This study has two goals. The first is to explain the geo-environmental determinants of the accelerated diffusion of COVID-19 that is generating a high level of deaths. The second is to suggest a strategy to cope with future epidemic threats similar to COVID-19 having an accelerated viral infectivity in society. Using data on sample of N = 55 Italian province capitals, and data of infected individuals at as of April 7th, 2020, resu<em>lt</em>s reveal that the accelerate and vast diffusion of COVID-19 in North Italy has a high association with air pollution of cities measured with days exceeding the limits set for PM<su<em>b</em>)10</su<em>b</em>) (particulate matter 10 μm or less in diameter) or ozone. In particular, hinterland cities with average high num<em>b</em>er of days exceeding the limits set for PM<su<em>b</em>)10</su<em>b</em>) (and also having a low wind speed) have a very high num<em>b</em>er of infected people on 7th April 2020 (arithmetic mean is a<em>b</em>out 2200 infected individuals, with average polluted days greater than 80 days per year), whereas coastal cities also having days exceeding the limits set for PM<su<em>b</em>)10</su<em>b</em>) or ozone <em>b</em>ut with high wind speed have a<em>b</em>out 944.70 average infected individuals, with a<em>b</em>out 60 average polluted days per year; moreover, cities having more than 100 days of air pollution (exceeding the limits set for PM<su<em>b</em>)10</su<em>b</em>)), they have a very high average num<em>b</em>er of infected people (a<em>b</em>out 3350 infected individuals, 7th April 2020), whereas cities having less than 100 days of air pollution per year, they have a lower average num<em>b</em>er of infected people (a<em>b</em>out 1014 individuals). The findings here also suggest that to minimize the impact of future epidemics similar to COVID-19, the max num<em>b</em>er of days per year that Italian provincial capitals or similar industrialized cities can exceed the limits set for PM<su<em>b</em>)10</su<em>b</em>) or for ozone, considering their meteorological conditions, is a<em>b</em>out 48 days. Moreover, resu<em>lt</em>s here reveal that the explanatory varia<em>b</em>le of air pollution in cities seems to <em>b</em>e a more important predictor in the initial phase of diffusion of viral infectivity (on 17th March 2020, <em>b</em><su<em>b</em>)1</su<em>b</em>) = 1.27, p &<em>lt</em>; 0.001) than interpersonal contacts (<em>b</em><su<em>b</em>)2</su<em>b</em>) = 0.31, p &<em>lt</em>; 0.05). In the second phase of maturity of the transmission dynamics of COVID-19, air pollution reduces intensity (on 7th April 2020 with <em>b</em>'<su<em>b</em>)1</su<em>b</em>) = 0.81, p &<em>lt</em>; 0.001) also <em>b</em>ecause of the indirect effect of lockdown, whereas regression coefficient of transmission <em>b</em>ased on interpersonal contacts has a sta<em>b</em>le level (<em>b</em>'<su<em>b</em>)2</su<em>b</em>) = 0.31, p &<em>lt</em>; 0.01). This resu<em>lt</em> reveals that accelerated transmission dynamics of COVID-19 is due to mainly to the mechanism of "air pollution-to-human transmission" (air<em>b</em>orne viral infectivity) rather than "human-to-human transmission". Overall, then, transmission dynamics of viral infectivity, such as COVID-19, is due to systemic causes: general factors that are the same for all regions (e.g., <em>b</em>iological characteristics of virus, incu<em>b</em>ation period, etc.) and specific factors which are different for each region and/or city (e.g., complex interaction <em>b</em>etween air pollution, meteorological conditions and <em>b</em>iological characteristics of viral infectivity) and hea<em>lt</em>h level of individuals (ha<em>b</em>its, immune system, age, sex, etc.). Lessons learned for COVID-19 in the case study here suggest that a proactive strategy to cope with future epidemics is also to apply especially an environmental and sustaina<em>b</em>le policy <em>b</em>ased on reduction of levels of air pollution mainly in hinterland and polluting cities- (having low wind speed, high percentage of moisture and num<em>b</em>er of fog days) -that seem to have an environment that foster a fast transmission dynamics of viral infectivity in society. Hence, in the presence of polluting industrialization in regions that can trigger the mechanism of air pollution-to-human transmission dynamics of viral infectivity, this study must conclude that a comprehensive strategy to prevent future epidemics similar to COVID-19 has to <em>b</em>e also designed in environmental and socioeconomic terms, that is also <em>b</em>ased on sustaina<em>b</em>ility science and environmental science, and not only in terms of <em>b</em>iology, medicine, hea<em>lt</em>hcare and hea<em>lt</em>h sector.

