , Barnoud Thibaut , Leu Julia I.-Ju , Leung Jessica C. , Ma Weili , Kirven Nicole A. , Poli Adi Naryana Reddy , Kossenkov Andrew V. , Liu Qin , Salvino Joseph M. , George Donna L. , Weeraratna Ashani T. , Chen Qing , Murphy Maureen E. 
Published: October 2021

NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against mutant NRAS, along with adaptive and acquired resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK have shown some promise for NRAS-mutant melanoma. In this work, we explored the use of MEK inhibitors for NRAS-mutant melanoma. At the same time, we investigated the impact of the brain microenvironment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. These parallel avenues led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcriptional regulator ID3, which confers resistance. This upregulation of ID3 is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEKi, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEKi against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma.

Significance:
MEKi are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEKi for the treatment of NRAS mutant melanoma.
Comprehensive Immunoprofiling of High-Risk Oral Proliferative and Localized Leukoplakia
Authors: Hanna Glenn J. , Villa Alessandro , Mistry Nikhil , Jia Yonghui , Quinn Charles T. , Turner Madison M. , Felt Kristen D. , Pfaff Kathleen , Haddad Robert I. , Uppaluri Ravindra , Rodig Scott J. , Woo Sook-Bin , Egloff Ann Marie , Hodi F. Stephen 
Published: October 2021

Oral leukoplakia is common and may, in some cases, progress to carcinoma. Proliferative leukoplakia is a progressive, often multifocal subtype with a high rate of malignant transformation compared with the more common localized leukoplakia. We hypothesized that the immune microenvironment and gene expression patterns would be distinct for proliferative leukoplakia compared with localized leukoplakia. We summarize key clinicopathologic features among proliferative leukoplakia and localized leukoplakia and compare cancer-free survival (CFS) between subgroups. We analyze immunologic gene expression profiling in proliferative leukoplakia and localized leukoplakia tissue samples (NanoString PanCancer Immune Oncology Profiling). We integrate immune cell activation and spatial distribution patterns in tissue samples using multiplexed immunofluorescence and digital image capture to further define proliferative leukoplakia and localized leukoplakia. Among N = 58 patients (proliferative leukoplakia, n = 29; localized leukoplakia, n = 29), only the clinical diagnosis of proliferative leukoplakia was associated with significantly decreased CFS (HR, 11.25; P &lt; 0.01; 5-year CFS 46.8% and 83.6% among patients with proliferative leukoplakia and localized leukoplakia, respectively). CD8+ T cells and T regulatory (Treg) were more abundant among proliferative leukoplakia samples (P &lt; 0.01) regardless of degree of epithelial dysplasia, and often colocalized to the dysplasia–stromal interface. Gene set analysis identified granzyme M as the most differentially expressed gene favoring the proliferative leukoplakia subgroup (log2 fold change, 1.93; Padj &lt; 0.001). Programmed death ligand 1 (PD-L1) was comparatively overexpressed among proliferative leukoplakia samples, with higher (&gt;5) PD-L1 scores predicting worse CFS (Padj &lt; 0.01). Proliferative leukoplakia predicts a high rate of malignant transformation within 5 years of diagnosis. A prominent CD8+ T-cell and Treg signature along with relative PD-L1 overexpression compared with localized leukoplakia provides strong rationale for PD-1/PD-L1 axis blockade using preventative immunotherapy.

Significance:
This is the first in-depth profiling effort to immunologically characterize high-risk proliferative leukoplakia as compared with the more common localized leukoplakia. We observed a notable cytotoxic T-cell and Treg signature with relative overexpression of PD-L1 in high-risk proliferative leukoplakia providing a strong preclinical rationale for investigating PD-1/PD-L1 axis blockade in this disease as preventative immunotherapy.
Prevalence and Prognostic Significance of Malnutrition Risk in Patients With Acute Ischemic Stroke: Results From the Third China National Stroke Registry
Authors: Zhang Guitao , Pan Yuesong , Zhang Runhua , Wang Mengxing , Meng Xia , Li Zixiao , Li Hao , Wang Yilong , Zhao Xingquan , Liu Gaifen , Wang Yongjun 
Published: October 2021

Background and Purpose:
To investigate the prevalence of malnutrition risk in patients with acute ischemic stroke (AIS) at admission, the association between malnutrition risk and long-term outcomes, and whether the predictive ability would be improved after adding to previous prognostic models for poor outcomes.

