Introduction
The impact of neoadjuvant therapy on postpancreatectomy complications is inadequately described.
Methods
Data from the NSQIP Pancreatectomy Demonstration Project (11/2011 to 12/2012) was ...used to identify patients with pancreatic adenocarcinoma who did and did not receive neoadjuvant therapy. Neoadjuvant therapy was classified as chemotherapy alone or radiation ± chemotherapy. Outcomes in the neoadjuvant vs. surgery first groups were compared.
Results
Of 1,562 patients identified at 43 hospitals, 199 (12.7 %) received neoadjuvant therapy (99 chemotherapy alone and 100 radiation ± chemotherapy). Preoperative biliary stenting (57.9 vs. 44.7 %,
p
= 0.0005), vascular resection (41.5 vs. 17.3 %,
p
< 0.0001), and open resections (94.0 vs. 91.4 %,
p
= 0.008) were more common in the neoadjuvant group. Thirty-day mortality (2.0 vs. 1.5 %,
p
= 0.56) and postoperative morbidity rates (56.3 vs. 52.8 %,
p
= 0.35) were similar between groups. Neoadjuvant therapy patients had fewer organ space infections (3.0 vs. 10.3 %,
p
= 0.001), and neoadjuvant radiation patients had fewer pancreatic fistulas (7.3 vs. 15.4 %,
p
= 0.03).
Conclusions
Despite evidence for more extensive disease, patients receiving neoadjuvant therapy did not experience more complications. Neoadjuvant radiation was associated with lower pancreatic fistula rates. These data provide evidence against higher postoperative complication rates in patients with pancreatic cancer who are treated with neoadjuvant therapy.
This study continues mechanistic development of heterogeneous electron transfer (ET) pathways at mineral surfaces in aquatic environments that enable the reduction U(VI) by surface-associated ...Fe(II). Using computational molecular simulation within the framework of Marcus theory, our findings highlight the importance of the configurations and interaction of the electron donor and acceptor species with the substrate, with respect to influencing its electronic structure and thereby the ability of semiconducting minerals to facilitate ET. U(VI) reduction by surface-associated Fe(II) (adsorbed or structurally incorporated into the lattice) on an insulating, corundum (001) surface (α-Al2O3) occurs when proximal inner-sphere (IS) surface complexes are formed, such that ET occurs through a combination of direct exchange (i.e., Fe d- and U f-orbitals overlap through space) and superexchange via intervening surface oxygen atoms. U(VI) reduction by coadsorbed Fe(II) on the isostructural semiconducting hematite (α-Fe2O3) basal surface requires either their direct electronic interaction (e.g., IS complexation) or mediation of this interaction indirectly through the surface via an intrasurface pathway. Conceptually possible longer-range ET by charge-hopping through surface Fe atoms was investigated to determine whether this indirect pathway is competitive with direct ET. The calculations show that energy barriers are large for this conduction-based pathway; interfacial ET into the hematite surface is endothermic (+80.1 kJ/mol) and comprises the rate-limiting step (10–6 s–1). The presence of the IS adsorbates appears to weaken the electronic coupling between underlying Fe ions within the surface, resulting in slower intrasurface ET (10–5 s–1) than expected in the bulk basal plane. Our findings lay out first insights into donor–acceptor communication via a charge-hopping pathway through the surface for heterogeneous reduction of U(VI) by Fe(II) and help provide a basis for experimental interrogation of this important process at mineral–water interfaces.
Objective To determine whether a difference in systolic blood pressure readings between arms can predict a reduced event free survival after 10 years.Design Cohort study.Setting Rural general ...practice in Devon, United Kingdom.Participants 230 people receiving treatment for hypertension in primary care.Intervention Bilateral blood pressure measurements recorded at three successive surgery attendances.Main outcome measures Cardiovascular events and deaths from all causes during a median follow-up of 9.8 years.Results At recruitment 24% (55/230) of participants had a mean interarm difference in systolic blood pressure of 10 mm Hg or more and 9% (21/230) of 15 mm Hg or more; these differences were associated with an increased risk of all cause mortality (adjusted hazard ratio 3.6, 95% confidence interval 2.0 to 6.5 and 3.1, 1.6 to 6.0, respectively). The risk of death was also increased in 183 participants without pre-existing cardiovascular disease with an interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more (2.6, 1.4 to 4.8 and 2.7, 1.3 to 5.4). An interarm difference in diastolic blood pressure of 10 mm Hg or more was weakly associated with an increased risk of cardiovascular events or death.Conclusions Differences in systolic blood pressure between arms can predict an increased risk of cardiovascular events and all cause mortality over 10 years in people with hypertension. This difference could be a valuable indicator of increased cardiovascular risk. Bilateral blood pressure measurements should become a routine part of cardiovascular assessment in primary care.
Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has ...become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.
