Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia.

Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain.

Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss.

Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.

Machine learning identifies candidates for drug repurposing in Alzheimer's disease.

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.

Reducing Door-to-Needle Time for Tissue Plasminogen Activator Administration in a Community Hospital: An Operations Study.

BACKGROUND AND OBJECTIVES: The benefit of tissue plasminogen activator (tPA) in acute ischemic stroke is time dependent. A 15-minute decrease in door-to-needle (DTN) time has been associated with increased odds of ambulating independently, faster discharge, and decreased odds of death. We investigated common causes of delay in DTN times in a community hospital setting in order to identify areas for improvement. METHODS: A retrospective medical record review was conducted at a 574-bed community hospital. This included 100 patients who received tPA from 2016 to 2019. Time segments were classified a priori to reflect key work elements from the time between hospital arrival to tPA and recorded for each chart. Linear regression models were used to identify work elements associated with increased DTN time. RESULTS: Median DTN time was 54:29 minutes. Linear regression analyses determined that differences in NIHSS score (P = .030), triage to computed tomography (CT) start (P = .017), triage to stroke physician page (P = .016), and CT report to tPA administration (P < .001) were associated with increased DTN time. CT report to tPA administration was most strongly associated with a Pearson coefficient of 0.868 (P < .001) with increased DTN time. CONCLUSIONS: The DTN time at our institution was above the recommended target. Our findings suggest that reducing the CT report time interval may decrease DTN time.

The influence of income on medical school admissions in Canada: a retrospective cohort study.

BACKGROUND: The socioeconomic status of applicants to Canadian medical schools has been understudied in the past two decades. Institutional efforts have been made to address the lack of socioeconomic diversity across Canada during this time. We investigated the income characteristics of medical school applicants, as well as the relationship between applicant income and offer of admission, to characterize the current state of socioeconomic diversity in medical admissions. METHODS: We conducted a retrospective cohort study on 26,120 applicants at one Ontario medical school from 2013 to 2018. Characteristics of applicants who were offered admission were compared to the general population and applicants not offered admission. Regression analyses were used to investigate the association between median total neighborhood income and successful admission. RESULTS: The median total neighborhood income for medical school applicants was $98,816, which was approximately $28,480 higher than the Canadian general population. Those not admitted to the medical school had a median total neighborhood income of $98,304 compared to $105,984 for those offered admission (p < 0.001). This trend was seen in every province and territory in Canada. Median total neighborhood income was a predictor of an offer of admission; applicants in the >75th percentile income group had 54% increased odds of being offered admission when compared to applicants in the <25th percentile in our unadjusted model. Income was not significant in our adjusted models but showed that the income medians drastically shifted between pre-interview and post-interview periods, from $98,816 to $104,960 (p < 0.001). CONCLUSION: Medical school applicants are from higher economic strata compared to the general population. Despite already representing a high economic stratum, a higher median total neighborhood income relative to other applicants was associated with an offer of admission.

Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients.

Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.

Pharmacological Treatment for Paroxysmal Sympathetic Hyperactivity.

BACKGROUND: Paroxysmal sympathetic hyperactivity, which affects up to 10% of all acquired brain injury survivors, is characterized by elevated heart rate, blood pressure, respiratory rate, and temperature; diaphoresis; and increased posturing. Pharmacological agents that have been studied in the management of this disorder include opiates, γ-aminobutyric acid agents, dopaminergic agents, and ß blockers. Although paroxysmal sympathetic hyperactivity is a relatively common complication after acquired brain injury, there is a paucity of recommendations or comparisons of agents for the management of this disorder. OBJECTIVE: To evaluate all relevant literature on pharmacological therapies used to manage patients with paroxysmal sympathetic hyperactivity to help elucidate possible best practices. METHODS: Of the 27 studies evaluated for inclusion, 10 studies received full review: 4 retrospective cohort studies, 5 single case studies, and 1 case series. RESULTS: Monotherapy is usually not effective in the management of paroxysmal sympathetic hyperactivity and multiple agents with different mechanisms of action should be considered. α2-Agonists such as dexmedetomidine may hold some slight clinical efficacy over agents like propofol, and with respect to oral medications, propranolol might convey some slight advantage compared to others. However, with the limited data available, these results must be interpreted with caution. CONCLUSIONS: As the treatment of paroxysmal sympathetic hyperactivity is reactive to symptomatic evolution over time, critical care nurses play a vital role in the monitoring and treatment of these patients. Limited data exist on the management of paroxysmal sympathetic hyperactivity and larger robust data sets are needed to guide decision-making. (Critical Care Nurse. 2020;40[3]:e9-e16).

Drought adaptation in Arabidopsis thaliana by extensive genetic loss-of-function.

Interdisciplinary syntheses are needed to scale up discovery of the environmental drivers and molecular basis of adaptation in nature. Here we integrated novel approaches using whole genome sequences, satellite remote sensing, and transgenic experiments to study natural loss-of-function alleles associated with drought histories in wild Arabidopsis thaliana. The genes we identified exhibit population genetic signatures of parallel molecular evolution, selection for loss-of-function, and shared associations with flowering time phenotypes in directions consistent with longstanding adaptive hypotheses seven times more often than expected by chance. We then confirmed predicted phenotypes experimentally in transgenic knockout lines. These findings reveal the importance of drought timing to explain the evolution of alternative drought tolerance strategies and further challenge popular assumptions about the adaptive value of genetic loss-of-function in nature. These results also motivate improved species-wide sequencing efforts to better identify loss-of-function variants and inspire new opportunities for engineering climate resilience in crops.