Keywords: Air Pollution; Airborne Transmission; Airborne disease; COVID-19; Coronavirus Infection; Disease Transmission; Epidemic Outbreak; Infection Prevention; Lung Disease; Opportunistic pathogen; Pandemic; Particulate Matter; Quarantine; SARS Coronavirus; SARS-CoV-2; Severe Acute Respiratory Syndrome Coronavirus 2; Transmission Dynamics; Viral infectivity; Virus Pneumonia; Virus Transmission.

The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that the cytokines tumor necrosis factor (TNF), lymphotoxin (LT) alpha, and LTbeta, as well as their receptors TNF receptor p55 (TNFRp55) and LTbetaR play essential roles in the development of GCs. To establish in which cell types expression of LTbetaR, LTbeta, and TNF is required for GC formation, LTbetaR-/-, LTbeta-/-, TNF-/-, B cell-deficient (BCR-/-), and wild-type mice were used to generate reciprocal or mixed bone marrow (BM) chimeric mice. GCs, herein defined as peanut agglutinin-binding (PNA+) clusters of centroblasts/centrocytes in association with follicular dendritic cell (FDC) networks, were not detectable in LTbetaR-/- hosts after transfer of wild-type BM. In contrast, the GC reaction was restored in LTbeta-/- hosts reconstituted with either wild-type or LTbetaR-/- BM. In BCR-/- recipients reconstituted with compound LTbeta-/-/BCR-/- or TNF-/-/BCR-/- BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent. Thus, development of splenic FDC networks depends on expression of LTbeta and TNF by B lymphocytes and LTbetaR by radioresistant stromal cells.

OBJECTIVE

To evaluate the feasibility and postoperative course of liver transplantation (LT) in cirrhotic patients who underwent liver resection prior to LT for HCC.

BACKGROUND

Although LT provides longer survival than liver resection for treatment of small HCCs, donor shortage and long LT wait time may argue against LT. The feasibility and survival following LT after hepatic resection have not been previously examined.

METHODS

Between 1991 and 2001, among 107 patients who underwent LT for HCC, 88 met Mazzafero's criteria upon pathologic analysis of the explant. Of these, 70 underwent primary liver transplantation (PLT) and 18 liver resection prior to secondary liver transplantation (SLT) for recurrence (n = 11), deterioration of liver function (n = 4), or high risk for recurrence (n = 3). Perioperative and postoperative factors and long-term survival were compared.

RESULTS

Comparison of PLT and SLT groups at the time of LT revealed similar median age (53 vs. 55 years), sex, and etiology of liver disease (alcohol/viral B/C/other). In the SLT group, the mean time between liver resection and listing for LT was 20 months (range 1-84 months). Overall time on LT waiting list of the two groups was similar (3 vs. 5 months). Pathologic analysis after LT revealed similar tumor size (2.2 vs. 2.3 cm) and number (1.6 vs. 1.7). Perioperative and postoperative courses were not different in terms of operative time (551 vs. 530 minutes), blood loss (1191 vs. 1282 mL), transfusion (3 vs. 2 units), ICU (9 vs. 10 days) or hospital stay (32 vs. 31 days), morbidity (51% vs. 56%) or 30-day mortality (5.7% vs. 5.6%). During a median follow-up of 32 months (3 to 158 months), 3 patients recurred after PLT and one after SLT. After transplantation, 3- and 5-year overall survivals were not different between groups (82 vs. 82% and 59 vs. 61%).

CONCLUSIONS

In selected patients, liver resection prior to transplantation does not increase the morbidity or impair long-term survival following LT. Therefore, liver resection prior to transplantation can be integrated in the treatment strategy for HCC.

