Abeta vaccination or passive transfer of human-specific anti-Abeta antibodies are approaches under investigation to prevent and/or treat Alzheimer's disease (AD). Successful active Abeta vaccination requires a strong and safe adjuvant to induce anti-Abeta antibody formation. We compared the adjuvants monophosphoryl lipid A (MPL)/trehalose dicorynomycolate (TDM), cholera toxin B subunit (CTB) and Escherichia coli heat-labile enterotoxin LT(R192G) for their ability to induce a humoral and cellular immune reaction, using fibrillar Abeta1-40/42 as a common immunogen in wildtype BLT(R192G). Using MPL/TDM, the anti-Abeta antibodies induced were mainly IgG2b, IgG1 and lower levels of IgG2a and IgM, with a moderate splenocyte proliferation and IFN-gamma production in vitro upon stimulation with Abeta1-40/42. LT(R192G), previously shown by us to induce robust titers of anti-Abeta antibodies, generated predominantly IgG2b and IgG1 anti-Abeta antibodies with very low splenocyte proliferation and IFN-gamma production. Weekly intranasal (i.n.) administration over 11 weeks of Abeta40/42 with CTB induced only moderate levels of antibodies. All immunogens generated antibodies that recognized mainly the Abeta1-7 epitope and specifically detected amyloid plaques on AD brain sections. In conclusion, MPL/TDM, in addition to LT(R192G), is an effective adjuvant when combined with Abeta40/42 and may aid in the design of Abeta immunotherapy.

We have compared the intraleukocytic survival of isogenic strains of Salmonella typhimurium, whose outer membrane lipopolysaccharide differed in O antigen and lipid A composition and whose susceptibility to nonoxidative antimicrobial granule proteins of human polymorphonuclear neutrophilis (PMN) could be established. We found that the order of resistance to the bactericidal activity of intact PMN of the three bacterial strains utilized closely resembled their ordered resistance to the purified human cationic antimicrobial 57,000-dalton protein (CAP57). LT-2, a smooth wild-type strain, was far more resistant than SH9178, its rough (Rb LPS) mutant. It was most significant that SH7426, a polymyxin B-resistant pmrA mutant of SH9178, not only was substantially more resistant to CAP57 and to intraphagocytic killing than SH9178 but also came close to being as resistant as LT-2. These experiments confirm earlier work that showed the importance of the glycosyl groups of O antigens of S. typhimurium for their resistance to O2-independent antimicrobial phagocytosis by PMN. The surprising result was that a rough strain, very susceptible to bactericide, became substantially more resistant when a mutation led to its lipid A phosphoryl groups being 100% substituted with amino pentoses. Yet unresolved is whether the protection is due to the loss of negative charges on the lipid A, the substitution of sugar molecules in vulnerable loci in the outer membrane, or both.

The primary aim of this study is to determine whether treatment with lamivudine improved pre-liver transplantation (pre-LT) and LT-free survival of patients awaiting LT for hepatitis B virus (HBV)-related cirrhosis. Data from 162 lamivudine-treated and 147 untreated transplant candidates managed at 20 North American transplant centers between 1996 and 1998 were collected and compared. Lamivudine-treated patients were more likely to be men, hepatitis B e antigen positive, HBV DNA positive, and have lower serum albumin levels at listing (P <.05). Actuarial pre-LT and LT-free survival were similar in lamivudine-treated and untreated patients. Using Cox regression analysis, the only significant predictor of pre-LT patient survival was the modified Child-Turcotte-Pugh (mCTP) score, whereas significant predictors of LT-free survival included ethnic background, lamivudine treatment, indication for LT, baseline serum alanine aminotransferase level, and baseline mCTP score. Lamivudine had no apparent effect on liver disease severity in patients undergoing LT, but appeared to improve disease severity in patients still awaiting LT. Breakthrough infection was noted in 11% of lamivudine-treated patients. We conclude that lamivudine therapy is not associated with improved pre-LT or LT-free survival in LT candidates with chronic hepatitis B. However, a subset of patients with less advanced liver failure may derive clinical benefit from lamivudine therapy, thus delaying the need for LT. In the absence of prospective, randomized, controlled trials of lamivudine in patients with decompensated cirrhosis, careful selection of patients and optimal timing of treatment are needed to balance the risk versus benefit of lamivudine therapy in LT candidates.

The three-dimensional structure of recombinant human lymphotoxin (residues 24-171 of the mature protein) has been determined by x-ray crystallography at 1.9-A resolution (Rcryst = 0.215 for I greater than 3 sigma (I)). Phases were derived by molecular replacement using tumor necrosis factor (TNF-alpha) as a search model. Like TNF-alpha, lymphotoxin (LT) folds to form a "jellyroll" beta-sheet sandwich. Three-fold related LT subunits form a trimer stabilized primarily by hydrophobic interactions. A cluster of 6 basic residues around the 3-fold axis may account for the acid lability of the trimer. Although the structural cores of TNF-alpha and LT are similar, insertions and deletions relative to TNF-alpha occur in loops at the "top" of the LT trimer and significantly alter the local structure and the overall shape trimer is highly conserved. The sites of two mutations (Asp-50 and Tyr-108) that abolish the cytotoxicity of LT are contained within poorly ordered loops of polypeptide chain that flank the cleft between neighboring subunits at the base of the molecule, suggesting that the receptor recognizes an intersubunit binding site.