Methods:
Based on the Third China National Stroke Registry data from August 2015 to March 2018, we evaluated malnutrition risk using objective scores, including the controlling nutritional status score, geriatric nutritional risk index, and prognostic nutritional index. The primary outcome was death or major disability (modified Rankin Scale score ≥3) at 1 year after stroke onset. We calculated the crude prevalence of malnutrition risk and investigated the association between malnutrition risk and clinical outcomes. Prognostic performance of 3 objective malnutrition scores for poor outcomes was assessed.

Results:

Moderate to severe malnutrition risk was identified in 5.89%, 5.30%, and 1.95% of the Third China National Stroke Registry AIS patients according to the controlling nutritional status score, geriatric nutritional risk index, and prognostic nutritional index, respectively. At 1-year follow-up, 1143 participants (13.5%) experienced death or major disability. After adjustment for traditional risk factors, moderate to severe malnutrition risk was associated with high risk of composite events (odds ratio, 2.25 [95% CI, 1.75–2.90], for controlling nutritional status score; odds ratio, 2.10 [95% CI, 1.63–2.69], for geriatric nutritional risk index; odds ratio, 3.36 [95% CI, 2.33–4.84], for prognostic nutritional index; all
P
<0.01). Addition of the 3 malnutrition scores to different predicted scales (iScore and Acute Stroke Registry and Analysis of Lausanne) improved predictive ability for long-term poor outcomes validated by the integrated discrimination index (all
P
<0.05).

Conclusions:
The prevalence of moderate or severe malnutrition risk in Chinese patients with AIS ranged from 1.95% to 5.89%. Malnutrition risk in patients with AIS was associated with increased risk of long-term death and major disability. Our study provides evidence supporting the prognostic significance of objective malnutrition scores after AIS.
Effect of the MJO on East Asian winter rainfall as revealed by an SVD analysis
Authors: Chen Yun-Lan , Sui Chung-Hsiung , Chang Chih-Pei , Tseng Kai-Chih 
Published: October 2021

AbstractThis paper studies the influences of the Madden Julian Oscillation (MJO) on East Asian (EA) winter rainfall using the Singular Value Decomposition (SVD) approach. This method uses two-dimensional instead of the latitudinally-averaged variables in the commonly used Real-time Multivariate MJO (RMM) index. A comparison of the two approaches is made using the same OLR and zonal wind data over 37 boreal winter seasons of December – March. The SVD composite reveals a more conspicuous and coherent variation throughout the MJO cycle, while the RMM composite is more ambiguous. In particular, the SVD analysis identifies the convection anomalies over the Maritime Continent and the subtropical western Pacific (MCWP) as a major cause of enhanced rainfall in EA at RMM phases 8 and 1. This is at least one-eighth cycle earlier than the phases of convection development over Indian Ocean (IO) that were emphasized by previous studies. A linearized global baroclinic model is used to demonstrate the mechanism of MJO forcing on EA rainfall during various phases, with a focus on the MCWP cooling. The result shows that the anomalous MCWP cooling and the resultant low-level anticyclonic flow interact with the East Asian Jet, leading to an overall weakened EA winter monsoon circulation. The associated anomalous overturning circulation, with ascending motion and low-level horizonal moisture convergence in EA, contributes to the enhanced rainfall. This model result supports the interpretation of the SVD analysis, in that the MCWP-cooling induced anomalous meridional circulation is a more direct cause of enhanced EA rainfall than the IO-heating (or the IO-MCWP heating dipole) induced Rossby wave teleconnection.
Unplanned Readmissions to the Intensive Care Unit Among Geriatric Trauma Patients
Authors: Santarelli Shana , Morgan Madison E. , Vernon Tawnya , Bradburn Eric , Perea Lindsey L. 
Published: October 2021