<A<em>b</em>stractText>Pem<em>b</em>rolizuma<em>b</em> improved progression-free survival and overall survival versus ipilimuma<em>b</em> in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present resu<em>lt</em>s from 5 years of follow-up of patients in KEYNOTE-006.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>KEYNOTE-006 was an open-la<em>b</em>el, mu<em>lt</em>icentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimuma<em>b</em>-naive histologically confirmed advanced melanoma with known BRAF^V600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pem<em>b</em>rolizuma<em>b</em> 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimuma<em>b</em> 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with <em>b</em>locked randomisation within strata. Exploratory com<em>b</em>ination of data from the two pem<em>b</em>rolizuma<em>b</em> dosing regimen groups was not protocol-specified. Pem<em>b</em>rolizuma<em>b</em> treatment continued for up to 24 months. Eligi<em>b</em>le patients who discontinued pem<em>b</em>rolizuma<em>b</em> with sta<em>b</em>le disease or <em>b</em>etter after receiving at least 24 months of pem<em>b</em>rolizuma<em>b</em> or discontinued with complete response after at least 6 months of pem<em>b</em>rolizuma<em>b</em> and then progressed could receive an additional 17 cycles of pem<em>b</em>rolizuma<em>b</em>. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, num<em>b</em>er NCT01866319.</p><A<em>b</em>stractText>Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pem<em>b</em>rolizuma<em>b</em> (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimuma<em>b</em> (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the com<em>b</em>ined pem<em>b</em>rolizuma<em>b</em> groups and 15·9 months (13·3-22·0) in the ipilimuma<em>b</em> group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the com<em>b</em>ined pem<em>b</em>rolizuma<em>b</em> groups versus 3·4 months (2·9-4·2) in the ipilimuma<em>b</em> group (HR 0·57, 95% CI 0·48-0·67, p&<em>lt</em>;0·0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the com<em>b</em>ined pem<em>b</em>rolizuma<em>b</em> groups and in 50 (20%) of 256 patients in the ipilimuma<em>b</em> group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [&<em>lt</em>;1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the com<em>b</em>ined pem<em>b</em>rolizuma<em>b</em> groups and in 45 (18%) patients in the ipilimuma<em>b</em> group. One patient assigned to pem<em>b</em>rolizuma<em>b</em> died from treatment-related sepsis.</A<em>b</em>stractText><A<em>b</em>stractText>Pem<em>b</em>rolizuma<em>b</em> continued to show superiority over ipilimuma<em>b</em> after almost 5 years of follow-up. These resu<em>lt</em>s provide further support for use of pem<em>b</em>rolizuma<em>b</em> in patients with advanced melanoma.</A<em>b</em>stractText><A<em>b</em>stractText>Merck Sharp & Dohme.</A<em>b</em>stractText>

The factors regulating growth and patterning of the spleen are poorly defined. We demonstrate here that spleens from B cell-deficient mice have 10-fold reduced expression of the T zone chemokine, CCL21, a threefold reduction in T cell and dendritic cell (DC) numbers, and reduced expression of the T zone stromal marker, gp38. Using cell transfer and receptor blocking approaches, we provide evidence that B cells play a critical role in the early postnatal development of the splenic T zone. This process involves B cell expression of lymphotoxin (LT)alpha1beta2, a cytokine that is required for expression of CCL21 and gp38. Introduction of a B cell specific LTalpha transgene on to the LTalpha-deficient background restored splenic CCL21 and gp38 expression, DC numbers, and T zone size. This work also demonstrates that the role of B cells in T zone development is distinct from the effect of B cells on splenic T cell numbers, which does not require LTalpha1beta2. Therefore, B cells influence spleen T zone development by providing: (a) signals that promote T cell accumulation, and: (b) signals, including LTalpha1beta2, that promote stromal cell development and DC accumulation. Defects in these parameters may contribute to the immune defects associated with B cell deficiency in mice and humans.

Specialized roles for the pro-inflammatory cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) were characterized in TNF/LT alpha -/- and TNF -/- mice established by direct gene targeting of C57BL/6 ES cells. The requirement for LT early in lymphoid tissue organogenesis is shown to be distinct from the more subtle and varied role of TNF in promoting correct microarchitectural organization of leukocytes in LN and spleen. Development of normal Peyer's patch (PP) structure, in contrast, is substantially dependent on TNF. Only mice lacking LT exhibit retarded B cell maturation in vivo and serum immunoglobulin deficiencies. A temporal hierarchy in lymphoid tissue development can now be defined, with LT being an essential participant in general lymphoid tissue organogenesis, developmentally preceeding TNF that has a more varied and subtle role in promotion of correct spatial organization of leukocytes in LN and spleen PP development in TNF -/- mice is unusual, indicating that TNF is a more critical participant for this structure than it is for other lymphoid tissues.

