Oncogenic RAS mutations drive cancers at many sites. Recent reports suggest that RAS dimerization, multimerization, and clustering correlate strongly with activation of RAS signaling. We have found ...that re-expression of DIRAS3, a RAS-related small GTPase tumor suppressor that is downregulated in multiple cancers, inhibits RAS/mitogen-activated protein kinase (MAPK) signaling by interacting directly with RAS-forming heteromers, disrupting RAS clustering, inhibiting Raf kinase activation, and inhibiting transformation and growth of cancer cells and xenografts. Disruption of K-RAS cluster formation requires the N terminus of DIRAS3 and interaction of both DIRAS3 and K-RAS with the plasma membrane. Interaction of DIRAS3 with both K-RAS and H-RAS suggests a strategy for inhibiting oncogenic RAS function.
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•Re-expression of DIRAS3 (ARHI) inhibits ovarian, lung, and pancreatic cancer growth•DIRAS3 (ARHI) interacts directly with RAS at the plasma membrane•Re-expression of DIRAS3 inhibits RAS clustering and downstream MAPK signaling•The N-terminal extension of DIRAS3 is required for its tumor-suppressive function
Sutton et. al. show that re-expression of DIRAS3 can inhibit the growth of multiple cancer types driven by K-RAS mutations by a direct interaction and disruption of K-RAS higher ordered clusters. This phenotype is driven by an N-terminal extension, which distinguishes DIRAS3 from other RAS-related small GTPases.
Although it is generally known that a combination of abiotic and biotic drivers shapes the distribution and abundance of parasites, our understanding of the interplay of these factors remains to be ...assessed for most marine host species. The present field survey investigated spatial patterns of richness, prevalence and abundance of parasites in Mytilus galloprovincialis along the coast of the northern Adriatic Sea. Herein, the relationships between biotic (host size, density and local parasite richness of mussel population) and abiotic (eutrophication and salinity) drivers and parasite richness of mussel individuals, prevalence and abundance were analysed. Local parasite richness was the most relevant factor driving parasite species richness in mussel individuals. Prevalence was mainly driven by eutrophication levels in three out of four parasite species analysed. Similarly, abundance was driven mainly by eutrophication in two parasite species. Mussel size, density and salinity had only minor contributions to the best fitting models. This study highlights that the influence of abiotic and biotic drivers on parasite infections in mussels can be differentially conveyed, depending on the infection measure applied, i.e. parasite richness, prevalence or abundance. Furthermore, it stresses the importance of eutrophication as a major factor influencing parasite prevalence and abundance in mussels in the Adriatic Sea.
Oncogene overexpression activates p53 by a mechanism posited to involve uncharacterized hyperproliferative signals. We determined whether such signals produce metabolic perturbations that generate ...DNA damage, a known p53 inducer. Biochemical, cytological, cell cycle, and global gene expression analyses revealed that brief c-Myc activation can induce DNA damage prior to S phase in normal human fibroblasts. Damage correlated with induction of reactive oxygen species (ROS) without induction of apoptosis. Deregulated c-Myc partially disabled the p53-mediated DNA damage response, enabling cells with damaged genomes to enter the cycle, resulting in poor clonogenic survival. An antioxidant reduced ROS, decreased DNA damage and p53 activation, and improved survival. We propose that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability.
Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells because of the lack of animal ...models. We investigated the role of tuft cells in pancreatic tumorigenesis.
We performed studies with LSL-KrasG12D/+;Ptf1aCre/+ mice (KC; develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice; do not develop tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice) and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA-sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasia (PanIN), 19 patients with intraductal papillary mucinous neoplasms (IPMNs), and 197 patients with PDA.
Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells after administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of prostaglandin D2, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury after administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and intraductal papillary mucinous neoplasm had gene expression signatures associated with tuft cells and increased expression of Hpgds messenger RNA compared with PDA.
In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of prostaglandin D2. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.