Background Unplanned readmission/bounceback to the intensive care unit (ICUBB) is a prevalent issue in the medical community. The geriatric population is incompletely studied in regard to ICUBB. We sought to determine if ICUBB in older patients was associated with higher risk of mortality. We hypothesized that, of those who were older, those with ICUBB would have higher mortality compared to those with no ICUBB. Further, we hypothesized that of those with ICUBB, older age would lead to higher mortality. Methods The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2003 to 2018 for all trauma patients of age ≥40 years. Those with advance directives were excluded. Adjusted analysis in the form of logistic regressions controlling for demographic and injury covariates and clustering by facility were used to assess the adjusted impact of ICUBB and age on mortality. Results 363,778 patients were aged ≥40 years. When comparing mortalities between the age 40 and 49 years group and those in older groups, a dramatic increase in mortality was observed between those in each respective age category with ICUBB vs non-ICUBB. This trend was most prominent in those in the 90+ years age group (ICUBB: AOR: 34.78, P < .001; non-ICUBB: AOR: 9.08, P < .001). A second model only including patients who had ICUBB found that patients of age ≥65 years had significantly higher odds of mortality (AOR: 4.10, P < .001) when compared to their younger counterparts (age <65 years). Discussion An ICUBB seems to exacerbate mortality rates as age increases. This profound increase in mortality calls for strategies to be developed, especially in the older population, to attempt to mitigate the factors leading to ICUBB.
Acute Vocal Fold Paresis and Paralysis After COVID-19 Infection: A Case Series
Authors: Rapoport Sarah K. , Alnouri Ghiath , Sataloff Robert T. , Woo Peak 
Published: October 2021

Objective: Evidence demonstrates neurotropism is a common feature of coronaviruses. In our laryngology clinics we have noted an increase in cases of “idiopathic” vocal fold paralysis and paresis in patients with no history of intubation who are recovering from the novel SARS-Cov-2 coronavirus (COVID-19). This finding is concerning for a post-viral vagal neuropathy (PVVN) as a result of infection with COVID-19. Our objective is to raise the possibility that vocal fold paresis may be an additional neuropathic sequela of infection with COVID-19. Methods: Retrospective review of patients who tested positive for COVID-19, had no history of intubation as a result of their infection, and subsequently presented with vocal fold paresis between May 2020 and January 2021. Charts were reviewed for demographic information, confirmation of COVID-19 infection, presenting symptoms, laryngoscopy and stroboscopy exam findings, and laryngeal electromyography (LEMG) results. Results: Sixteen patients presented with new-onset dysphonia during and after recovering from a COVID-19 infection and were found to have unilateral or bilateral vocal fold paresis or paralysis. LEMG was performed in 25% of patients and confirmed the diagnosis of neuropathy in these cases. Conclusions: We believe that COVID-19 can cause a PVVN resulting in abnormal vocal fold mobility. This diagnosis should be included in the constellation of morbidities that can result from COVID-19 as the otolaryngologist can identify this entity through careful history and examination.
Fate of Manuscripts Rejected by a Specialty Psychiatry Journal: A Retrospective Cohort Study
Authors: Menon Vikas , Jayaprakashan Karumarakandy Puthiyapurayil , Varadharajan Natarajan , Ameen Shahul , Praharaj Samir Kumar 
Published: October 2021

Background: Little is known about the publication outcomes of submissions rejected by specialty psychiatry journals. We aimed to investigate the publication fate of original research manuscripts previously rejected by the Indian Journal of Psychological Medicine (IJPM). Methods: A random sampling of manuscripts was drawn from all submissions rejected between January 1, 2018, and December 31, 2019. Using the titles of these papers and the author names, a systematic search of electronic databases was carried out to examine if these manuscripts have been published elsewhere or not. We extracted data on a range of scientific and nonscientific parameters from the journal’s manuscript management portal for every rejected manuscript. Multivariable analysis was used to detect factors associated with eventual publication. Results: Out of 302 manuscripts analyzed, 139 (46.0%) were published elsewhere; of these, only 18 articles (13.0%) were published in a journal with higher standing than IJPM. Manuscripts of foreign origin (odds ratio [OR] 1.77, 95% confidence interval [CI] = 1.06–2.97) and rejection following peer review or editorial re-review (OR 2.41, 95% CI = 1.22–4.74) were significantly associated with publication. Conclusion: Nearly half of the papers rejected by IJPM were eventually published in other journals, though such papers are more often published in journals with lower standing. Manuscripts rejected following peer review were more likely to reach full publication status compared to those which were desk rejected.
T2* reduction in patients with acute post-traumatic headache
Authors: Nikolova Simona , Schwedt Todd J , Li Jing , Wu Teresa , Dumkrieger Gina M , Ross Katherine B , Berisha Visar , Chong Catherine D. 
Published: October 2021