The heat-labile enterotoxins of Vibrio cholerae and Escherichia coli are related in structure and function. They are oligomers consisting of A and B polypeptide subunits. They bind to gangliosides, and they activate adenylate cyclase. The toxins form two antigenically distinct groups; members of each group cross-react but are not necessarily identical. Serogroup I includes cholera toxin (CT) and type I heat-labile enterotoxin (LT-I) of E. coli. LTh-I and LTp-I are antigenic variants of LT-I produced by strains of E. coli from humans and pigs, respectively. Serogroup II contains the type II heat-labile enterotoxin (LT-II) of E. coli. Two antigenic variants designated LT-IIa and LT-IIb have been described. The binding of CT, LTh-I, LT-IIa, and LT-IIb to gangliosides was analyzed by immunostaining thin-layer chromatograms and by solid-phase radioimmunoassay. The four toxins have different glycolipid-binding specificities. LTh-I and CT bind strongly to ganglioside GM1 and less strongly to ganglioside GD1b. However, LTh-I, unlike CT, also binds weakly to GM2 and asialo GM1. LTh-I, like CT, probably binds to the terminal sugar sequence Gal beta 1-3GalNAc beta 1-4(NeuAc alpha 2-3)Gal . . ., where GalNAc is N-acetylgalactosamine and NeuAc is N-acetylneuraminic acid. LT-IIa probably binds to the same sugar sequence to which CT and LTh-I bind, with the additional contribution to binding of a second NeuAc as in GD1b and GD2. Also, LT-IIa must bind the Gal beta 1-3GalNAc . . . sequence in such a way that its binding is relatively unaffected by attachment of NeuAc to the terminal galactose residue as in GD1a, GT1b, and GQ1b. LT-IIb probably binds to the terminal sugar sequence NeuAc alpha 2-3Gal beta 1-4GalNAc . . ., as it binds to gangliosides GD1a and GT1b but not to GM1.

The gastrointestinal mucosa contains a complex network of lymphoid compartments that have evolved to efficiently protect the host from invading pathogens. Recently, an additional lymphoid structure resembling Peyer's patches (PP) in composition and architecture has been identified in the murine small intestine, the isolated lymphoid follicle (ILF). In this study we examine the nature and factors required for ILF formation. We observed a spectrum of structures fitting the previous descriptions of ILFs, ranging from clusters of BLT)- and LT beta receptor-dependent events. However unlike PP formation, the LT- and LT beta receptor-dependent events required for ILF formation can occur in adulthood and require LT-sufficient B lymphocytes. We demonstrate that mature ILF formation occurs in response to lumenal stimuli, including normal bacterial flora, and requires TNF receptor I function. These findings suggest that ILFs are organized intestinal lymphoid structures whose formation can be induced and whose mass can be expanded in response to mucosal challenges.

Self-renewal is a defining characteristic of stem cells; however, the molecular pathways underlying its regulation are poorly understood. Here, we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell-cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes is associated with the TGF-beta pathway, which serves a major role in maintaining HSC quiescence. Prospectively isolated, Pbx1-deficient LT-HSCs display altered transcriptional responses to TGF-beta stimulation in vitro, suggesting a possible mechanism through which Pbx1 maintenance of stem cell quiescence may in part be achieved.

The B subunit (BS) of cholera toxin and that of the heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli (ETEC) are antigenically similar. We therefore assessed whether a combined cholera toxin BS/whole-cell (BS-WC) oral vaccine against cholera conferred cross-protection against LT-producing ETEC (LT-ETEC) diarrhea in a randomized, double-blind field trial among rural Bangladeshi children and women. The 24,770 persons who ingested two or more doses of BS-WC vaccine were compared with 24,842 controls who took two or more doses of killed whole-cell (WC) oral cholera vaccine. Sixty-seven percent fewer episodes of LT-ETEC diarrhea were noted in the BS-WC group than in the WC group during short-term (three-month) follow-up (P less than .01), but no reduction was evident during the ensuing nine months. Short-term protection was particularly notable against LT-ETEC diarrhea causing life-threatening dehydration (protective efficacy, 86%; P less than .05).

