The single cell transcriptional landscape of esophageal adenocarcinoma and its modulation by neoadjuvant chemotherapy

Immune checkpoint blockade has recently proven effective in subsets of patients with esophageal adenocarcinoma (EAC) but little is known regarding the EAC immune microenvironment. We determined the single cell transcriptional profile of EAC in 8 patients who were treatment-naive (n = 4) or had received neoadjuvant chemotherapy (n = 4). Analysis of 52,387 cells revealed 10 major cell subsets of tumor, immune and stromal cells. Prior to chemotherapy tumors were heavy infiltrated by T regulatory cells and exhausted effector T cells whilst plasmacytoid dendritic cells were markedly expanded. Two dominant cancer-associated fibroblast populations were also observed whilst endothelial populations were suppressed. Pathological remission following chemotherapy associated with broad reversal of immune abnormalities together with fibroblast transition and an increase in endothelial cells whilst a chemoresistant epithelial stem cell population correlated with poor response. These findings reveal features that underlie and limit the response to current immunotherapy and identify a range of novel opportunities for targeted therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01666-x

A multifaceted quality improvement project improves intraoperative redosing of surgical antimicrobial prophylaxis during pediatric surgery

BackgroundAccurate intraoperative antibiotic redosing contributes to prevention of surgical site infections in pediatric patients. Ensuring compliance with evolving national guidelines of weight‐based, intraoperative redosing of antibiotics is challenging to pediatric anesthesiologists.AimsOur primary aim was to increase compliance of antibiotic redoses at the appropriate time and appropriate weight‐based dose to 70%. Secondary aims included a subset analysis of time compliance and dose compliance individually, and compliance based on order entry method of the first dose (verbal or electronic).MethodsAt a freestanding, academic pediatric hospital, we reviewed surgical cases between May 1, 2014, and October 31, 2017 requiring antibiotic redoses. After an institutional change in cefazolin dosing in May 2015, phased interventions to improve compliance included electronic countermeasures to display previous and next dose timing, an alert 5 minutes prior to next dose, and weight‐based dose recommendation (September 2015). Physical countermeasures include badge cards, posting of guidelines, and updates to housestaff manual (September 2015). Statistical process control charts were used to assess overall antibiotic redose compliance, time compliance, and dose compliance. The chi‐square test was used to analyze group differences.ResultsA total of 3015 antibiotic redoses were administered during 2341 operative cases between May 1, 2014, and October 31, 2017. Mean monthly compliance with redosing was 4.3% (May 2014‐April 2015) and 73% (November 2015‐October 2017) (P < 0.001). Dose‐only compliance increased from 76% to 89% (P < 0.001), and time‐only compliance increased from 4.9% to 82% (P < 0.001). After implementation of countermeasures, electronic order entry compared with verbal order was associated with higher dose compliance, 90% vs 86% (P = 0.015).ConclusionThis quality improvement project, utilizing electronic and physical interventions, was effective in improving overall prophylactic antibiotic redosing compliance in accordance with institutional redosing guidelines.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150557/1/pan13651_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150557/2/pan13651.pd

Qubit-Qutrit Separability-Probability Ratios

Paralleling our recent computationally-intensive (quasi-Monte Carlo) work for the case N=4 (quant-ph/0308037), we undertake the task for N=6 of computing to high numerical accuracy, the formulas of Sommers and Zyczkowski (quant-ph/0304041) for the (N^2-1)-dimensional volume and (N^2-2)-dimensional hyperarea of the (separable and nonseparable) N x N density matrices, based on the Bures (minimal monotone) metric -- and also their analogous formulas (quant-ph/0302197) for the (non-monotone) Hilbert-Schmidt metric. With the same seven billion well-distributed (``low-discrepancy'') sample points, we estimate the unknown volumes and hyperareas based on five additional (monotone) metrics of interest, including the Kubo-Mori and Wigner-Yanase. Further, we estimate all of these seven volume and seven hyperarea (unknown) quantities when restricted to the separable density matrices. The ratios of separable volumes (hyperareas) to separable plus nonseparable volumes (hyperareas) yield estimates of the separability probabilities of generically rank-six (rank-five) density matrices. The (rank-six) separability probabilities obtained based on the 35-dimensional volumes appear to be -- independently of the metric (each of the seven inducing Haar measure) employed -- twice as large as those (rank-five ones) based on the 34-dimensional hyperareas. Accepting such a relationship, we fit exact formulas to the estimates of the Bures and Hilbert-Schmidt separable volumes and hyperareas.(An additional estimate -- 33.9982 -- of the ratio of the rank-6 Hilbert-Schmidt separability probability to the rank-4 one is quite clearly close to integral too.) The doubling relationship also appears to hold for the N=4 case for the Hilbert-Schmidt metric, but not the others. We fit exact formulas for the Hilbert-Schmidt separable volumes and hyperareas.Comment: 36 pages, 15 figures, 11 tables, final PRA version, new last paragraph presenting qubit-qutrit probability ratios disaggregated by the two distinct forms of partial transpositio