Aneurysmal lesions of patients with abdominal aortic aneurysm contain clonally expanded T cells.

Abdominal aortic aneurysm (AAA) is a common disease with often life-threatening consequences. This vascular disorder is responsible for 1-2% of all deaths in men aged 65 years or older. Autoimmunity may be responsible for the pathogenesis of AAA. Although it is well documented that infiltrating T cells are essentially always present in AAA lesions, little is known about their role in the initiation and/or progression of the disease. To determine whether T cells infiltrating AAA lesions contain clonally expanded populations of T cells, we amplified ß-chain TCR transcripts by the nonpalindromic adaptor-PCR/Vß-specific PCR and/or Vß-specific PCR, followed by cloning and sequencing. We report in this article that aortic abdominal aneurysmal lesions from 8 of 10 patients with AAA contained oligoclonal populations of T cells. Multiple identical copies of ß-chain TCR transcripts were identified in these patients. These clonal expansions are statistically significant. These results demonstrate that αß TCR(+) T lymphocytes infiltrating aneurysmal lesions of patients with AAA have undergone proliferation and clonal expansion in vivo at the site of the aneurysmal lesion, in response to unidentified self- or nonself Ags. This evidence supports the hypothesis that AAA is a specific Ag-driven T cell disease.

Regional variations in the health, environmental, and climate benefits of wind and solar generation.

When wind or solar energy displace conventional generation, the reduction in emissions varies dramatically across the United States. Although the Southwest has the greatest solar resource, a solar panel in New Jersey displaces significantly more sulfur dioxide, nitrogen oxides, and particulate matter than a panel in Arizona, resulting in 15 times more health and environmental benefits. A wind turbine in West Virginia displaces twice as much carbon dioxide as the same turbine in California. Depending on location, we estimate that the combined health, environmental, and climate benefits from wind or solar range from $10/MWh to $100/MWh, and the sites with the highest energy output do not yield the greatest social benefits in many cases. We estimate that the social benefits from existing wind farms are roughly 60% higher than the cost of the Production Tax Credit, an important federal subsidy for wind energy. However, that same investment could achieve greater health, environmental, and climate benefits if it were differentiated by region.

Marginal emissions factors for the U.S. electricity system.

There is growing interest in reducing emissions from electricity generation in the United States (U.S.). Renewable energy, energy efficiency, and energy conservation are all commonly suggested solutions. Both supply- and demand-side interventions will displace energy-and emissions-from conventional generators. Marginal emissions factors (MEFs) give a consistent metric for assessing the avoided emissions resulting from such interventions. This paper presents the first systematic calculation of MEFs for the U.S. electricity system. Using regressions of hourly generation and emissions data from 2006 through 2011, we estimate regional MEFs for CO(2), NO(x), and SO(2), as well as the share of marginal generation from coal-, gas-, and oil-fired generators. Trends in MEFs with respect to system load, time of day, and month are explored. We compare marginal and average emissions factors (AEFs), finding that AEFs may grossly misestimate the avoided emissions resulting from an intervention. We find significant regional differences in the emissions benefits of avoiding one megawatt-hour of electricity: compared to the West, an equivalent energy efficiency measure in the Midwest is expected to avoid roughly 70% more CO(2), 12 times more SO(2), and 3 times more NO(x) emissions.

Peroxisome proliferator-activated receptor (PPAR): balance for survival in parasitic infections.

Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology.

Abdominal aortic aneurysm is a specific antigen-driven T cell disease.

To determine whether monoclonal/oligoclonal T cells are present in abdominal aortic aneurysm (AAA) lesions, we amplified beta-chain T cell receptor (TCR) transcripts from these lesions by the nonpalindromic adaptor (NPA)-polymerase chain reaction (PCR)/V-beta-specific PCR followed by cloning and sequencing. Sequence analysis revealed the presence of substantial proportions of identical beta-chain TCR transcripts in AAA lesions in 9 of 10 patients examined, strongly suggesting the presence of oligoclonal populations of alphabeta TCR+ T cells. We have also shown the presence of oligoclonal populations of gammadelta TCR+ T cells in AAA lesions. Sequence analysis after appropriate PCR amplification and cloning revealed the presence of substantial proportions of identical VgammaI and VgammaII TCR transcripts in 15 of 15 patients examined, and of Vdelta1 and Vdelta2 TCR transcripts in 12 of 12 patients. These clonal expansions were very strong. All these clonal expansions were statistically significant by the binomial distribution. In other studies, we determined that mononuclear cells infiltrating AAA lesions express early- (CD69), intermediate- (CD25, CD38), and late- (CD45RO, HLA class II) activation antigens. These findings suggest that active ongoing inflammation is present in the aortic wall of patients with AAA. These results demonstrate that oligoclonal alphabeta TCR+ and gammadelta TCR+T cells are present in AAA lesions. These oligoclonal T cells have been clonally expanded in vivo in response to yet unidentified antigens. Although the antigenic specificity of these T cells remains to be determined, these T cells may play a significant role in the initiation and/or the propagation of the AAA. It appears that AAA is a specific antigen-driven T cell disease.