This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines' synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes' expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.

Background: COVID-19 has spread globally. Epidemiological susceptibility to COVID-19 has been reported in patients with cancer. We aimed to systematically characterise clinical features and determine risk factors of COVID-19 disease severity for patients with cancer and COVID-19.

Methods: In this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, 2020. Enrolled patients were statistically matched (2:1) with patients admitted with COVID-19 who did not have cancer with propensity score on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, illness severity, and clinical interventions were compared between patients with COVID-19 with or without cancer as well as between patients with cancer with non-severe or severe COVID-19. COVID-19 disease severity was defined on admission on the basis of the WHO guidelines. Univariable and multivariable logistic regression, adjusted for age, sex, comorbidities, cancer type, tumour stage, and antitumour treatments, were used to explore risk factors associated with COVID-19 disease severity. This study was registered in the Chinese Clinical Trial Register, ChiCTR2000030807.

Findings: Between Jan 13 and March 18, 2020, 13 077 patients with COVID-19 were admitted to the nine hospitals in Wuhan and 232 patients with cancer and 519 statistically matched patients without cancer were enrolled. Median follow-up was 29 days (IQR 22-38) in patients with cancer and 27 days (20-35) in patients without cancer. Patients with cancer were more likely to have severe COVID-19 than patients without cancer (148 [64%] of 232 vs 166 [32%] of 519; odds ratio [OR] 3·61 [95% CI 2·59-5·04]; p&lt;0·0001). Risk factors previously reported in patients without cancer, such as older age; elevated interleukin 6, procalcitonin, and D-dimer; and reduced lymphocytes were validated in patients with cancer. We also identified advanced tumour stage (OR 2·60, 95% CI 1·05-6·43; p=0·039), elevated tumour necrosis factor α (1·22, 1·01-1·47; p=0·037), elevated N-terminal pro-B-type natriuretic peptide (1·65, 1·03-2·78; p=0·032), reduced CD4+ T cells (0·84, 0·71-0·98; p=0·031), and reduced albumin-globulin ratio (0·12, 0·02-0·77; p=0·024) as risk factors of COVID-19 severity in patients with cancer.

Interpretation: Patients with cancer and COVID-19 were more likely to deteriorate into severe illness than those without cancer. The risk factors identified here could be helpful for early clinical surveillance of disease progression in patients with cancer who present with COVID-19.

Funding: China National Natural Science Foundation.

Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20,000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM), human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM, the compound produced little or no inhibition of several related enzymes, such as platelet 12-lipoxygenase, soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog, zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat, the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation, zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro, ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.

Tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) are members of a family of secreted and cell surface cytokines that participate in the regulation of immune and inflammatory responses. The cell surface form of LT-alpha is assembled during biosynthesis as a heteromeric complex with lymphotoxin-beta (LT-beta), a type II transmembrane protein that is another member of the TNF ligand family. Secreted LT-alpha is a homotrimer that binds to distinct TNF receptors of 60 and 80 kilodaltons; however, these receptors do not recognize the major cell surface LT-alpha-LT-beta complex. A receptor specific for human LT-beta was identified, which suggests that cell surface LT may have functions that are distinct from those of secreted LT-alpha.

Lymph node (LN) function depends on T and B cell compartmentalization, antigen presenting cells, and high endothelial venules (HEVs) expressing mucosal addressin cell adhesion molecule (MAdCAM-1) and peripheral node addressin (PNAd), ligands for naive cell entrance into LNs. Luminal PNAd expression requires a HEV-restricted sulfotransferase (HEC-6ST). To investigate LT alpha beta's activities in lymphoid organogenesis, mice simultaneously expressing LT alpha and LT beta under rat insulin promoter II (RIP) control were compared with RIPLT alpha mice in a model of lymphoid neogenesis and with LT beta-/- mice. RIPLT alpha beta pancreata exhibited massive intra-islet mononuclear infiltrates that differed from the more sparse peri-islet cell accumulations in RIPLT alpha pancreata: separation into T and B cell areas was more distinct with prominent FDC networks, expression of lymphoid chemokines (CCL21, CCL19, and CXCL13) was more intense, and L-selectin+ cells were more frequent. In contrast to the predominant abluminal PNAd pattern of HEV in LT beta-/- MLN and RIPLT alpha pancreatic infiltrates, PNAd was expressed at the luminal and abluminal aspects of HEV in wild-type LN and in RIPLT alpha beta pancreata, coincident with HEC-6ST. These data highlight distinct roles of LT alpha and LT alpha beta in lymphoid organogenesis supporting the notion that HEC-6ST-dependent luminal PNAd is under regulation by LT alpha beta.

