<p><div>(<em>b</em>)PURPOSE</<em>b</em>)</div>Tumors are continuously evolving <em>b</em>iological systems, and medical imaging is uniquely positioned to monitor changes throughout treatment. A<em>lt</em>hough qualitatively tracking lesions over space and time may <em>b</em>e trivial, the development of clinically relevant, automated radiomics methods that incorporate serial imaging data is far more challenging. In this study, we evaluated deep learning networks for predicting clinical outcomes through analyzing time series CT images of patients with locally advanced non-small cell lung cancer (NSCLC).(<em>b</em>)Experimental Design:</<em>b</em>) Dataset A consists of 179 patients with stage III NSCLC treated with definitive chemoradiation, with pretreatment and posttreatment CT images at 1, 3, and 6 months follow-up (581 scans). Models were developed using transfer learning of convolutional neural networks (CNN) with recurrent neural networks (RNN), using single seed-point tumor localization. Pathologic response validation was performed on dataset <em>B</em>, comprising 89 patients with NSCLC treated with chemoradiation and surgery (178 scans).</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Deep learning models using time series scans were significantly predictive of survival and cancer-specific outcomes (progression, distant metastases, and local-regional recurrence). Model performance was enhanced with each additional follow-up scan into the CNN model (e.g., 2-year overall survival: AUC = 0.74, <i>P</i> &<em>lt</em>; 0.05). The models stratified patients into low and high mortality risk groups, which were significantly associated with overall survival [HR = 6.16; 95% confidence interval (CI), 2.17-17.44; <i>P</i> &<em>lt</em>; 0.001]. The model also significantly predicted pathologic response in dataset <em>B</em> (<i>P</i> = 0.016).</p><A<em>b</em>stractText>We demonstrate that deep learning can integrate imaging scans at mu<em>lt</em>iple timepoints to improve clinical outcome predictions. AI-<em>b</em>ased noninvasive radiomics <em>b</em>iomarkers can have a significant impact in the clinic given their low cost and minimal requirements for human input.</A<em>b</em>stractText>

<A<em>b</em>stractText>The anti-<em>B</em>-cell maturation antigen <em>B</em>iTE molecule AMG 420 was assessed in patients with relapsed/refractory mu<em>lt</em>iple myeloma.</A<em>b</em>stractText><p><div>(<em>b</em>)PATIENTS AND METHODS</<em>b</em>)</div>In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as &<em>lt</em>; 1 tumor cell/10⁴ <em>b</em>one marrow cells <em>b</em>y flow cytometry.</p><A<em>b</em>stractText>Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 anti<em>b</em>odies. In this study, 800 μg/d was considered to not <em>b</em>e tolera<em>b</em>le <em>b</em>ecause of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, <em>b</em>oth of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year.</A<em>b</em>stractText><A<em>b</em>stractText>In this study of AMG 420 in patients with relapsed/refractory mu<em>lt</em>iple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.</A<em>b</em>stractText>

<A<em>b</em>stractText>Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivoluma<em>b</em>, an immune checkpoint inhi<em>b</em>itor, for the treatment of advanced or metastatic MPM.</A<em>b</em>stractText><A<em>b</em>stractText>Japanese patients with unresecta<em>b</em>le, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measura<em>b</em>le lesion(s) were enrolled. Patients received nivoluma<em>b</em> 240 mg intravenously every 2 weeks until progressive disease or unaccepta<em>b</em>le toxicity. The primary endpoint was o<em>b</em>jective response rate <em>b</em>y central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated.</A<em>b</em>stractText><A<em>b</em>stractText>Thirty-four patients were enrolled <em>b</em>etween July 2016 and Octo<em>b</em>er 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed o<em>b</em>jective response. The o<em>b</em>jective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and <em>b</em>iphasic histologic su<em>b</em>types, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The o<em>b</em>jective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with &<em>lt</em>;1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs.</A<em>b</em>stractText><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>Nivoluma<em>b</em> met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with managea<em>b</em>le toxicity.<i>See related commentary <em>b</em>y Mansfield and Zauderer, p. 5438</i>.</p>

BACKGROUND

Unsafe water supplies continue to raise public health concerns, especially in urban areas in low resource countries. To understand the extent of public health risk attributed to supply water in Dhaka city, Bangladesh, Escherichia coli isolated from tap water samples collected from different locations of the city were characterized for their antibiotic resistance, pathogenic properties and genetic diversity.