The ability to elicit protective immune responses after intranasal immunization with rotavirus particles, either with or without the attenuated Escherichia coli heat-labile enterotoxin LT(R192G) as an adjuvant, was examined in the adult mouse model. BALB/c mice were administered one or two inoculations of psoralen/UV-inactivated, triple-layered (tl) or double-layered (dl) purified rotavirus particles. Four weeks after immunization, mice were challenged with the murine rotavirus strain EDIM, and the shedding of rotavirus antigen was quantified. Rotaviruses used for immunization included EDIM and heterotypic simian (RRV), bovine (WC3), and human (89-12) strains. tl EDIM stimulated both systemic and intestinal rotavirus antibody responses and complete protection with as little as one 1-microgram dose. Inclusion of LT(R192G) (10 micrograms) significantly increased rotavirus antibody responses and reduced antigen concentrations needed for full protection. Both dl EDIM and heterotypic dl and tl particles stimulated protection, but they did so less than tl EDIM at comparable concentrations, either with or without LT(R192G). When B-cell-deficient microMt mice were immunized with tl EDIM particles, protection was reduced to levels similar to those induced with dl EDIM and heterotypic particles in BALB/c mice. However, dl EDIM particles induced similar levels of protection in both mouse strains. The protection stimulated by tl or dl EDIM particles was not diminished by CD8 cell depletion prior to immunization in either strain of mice. These results indicate that tl EDIM induced immunity at least partially through responses to its outer capsid proteins, presumably by stimulation of serotype-specific neutralizing antibody. In contrast, the other particles stimulated protection primarily by an antibody-independent mechanism. Finally, depletion of CD8 cells had no effect on protection by either mechanism.

The heat-labile toxin (LT) of Escherichia coli is a potent mucosal adjuvant that has been used to induce protective immunity against Helicobacter felis and Helicobacter pylori infection in mice. We studied whether recombinant LT or its B subunit (LTB) has adjuvant activity in mice when delivered with H. pylori urease antigen via the parenteral route. Mice were immunized subcutaneously or intradermally with urease plus LT, recombinant LTB, or a combination of LT and LTB prior to intragastric challenge with H. pylori. Control mice were immunized orally with urease plus LT, a regimen shown previously to protect against H. pylori gastric infection. Parenteral immunization using either LT or LTB as adjuvant protected mice against H. pylori challenge as effectively as oral immunization and enhanced urease-specific immunoglobulin G (IgG) responses in serum as effectively as aluminum hydroxide adjuvant. LT and LTB had adjuvant activity at subtoxic doses and induced more consistent antibody responses than those observed with oral immunization. A mixture of a low dose of LT and a high dose of LTB stimulated the highest levels of protection and specific IgG in serum. Urease-specific IgG1 and IgG2a antibody subclass responses were stimulated by all immunization regimens tested, but relative levels were dependent on the adjuvant used. Compared to parenteral immunization with urease alone, LT preferentially enhanced IgG1, while LTB or the LT-LTB mixture preferentially enhanced IgG2a. Parenteral immunization using LT or LTB as adjuvant also induced IgA to urease in the saliva of some mice. These results show that LT and LTB stimulate qualitatively different humoral immune responses to urease but are both effective parenteral adjuvants for immunization of mice against H. pylori infection.

Objective: Data on serial liver biochemistries of patients infected by different human coronaviruses (HCoVs) are lacking. The impact of liver injury on adverse clinical outcomes in coronavirus disease 2019 (COVID-19) patients remains unclear.

Design: This was a retrospective cohort study using data from a territory-wide database in Hong Kong. COVID-19, severe acute respiratory syndrome (SARS) and other HCoV patients were identified by diagnosis codes and/or virological results. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2 × upper limit of normal (ie, 80 U/L). The primary end point was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation and/or death.

Results: We identified 1040 COVID-19 patients (mean age 38 years, 54% men), 1670 SARS patients (mean age 44 years, 44% men) and 675 other HCoV patients (mean age 20 years, 57% men). ALT/AST elevation occurred in 50.3% SARS patients, 22.5% COVID-19 patients and 36.0% other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation and 4 (0.4%) died. ALT/AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p&lt;0.001) after adjusted for albumin, diabetes and hypertension. Use of lopinavir-ritonavir ±ribavirin + interferon beta (aOR 1.94, 95% CI 1.20 to 3.13, p=0.006) and corticosteroids (aOR 3.92, 95% CI 2.14 to 7.16, p&lt;0.001) was independently associated with ALT/AST elevation.