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Background Seeking and obtaining effective health care for Long COVID remains a challenge in the USA. Women have particularly been impacted, as they are both at higher risk of developing Long COVID ...and of facing gendered barriers to having symptoms acknowledged. Long COVID clinics, which provide multidisciplinary and coordinated care, have emerged as a potential solution. To date, however, there has been little examination of U.S. patient experiences with Long COVID clinics and how patients may or may not have come to access care at a Long COVID clinic. Methods We conducted semi-structured interviews with 30 U.S. women aged 18 or older who had experienced Long COVID symptoms for at least 3 months, who had not been hospitalized for acute COVID-19, and who had seen at least one medical provider about their symptoms. Participants were asked about experiences seeking medical care for Long COVID. Long COVID clinic-related responses were analyzed using qualitative framework analysis to identify key themes in experiences with Long COVID clinics. Results Of the 30 women, 43.3% (n = 13) had been seen at a Long COVID clinic or by a provider affiliated with a Long COVID clinic and 30.0% (n = 9) had explored or attempted to see a Long COVID clinic but had not been seen at time of interview. Participants expressed five key themes concerning their experiences with seeking care from Long COVID clinics: (1) Access to clinics remains an issue, (2) Clinics are not a one stop shop, (3) Not all clinic providers have sufficient Long COVID knowledge, (4) Clinics can offer validation and care, and (5) Treatment options are critical and urgent. Conclusions While the potential for Long COVID clinics is significant, findings indicate that ongoing barriers to care and challenges related to quality and coordination of care hamper that potential and contribute to distress among women seeking Long COVID care. Since Long COVID clinics are uniquely positioned and framed as being the place to go to manage complex symptoms, it is critical to patient wellbeing that they be properly resourced to provide a level of care that complies with emerging best practices. Keywords: Long COVID, Women, Qualitative, Post COVID, Access to care, Quality of care
Protein-protein interactions (PPIs) play central roles in orchestrating biological processes. While some PPIs are stable, many important ones are transient and hard to detect with conventional ...approaches. We developed ReBiL, a recombinase enhanced bimolecular luciferase complementation platform, to enable detection of weak PPIs in living cells. ReBiL readily identified challenging transient interactions between an E3 ubiquitin ligase and an E2 ubiquitin-conjugating enzyme. ReBiL's ability to rapidly interrogate PPIs in diverse conditions revealed that some stapled α-helical peptides, a class of PPI antagonists, induce target-independent cytosolic leakage and cytotoxicity that is antagonized by serum. These results explain the requirement for serum-free conditions to detect stapled peptide activity, and define a required parameter to evaluate for peptide antagonist approaches. ReBiL's ability to expedite PPI analysis, assess target specificity and cell permeability, and reveal off-target effects of PPI modifiers should facilitate the development of effective, cell-permeable PPI therapeutics and the elaboration of diverse biological mechanisms.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating and neurodegenerative disorder of the central nervous system characterized by multifocal white matter brain lesions leading to ...alterations in connectivity at the subcortical and cortical level. Graph theory, in combination with neuroimaging techniques, has been recently developed into a powerful tool to assess the large-scale structure of brain functional connectivity. Considering the structural damage present in the brain of MS patients, we hypothesized that the topological properties of resting-state functional networks of early MS patients would be re-arranged in order to limit the impact of disease expression. A standardized dual task (Paced Auditory Serial Addition Task simultaneously performed with a paper and pencil task) was administered to study the interactions between behavioral performance and functional network re-organization. We studied a group of 16 early MS patients (35.3±8.3years, 11 females) and 20 healthy controls (29.9±7.0years, 10 females) and found that brain resting-state networks of the MS patients displayed increased network modularity, i.e. diminished functional integration between separate functional modules. Modularity correlated negatively with dual task performance in the MS patients. Our results shed light on how localized anatomical connectivity damage can globally impact brain functional connectivity and how these alterations can impair behavioral performance. Finally, given the early stage of the MS patients included in this study, network modularity could be considered a promising biomarker for detection of earliest-stage brain network reorganization, and possibly of disease progression.