RESULTS

A total of 233 E. coli isolates obtained from 175 tap water samples were analysed for susceptibility to 16 different antibiotics and for the presence of genes associated with virulence and antibiotic resistance. Nearly 36% (n = 84) of the isolates were multi-drug(≥ 3 classes of antibiotics) resistant (MDR) and 26% (n = 22) of these were positive for extended spectrum β-lactamase (ESBL). Of the 22 ESBL-producers, 20 were positive for bla CTX-M-15, 7 for bla OXA-1-group (all had bla OXA-47) and 2 for bla CMY-2. Quinolone resistance genes, qnrS and qnrB were detected in 6 and 2 isolates, respectively. Around 7% (n = 16) of the isolates carried virulence gene(s) characteristic of pathogenic E. coli; 11 of these contained lt and/or st and thus belonged to enterotoxigenic E. coli and 5 contained bfp and eae and thus belonged to enteropathogenic E. coli. All MDR isolates carried multiple plasmids (2 to 8) of varying sizes ranging from 1.2 to >120 MDa. Ampicillin and ceftriaxone resistance were co-transferred in conjugative plasmids of 70 to 100 MDa in size, while ampicillin, trimethoprim-sulfamethoxazole and tetracycline resistance were co-transferred in conjugative plasmids of 50 to 90 MDa. Pulsed-field gel electrophoresis analysis revealed diverse genetic fingerprints of pathogenic isolates.

CONCLUSIONS

Multi-drug resistant E. coli are wide spread in public water supply in Dhaka city, Bangladesh. Transmission of resistant bacteria and plasmids through supply water pose serious threats to public health in urban areas.

<A<em>b</em>stractText>Pyrotini<em>b</em>, an irreversi<em>b</em>le pan-Er<em>b</em>B inhi<em>b</em>itor, showed promising antitumor activity and accepta<em>b</em>le tolera<em>b</em>ility in a phase I trial. We assessed the efficacy and tolera<em>b</em>ility of pyrotini<em>b</em> versus lapatini<em>b</em>, <em>b</em>oth in com<em>b</em>ination with capecita<em>b</em>ine, in women with human epidermal growth factor receptor 2 (HER2)-positive metastatic <em>b</em>reast cancer in an open-la<em>b</em>el, mu<em>lt</em>icenter, randomized phase II study.</A<em>b</em>stractText><p><div>(<em>b</em>)PATIENTS AND METHODS</<em>b</em>)</div>Chinese patients with HER2-positive relapsed or metastatic <em>b</em>reast cancer previously treated with taxanes, anthracyclines, and/or trastuzuma<em>b</em> were assigned (1:1) to receive 400 mg pyrotini<em>b</em> or lapatini<em>b</em> 1,250 mg orally once per day for 21-day cycles in com<em>b</em>ination with capecita<em>b</em>ine (1,000 mg/m² orally twice per day on days 1 to 14). The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Between May 29, 2015, and March 15, 2016, 128 eligi<em>b</em>le patients were randomly assigned to the pyrotini<em>b</em> (n = 65) or lapatini<em>b</em> (n = 63) treatment groups. The overall response rate was 78.5% (95% CI, 68.5% to 88.5%) with pyrotini<em>b</em> and 57.1% (95% CI, 44.9% to 69.4%) with lapatini<em>b</em> (treatment difference, 21.3%; 95% CI, 4.0% to 38.7%; <i>P</i> = .01). The median progression-free survival was 18.1 months (95% CI, 13.9 months to not reached) with pyrotini<em>b</em> and 7.0 months (95% CI, 5.6 to 9.8 months) with lapatini<em>b</em> (adjusted hazard ratio, 0.36; 95% CI, 0.23 to 0.58; <i>P</i> &<em>lt</em>; .001). The most frequent grade 3 to 4 adverse events were hand-foot syndrome in 16 of 65 patients (24.6%) in the pyrotini<em>b</em> group versus 13 of 63 (20.6%) in the lapatini<em>b</em> group; diarrhea in 10 patients (15.4%) versus three patients (4.8%), respectively; and decreased neutrophil count in six patients (9.2%) versus two patients (3.2%), respectively.</p><A<em>b</em>stractText>In women with HER2-positive metastatic <em>b</em>reast cancer previously treated with taxanes, anthracyclines, and/or trastuzuma<em>b</em>, pyrotini<em>b</em> plus capecita<em>b</em>ine yielded statistically significant <em>b</em>etter overall response rate and progression-free survival than lapatini<em>b</em> plus capecita<em>b</em>ine in this randomized phase II trial.</A<em>b</em>stractText>