Conclusion: ALT/AST elevation was common and independently associated with adverse clinical outcomes in COVID-19 patients. Use of lopinavir-ritonavir, with or without ribavirin, interferon beta and/or corticosteroids was independently associated with ALT/AST elevation.

Keywords: cholestasis; hepatitis; liver function test.

Background: Lung ultrasound (LUS) is an accurate, safe, and cheap tool assisting in the diagnosis of several acute respiratory diseases. The diagnostic value of LUS in the workup of coronavirus disease-19 (COVID-19) in the hospital setting is still uncertain.

Objectives: The aim of this observational study was to explore correlations of the LUS appearance of COVID-19-related pneumonia with CT findings.

Methods: Twenty-six patients (14 males, age 64 ± 16 years) urgently hospitalized for COVID-19 pneumonia, who underwent chest CT and bedside LUS on the day of admission, were enrolled in this observational study. CT images were reviewed by expert chest radiologists, who calculated a visual CT score based on extension and distribution of ground-glass opacities and consolidations. LUS was performed by clinicians with certified competency in thoracic ultrasonography, blind to CT findings, following a systematic approach recommended by ultrasound guidelines. LUS score was calculated according to presence, distribution, and severity of abnormalities.

Results: All participants had CT findings suggestive of bilateral COVID-19 pneumonia, with an average visual scoring of 43 ± 24%. LUS identified 4 different possible -abnormalities, with bilateral distribution (average LUS score 15 ± 5): focal areas of nonconfluent B lines, diffuse confluent B lines, small subpleural microconsolidations with pleural line irregularities, and large parenchymal consolidations with air bronchograms. LUS score was significantly correlated with CT visual scoring (r = 0.65, p &lt; 0.001) and oxygen saturation in room air (r = -0.66, p &lt; 0.001).

Conclusion: When integrated with clinical data, LUS could represent a valid diagnostic aid in patients with suspect COVID-19 pneumonia, which reflects CT findings.

Keywords: Chest ultrasound; Coronavirus pneumonia; Point-of-care ultrasonography; SARS-CoV-2; Thoracic ultrasound.

The biocontrol potential of entomopathogenic fungi against arthropod pests depends on not only their virulence to target pests but tolerance to outdoor high temperature and solar UV irradiation. Two Beauveria bassiana superoxide dismutases (SODs), BbSod2 and BbSod3, were characterized as cytosolic and mitochondrial manganese-cored isoenzymes (MnSODs) dominating the total SOD activity of the fungal entomopathogen under normal growth conditions. To probe their effects on the biocontrol potential of B. bassiana, ΔBbSod2, ΔBbSod3, and three hairpin RNA-interfered (RNAi) mutants with the transcripts of both BbSod2 and BbSod3 being suppressed by 91-97% were constructed and assayed for various phenotypic parameters in conjunction with ΔBbSod2/BbSod2, ΔBbSod3/BbSod3 and wild-type (control strains). In normal cultures, the knockout and RNAi mutants showed significant phenotypic alterations, including delayed sporulation, reduced conidial yields, and impaired conidial quality, but little change in colony morphology. Their mycelia or conidia became much more sensitive to menadione or H(2)O(2)-induced oxidative stress but had little change in sensitivity to the hyperosmolarity of NaCl and the high temperature of 45°C. Accompanied with the decreased antioxidative capability, conidial tolerances to UV-A and UV-B irradiations were reduced by 16.8% and 45.4% for ΔBbSod2, 18.7% and 44.7% for ΔBbSod3, and ∼33.7% and ∼63.8% for the RNAi mutants, respectively. Their median lethal times (LT(50)s) against Myzus persicae apterae, which were topically inoculated under a standardized spray, were delayed by 18.8%, 14.5% and 37.1%, respectively. Remarkably, the effects of cytosolic BbSod2 and mitochondrial BbSod3 on the phenotypic parameters important for the fungal bioncontrol potential were additive, well in accordance with the decreased SOD activities and the increased superoxide levels in the knockout and RNAi mutants. Our findings highlight for the first time that the two MnSODs co-contribute to the biocontrol potential of B. bassiana by mediating cellular antioxidative response.

Faeces samples from diarrhoeic and non-diarrhoeic lambs and goat kids aged 1-45 days were examined for enteric pathogens. Cryptosporidium parvum was detected in both diarrhoeic lambs (45%) and goat kids (42%) but not in non-diarrhoeic animals. F5+ (K99+) and/or F41+ Escherichia coli strains were isolated from 26% and 22% of the diarrhoeic lambs and goat kids, respectively, although these strains, which did not produce enterotoxins ST I or LT I, were found with similar frequencies in non-diarrhoeic animals. A F5-F41-ST I+ E. coli strain was isolated from a diarrhoeic lamb (0.6%). Verotoxigenic E. coli was isolated from both diarrhoeic and non-diarrhoeic lambs (4.1% and 8.2%, respectively) and there was no association between infection and diarrhoea. The prevalence of group A rotavirus infection in diarrhoeic lambs was very low (2.1%). Groups A and B rotaviruses were detected in three (8.1%) and five (13.5%) diarrhoeic goat kids from two single outbreaks. Group C rotaviruses were detected in four non-diarrhoeic goat kids. An association of diarrhoea and infection was demonstrated only for group B rotavirus. Clostridium perfringens was isolated from 10.8% of the diarrhoeic goat kids but not from non-diarrhoeic goat kids or lambs. Salmonella arizonae was isolated from a diarrhoeic goat kid (2.7%) and the clinical characteristics of the outbreaks where these two latter enteropathogens were found different from the rest. Picobirnaviruses were detected in a diarrhoeic lamb. No coronaviruses were detected using a bovine coronavirus ELISA. No evidence was found of synergistic effect between the agents studied. Enteric pathogens were not found in four (8.7%) and three (20%) outbreaks of diarrhoea in lambs and goat kids, respectively.

