Citations

Abstract Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier function and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke create a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) or cancer cases (n=143), we conducted 16S rRNA gene sequencing (MiSeq), with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort. We demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue, indicating a shift in the overall microbial community in lung cancer patients as compared to those without cancer. Lung cancer cases were classified by the relative abundance of two taxa, Variovorax and Streptococcus, with an increase in Variovorax abundance in tumors as compared to non-tumor adjacent paired lung tissue (FDR corrected P=0.013). The species of Variovorax was identified histologically, and also by two additional 16S rRNA strategies (Resphera Insight analysis and PacBio sequencing). A group of taxa were associated with squamous cell carcinoma (SCC), of which Acidovorax were enriched in smokers (P =0.0013). Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD). Therefore, we observed a microbiome-gene and a microbiome-exposure interaction in SCC lung cancer tissue. Together, these results open the door for future biomarker research that could be used to improve screening and direct mechanistic studies of lung cancer therapy. Citation Format: Leigh Greathouse, James White, Valery Bliskovsky, Ashley Vargas, Eric Polley, Elise Bowman, Mohammed Khan, Ana Robles, Brid Ryan, Amiran Dzutsev, Giorgio Trinchieri, Marbin Pineda, Sven Bilke, Paul Meltzer, Marina Walther-Antonio, Garth Ehrlich, Joshua Mell, Joshua Earl, Sergey Balashov, Archana Bhat, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie Segre, Curtis Harris. Microbiome-TP53 gene interaction in human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4925. doi:10.1158/1538-7445.AM2017-4925

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1CD;Cux1tm2Ejn). While kidneys isolated from newborn Pkd1CDmice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1CD;Cux1tm2Ejn−/−mice did not show any cysts. Because Cux1tm2Ejn−/−are perinatal lethal, we evaluated Pkd1CDmice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1CD;Cux1tm2Ejn−/−mice, newborn Pkd1CD;Cux1tm2Ejn+/−mice did not show any cysts. Comparison of Pkd1CDand Pkd1CD;Cux1tm2Ejn+/−mice at later stages of development showed a reduction in the severity of PKD in the Pkd1CD;Cux1tm2Ejn+/−mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.

PurposeTo investigate the effect of the asymmetric gradient concomitant fields (CF) with zeroth and first‐order spatial dependence on fast/turbo spin‐echo acquisitions, and to demonstrate the effectiveness of their real‐time compensation.MethodsAfter briefly reviewing the CF produced by asymmetric gradients, the effects of the additional zeroth and first‐order CFs on these systems are investigated using extended‐phase graph simulations. Phantom and in vivo experiments are performed to corroborate the simulation. Experiments are performed before and after the real‐time compensations using frequency tracking and gradient pre‐emphasis to demonstrate their effectiveness in correcting the additional CFs. The interaction between the CFs and prescan‐based correction to compensate for eddy currents is also investigated.ResultsIt is demonstrated that, unlike the second‐order CFs on conventional gradients, the additional zeroth/first‐order CFs on asymmetric gradients cause substantial signal loss and dark banding in fast spin‐echo acquisitions within a typical brain‐scan field of view. They can confound the prescan correction for eddy currents and degrade image quality. Performing real‐time compensation successfully eliminates the artifacts.ConclusionsWe demonstrate that the zeroth/first‐order CFs specific to asymmetric gradients can cause substantial artifacts, including signal loss and dark bands for brain imaging. These effects can be corrected using real‐time compensation. Magn Reson Med 79:1354–1364, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