Objectives Although iron accumulation in pain-processing brain regions has been associated with repeated migraine attacks, brain structural changes associated with post-traumatic headache have yet to be elucidated. To determine whether iron accumulation is associated with acute post-traumatic headache, magnetic resonance transverse relaxation rates (T2*) associated with iron accumulation were investigated between individuals with acute post-traumatic headache attributed to mild traumatic brain injury and healthy controls. Methods Twenty individuals with acute post-traumatic headache and 20 age-matched healthy controls underwent 3T brain magnetic resonance imaging including quantitative T2* maps. T2* differences between individuals with post-traumatic headache versus healthy controls were compared using age-matched paired t-tests. Associations of T2* values with headache frequency and number of mild traumatic brain injuries were investigated using multiple linear regression in individuals with post-traumatic headache. Significance was determined using uncorrected p-value and cluster size threshold. Results Individuals with post-traumatic headache had lower T2* values compared to healthy controls in cortical (bilateral frontal, bilateral anterior and posterior cingulate, right postcentral, bilateral temporal, right supramarginal, right rolandic, left insula, left occipital, right parahippocampal), subcortical (left putamen, bilateral hippocampal) and brainstem regions (pons). Within post-traumatic headache subjects, multiple linear regression showed a negative association between T2* in the right inferior parietal/supramarginal regions and number of mild traumatic brain injuries and a negative association between T2* in bilateral cingulate, bilateral precuneus, bilateral supplementary motor areas, bilateral insula, right middle temporal and right lingual areas and headache frequency. Conclusions Acute post-traumatic headache is associated with iron accumulation in multiple brain regions. Correlations with headache frequency and number of lifetime mild traumatic brain injuries suggest that iron accumulation is part of the pathophysiology or a marker of mild traumatic brain injury and post-traumatic headache.
Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: A multi-center retrospective cohort study
Authors: Overeem Lucas Hendrik , Peikert Andreas , Hofacker Maxi Dana , Kamm Katharina , Ruscheweyh Ruth , Gendolla Astrid , Raffaelli Bianca , Reuter Uwe , Neeb Lars 
Published: October 2021

Background Switching between antibody classes might be a treatment option in migraine patients who have not responded to one class of a CGRP-(receptor) monoclonal antibody (mAb), but there are no efficacy data so far. In this real-world analysis, we assessed the treatment response to a CGRP-mAb in patients that have previously failed the CGRP-receptor-mAb erenumab. Methods We analyzed retrospective headache diary data of 78 patients with migraine who switched between CGRP-mAbs classes at four German headache centers either due to lack of efficacy or intolerable side effects. Among these, we identified 25 patients who did not respond to erenumab after three treatment cycles (defined as <30% reduction of monthly headache days) and had complete headache documentation at least one month before and during both treatments. We assessed the ≥30% responder rate at month three after switching from erenumab to a CGRP-mAb (galcanezumab or fremanezumab) (primary endpoint). Secondary endpoints included ≥50% responder rate, monthly headache days, and monthly days with acute medication use. In an exploratory subgroup analysis patients were stratified for daily and non-daily headache. Results The switch from erenumab to a CGRP-mAb led to a ≥30% response in one-third (32%) of the patients after three treatment cycles. A ≥50% response was achieved in 12% of the patients. Monthly headache days were reduced in month three compared to baseline (20.8 ± 7.1 to 17.8 ± 9.1; p = 0.009). Stratified analysis revealed that no patient with daily headache (n = 9) responded to the treatment switch, while a 30% response was achieved by 50% of patients with non-daily headache (n = 16). Conclusion Our findings demonstrate that a relevant proportion of erenumab non-responders might benefit from a treatment switch to a CGRP-mAb. Switching seems to be a promising treatment option especially in migraine patients with non-daily headache.
Cytotoxicity of mancozeb on Sertoli–germ cell co-culture system: Role of MAPK signaling pathway
Authors: Mohammadi-Sardoo Mohaddeseh , Mandegary Ali , Nematollahi-Mahani Seyed Noureddin , Moballegh Nasery Mahshid , Nabiuni Mohammad , Amirheidari Bagher 
Published: October 2021