Alpharetroviruses provide a useful system for the study of the molecular mechanisms of host range and receptor interaction. These viruses can be divided into subgroups based on diverse receptor usage due to variability within the two host range determining regions, hr1 and hr2, in their envelope glycoprotein SU (gp85). In previous work, our laboratory described selection from a subgroup B avian sarcoma-leukosis virus of an extended-host-range variant (LT/SI) with two adjacent amino acid substitutions in hr1. This virus retains its ability to use the subgroup BD receptor but can also infect QT6/BD cells, which bear a related subgroup E receptor (R. A. Taplitz and J. M. Coffin, J. Virol 71:7814-7819, 1997). Here, we report further analysis of this unusual variant. First, one (L154S) of the two substitutions is sufficient for host range extension, while the other (T155I) does not alter host range. Second, these mutations extend host range to non-avian cell types, including human, dog, cat, mouse, rat, and hamster. Third, interference experiments imply that the mutants interact efficiently with the subgroup BD receptor and possibly the related subgroup E receptor, but they have another means of entry that is not dependent on these interactions. Fourth, binding studies indicate that the mutant SU proteins retain the ability to interact as monomers with subgroup BD and BDE receptors but only bind the subgroup E receptor in the context of an Env trimer. Further, the mutant SU proteins bind well to chicken cells but do not bind any better than wild-type subgroup B to QT6 or human cells, even though the corresponding viruses are capable of infecting these cells.

Previous studies have suggested reversibility of minimal hepatic encephalopathy in patients with liver cirrhosis after liver transplantation (LT), however, this topic is controversially discussed. We investigated this issue in a prospective study on liver cirrhotic patients listed for LT. Patients were investigated before and after liver transplantation (on average 21 months later) using a neuropsychological test battery which measured visuo-constructive and visuo-motor ability, verbal fluency, and memory function. To assess visuo-motor and visuo-constructive functions, we performed 4 tests: Rey Complex Figure Test copy, trail making tests A and B, and digital symbol test. The average percentile score of the tests, arbitrarily named the visuo-motor and visuo-constructive performance score (VMCP), was calculated. After LT, the patients did not demonstrate a significant increase of VMCP (P =.29) and additionally showed significantly lower VMCP score (P =.041) compared to control group. Analysis of individual responses showed that only 7 of 14 patients improved their VMCP values after LT. These data indicate that the cirrhosis-associated visuo-motor deficits subside or disappear only in some of the patients after LT, whereas a significant number of patients show no improvement of the visuo-motor and visuo-constructive function. We concluded that monitoring of cognitive and visuo-motor functioning is important for the post-transplant rehabilitation of patients with liver cirrhosis.

<A<em>b</em>stractText>Fear of cancer recurrence (FCR) is a significantly distressing pro<em>b</em>lem that affects a su<em>b</em>stantial num<em>b</em>er of patients with and survivors of cancer; however, the overall efficacy of availa<em>b</em>le psychological interventions on FCR remains unknown. We therefore evaluated this in the present systematic review and meta-analysis.</A<em>b</em>stractText><A<em>b</em>stractText>We searched key electronic data<em>b</em>ases to identify trials that evaluated the effect of psychological interventions on FCR among patients with and survivors of cancer. Controlled trials were su<em>b</em>jected to meta-analysis, and the moderating influence of study characteristics on the effect were examined. Overall quality of evidence was evaluated using the GRADE system. Open trials were narratively reviewed to explore ongoing developments in the field (PROSPERO registration no.: CRD42017076514).</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 23 controlled trials (21 randomized controlled trials) and nine open trials were included. Small effects (Hedges's <i>g</i>) were found <em>b</em>oth at postintervention (<i>g</i> = 0.33; 95% CI, 0.20 to 0.46; <i>P</i> &<em>lt</em>; .001) and at follow-up (<i>g</i> = 0.28; 95% CI, 0.17 to 0.40; <i>P &<em>lt</em>;</i> .001). Effects at postintervention of contemporary cognitive <em>b</em>ehavioral therapies (CBTs; <i>g</i> = 0.42) were larger than those of traditional CBTs (<i>g</i> = 0.24; <em>β</em> = .22; 95% CI, .04 to .41; <i>P</i> = .018). At follow-up, larger effects were associated with shorter time to follow-up (<em>β</em> = -.01; 95% CI, -.01 to -.00; <i>P</i> = .027) and group-<em>b</em>ased formats (<em>β</em> = .18; 95% CI, .01 to .36; <i>P</i> = .041). A GRADE evaluation indicated evidence of moderate strength for effects of psychological intervention for FCR.</p><A<em>b</em>stractText>Psychological interventions for FCR revealed a small <em>b</em>ut ro<em>b</em>ust effect at postintervention, which was largely maintained at follow-up. Larger postintervention effects were found for contemporary CBTs that were focused on processes of cognition-for example, worry, rumination, and attentional <em>b</em>ias-rather than the content, and aimed to change the way in which the individual relates to his or her inner experiences. Future trials could investigate how to further optimize and tailor interventions to individual patients' FCR presentation.</A<em>b</em>stractText>