Bone defect repair is a challenging clinical problem in musculoskeletal system, especially in orthopaedic disorders such as steroid associated osteonecrosis (SAON). Magnesium (Mg) as a biodegradable metal with properly mechanical properties has been investigating for a long history. In this study, Mg powder, poly (lactide-co-glycolide) (PLGA), β-tricalcium phosphate (β-TCP) were the elements to formulate a novel porous PLGA/TCP/Mg (PTM) scaffolds using low temperature rapid prototyping (LT-RP) technology. The physical characterization of PTM scaffold and Mg ions release were analyzed in vitro. The osteogenic and angiogenic properties of PTM scaffolds, as well as the biosafety after implantation were assessed in an established SAON rabbit model. Our results showed that the PTM scaffold possessed well-designed bio-mimic structure and improved mechanical properties. Findings of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and micro-computed tomography (micro CT)-based angiography indicated that PTM scaffold could increase blood perfusion and promote new vessel ingrowth at 4 weeks after surgery, meanwhile, a plenty of newly formed vessels with well-architective structure were observed at 8 weeks. Correspondingly, at 12 weeks after surgery, micro-CT, histological and mechanical properties analysis showed that PTM could significant enhance new bone formation and strengthen newly formed bone mechanical properties. The mean bone volume in PTM group was 56.3% greater than that in PT group. Biosafety assessments from 0 to 12 weeks after implantation did not induce increase in serum Mg ions concentration, and immune response, liver and kidney function parameters were all at normal level. These findings suggested that the PTM scaffold had both osteogenic and angiogenic abilities which were synergistic effect in enhancing new bone formation and strengthen newly formed bone quality in SAON. In summary, PTM scaffolds are promising composite biomaterials for repairing challenging bone defect that would have great potential for its clinical translation.

<A<em>b</em>stractText>In this systematic review and meta-analysis, we aimed to explore the association <em>b</em>etween cardiac injury and mortality, the need for intensive care unit (ICU) care, acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19) in patients with COVID-19 pneumonia.</A<em>b</em>stractText><A<em>b</em>stractText>We performed a comprehensive literature search from several data<em>b</em>ases. Definition of cardiac injury follows that of the included studies, which includes highly sensitive cardiac troponin I (hs-cTnl) >99th percentile.The primary outcome was mortality, and the secondary outcomes were ARDS, the need for ICU care, and severe COVID-19. ARDS and severe COVID-19 were defined per the World Hea<em>lt</em>h Organization (WHO) interim guidance of severe acute respiratory infection (SARI) of COVID-19.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>There were a total of 2389 patients from 13 studies. This meta-analysis showed that cardiac injury was associated with higher mortality (RR 7.95 [5.12, 12.34], p &<em>lt</em>; 0.001; I²: 65%). Cardiac injury was associated with higher need for ICU care (RR 7.94 [1.51, 41.78], p = 0.01; I²: 79%), and severe COVID-19 (RR 13.81 [5.52, 34.52], p &<em>lt</em>; 0.001; I²: 0%). The cardiac injury was not significant for increased risk of ARDS (RR 2.57 [0.96, 6.85], p = 0.06; I²: 84%). The level of hs-cTnI was higher in patients with primary + secondary outcome (mean difference 10.38 pg/mL [4.44, 16.32], p = 0.002; I²: 0%).</p><A<em>b</em>stractText>Cardiac injury is associated with mortality, need for ICU care, and severity of disease in patients with COVID-19.</A<em>b</em>stractText>