•Network modularity (Q) increased in early stage Multiple Sclerosis patients•Impaired dual task performance in patients may predict early cognitive decline.•Modularity is a promising biomarker for detection of early stage brain reorganization.•Modularity is a promising biomarker for possibly detection of disease progression.
is defined as the expected number of secondary infections arising from a single individual during his or her entire infectious
period, in a population of susceptibles. This concept is fundamental to ...the study of epidemiology and within-host pathogen
dynamics. Most importantly,, often serves as a threshold parameter that predicts whether an infection will spread. Related parameters which share this
threshold behaviour, however, may or may not give the true value of, from epidemiological data. Finally, we survey the recent use of, The basic reproductive ratio,, and surrogate threshold parameters from deterministic, non-structured models. We also review common means of estimating, in assessing emerging diseases, such as severe acute respiratory syndrome and avian influenza, a number of recent livestock
diseases, and vector-borne diseases malaria, dengue and West Nile virus., . In this paper we give a brief overview of common methods of formulating
Innate and adaptive immunity function to eliminate foreign invaders and respond to injury while enabling coexistence with commensal microbes and tolerance against self and innocuous agents. Although ...most often effective in accomplishing these objectives, immunologic processes are not fail-safe and may underserve or be excessive in protecting the host. Checks and balances to maintain control of the immune system are in place and are becoming increasingly appreciated as targets for manipulating immunopathologic responses. One of the most recognized mediators of immune regulation is the cytokine transforming growth factor-beta (TGF-beta), a product of immune and nonimmune cells. Emerging data have unveiled a pivotal role for TGF-beta as a perpetrator of suppression by CD4(+)CD25(+) regulatory T (Treg) cells and in apoptotic sequelae. Through its immunosuppressive prowess, TGF-beta effectively orchestrates resolution of inflammation and control of autoaggressive immune reactions by managing T cell anergy, defining unique populations of Treg cells, regulating T cell death, and influencing the host response to infections.
Institutional review board-approved, prospective, multicenter, comparative study.
To assess the accuracy and utility of a computer-assisted fluoroscopic navigation method for percutaneous placement ...of lumbar pedicle screws compared with conventional fluoroscopic placement.
Recent reports indicate that cortical breaches during percutaneous pedicle screw placement can exceed 15%. Computed tomography (CT)- and fluoroscopy-based navigation systems may facilitate increased placement accuracy with reduced radiation exposure and operative times.
Patients were alternately assigned to either the Guidance or Control group. The Guidance group underwent lumbar pedicle screw placement using the oblique visualization technique and computer-assisted fluoroscopic navigation. The Control group underwent lumbar pedicle screw placement per standard percutaneous technique aided by fluoroscopy alone. Baseline demographics, visual analog scale (VAS) pain scores, and American Spinal Injury Association scores were obtained preoperatively and in the immediate postoperative period. Fluoroscopy times and guidewire insertion times were recorded intraoperatively. All postoperative CT scans were reviewed by an independent spine surgeon to grade screw placement accuracy.
Forty-two patients (210 screws) were assigned to the Guidance group and 34 patients (152 screws) were assigned to the Control group. Use of Guidance resulted in reduced average fluoroscopy usage per pedicle 6.6 sec (SD = 5.1) vs. 9.6 sec (SD 6.2), P < 0.001 and more expedient placement of guidewires per pedicle 3.65 min (SD = 2.31) vs. 4.43 min (SD = 2.56), P = 0.003. The Guidance group experienced less than half of the breach rate of the Control group (3.0% vs. 7.2%, P = 0.055) and reduced breach magnitudes. None of the breaches resulted in a corresponding neurological deficit or required revision. All patient-reported outcomes were significantly improved after surgery and there were no significant differences in average postoperative VAS scores between treatment groups.
Use of Guidance reduces fluoroscopy and insertion times with increased accuracy compared with conventional fluoroscopic methods of percutaneous pedicle screw insertion.
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