Highly organized lymphoid structures provide the intricate microenvironment essential for the mediation of the effective immune responses. Compared with lymphotoxin beta knockout mice (LTbeta-/-), LTbeta receptor knockout (LTbetaR-/-) mice present with more severely disorganized splenic structures, suggesting the potential involvement of another ligand. LIGHT, a newly identified TNF family member, is a costimulatory molecule for T cells and binds to LTbetaR and herpes virus entry mediator (HVEM) in vitro. Here, we show that the complementation of LTalpha-/- mice with a LIGHT transgene (LIGHT Tg/LTalpha-/-) leads to the restoration of secondary lymphoid tissue chemokine and T/B cell zone segregation. LIGHT Tg/LTalpha-/- mice also preserve dendritic cells, follicular dendritic cell networks, and germinal centers, though not the marginal zone. Consequently, IgG responses to soluble, but not particulate, antigens are restored, confirming the role of primary follicle and marginal zone in the responses to soluble and particulate antigens. The failure of the LIGHT transgene to rescue the defective splenic structures in LTbetaR-/- mice demonstrates that LIGHT can interact with LTbetaR in vivo. More severely disorganized splenic structures developed after blockade of endogenous LIGHT in LTbeta-/- mice. These findings uncover the potential interaction between LIGHT and one of its receptors, LTbetaR, in supporting even in the absence of LT the development and maintenance of lymphoid microenvironment.

RNA-binding motif protein 15 (RBM15) is involved in the RBM15-megakaryoblastic leukemia 1 fusion in acute megakaryoblastic leukemia. Although Rbm15 has been reported to be required for B-cell differentiation and to inhibit myeloid and megakaryocytic expansion, it is not clear what the normal functions of Rbm15 are in the regulation of hematopoietic stem cell (HSC) and megakaryocyte development. In this study, we report that Rbm15 may function in part through regulation of expression of the proto-oncogene c-Myc. Similar to c-Myc knockout (c-Myc-KO) mice, long-term (LT) HSCs are significantly increased in Rbm15-KO mice due to an apparent LT-HSC to short-term HSC differentiation defect associated with abnormal HSC-niche interactions caused by increased N-cadherin and beta(1) integrin expression on mutant HSCs. Both serial transplantation and competitive reconstitution capabilities of Rbm15-KO LT-HSCs are greatly compromised. Rbm15-KO and c-Myc-KO mice also share related abnormalities in megakaryocyte development, with mutant progenitors producing increased, abnormally small low-ploidy megakaryocytes. Consistent with a possible functional interplay between Rbm15 and c-Myc, the megakaryocyte increase in Rbm15-KO mice could be partially reversed by ectopic c-Myc. Thus, Rbm15 appears to be required for normal HSC-niche interactions, for the ability of HSCs to contribute normally to adult hematopoiesis, and for normal megakaryocyte development; these effects of Rbm15 on hematopoiesis may be mediated at least in part by c-Myc.

<A<em>b</em>stractText>Circular RNA (circRNA) CDR1as plays an important role in the occurrence and development of human tumors. The purpose of this study is to investigate the molecular mechanism of circRNA CDR1as in the development of nasopharyngeal carcinoma (NPC).</A<em>b</em>stractText><A<em>b</em>stractText>The mRNA expressions of circRNA CDR1as, miR-7-5p, and E2F3 were detected <em>b</em>y qRT-PCR. The effects of circRNA CDR1as, miR-7-5p, and E2F3 on NPC cells were investigated using cell counting kit-8 (CCK8) method, colony formation assay, and representative meta<em>b</em>olite assay. The molecular mechanism of circRNA CDR1 in NPC was studied <em>b</em>y <em>b</em>ioinformatics and luciferase reporter assay. In addition, the <em>b</em>iological activity of circRNA CDR1as was also investigated in NPC xenograft tumor mice model.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>The resu<em>lt</em>s showed that the circRNA CDR1as expression was significantly up-regulated in NPC tissues <em>b</em>y comparison with non-tumor NPE tissues (<i>p </i>&<em>lt</em>; 0.01), suggesting that circRNA CDR1as was associated with poor prognosis in NPC patients. Moreover, circRNA CDR1as could up-regulate E2F3 expression <em>b</em>y <em>b</em>inding miR-7-5p, and promote the growth and glucose meta<em>b</em>olism of NPC cells. Meanwhile, circRNA CDR1as could promote NPC progression through the negative regulation of miR-7-5p in the xenograft tumor model.</p><p><div>(<em>b</em>)Conclusion</<em>b</em>)</div>CircRNA CDR1as promoted the occurrence and development of NPCs <em>b</em>y successively up-regulating the expression of miR-7-5p and E2F3, suggesting CircRNA CDR1as as a potential target for the treatment of NPC patients.<i>Trial registration</i> The study was approved <em>b</em>y the cancer center's institutional research ethics committee on Oct 18, 2008 (2008GZ2847462).</p>