(<em>b</em>)<i>Background:</i></<em>b</em>) Since the out<em>b</em>reak of the coronavirus disease 2019 (COVID-19) caused <em>b</em>y severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Decem<em>b</em>er 2019, it has affected >200 countries, areas, or territories in 6 continents. At present, whether COVID-19 has an effect on thyroid function is unclear. The aim of this study was to evaluate thyroid function in patients with COVID-19. (<em>b</em>)<i>Methods:</i></<em>b</em>) Clinical manifestations, la<em>b</em>oratory resu<em>lt</em>s, and chest computed tomography scans were retrospectively reviewed for 50 patients with la<em>b</em>oratory-confirmed COVID-19 without a history of thyroid disease who underwent thyroid function testing during their course of COVID-19 infection and after recovery. They were admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, <em>b</em>etween January and March 2020. Hea<em>lt</em>hy participants who underwent routine physical checkups and non-COVID-19 pneumonia patients with a similar degree of severity during the same period were included in the study as the control group. Thyroid hormone and thyrotropin (TSH) levels were analyzed and compared <em>b</em>etween the COVID-19 and control groups. (<em>b</em>)<i>Resu<em>lt</em>s:</i></<em>b</em>) TSH lower than the normal range was present in 56% (28/50) of the patients with COVID-19. The levels of TSH and serum total triiodothyronine (TT3) of the patients with COVID-19 were significantly lower than those of the hea<em>lt</em>hy control group and non-COVID-19 pneumonia patients. The more severe the COVID-19, the lower the TSH and TT3 levels were, with statistical significance (<i>p</i> &<em>lt</em>; 0.001). The degree of the decreases in TSH and TT3 levels was positively correlated with the severity of the disease. The total thyroxine (TT4) level of the patients with COVID-19 was not significantly different from the control group. All the patients did not receive thyroid hormone replacement therapy. After recovery, no significant differences in TSH, TT3, TT4, free triiodothyronine (fT3), and free thyroxine (fT4) levels were found <em>b</em>etween the COVID-19 and control groups. (<em>b</em>)<i>Conclusions:</i></<em>b</em>) The changes in serum TSH and TT3 levels may <em>b</em>e important manifestations of the courses of COVID-19.

Keywords: COVID-19; SARS-CoV-2; TSH; euthyroid sick syndrome; thyroid hormone.

The follicle-associated epithelium (FAE) of Peyer's patches (PPs) transports antigens and microorganisms into mucosal lymphoid tissues where they are captured by subepithelial dendritic cells (DCs). Feeding of cholera toxin (CT) induced migration of subepithelial DCs to interfollicular T-cell areas within 24 h. This study investigated short-term effects of CT, Escherichia coli heat-labile toxin, and non-toxic derivatives on DC migration. CT or CTB injected into ligated intestinal loops induced significant increase in CD11c+ DCs within the FAE within 90 min. In mice fed CT intragastrically, DC numbers in the FAE increased by 1 h, were maximal by 2 h, declined between 8 and 12 h, and were reversed by 24 h. Feeding of native LT, recombinant CTB, dibutyryl cyclic AMP, and to a lesser extent mutated CT(E29H) or mutated LT(R192G) had the same effect. Thus, both A and B subunits of enterotoxins, presumably acting through distinct signaling pathways, may promote capture of incoming antigens and pathogens by PP DCs.

Leukotriene (LT)B4 promotes leukocyte chemotaxis and adhesion to the endothelium of postcapillary venules. The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, elicit macromolecular leakage from this vessel segment. Both leukocyte adhesion to the endothelium and macromolecular leakage from postcapillary venules hallmark the microcirculatory failure after ischemia-reperfusion, suggesting a role of leukotrienes as mediators of ischemia-reperfusion injury. Using the dorsal skinfold chamber model for intravital fluorescence microscopy of the microcirculation in striated muscle in awake hamsters and sequential RP-HPLC and RIA for leukotrienes, we demonstrate in this study that (a) the leukotrienes (LT)B4 and LTD4 elicit leukocyte/endothelium interaction and macromolecular leakage from postcapillary venules, respectively, that (b) leukotrienes accumulate in the tissue after ischemia and reperfusion, and that (c) selective inhibition of leukotriene biosynthesis (by MK-886) prevents both postischemic leukotriene accumulation and the microcirculatory changes after ischemia-reperfusion, while blocking of LTD4/E4 receptors (by MK-571) inhibits postischemic macromolecular leakage. These results demonstrate a key role of leukotrienes in ischemia-reperfusion injury in striated muscle in vivo.