The recently described tumor necrosis factor (TNF) family member LIGHT (herpes virus entry mediator [HVEM]-L/TNFSF14), a ligand for the lymphotoxin (LT)beta receptor, HVEM, and DcR3, was inactivated in the mouse. In contrast to mice deficient in any other member of the LT core family, LIGHT(-/-) mice develop intact lymphoid organs. Interestingly, a lower percentage of LIGHT(-/-)LTbeta(-/-) animals contain mesenteric lymph nodes as compared with LTbeta(-/-) mice, whereas the splenic microarchitecture of LIGHT(-/-)LTbeta(-/-) and LTbeta(-/-) mice shows a comparable state of disruption. This suggests the existance of an additional undiscovered ligand for the LTbeta receptor (LTbetaR) or a weak LTalpha(3)-LTbetaR interaction in vivo involved in the formation of secondary lymphoid organs. LIGHT acts synergistically with CD28 in skin allograft rejection in vivo. The underlying mechanism was identified in in vitro allogeneic MLR studies, showing a reduced cytotoxic T lymphocyte activity and cytokine production. Detailed analyses revealed that proliferative responses specifically of CD8+ T cells are impaired and interleukin 2 secretion of CD4+ T cells is defective in the absence of LIGHT. Furthermore, a reduced 3[H]-thymidine incorporation after T cell receptor stimulation was observed. This for the first time provides in vivo evidence for a cooperative role for LIGHT and LTbeta in lymphoid organogenesis and indicates important costimulatory functions for LIGHT in T cell activation.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To explore the clinical characteristics and prognosis of the new coronavirus 2019-nCoV patients com<em>b</em>ined with cardiovascular disease (CVD). (<em>b</em>)Methods:</<em>b</em>) A retrospective analysis was performed on 112 COVID-19 patients with CVD admitted to the western district of Union Hospital in Wuhan, from January 20, 2020 to Fe<em>b</em>ruary 15, 2020. They were divided into critical group (ICU, <i>n</i>=16) and general group (<i>n</i>=96) according to the severity of the disease and patients were followed up to the clinical endpoint. The o<em>b</em>servation indicators included total <em>b</em>lood count, C-reactive protein (CRP), arterial <em>b</em>lood gas analysis, myocardial injury markers, coagulation function, liver and kidney function, electrolyte, procalcitonin (PCT), <em>B</em>-type natriuretic peptide (<em>B</em>NP), <em>b</em>lood lipid, pulmonary CT and pathogen detection. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) Compared with the general group, the lymphocyte count (0.74×10(9) (0.34×10(9), 0.94×10(9))/L vs. 0.99×10(9) (0.71×10(9), 1.29×10(9))/L, <i>P</i>=0.03) was extremely lower in the critical group, CRP (106.98 (81.57, 135.76) mg/L vs. 34.34 (9.55,76.54) mg/L, <i>P</i>&<em>lt</em>;0.001) and PCT (0.20 (0.15,0.48) μg/L vs. 0.11 (0.06,0.20)μg/L, <i>P</i>&<em>lt</em>;0.001) were significantly higher in the critical group. The <em>B</em>MI of the critical group was significantly higher than that of the general group (25.5 (23.0, 27.5) kg/m(2) vs. 22.0 (20.0, 24.0) kg/m(2), <i>P</i>=0.003). Patients were further divided into non-survivor group (17, 15.18%) group and survivor group (95, 84.82%). Among the non-survivors, there were 88.24% (15/17) patients with <em>B</em>MI> 25 kg/m(2), which was significantly higher than that of survivors (18.95% (18/95), <i>P</i>&<em>lt</em>;0.001). Compared with the survived patients, oxygenation index (130 (102, 415) vs. 434 (410, 444), <i>P</i>&<em>lt</em>;0.001) was significantly lower and lactic acid (1.70 (1.30, 3.00) mmol/L vs. 1.20 (1.10, 1.60) mmol/L, <i>P</i>&<em>lt</em>;0.001) was significantly higher in the non-survivors. There was no significant difference in the proportion of ACEI/AR<em>B</em> medication <em>b</em>etween the critical group and the general group or <em>b</em>etween non-survivors and survivors (all <i>P</i>>0.05). (<em>b</em>)Conclusion:</<em>b</em>) COVID-19 patients com<em>b</em>ined with CVD are associated with a higher risk of mortality. Critical patients are characterized with lower lymphocyte counts. Higher <em>B</em>MI are more often seen in critical patients and non-survivor. ACEI/AR<em>B</em> use does not affect the mor<em>b</em>idity and mortality of COVID-19 com<em>b</em>ined with CVD. Aggravating causes of death include fulminant inflammation, lactic acid accumulation and throm<em>b</em>otic events.