To understand the meaning of the lactate threshold (LT) and to test the hypothesis that endurance training augments lactate kinetics [i.e., rates of appearance and disposal (Ra and Rd, respectively, mg·kg(-1)·min(-1)) and metabolic clearance rate (MCR, ml·kg(-1)·min(-1))], we studied six untrained (UT) and six trained (T) subjects during 60-min exercise bouts at power outputs (PO) eliciting the LT. Trained subjects performed two additional exercise bouts at a PO 10% lower (LT-10%), one of which involved a lactate clamp (LC) to match blood lactate concentration ([lactate]b) to that achieved during the LT trial. At LT, lactate Ra was higher in T (24.1 ± 2.7) than in UT (14.6 ± 2.4; P < 0.05) subjects, but Ra was not different between UT and T when relative exercise intensities were matched (UT-LT vs. T-LT-10%, 67% Vo2max). At LT, MCR in T (62.5 ± 5.0) subjects was 34% higher than in UT (46.5 ± 7.0; P < 0.05), and a reduction in PO resulted in a significant increase in MCR by 46% (LT-10%, 91.5 ± 14.9, P < 0.05). At matched relative exercise intensities (67% Vo2max), MCR in T subjects was 97% higher than in UT (P < 0.05). During the LC trial, MCR in T subjects was 64% higher than in UT (P < 0.05), in whom %Vo2max and [lactate]b were similar. We conclude that 1) lactate MCR reaches an apex below the LT, 2) LT corresponds to a limitation in MCR, and 3) endurance training augments capacities for lactate production, disposal and clearance.

BACKGROUND

Cysteinyl leukotrienes (CysLTs) are important mediators of innate immune responsiveness and chronic inflammatory diseases. CysLTs acting through CysLT receptors can influence the migration and activity of cells, such as eosinophils, monocytes, and dendritic cells.

OBJECTIVE

We sought to determine the gene expression signature of human monocytes in response to CysLTs and to elucidate the signaling pathways involved in monocyte activation.

METHODS

Gene expression was analyzed by using oligonucleotide microarrays. Responsiveness to CysLTs was assessed by using real-time PCR, calcium flux, kinase activation, and chemotaxis assays.

RESULTS

CysLT type 1 receptor (CysLTR(1)) transcript 1 is predominantly expressed in human monocytes, and CysLTs signal through CysLTR(1) in these cells. Several immediate-early genes, including early growth response 2 and 3, FBJ murine osteosarcoma viral oncogene homolog B, activating transcription factor 3, and nuclear receptor subfamily 4 were significantly induced by leukotriene (LT) D(4). This effect was mediated by CysLTR(1) coupled to the G protein alpha inhibitory subunit, activation of phospholipase C, and inositol-1,4,5-triphosphate and store-operated calcium channels. LTD(4) induced p38 mitogen-activated protein kinase phosphorylation, a pathway also involved in the regulation of immediate-early gene expression in monocytes. LTD(4) stimulated monocyte chemotactic activity that was fully blocked by a selective CysLTR(1) inhibitor, MK571, and pertussis toxin, suggesting that CysLTR(1) coupled to the G protein alpha inhibitory subunit is a dominant functional pathway in human monocytes.

CONCLUSIONS

Our data show that CysLTs acting through CysLTR(1) can significantly influence the activation and migration of human monocytes and that these effects can be fully inhibited by CysLTR(1) antagonists.