Type II heat-labile enterotoxin (LT-II) of Escherichia coli has several biologic activities similar to cholera toxin (CT) and E. coli type I heat-labile enterotoxin (LT-I), but it is not neutralized by antiserum prepared against CT or LT-I. LT-II was purified from E. coli SA53 and from E. coli HBLT-II genes in a hybrid plasmid and produces up to 600 times more LT-II than does SA53. Purification involved sonic disruption of bacterial cells, ammonium sulfate fractionation, chromatography on Affi-Gel Blue, chromatofocusing, and gel filtration on Sephadex G-100. The LT-II purified to apparent homogeneity from HBLT-I in the Y1 adrenal-cell assay. In contrast, purified LT-II did not cause secretion in ligated rabbit ileal segments at doses corresponding to CT controls that gave strongly positive reactions. LT-II was composed of two different polypeptides with MrS of 28,000 (A) and 11,800 (B); treatment of LT-II with trypsin cleaved the A polypeptide to fragments A1 (Mr, 21,000) and A2 (Mr, 7,000). The activity of LT-II was not blocked by ganglioside GM1 at concentrations that inactivated LT-I or CT. Antiserum against the LT-II from E. coli HBLT-II and the LT-II in crude extracts of SA53, but it did not neutralize purified LT-I or CT.

We have recently described a needle-free method of vaccination, transcutaneous immunization, consisting of the topical application of vaccine antigens to intact skin. While most proteins themselves are poor immunogens on the skin, we have shown that the addition of cholera toxin (CT), a mucosal adjuvant, results in cellular and humoral immune responses to the adjuvant and coadministered antigens. The present study explores the breadth of adjuvants that have activity on the skin, using diphtheria toxoid (DTx) and tetanus toxoid as model antigens. Heat-labile enterotoxin (LT) displayed adjuvant properties similar to those of CT when used on the skin and induced protective immune responses against tetanus toxin challenge when applied topically at doses as low as 1 microg. Interestingly, enterotoxin derivatives LTR192G, LTK63, and LTR72 and the recombinant CT B subunit also exhibited adjuvant properties on the skin. Consistent with the latter finding, non-ADP-ribosylating exotoxins, including an oligonucleotide DNA sequence, as well as several cytokines (interleukin-1beta [IL-1beta] fragment, IL-2, IL-12, and tumor necrosis factor alpha) and lipopolysaccharide also elicited detectable anti-DTx immunoglobulin G titers in the immunized mice. These results indicate that enhancement of the immune response to topical immunization is not restricted to CT or the ADP-ribosylating exotoxins as adjuvants. This study also reinforces earlier findings that addition of an adjuvant is important for the induction of robust immune responses to vaccine antigens delivered by topical application.

We show the cowpox genome (Brighton Red strain) contains a single copy gene, crmC, expressed at late times during viral infection, encoding a soluble, secreted protein whose sequence marks it as a new member of the TNF receptor family. The cysteine-rich protein contains 186 amino acids, the N-terminal 21 of which constitute a signal peptide, and two potential N-linked glycosylation sites. The approximately 25-kDa recombinant protein binds TNF specifically and completely inhibits TNF-mediated cytolysis. The strongest sequence homologues are the ligand-binding regions of the type II cellular TNF receptor (TNFRII) and CrmB, a distinct pox virus gene also encoding a soluble TNF binding protein. Unlike TNFRII and CrmB, CrmC does not bind lymphotoxin (LT alpha, TNF beta) and lacks the conserved (but nonhomologous) approximately 150-residue C-terminal domain of CrmB proteins. The presumed function of CrmC is viral inhibition of host-elicited TNF.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To explore and analyze the possi<em>b</em>le mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). (<em>b</em>)Methods:</<em>b</em>) The correlation <em>b</em>etween ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed <em>b</em>ased on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. <i>t</i>-test or Spearman rank correlation analysis was used for statistical analysis. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) ALT and AST were a<em>b</em>normally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue resu<em>lt</em>s of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in <em>b</em>ile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, <em>b</em>ut it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the <em>b</em>ile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of ACE2 (r > 0.2, FDR &<em>lt</em>; 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. (<em>b</em>)Conclusion:</<em>b</em>) We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused <em>b</em>y compensatory proliferation of hepatocytes derived from <em>b</em>ile duct epithelial cells may also <em>b</em>e the possi<em>b</em>le mechanism of liver tissue injury caused <em>b</em>y 2019 novel coronavirus infection.