Anthrax is an infection caused by pathogenic strains of Bacillus anthracis, which secretes a three-component toxic complex consisting of protective antigen (PA), edema factor (EF), and lethal factor (LF). PA forms binary complexes with either LF or EF and mediates their entry into host cells. Although the initial phases of bacterial growth occur in the lymph node, the host fails to mount an effective immune response. Here, we show that LT and ET are potent suppressors of human T cell activation and proliferation triggered through the antigen receptor. Both LT and ET inhibit the mitogen-activated protein and stress kinase pathways, and both toxins inhibit activation of NFAT and AP-1, two transcription factors essential for cytokine gene expression. These data identify a novel strategy of immune evasion by B. anthracis, based on both effector subunits of the toxic complex, and targeted to a key cellular component of adaptive immunity.

Lymphoid tissue development is associated with local accumulation of CD4+ CD3- IL-7R alpha hi hematopoietic cells that deliver lymphotoxin (LT)alpha 1 beta 2 signals to resident stromal cells. Previous studies have established an important role for CXCL13 (BLC) in the development of Peyer's patches (PP) and some peripheral lymph nodes (LNs), but the chemokine requirements for several LN types, including mesenteric LNs, remain undefined. Using CXCL13-/- mice that additionally carry the paucity of LN T cell mutation (plt/plt), we discovered that CCR7 ligands function in peripheral LN development. We also tested for a genetic interaction during LN development between CXCL13 and a cytokine receptor required in PP development, IL-7R alpha. Mice deficient for both CXCL13 and IL-7R alpha displayed a striking absence of LNs, including mesenteric LNs. These data extend the role of CXCL13 to the development of all LNs and establish a previously unappreciated role for IL-7R alpha in this process. Both circulating and LN CD4+ CD3- IL-7R alpha hi cells are shown to express LT alpha 1 beta 2 in an IL-7R alpha-dependent manner. Furthermore, CXCL13 was found to be sufficient to mediate CD4+ CD3- IL-7R alpha hi cell recruitment in vivo to an ectopic site. These findings indicate that CXCL13 and CCR7 ligands promote accumulation of CD4+ CD3- IL-7R alpha hi cells, delivering IL-7R alpha-dependent LT alpha 1 beta 2 signals critical for LN development.

Proper lymph node (LN) development requires tumor necrosis factor-related activation-induced cytokine (TRANCE) expression. Here we demonstrate that the defective LN development in TRANCE(-/)- mice correlates with a significant reduction in lymphotoxin (LT)alphabeta(+)alpha(4)beta(7)(+)CD45(+)CD4(+)CD3(-) cells and their failure to form clusters in rudimentary mesenteric LNs. Transgenic TRANCE overexpression in TRANCE(-/)- mice results in selective restoration of this cell population into clusters, and results in full LN development. Transgenic TRANCE-mediated restoration of LN development requires LTalphabeta expression on CD45(+) CD4(+)CD3(-) cells, as LNs could not be induced in LTalpha(-/)- mice. LTalpha(-/)- mice also showed defects in the fate of CD45(+)CD4(+)CD3(-) cells similar to TRANCE(-/)- mice. Thus, we propose that both TRANCE and LTalphabeta regulate the colonization and cluster formation by CD45(+) CD4(+)CD3(-) cells in developing LNs, the degree of which appears to correlate with the state of LN organogenesis.