<A<em>b</em>stractText>Our recent meta-analysis indicated that vitamin C may shorten the length of ICU stay and the duration of mechanical ventilation. Here we analyze modification of the vitamin C effect on ventilation time, <em>b</em>y the control group ventilation time (which we used as a proxy for severity of disease in the patients of each trial).</A<em>b</em>stractText><A<em>b</em>stractText>We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials and reference lists of relevant pu<em>b</em>lications. We included controlled trials in which the administration of vitamin C was the only difference <em>b</em>etween the study groups. We did not limit our search to randomized trials and did not require place<em>b</em>o control. We included all doses and all durations of vitamin C administration. One author extracted study characteristics and outcomes from the trial reports and entered the data in a spreadsheet. Both authors checked the data entered against the original reports. We used meta-regression to examine whether the vitamin C effect on ventilation time depends on the duration of ventilation in the control group.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>We identified nine potentially eligi<em>b</em>le trials, eight of which were included in the meta-analysis. We pooled the resu<em>lt</em>s of the eight trials, including 685 patients in total, and found that vitamin C shortened the length of mechanical ventilation on average <em>b</em>y 14% (<i>P</i> = 0.00001). However, there was significant heterogeneity in the effect of vitamin C <em>b</em>etween the trials. Heterogeneity was fully explained <em>b</em>y the ventilation time in the untreated control group. Vitamin C was most <em>b</em>eneficial for patients with the longest ventilation, corresponding to the most severely ill patients. In five trials including 471 patients requiring ventilation for over 10 h, a dosage of 1-6 g/day of vitamin C shortened ventilation time on average <em>b</em>y 25% (<i>P</i> &<em>lt</em>; 0.0001).</p><A<em>b</em>stractText>We found strong evidence that vitamin C shortens the duration of mechanical ventilation, <em>b</em>ut the magnitude of the effect seems to depend on the duration of ventilation in the untreated control group. The level of <em>b</em>aseline illness severity should <em>b</em>e considered in further research. Different doses should <em>b</em>e compared directly in future trials.</A<em>b</em>stractText>

<A<em>b</em>stractText>To investigate <em>b</em>lood-<em>b</em>ased dynamic <em>b</em>iomarkers that predict responses to anti-programmed cell death protein 1 (PD-1) therapy in solid tumors.</A<em>b</em>stractText><p><div>(<em>b</em>)EXPERIMENTAL DESIGN</<em>b</em>)</div>Preplanned <em>b</em>iomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; <i>n</i> = 31) who received pem<em>b</em>rolizuma<em>b</em>. The <em>b</em>iomarker was further tested in an independent cohort of prospectively recruited patients with metastatic non-small cell lung cancer (NSCLC) who received pem<em>b</em>rolizuma<em>b</em> or nivoluma<em>b</em> (NSCLC cohort 1; <i>n</i> = 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; <i>n</i> = 46). Peripheral <em>b</em>lood samples were o<em>b</em>tained immediately <em>b</em>efore treatment (D0) and 7 days after the first dose (D7) and analyzed using mu<em>lt</em>i-color flow cytometry.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A higher fold-change in the percentage of Ki-67⁺ cells among PD-1⁺CD8⁺ T cells 7 days after the first dose (Ki-67<su<em>b</em>)D7/D0</su<em>b</em>)) significantly predicted dura<em>b</em>le clinical <em>b</em>enefit (DCB; <i>P</i> &<em>lt</em>; 0.001) and prolonged progression-free survival (PFS; <i>P</i> = 0.027) in patients with TETs. Ki-67<su<em>b</em>)D7/D0</su<em>b</em>) ≥ 2.8 was also associated with <em>b</em>etter DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all <i>P</i> &<em>lt</em>; 0.05). Ki-67<su<em>b</em>)D7/D0</su<em>b</em>) was su<em>b</em>sequently validated in NSCLC cohort 2, and Ki-67<su<em>b</em>)D7/D0</su<em>b</em>) ≥ 2.8 significantly predicted <em>b</em>etter DCB (<i>P</i> = 0.001), PFS (<i>P</i> = 0.002), and OS (<i>P</i> = 0.037). Ki-67<su<em>b</em>)D7/D0</su<em>b</em>) had a low correlation with tumor PD-L1 expression and com<em>b</em>ining <em>b</em>oth factors did not improve the predictive power of Ki-67<su<em>b</em>)D7/D0</su<em>b</em>).</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>The proliferative response of peripheral <em>b</em>lood PD-1⁺CD8⁺ T cells, measured as the fold-change in the percentage of Ki-67⁺ cells 7 days after treatment (Ki-67<su<em>b</em>)D7/D0</su<em>b</em>)), may <em>b</em>e a useful surrogate <em>b</em>iomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.</p>

Airborne particulate matter (PM) has a complex composition, and the relative contribution of different compounds to PM-induced effects is only partly understood. The present study compared the capability of selected components commonly found in PM, to induce pro-inflammatory responses in lung epithelial cells. Ultrafine carbon black (ufCB), ZnCl(2), FeSO(4), 1-nitropyrene (1-NP), lipopolysaccharide (LPS), and crystalline silica (positive control) were screened for effects on the expression of 84 inflammation-related genes in the bronchial epithelial cell line, BEAS-2B. A total of 22 genes were up-regulated by one or more of the tested compounds, and 5 cytokine and 11 chemokine genes were selected for further studies. After 10h exposure, silica induced significantly increased expression of CCL20, CXCL1/-3/-8/-10/-11, lymphotoxin (LT)beta and interleukin (IL)-6; ufCB induced CXCL8/-10 and -11; ZnCl(2) induced CCL11/-20/-26, CXCL1/-5/-8/-14 and tumor necrosis factor (TNF)-alpha; FeSO(4) induced a weak up-regulation of CXCL8 and TNF-alpha; LPS induced CCL20, CXCL1/-5/-8/-10/-11, LTbeta and IL-6; and 1-NP induced expression of CCL20, CXCL1/-3/-8, TNF-alpha and IL-6. Despite obvious differences, all compounds induced response-patterns that correlated relatively well with that of silica, the positive control. The predominant response appeared to be increased gene expression of neutrophil-recruiting CXC-chemokines. CXCL8 was the only gene induced by all tested PM-components, the most up-regulated on average, and also dominating the gene-expression patterns induced by coarse PM. The data show quantitative, and to a certain extent qualitative differences in cytokine/chemokine gene-expression profiles of the compounds tested. However, there were also striking similarities in the response-patterns induced by these physically/chemically widely different compounds.