In motor cortex, long-range output to subcortical motor circuits depends on excitatory and inhibitory inputs converging on projection neurons in layers 5A/B. How interneurons interconnect with these projection neurons, and whether these microcircuits are interneuron and/or projection specific, is unclear. We found that fast-spiking interneurons received strong intralaminar (horizontal) excitation from pyramidal neurons in layers 5A/B including corticostriatal and corticospinal neurons, implicating them in mediating disynaptic recurrent, feedforward, and feedback inhibition within and across the two projection classes. Low-threshold-spiking (LTS) interneurons were instead strongly excited by descending interlaminar (vertical) input from layer 2/3 pyramidal neurons, implicating them in mediating disynaptic feedforward inhibition to both projection classes. Furthermore, in a novel pattern, lower layer 2/3 preferentially excited interneurons in one layer (5A/LTS) and excitatory neurons in another (5B/corticospinal). Thus, these inhibitory microcircuits in mouse motor cortex follow an orderly arrangement that is laminarly orthogonalized by interneuron-specific, projection-nonspecific connectivity.

Mice with inactivation of lymphotoxin beta receptor (LTbetaR) system have profound defects in the development and maintenance of peripheral lymphoid organs. As surface LT is expressed by lymphocytes, natural killer cells, and lymphoid tissue-initiating cells as well as by some other cell types, we dissected cell type-specific LT contribution into the complex LT-deficient phenotype by conditional gene targeting. B-LTbeta knockout (KO) mice displayed an intermediate phenotype in spleen as compared with mice with complete LTbeta deficiency. In contrast, T-LTbeta KO mice displayed normal structure of the spleen. However, inactivation of LTbeta in both T and B cells resulted in additional defects in the structure of the marginal zone and in the development of follicular dendritic cells in spleen. Structure of lymph nodes (LN) and Peyer's patches (PP) was normal in both B-LTbeta KO and T- and B-LTbeta KO mice, except that PPs were of reduced size. When compared across the panel of lymphocyte-specific LT KOs, the defects in antibody responses to T-cell-dependent antigens correlated with the severity of defects in spleen structure. Expression of CCL21 and CCL19 chemokines was not affected in spleen, LN and PP of B-LTbeta KO and T- and B-LTbeta KO mice, while CXCL13 was slightly reduced only in spleen. Collectively, our data suggest the following: (i). requirements for LT signaling to support architecture of spleen, LN and PP are different; (ii). LT complex expressed by B cells plays a major role in the maintenance of spleen structure, while surface LT expressed by T cells provides a complementary but distinct signal; and (iii). in a non-transgenic model, expression of lymphoid tissue chemokines is only minimally dependent on the expression of surface LT complex on B and T lymphocytes.

<A<em>b</em>stractText>No standard adjuvant treatment currently is recommended in localized <em>b</em>iliary tract cancer (<em>B</em>TC) after surgical resection. We aimed to assess whether gemcita<em>b</em>ine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining hea<em>lt</em>h-related quality of life (HRQOL) in patients who undergo resection.</A<em>b</em>stractText><p><div>(<em>b</em>)PATIENTS AND METHODS</<em>b</em>)</div>We performed a mu<em>lt</em>icenter, open-la<em>b</em>el, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized <em>B</em>TC to receive either GEMOX (gemcita<em>b</em>ine 1,000 mg/m² on day 1 and oxaliplatin 85 mg/m² infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm <em>B</em>). Primary end points were RFS and HRQOL.</p><A<em>b</em>stractText><em>B</em>etween July 2009 and Fe<em>b</em>ruary 2014, 196 patients were included. <em>B</em>aseline characteristics were <em>b</em>alanced <em>b</em>etween the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS <em>b</em>etween the two arms (median, 30.4 months in arm A v 18.5 months in arm <em>B</em>; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of glo<em>b</em>al HRQOL (median, 31.8 months in arm A v 32.1 months in arm <em>B</em>; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm <em>B</em>; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm <em>B</em>) and grade 4 in 11% versus 3% ( P &<em>lt</em>; .001).</A<em>b</em>stractText><A<em>b</em>stractText>There was no <em>b</em>enefit of adjuvant GEMOX in resected <em>B</em>TC despite adequate tolerance and delivery of the regimen.</A<em>b</em>stractText>

