KRAS and PIK3CA mutation frequencies in patient derived xenograft (PDX) models of pancreatic and colorectal cancer are reflective of patient tumors and stable across passages

One key obstacle to the translation of advances in cancer research into the clinic is a deficiency of adequate preclinical models that recapitulate human disease. The development and application of validated preclinical models that reflect patient histological, cellular, and molecular characteristics is needed. Current preclinical models rely heavily on conventional cell line xenograft models which are established by engrafting human tumor cell lines cultured in the laboratory into mice. This model is widely acknowledged to provide useful, but unreliable predictive capacity for anti-tumor activity in humans (Sharpless and Depinho 2006). One possible explanation for the unreliability of cell line xenograft results translating to the clinic, is that these cells represent clonal tumor populations that have selectively grown on plastic and have adapted to growth outside of the natural tumor microenvironment (Frese and Tuveson 2007; Tentler et al. 2012). Because cell line xenograft models lack stromal cells, which are increasingly recognized as a critical element for tumorigenesis, these models fail to accurately recapitulate tumor biology and tumor response to therapy (Bhowmick et al. 2004; Sharpless and Depinho 2006; Frese and Tuveson 2007)

Utilization of Intensive Care Unit Nutrition Consultation Is Associated With Reduced Mortality

BackgroundThe aim of this project was to investigate the prevalence of nutrition consultation (NC) in U.S. intensive care units (ICUs) and to examine its association with patient outcomes.MethodsData from the Healthcare Cost and Utilization Project’s state inpatient databases was utilized from 2010 â 2014. A multilevel logistic regression model was used to evaluate the relationship between NC and clinical outcomes.ResultsInstitutional ICU NC rates varied significantly (mean: 14%, range: 0.1%â 73%). Significant variation among underlying disease processes was identified, with burn patients having the highest consult rate (P < 0.001, mean: 6%, range: 2%â 25%). ICU patients who received NC had significantly lower inâ hospital mortality (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.48â 0.74, P < 0.001), as did the subset with malnutrition (OR 0.72, 95% CI 0.53â 0.99, P = 0.047) and the subset with concomitant physical therapy consultation (OR 0.53, 95% CI 0.38â 0.74, P < 0.001). NC was associated with significantly lower rates of intubation, pulmonary failure, pneumonia, and gastrointestinal bleeding (P < 0.05). Furthermore, patients who received NC were more likely to receive enteral or parenteral nutrition (ENPN) (OR 1.8, 95% CI 1.4â 2.3, P < 0.001). Patients who received followâ up NC were even more likely to receive ENPN (OR 3.0, 95% CI 2.1â 4.2, P < 0.001).ConclusionsRates of NC were low in critically ill patients. This study suggests that increased utilization of NC in critically ill patients may be associated with improved clinical outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154413/1/jpen1534_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154413/2/jpen1534.pd

Circulating Tumor Cells as a Biomarker of Response to Treatment in Patient-Derived Xenograft Mouse Models of Pancreatic Adenocarcinoma

Circulating tumor cells (CTCs) are cells shed from solid tumors into circulation and have been shown to be prognostic in the setting of metastatic disease. These cells are obtained through a routine blood draw and may serve as an easily accessible marker for monitoring treatment effectiveness. Because of the rapid progression of pancreatic ductal adenocarcinoma (PDAC), early insight into treatment effectiveness may allow for necessary and timely changes in treatment regimens. The objective of this study was to evaluate CTC burden as a biomarker of response to treatment with a oral phosphatidylinositol-3-kinase inhibitor, BKM120, in patient-derived xenograft (PDX) mouse models of PDAC. PDX mice were randomized to receive vehicle or BKM120 treatment for 28 days and CTCs were enumerated from whole blood before and after treatment using a microfluidic chip that selected for EpCAM (epithelial cell adhesion molecule) positive cells. This microfluidic device allowed for the release of captured CTCs and enumeration of these cells via their electrical impedance signatures. Median CTC counts significantly decreased in the BKM120 group from pre- to post-treatment (26.61 to 2.21 CTCs/250 µL, p = 0.0207) while no significant change was observed in the vehicle group (23.26 to 11.89 CTCs/250 µL, p = 0.8081). This reduction in CTC burden in the treatment group correlated with tumor growth inhibition indicating CTC burden is a promising biomarker of response to treatment in preclinical models. Mutant enriched sequencing of isolated CTCs confirmed that they harbored KRAS G12V mutations, identical to the matched tumors. In the long-term, PDX mice are a useful preclinical model for furthering our understanding of CTCs. Clinically, mutational analysis of CTCs and serial monitoring of CTC burden may be used as a minimally invasive approach to predict and monitor treatment response to guide therapeutic regimens

Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009

UV activation of polymeric high aspect ratio microstructures: Ramifications in antibody surface loading for circulating tumor cell selection