Proposal of an extended t-J Hamiltonian for high-Tc cuprates from ab initio calculations on embedded clusters

A series of accurate ab initio calculations on Cu_pO-q finite clusters, properly embedded on the Madelung potential of the infinite lattice, have been performed in order to determine the local effective interactions in the CuO_2 planes of La_{2-x}Sr_xCuO_4 compounds. The values of the first-neighbor interactions, magnetic coupling (J_{NN}=125 meV) and hopping integral (t_{NN}=-555 meV), have been confirmed. Important additional effects are evidenced, concerning essentially the second-neighbor hopping integral t_{NNN}=+110meV, the displacement of a singlet toward an adjacent colinear hole, h_{SD}^{abc}=-80 meV, a non-negligible hole-hole repulsion V_{NN}-V_{NNN}=0.8 eV and a strong anisotropic effect of the presence of an adjacent hole on the values of the first-neighbor interactions. The dependence of J_{NN} and t_{NN} on the position of neighbor hole(s) has been rationalized from the two-band model and checked from a series of additional ab initio calculations. An extended t-J model Hamiltonian has been proposed on the basis of these results. It is argued that the here-proposed three-body effects may play a role in the charge/spin separation observed in these compounds, that is, in the formation and dynamic of stripes.Comment: 24 pages, 4 figures, submitted to Phys. Rev.

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Caucasian Infants Scan Own- and Other-Race Faces Differently

Young infants are known to prefer own-race faces to other race faces and recognize own-race faces better than other-race faces. However, it is entirely unclear as to whether infants also attend to different parts of own- and other-race faces differently, which may provide an important clue as to how and why the own-race face recognition advantage emerges so early. The present study used eye tracking methodology to investigate whether 6- to 10-month-old Caucasian infants (N = 37) have differential scanning patterns for dynamically displayed own- and other-race faces. We found that even though infants spent a similar amount of time looking at own- and other-race faces, with increased age, infants increasingly looked longer at the eyes of own-race faces and less at the mouths of own-race faces. These findings suggest experience-based tuning of the infant's face processing system to optimally process own-race faces that are different in physiognomy from other-race faces. In addition, the present results, taken together with recent own- and other-race eye tracking findings with infants and adults, provide strong support for an enculturation hypothesis that East Asians and Westerners may be socialized to scan faces differently due to each culture's conventions regarding mutual gaze during interpersonal communication

Phage Displayed Peptides to Avian H5N1 Virus Distinguished the Virus from Other Viruses

The purpose of the current study was to identify potential ligands and develop a novel diagnostic test to highly pathogenic avian influenza A virus (HPAI), subtype H5N1 viruses using phage display technology. The H5N1 viruses were used as an immobilized target in a biopanning process using a 12-mer phage display random peptide library. After five rounds of panning, three phages expressing peptides HAWDPIPARDPF, AAWHLIVALAPN or ATSHLHVRLPSK had a specific binding activity to H5N1 viruses were isolated. Putative binding motifs to H5N1 viruses were identified by DNA sequencing. In terms of the minimum quantity of viruses, the phage-based ELISA was better than antiserum-based ELISA and a manual, semi-quantitative endpoint RT-PCR for detecting H5N1 viruses. More importantly, the selected phages bearing the specific peptides to H5N1 viruses were capable of differentiating this virus from other avian viruses in enzyme-linked immunosorbent assays