LIGHT is a member of the TNF cytokine superfamily that signals through the lymphotoxin (LT)beta receptor and the herpesvirus entry mediator. LIGHT may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus, which may provide significant selective pressure shaping the evolution of LIGHT. Here, we define the molecular genetics of the human LIGHT locus, revealing its close linkage to the TNF superfamily members CD27 ligand and 4-1BB ligand, and the third complement protein (C3), which positions LIGHT within the MHC paralog on chromosome 19p13.3. An alternately spliced isoform of LIGHT mRNA that encodes a transmembrane-deleted form is detected in activated T cells and gives rise to a nonglycosylated protein that resides in the cytosol. Furthermore, membrane LIGHT is shed from the cell surface of human 293 T cells. These studies reveal new mechanisms involved in regulating the physical forms and cellular compartmentalization of LIGHT that may contribute to the regulation and biological function of this cytokine.

(<em>b</em>)Rationale:</<em>b</em>) Microglia play a critical role in modulating cell death and neuro<em>b</em>ehavioral recovery in response to <em>b</em>rain injury either <em>b</em>y direct cell-cell interaction or indirect secretion of trophic factors. Exosomes secreted from cells are well documented to deliver <em>b</em>ioactive molecules to recipient cells to modulate cell function. Here, we aimed to identify whether M2 microglia exert neuroprotection after ischemic attack through an exosome-mediated cell-cell interaction. (<em>b</em>)Methods:</<em>b</em>) M2 microglia-derived exosomes were intravenously injected into the mouse <em>b</em>rain immediately after middle cere<em>b</em>ral artery occlusion. Infarct volume, neurological score, and neuronal apoptosis were examined 3 days after ischemic attack. Exosome RNA and target protein expression levels in neurons and <em>b</em>rain tissue were determined for the mechanistic study. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) Our resu<em>lt</em>s showed that the M2 microglia-derived exosomes were taken up <em>b</em>y neurons <i>in vitro</i> and <i>in vivo</i>. M2 microglia-derived exosome treatment attenuated neuronal apoptosis after oxygen-glucose deprivation (p&<em>lt</em>;0.05). <i>In vivo</i> resu<em>lt</em>s showed that M2 microglia-derived exosome treatment significantly reduced infarct volume and attenuated <em>b</em>ehavioral deficits 3 days after transient <em>b</em>rain ischemia (p&<em>lt</em>;0.05), whereas injection of miR-124 knockdown (miR-124k/d) M2 microglia-derived exosomes partly reversed the neuroprotective effect. Our mechanistic study further demonstrated that u<em>b</em>iquitin-specific protease 14 (USP14) was the direct downstream target of miR-124. Injection of miR-124k/d M2 exosomes plus the USP14 inhi<em>b</em>itor, IU1, achieved compara<em>b</em>le neuroprotective effect as injection of M2 exosomes alone. (<em>b</em>)Conclusions:</<em>b</em>) We demonstrated that M2 microglia-derived exosomes attenuated ischemic <em>b</em>rain injury and promoted neuronal survival via exosomal miR-124 and its downstream target USP14. M2 microglia-derived exosomes represent a promising avenue for treating ischemic stroke.

Liver transplantation (LT) candidates today are increasingly older, have greater medical acuity, and have more cardiovascular comorbidities than ever before. Steadily rising model for end-stage liver disease (MELD) scores at the time of transplant, resulting from high organ demand, reflect the escalating risk profiles of LT candidates. In addition to advanced age and the presence of comorbidities, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Patients with cirrhosis requiring LT usually demonstrate increased cardiac output and a compromised ventricular response to stress, a condition termed cirrhotic cardiomyopathy. These cardiac disturbances are likely mediated by decreased beta-agonist transduction, increased circulating inflammatory mediators with cardiodepressant properties, and repolarization changes. Low systemic vascular resistance and bradycardia are also commonly seen in cirrhosis and can be aggravated by beta-blocker use. These physiologic changes all contribute to the potential for cardiovascular complications, particularly with the altered hemodynamic stresses that LT patients face in the immediate post-operative period. Post-transplant reperfusion may result in cardiac death due to a multitude of causes, including arrhythmia, acute heart failure, and myocardial infarction. Recognizing the hemodynamic challenges encountered by LT patients in the perioperative period and how these responses can be exacerbated by underlying cardiac pathology is critical in developing recommendations for the pre-operative risk assessment and management of these patients. The following provides a review of the cardiovascular challenges in LT candidates, as well as evidence-based recommendations for their evaluation and management.