The need to activate thermoplastic surfaces using robust and efficient methods has been driven by the fact that replication techniques can be used to produce microfluidic devices in a high production mode and at low cost, making polymer microfluidics invaluable for in vitro diagnostics, such as circulating tumor cell (CTC) analysis, where device disposability is critical to mitigate artifacts associated with sample carryover. Modifying the surface chemistry of thermoplastic devices through activation techniques can be used to increase the wettability of the surface or to produce functional scaffolds to allow for the covalent attachment of biologics, such as antibodies for CTC recognition. Extensive surface characterization tools were used to investigate UV activation of various surfaces to produce uniform and high surface coverage of functional groups, such as carboxylic acids in microchannels of different aspect ratios. We found that the efficiency of the UV activation process is highly dependent on the microchannel aspect ratio and the identity of the thermoplastic substrate. Colorimetric assays and fluorescence imaging of UV-activated microchannels following EDC/NHS coupling of Cy3-labeled oligonucleotides indicated that UV-activation of a PMMA microchannel with an aspect ratio of ???3 was significantly less efficient toward the bottom of the channel compared to the upper sections. This effect was a consequence of the bulk polymer&apos;s damping of the modifying UV radiation due to absorption artifacts. In contrast, this effect was less pronounced for COC. Moreover, we observed that after thermal fusion bonding of the device&apos;s cover plate to the substrate, many of the generated functional groups buried into the bulk rendering them inaccessible. The propensity of this surface reorganization was found to be higher for PMMA compared to COC. As an example of the effects of material and microchannel aspect ratios on device functionality, thermoplastic devices for the selection of CTCs from whole blood were evaluated, which required the immobilization of monoclonal antibodies to channel walls. From our results, we concluded the CTC yield and purity of isolated CTCs were dependent on the substrate material with COC producing the highest clinical yields for CTCs as well as better purities compared to PMMA.close9

Hospital Based Nutrition Support: A Review of the Latest Evidence

International audienc

Metabolic surgery may protect against admission for COVID-19 in persons with nonalcoholic fatty liver disease

SARS-CoV-2 (COVID-19) disease causes significant morbidity and mortality through increased inflammation and thrombosis. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are states of chronic inflammation and indicate advanced metabolic disease. The purpose of this observational study was to characterize the risk of hospitalization for COVID-19 in patients with NAFLD/NASH and evaluate the mitigating effect of various metabolic treatments. Retrospective analysis of electronic medical record data of 26,896 adults from a 12-hospital Midwest healthcare system with a positive COVID-19 polymerase chain reaction (PCR) test from March 1, 2020, to January 26, 2021. Variable selection was guided by the least absolute shrinkage and selection operator (LASSO) method, and multiple imputation was used to account for missing data. Multivariable logistic regression and competing risk models were used to assess the odds of being hospitalized within 45 days of a COVID-19 diagnosis. Analysis assessed the risk of hospitalization among patients with a prescription for metformin and statin use within the 3 months prior to the COVID-19 PCR result, history of home glucagon-like peptide 1 receptor agonist (GLP-1 RA) use, and history of metabolic and bariatric surgery (MBS). Interactions were assessed by sex and race. A history of NAFLD/NASH was associated with increased odds of admission for COVID-19 (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.57–2.26; P < .001) and mortality (OR, 1.96; 95% CI, 1.45–2.67; P < .001). Each additional year of having NAFLD/NASH was associated with a significant increased risk of being hospitalized for COVID-19 (OR, 1.24; 95% CI, 1.14–1.35; P < .001). NAFLD/NASH increased the risk of hospitalization in men, but not women, and increased the risk of hospitalization in all multiracial/multiethnic subgroups. Medication treatments for metabolic syndrome were associated with significantly reduced risk of admission (OR, .81; 95% CI, .67–.99; P < .001 for home metformin use; OR, .71; 95% CI, .65–.83; P < .001 for home statin use). MBS was associated with a significant decreased risk of admission (OR, .48; 95% CI, .33–.69; P < .001). NAFLD/NASH is a significant risk factor for hospitalization for COVID-19 and appears to account for risk attributed to obesity. Other significant risks include factors associated with socioeconomic status and other co-morbidities, such as history of venous thromboembolism. Treatments for metabolic disease mitigated risks from NAFLD/NASH. More research is needed to confirm the risk associated with visceral adiposity, and patients should be screened for and informed of treatments for metabolic syndrome

Predictors of discharge disposition and mortality following hospitalization with SARS-CoV-2 infection.