Mancozeb (MZB) is a worldwide fungicide for the management of fungal diseases in agriculture and industrial contexts. Human exposure occurs by consuming contaminated plants, drinking water, and occupational exposure. There are reports on MZB’s reprotoxicity such as testicular structure damage, sperm abnormalities, and decrease in sperm parameters (number, viability, and motility), but its molecular mechanism on apoptosis in testis remains limited. To investigate the molecular mechanisms involved in male reprotoxicity induced by MZB, we used primary cultures of mouse Sertoli–germ cells. Cells were exposed to MZB (1.5, 2.5, and 3.5 μM) for 3 h to evaluate viability by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, reactive oxygen species (ROS) generation, and oxidative stress parameters (lipid peroxidation). Cell death and mitogen-activated protein kinase (MAPK) signaling were measured in these cells using flow cytometry and western blotting. In addition, some groups were exposed to N-acetylcysteine (NAC, 5 mM) in the form of co-treatment with MZB. Mancozeb reduced viability and increased the level of intracellular ROS, p38 and c-Jun N-terminal kinases (JNK) MAPK proteins phosphorylation, and apoptotic cell death, which could be blocked by NAC as an inhibitor of oxidative stress. The present study indicated for the first time the toxic manifestations of MZB on the Sertoli–germ cell co-culture. Redox imbalance and p38 and JNK signaling pathway activation might play critical roles in MZB-induced apoptosis in the male reproductive system.
Antibiotic Administration in an Animal Model of Chronic Peritoneal Dialysate Exposure
Authors: Mortier Siska , De Vriese An S. , Leyssens Anne , Vanacker Nele J. , Faict Dirk , Comelissen Maria , De Ridder Leo , Lameire Norbert H. 
Published: October 2021

♦ Objectives The high incidence of intraperitoneal infection remains an important problem in animal models of chronic dialysate exposure. Prophylactic antibiotic administration can be used to resolve this problem, but the isolated effects of antibiotics on peritoneal membrane function and structure are unknown. The present study examined the effects of prophylactic antibiotics on infection rate and peritoneal membrane function and structure in a rat model of chronic dialysate exposure. ♦ Design A first group of rats (A; n = 12) received 10 mL 3.86% glucose dialysate twice daily through a heparin-coated catheter. In a second group of animals (B; n = 12), oxacillin 2.5 mg/day and gentamicin 0.04 mg/day were added to the dialysate. Group C ( n= 12) was injected twice daily with an identical dose of antibiotics dissolved in 1 mL of buffer solution. Group D ( n = 12) was left untreated. Dialysate cultures were obtained regularly. After 8 weeks of exposure, peritoneal transport studies were performed and samples for histology were obtained. ♦ Results Technique survival was 92% in group A and 100% in the remaining groups. Five rats in group A but none of the animals in the other groups developed peritonitis. The transport rates of small solutes were elevated and net ultrafiltration was decreased in group A compared to the controls. Fibrosis, as evaluated by quantifying Picro Sirius Red staining with image analysis, was significantly elevated in group A (3.48% ± 1.06% vs 0.72% ± 0.51% in group D, p < 0.05) but not in group B (0.29% ± 0.07%) or in group C (0.52% ± 0.28%). Vascular density, measured by counting the number of blood vessels that stained positive for endothelial NO synthase, was increased in both groups that were exposed to dialysate: 153.0 ± 12.9/μm2 in group A and 131.6 ± 14.3/μm2 in group B, versus 76.76 ± 12.37/μm2 in group C and 73.2 ± 10.4/μm2 in group D ( p < 0.01). ♦ Conclusions Prophylactic administration of oxacillin and gentamicin adequately prevented intraperitoneal infection in an animal model of chronic dialysate exposure. In addition, fibrosis was absent, suggesting intra-peritoneal infection rather than dialysate exposure is a causative factor.