The transcription factor Runx1 is essential for the formation of yolk sac-derived erythroid/myeloid progenitors (EMPs) and hematopoietic stem cells (HSCs) from hemogenic endothelium during embryogenesis. However, long-term repopulating HSCs (LT-HSCs) persist when Runx1 is conditionally deleted in fetal liver cells, demonstrating that the requirement for Runx1 changes over time. To define more precisely when Runx1 transitions from an essential factor to a homeostatic regulator of EMPs and HSCs, and whether that transition requires fetal liver colonization, we performed conditional, timed deletions of Runx1 between E7.5 and E13.5. We determined that Runx1 loss reduces the formation or function of EMPs up through E10.5. The Runx1 requirement in HSCs ends later, as deletion up to E11.5 eliminates HSCs. At E11.5, there is an abrupt transition to Runx1 independence in at least a subset of HSCs that does not require fetal liver colonization. The transition to Runx1 independence in EMPs is not mediated by other core binding factors (Runx2 and/or Runx3); however, deleting the common non-DNA-binding β subunit (CBFβ) severely compromises LT-HSC function. Hence, the requirements for Runx1 in EMP and HSC formation are temporally distinct, and LT-HSC function is highly reliant on continued core binding factor activity.

NOD-like receptors (NLRs) are a group of cytoplasmic molecules that recognize microbial invasion or 'danger signals'. Activation of NLRs can induce rapid caspase-1 dependent cell death termed pyroptosis, or a caspase-1 independent cell death termed pyronecrosis. Bacillus anthracis lethal toxin (LT), is recognized by a subset of alleles of the NLR protein Nlrp1b, resulting in pyroptotic cell death of macrophages and dendritic cells. Here we show that LT induces lysosomal membrane permeabilization (LMP). The presentation of LMP requires expression of an LT-responsive allele of Nlrp1b, and is blocked by proteasome inhibitors and heat shock, both of which prevent LT-mediated pyroptosis. Further the lysosomal protease cathepsin B is released into the cell cytosol and cathepsin inhibitors block LT-mediated cell death. These data reveal a role for lysosomal membrane permeabilization in the cellular response to bacterial pathogens and demonstrate a shared requirement for cytosolic relocalization of cathepsins in pyroptosis and pyronecrosis.

This study analyzed the results of the decentralized management of biliary atresia (BA) in France, where an improved collaboration between centers has been promoted since 1997. Results were compared to those obtained in England and Wales, where BA patients have been centralized in three designated centers since 1999. According to their birth dates, BA patients were divided into two cohorts: cohort A, with patients born between 1986 and 1996, had 472 patients; and cohort B, with patients born between 1997 and 2002, had 271 patients. Survival rates were calculated according to the Kaplan-Meier method and compared by using the log rank test and the Cox model. Four-year overall BA patient survival was 73.6% (95% CI 69.5%-77.7%) and 87.1% (CI 82.6%-91.6%) in cohorts A and B, respectively (P < .001). Median age at time of the Kasai operation was 61 and 57 days in cohorts A and B, respectively (NS). Four-year survival with native liver after the Kasai operation was 40.1% and 42.7% in cohorts A and B, respectively (NS): 33.9% (cohort A) and 33.4% (cohort B) in the centers with two or fewer caseloads a year, 30.9% (cohort A) and 44.5% (cohort B) in the centers with 3-5 cases/year, 47.8% (cohort A) and 47.7% (cohort B) in the center with more than 20 caseloads a year. In cohorts A and B, 74 (15.7%) and 19 (7%) patients, respectively, died without liver transplantation (LT). Four-year survival after LT was 75.1% and 88.8% in cohorts A and B, respectively (P = .006). In conclusion, BA patients currently have the same chance of survival in France as in England and Wales. The early success rate of the Kasai operation remains inferior in the centers with limited caseloads in France, leading to a greater need for LTs in infancy and early childhood.