Highly purified interleukin 1 (IL 1) obtained from stimulated human monocytes appeared to be growth inhibitory and cytocidal for a human melanoma cell line, A375. Although IL 1 did not have an immediate cytolytic effect, with time in culture the growth of the target cells was irreversibly inhibited. The cells eventually lysed and decreased markedly in number; the IL 1 effect can therefore be said to be cytocidal. IL 1 activity could not be separated from the cytocidal activity by a variety of chromatography procedures by using conventional and high-performance liquid chromatography (HPLC). The A375 melanoma cell line was also sensitive to another human cytokine alpha-lymphotoxin (alpha-LT) derived from a human B cell line. IL 1 also appeared to be partially growth inhibitory and cytocidal for a LT-sensitive mouse fibroblast cell line, L929; but not for LT-resistant cells, including a subline of L929; a human epithelial carcinoma cell line, HeLa; a human osteosarcoma cell line, HOS; and a mouse SV40-transformed kidney cell line, TU5. However, the LT-sensitive mouse fibroblast cell line, L-M, was resistant to IL 1. Therefore, the cytocidal activity of IL 1 only partially overlapped the target cell selectivity of alpha-LT. Although natural IFN-alpha and recombinant IFN-beta were appreciably growth inhibitory for the A375 cell line, natural and recombinant IFN-alpha and recombinant IFN-beta and IFN-gamma exhibited little cytocidal activity. Purified IL 1 did not have any antiviral activity, and conversely, IFN and alpha-LT were not co-mitogenic for thymocytes. Furthermore, by ELISA and radioimmunoassays, antibodies against human alpha-LT, tumor necrosis factor, and IFN-gamma did not react with IL 1, indicating that IL 1 is antigenically distinct from these other cytokines. These in vitro results suggest that IL 1 may play a role in host defense against some tumors as a cytocidal factor.

The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at positions -308 and -238 in the TNF alpha gene (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF alpha and LT alpha secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNF alpha secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNF alpha (17 408 pg/ml; P=0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype thus defines a 'low secretor phenotype'. In conclusion, this is the first study to show associations between TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To analyze the clinical characteristics of 2019 novel coronavirus (2019-nCoV) pneumonia and to investigate the correlation <em>b</em>etween serum inflammatory cytokines and severity of the disease. (<em>b</em>)Methods:</<em>b</em>) 29 patients with 2019-ncov admitted to the isolation ward of Tongji hospital affiliated to Tongji medical college of Huazhong University of Science and Technology in January 2020 were selected as the study su<em>b</em>jects. Clinical data were collected and the general information, clinical symptoms, <em>b</em>lood test and CT imaging characteristics were analyzed. According to the relevant diagnostic criteria, the patients were divided into three groups: mild (15 cases), severe (9 cases) and critical (5 cases). The expression levels of inflammatory cytokines and other markers in the serum of each group were detected, and the changes of these indicators of the three groups were compared and analyzed, as well as their relationship with the clinical classification of the disease. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) (1) The main symptoms of 2019-nCoV pneumonia was fever (28/29) with or without respiratory and other systemic symptoms. Two patients died with underlying disease and co-<em>b</em>acterial infection, respectively. (2) The <em>b</em>lood test of the patients showed normal or decreased white <em>b</em>lood cell count (23/29), decreased lymphocyte count (20/29), increased hypersensitive C reactive protein (hs-CRP) (27/29), and normal procalcitonin. In most patients,serum lactate dehydrogenase (LDH) was significantly increased (20/29), while al<em>b</em>umin was decreased(15/29). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total <em>b</em>iliru<em>b</em>in (T<em>b</em>il), serum creatinine (Scr) and other items showed no significant changes. (3) CT findings of typical cases were single or mu<em>lt</em>iple patchy ground glass shadows accompanied <em>b</em>y septal thickening. When the disease progresses, the lesion increases and the scope expands, and the ground glass shadow coexists with the solid shadow or the stripe shadow. (4) There were statistically significant differences in the expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of the three groups (P&<em>lt</em>;0.05), among which the critical group was higher than the severe group and the severe group was higher than the mildgroup. However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-α), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (P>0.05). (<em>b</em>)Conclusion:</<em>b</em>) The clinical characteristics of 2019-nCoV pneumonia are similar to those of common viral pneumonia. High resolution CT is of great value in the differential diagnosis of this disease. The increased expression of IL-2R and IL-6 in serum is expected to predict the severity of the 2019-nCoV pneumonia and the prognosis of patients.