ImportanceThe SARS-CoV-2 pandemic has overwhelmed hospital capacity, prioritizing the need to understand factors associated with type of discharge disposition.ObjectiveCharacterization of disposition associated factors following SARS-CoV-2.DesignRetrospective study of SARS-CoV-2 positive patients from March 7th, 2020, to May 4th, 2022, requiring hospitalization.SettingMidwest academic health-system.ParticipantsPatients above the age 18 years admitted with PCR + SARS-CoV-2.InterventionNone.Main outcomesDischarge to home versus PAC (inpatient rehabilitation facility (IRF), skilled-nursing facility (SNF), long-term acute care (LTACH)), or died/hospice while hospitalized (DH).ResultsWe identified 62,279 SARS-CoV-2 PCR+ patients; 6,248 required hospitalizations, of whom 4611(73.8%) were discharged home, 985 (15.8%) to PAC and 652 (10.4%) died in hospital (DH). Patients discharged to PAC had a higher median age (75.7 years, IQR: 65.6-85.1) compared to those discharged home (57.0 years, IQR: 38.2-69.9), and had longer mean length of stay (LOS) 14.7 days, SD: 14.0) compared to discharge home (5.8 days, SD: 5.9). Older age (RRR:1.04, 95% CI:1.041-1.055), and higher Elixhauser comorbidity index [EI] (RRR:1.19, 95% CI:1.168-1.218) were associated with higher rate of discharge to PAC versus home. Older age (RRR:1.069, 95% CI:1.060-1.077) and higher EI (RRR:1.09, 95% CI:1.071-1.126) were associated with more frequent DH versus home. Blacks, Asians, and Hispanics were less likely to be discharged to PAC (RRR, 0.64 CI 0.47-0.88), (RRR 0.48 CI 0.34-0.67) and (RRR 0.586 CI 0.352-0.975). Having alpha variant was associated with less frequent PAC discharge versus home (RRR 0.589 CI 0.444-780). The relative risks for DH were lower with a higher platelet count 0.998 (CI 0.99-0.99) and albumin levels 0.342 (CI 0.26-0.45), and higher with increased CRP (RRR 1.006 CI 1.004-1.007) and D-Dimer (RRR 1.070 CI 1.039-1.101). Increased albumin had lower risk to PAC discharge (RRR 0.630 CI 0.497-0.798. An increase in D-Dimer (RRR1.033 CI 1.002-1.064) and CRP (RRR1.002 CI1.001-1.004) was associated with higher risk of PAC discharge. A breakthrough (BT) infection was associated with lower likelihood of DH and PAC.ConclusionOlder age, higher EI, CRP and D-Dimer are associated with PAC and DH discharges following hospitalization with COVID-19 infection. BT infection reduces the likelihood of being discharged to PAC and DH

Predictors of discharge disposition and mortality following hospitalization with SARS-CoV-2 infection

Importance The SARS-CoV-2 pandemic has overwhelmed hospital capacity, prioritizing the need to understand factors associated with type of discharge disposition. Objective Characterization of disposition associated factors following SARS-CoV-2. Design Retrospective study of SARS-CoV-2 positive patients from March 7th, 2020, to May 4th, 2022, requiring hospitalization. Setting Midwest academic health-system. Participants Patients above the age 18 years admitted with PCR + SARS-CoV-2. Intervention None. Main outcomes Discharge to home versus PAC (inpatient rehabilitation facility (IRF), skilled-nursing facility (SNF), long-term acute care (LTACH)), or died/hospice while hospitalized (DH). Results We identified 62,279 SARS-CoV-2 PCR+ patients; 6,248 required hospitalizations, of whom 4611(73.8%) were discharged home, 985 (15.8%) to PAC and 652 (10.4%) died in hospital (DH). Patients discharged to PAC had a higher median age (75.7 years, IQR: 65.6–85.1) compared to those discharged home (57.0 years, IQR: 38.2–69.9), and had longer mean length of stay (LOS) 14.7 days, SD: 14.0) compared to discharge home (5.8 days, SD: 5.9). Older age (RRR:1.04, 95% CI:1.041–1.055), and higher Elixhauser comorbidity index [EI] (RRR:1.19, 95% CI:1.168–1.218) were associated with higher rate of discharge to PAC versus home. Older age (RRR:1.069, 95% CI:1.060–1.077) and higher EI (RRR:1.09, 95% CI:1.071–1.126) were associated with more frequent DH versus home. Blacks, Asians, and Hispanics were less likely to be discharged to PAC (RRR, 0.64 CI 0.47–0.88), (RRR 0.48 CI 0.34–0.67) and (RRR 0.586 CI 0.352–0.975). Having alpha variant was associated with less frequent PAC discharge versus home (RRR 0.589 CI 0.444–780). The relative risks for DH were lower with a higher platelet count 0.998 (CI 0.99–0.99) and albumin levels 0.342 (CI 0.26–0.45), and higher with increased CRP (RRR 1.006 CI 1.004–1.007) and D-Dimer (RRR 1.070 CI 1.039–1.101). Increased albumin had lower risk to PAC discharge (RRR 0.630 CI 0.497–0.798. An increase in D-Dimer (RRR1.033 CI 1.002–1.064) and CRP (RRR1.002 CI1.001–1.004) was associated with higher risk of PAC discharge. A breakthrough (BT) infection was associated with lower likelihood of DH and PAC. Conclusion Older age, higher EI, CRP and D-Dimer are associated with PAC and DH discharges following hospitalization with COVID-19 infection. BT infection reduces the likelihood of being discharged to PAC and DH