The current view of the midbrain dopaminergic system is evolving towards a complex system of subpopulations of neurons with distinct afferent and efferent connections and, importantly, functionally ...different intrinsic characteristics. Recent literature on the phenotypic diversity of dopaminergic neurons has outlined that in the ventral tegmental area dopaminergic neurons are not as anatomically or electrophysiologically homogeneous as they were once thought to be. Instead, the midbrain dopaminergic system is now understood to be composed of anatomically and functionally heterogeneous dopaminergic subpopulations receiving specific afferent inputs and with different axonal projections. An additional layer of complexity is the neuromodulation of each of these dopaminergic circuits. This review will examine the distinguishing electrophysiological and neuromodulatory characteristics of the afferent and efferent connections of midbrain dopaminergic neurons.
Linked Articles
This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc
The majority of known Toxoplasma gondii isolates from Europe and North America belong to three clonal lines that differ dramatically in their virulence, depending on the host. To identify the ...responsible genes, we mapped virulence in F₁ progeny derived from crosses between type II and type III strains, which we introduced into mice. Five virulence (VIR) loci were thus identified, and for two of these, genetic complementation showed that a predicted protein kinase (ROP18 and ROP16, respectively) is the key molecule. Both are hypervariable rhoptry proteins that are secreted into the host cell upon invasion. These results suggest that secreted kinases unique to the Apicomplexa are crucial in the host-pathogen interaction.
Cystic fibrosis (CF) is a life-shortening, multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory ...responses that contribute to tissue injury. To define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.
To define the transcriptional profile of sputum cells and its implication in the pathogenesis of immune function and the development of CF lung disease.
We performed single-cell RNA sequencing of sputum cells from nine subjects with CF and five healthy control subjects. We applied novel computational approaches to define expression-based cell function and maturity profiles, herein called transcriptional archetypes.
The airway immune cell repertoire shifted from alveolar macrophages in healthy control subjects to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF and were separated into the following three archetypes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Neutrophils were the most prevalent in CF, with a dominant immature proinflammatory archetype. Although CF monocytes exhibited proinflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs.
Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in CF. As we progress toward personalized applications of therapeutic and genomic developments, we hope this inflammation-profiling approach will enable further discoveries that change the natural history of CF lung disease.
Animal tissues comprise diverse cell types. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we report that different cell ...types utilize distinct strategies to control population numbers. Proliferation of fibroblasts, stromal cells important for tissue integrity, is limited by space availability. In contrast, proliferation of macrophages, innate immune cells involved in defense, repair, and homeostasis, is constrained by growth factor availability. Examination of density-dependent gene expression in fibroblasts revealed that Hippo and TGF-β target genes are both regulated by cell density. We found YAP1, the transcriptional coactivator of the Hippo signaling pathway, directly regulates expression of
, the lineage-specific growth factor for macrophages, through an enhancer of
that is specifically active in fibroblasts. Activation of YAP1 in fibroblasts elevates
expression and is sufficient to increase the number of macrophages at steady state. Our data also suggest that expression programs in fibroblasts that change with density may result from sensing of mechanical force through actin-dependent mechanisms. Altogether, we demonstrate that two different modes of population control are connected and coordinated to regulate cell numbers of distinct cell types. Sensing of the tissue environment may serve as a general strategy to control tissue composition.
The amino acid acridon-2-ylalanine (Acd) can be a valuable probe of protein conformational change because it is a long lifetime, visible wavelength fluorophore that is small enough to be incorporated ...during ribosomal biosynthesis. Incorporation of Acd into proteins expressed in Escherichia coli requires efficient chemical synthesis to produce large quantities of the amino acid and the generation of a mutant aminoacyl tRNA synthetase that can selectively charge the amino acid onto a tRNA. Here, we report the synthesis of Acd in 87% yield over five steps from Tyr and the identification of an Acd synthetase by screening candidate enzymes previously evolved from Methanococcus janaschii Tyr synthetase for unnatural amino acid incorporation. Furthermore, we characterize the photophysical properties of Acd, including quenching interactions with select natural amino acids and Förster resonance energy transfer (FRET) interactions with common fluorophores such as methoxycoumarin (Mcm). Finally, we demonstrate the value of incorporation of Acd into proteins, using changes in Acd fluorescence lifetimes, Mcm/Acd FRET, or energy transfer to Eu(3+) to monitor protein folding and binding interactions.
Key Points
This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential ...underlying mechanism.
The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise.
Firing of these interneurons probably contributes to the development of central fatigue during physical activity.
We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus‐lateralis EMG signal (∼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant‐load cycling exercise (80% Wpeak; 221 ± 10 W; ∼8 min). During, PRE and POST cycling, single and paired‐pulse (100 ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor‐evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100 ms interval) cervicomedullary motor‐evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P < 0.05). This paralleled a reduction in conditioned MEP (P < 0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P > 0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABAB intracortical interneurons.
Key Points
This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron‐mediated inhibition as a potential underlying mechanism.
The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise.
Firing of these interneurons probably contributes to the development of central fatigue during physical activity.
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