Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival ...of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived “TAK1 dependency signature” is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation.
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► The TAK1 kinase promotes survival of KRAS-dependent colon cancer cells ► TAK1 dependency correlates with KRAS-mediated activation of Wnt signaling ► KRAS activates Wnt signaling via TAK1 in APC-deficient cancer cells ► KRAS upregulates BMP signaling, leading to increased TAK1 kinase activity
Profiling of colon cancer cells dependent on KRAS-mediated signaling defines a “TAK1 dependency signature” for stratifying heterogeneous patient populations. TAK1 inhibition may provide a potential therapeutic strategy for a treatment-refractory subset of colon cancers.
Vascular contributions to dementia and Alzheimer's disease are increasingly recognized
. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human ...cognitive dysfunction
, including the early clinical stages of Alzheimer's disease
. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease
, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes
, which maintain BBB integrity
. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography
. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ
in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway
in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
Vascular contributions to cognitive impairment are increasingly recognized
as shown by neuropathological
, neuroimaging
, and cerebrospinal fluid biomarker
studies. Moreover, small vessel disease of ...the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)
. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)
, and more recently tau
. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown
. Although neurovascular dysfunction
and BBB breakdown develop early in AD
, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia
, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β
, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging
. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.
Cross-species disease transmission between wildlife, domestic animals and humans is an increasing threat to public and veterinary health. Wild pigs are increasingly a potential veterinary and public ...health threat. Here we investigate 84 pathogens and the host species most at risk for transmission with wild pigs using a network approach. We assess the risk to agricultural and human health by evaluating the status of these pathogens and the co-occurrence of wild pigs, agriculture and humans. We identified 34 (87%) OIE listed swine pathogens that cause clinical disease in livestock, poultry, wildlife, and humans. On average 73% of bacterial, 39% of viral, and 63% of parasitic pathogens caused clinical disease in other species. Non-porcine livestock in the family Bovidae shared the most pathogens with swine (82%). Only 49% of currently listed OIE domestic swine diseases had published wild pig surveillance studies. The co-occurrence of wild pigs and farms increased annually at a rate of 1.2% with as much as 57% of all farms and 77% of all agricultural animals co-occurring with wild pigs. The increasing co-occurrence of wild pigs with livestock and humans along with the large number of pathogens shared is a growing risk for cross-species transmission.
Advances in the understanding of the human microbiome outside of the ICU have led investigators to consider the role of the microbiome in critical illness. The picture that is being elucidated is one ...of dysbiosis occurring at multiple sites in the critically ill patient. This review describes the changes that occur in the various microbiomes of a critically ill patient, the implications of these changes and shows how advances in the understanding of dysbiosis may lead to microbiome-targeted therapies.
Critically ill patients undergo dysbiosis at several organ sites including the skin, gastrointestinal system and the lungs with loss of microbial diversity and a propensity for potentially pathogenic organisms to dominate a particular microbiome. These microbiome changes appear to be predictive of clinical outcome. While the use of fecal microbial transplantation has been demonstrated to be an effective treatment for recurrent Clostridium difficile infection, the use of fecal microbial transplantation and other microbiome modifying therapies may have a role in managing critical illness in the ICU.
A growing understanding of the microbiome in the critically ill may modify current dogma regarding the pathogenesis of sepsis and other life-threatening conditions seen in the ICU, thereby fundamentally changing antibiotic stewardship and the management of the critically ill patient.
Neurovascular dysfunction, including blood–brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer’s disease ...(AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other.
Specific therapies for the treatment of coronavirus disease 2019 (COVID-19) have limited efficacy in the event a patient worsens clinically and requires admission to the intensive care unit (ICU). ...Thus, providing quality supportive care is essential to the overall management of patients with critical COVID-19. Patients with respiratory failure not requiring intubation should be supported with noninvasive positive pressure ventilation, continuous positive airway pressure, or high flow oxygenation. Use of these respiratory modalities may prevent patients from subsequently requiring intubation. Basic components of supportive care for the critically ill should be applied equally to patients with COVID-19 in the ICU.
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