PurposeImaging gradients result in the generation of concomitant fields, or Maxwell fields, which are of increasing importance at higher gradient amplitudes. These time‐varying fields cause additional phase accumulation, which must be compensated for to avoid image artifacts. In the case of gradient systems employing symmetric design, the concomitant fields are well described with second‐order spatial variation. Gradient systems employing asymmetric design additionally generate concomitant fields with global (zeroth‐order or B0) and linear (first‐order) spatial dependence.MethodsThis work demonstrates a general solution to eliminate the zeroth‐order concomitant field by applying the correct B0 frequency shift in real time to counteract the concomitant fields. Results are demonstrated for phase contrast, spiral, echo‐planar imaging (EPI), and fast spin‐echo imaging.ResultsA global phase offset is reduced in the phase‐contrast exam, and blurring is virtually eliminated in spiral images. The bulk image shift in the phase‐encode direction is compensated for in EPI, whereas signal loss, ghosting, and blurring are corrected in the fast‐spin echo images.ConclusionA user‐transparent method to compensate the zeroth‐order concomitant field term by center frequency shifting is proposed and implemented. This solution allows all the existing pulse sequences—both product and research—to be retained without any modifications. Magn Reson Med 79:1538–1544, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Mechanical ventilation is necessary to support patients with acute lung injury, but also exacerbates injury through mechanical stress–activated signaling pathways. We show that stretch applied to cultured human cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by high tidal volume mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF1. We further show that mouse dietary zinc deficiency potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients who go on to develop acute respiratory distress syndrome (ARDS) compared with healthy and non-ARDS intensive care unit (ICU) controls, as well as with other ICU patients without ARDS. Taken together, our findings identify a potentially novel adaptive response of the lung to stretch and a critical role for zinc in defining the lung’s tolerance for mechanical ventilation. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating mechanical ventilator–induced lung injury, and identify zinc and metallothionein as targets for lung-protective interventions in patients requiring mechanical ventilation.

Aims and objectivesTo compare the incidence of femoral access puncture site complications in the control group, who underwent 6 hr of bed rest, with patients in the case group, who underwent 4 hr of bed rest.BackgroundThe ideal bed rest length after percutaneous coronary intervention with a 7‐French arterial sheath has been investigated by nursing practice. However, in this larger‐sheath‐size group, best practices have not been determined, and bed rest time continues to vary markedly among institutions.DesignRetrospective study.MethodsData were retrieved from the National Cardiovascular Data Registry and electronic health records in this retrospective study. Sample size was 401 patients: 152 case patients with 4‐hr bed rest and 249 controls with 6‐hr bed rest. Case group data were obtained from 20 May 2013–31 December 2014; and control group data, 15 June 2011–20 May 2013.ResultsNational Cardiovascular Data Registry event rates were generally low in both groups: Only three patients in each group had a bleeding event within 72 hr (2% vs. 1%) and no patient and only two controls had arteriovenous fistula (0% vs. 1%). Complications documented in the electronic health records with institutional femoral access puncture site complication definitions identified bleeding at the access site in eight case patients (5%) and nine controls (4%). Haematoma at the access site occurred in 21 case patients (14%) and 25 controls (10%).ConclusionsThe practice change of decreasing bed rest from 6–4 hr for patients with 7‐French arterial sheaths post‐percutaneous coronary intervention was associated with no significant change in femoral access puncture site complications in either National Cardiovascular Data Registry data or institutional electronic health records data.Relevance to clinical practiceThis introduces expanded evidence of safety in decreasing bed rest length in larger (7‐French) arterial sheaths post‐percutaneous coronary intervention.

AbstractAfter decades on the margins of primary health care, surgical and anaesthesia care is gaining increasing priority within the global development arena. The 2015 publications of the Disease Control Priorities third edition on Essential Surgery and the Lancet Commission on Global Surgery created a compelling evidenced‐based argument for the fundamental role of surgery and anaesthesia within cost‐effective health systems strengthening global strategy. The launch of the Global Alliance for Surgical, Obstetric, Trauma, and Anaesthesia Care in 2015 has further coordinated efforts to build priority for surgical care and anaesthesia. These combined efforts culminated in the approval of a World Health Assembly resolution recognizing the role of surgical care and anaesthesia as part of universal health coverage. Momentum gained from these milestones highlights the need to identify consensus goals, targets and indicators to guide policy implementation and track progress at the national level. Through an open consultative process that incorporated input from stakeholders from around the globe, a global target calling for safe surgical and anaesthesia care for 80% of the world by 2030 was proposed. In order to achieve this target, we also propose 15 consensus indicators that build on existing surgical systems metrics and expand the ability to prioritize surgical systems strengthening around the world.