<A<em>b</em>stractText>Single-agent PD-1 <em>b</em>lockade exhi<em>b</em>its limited efficacy in epithelial ovarian cancer (EOC). We evaluated ipilimuma<em>b</em> plus nivoluma<em>b</em> compared with nivoluma<em>b</em> alone in women with persistent or recurrent EOC.</A<em>b</em>stractText><A<em>b</em>stractText>Eligi<em>b</em>ility criteria included measura<em>b</em>le disease, 1-3 prior regimens, and platinum-free interval (PFI) &<em>lt</em>; 12 months. Participants were randomly allocated to intravenous nivoluma<em>b</em> (every 2 weeks) or induction with nivoluma<em>b</em> plus ipilimuma<em>b</em> for 4 doses (every 3 weeks), followed <em>b</em>y every-2-week maintenance nivoluma<em>b</em> for a maximum of 42 doses. The primary null hypothesis was equal pro<em>b</em>a<em>b</em>ility of o<em>b</em>jective response within 6 months of random allocation in each arm.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>One hundred patients were allocated to receive either nivoluma<em>b</em> (n = 49), or nivoluma<em>b</em> plus ipilimuma<em>b</em> (n = 51), with PFI of &<em>lt</em>; 6 months in 62%. Six (12.2%) responses occurred within 6 months in the nivoluma<em>b</em> group and 16 (31.4%) in the nivoluma<em>b</em> plus ipilimuma<em>b</em> group (odds ratio, 3.28; 85% CI, 1.54 to infinity; <i>P</i> = .034). The median progression-free survival (PFS) was 2 and 3.9 months in the nivoluma<em>b</em> and nivoluma<em>b</em> plus ipilimuma<em>b</em> groups, respectively, with a PFI-stratified hazard ratio of 0.53 (95% CI, 0.34 to 0.82); the respective hazard ratio for death was 0.79 (95% CI, 0.44 to 1.42). Grade ≥ 3 related adverse events occurred in 33% of patients in the nivoluma<em>b</em> group and 49% in the com<em>b</em>ination group, with no treatment-related deaths. PD-L1 expression was not significantly associated with response in either treatment group.</p><A<em>b</em>stractText>Compared with nivoluma<em>b</em> alone, the com<em>b</em>ination of nivoluma<em>b</em> and ipilimuma<em>b</em> in EOC resu<em>lt</em>ed in superior response rate and longer, al<em>b</em>eit limited, PFS, with toxicity of the com<em>b</em>ination regimen compara<em>b</em>le to prior reports. Additional com<em>b</em>ination studies to enhance dura<em>b</em>ility of the dual regimen are warranted.</A<em>b</em>stractText>

Exercise plays a key role in healthy aging by promoting both physical and cognitive function. Physical function and cognitive function appear to be interrelated and may share common mechanisms. Thus, exercise-induced improvements in physical function and cognitive function may co-occur and be associated with each other. However, no systematic review has specifically assessed and compared the effects of exercise on both physical function and cognitive function in older adults, and the association between changes in both outcomes after exercise training. Thus, we conducted a systematic review and meta-analysis (N = 48 studies) among older adults (60+ years). These data suggest exercise training has a significant benefit for both physical function (g = 0.39; p &lt; 0.001) and cognitive function (g = 0.24; p &lt; 0.001). At the study level, there was a positive correlation between the size of the exercise-induced effect on physical function and on cognitive function (b = 0.41; p = 0.002). Our results indicate exercise improves both physical and cognitive function, reiterating the notion that exercise is a panacea for aging well.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) In early 2020, Italy struggled with an unprecedented hea<em>lt</em>h emergency related to the COVID-19 pandemic. Medical care of chronic neurological diseases, such as epilepsy, is <em>b</em>eing sorely neglected. In this national survey, we aimed at understanding the impact of COVID-19 lockdown on the care of people with epilepsy (PwE) and identifying PwE risk factors for seizure worsening to direct telemedicine efforts. (<em>b</em>)Methods:</<em>b</em>) We administered a 48-items online survey (pu<em>b</em>lished on April 11, 2020) including socio-demographic, epilepsy-related, and psychometric varia<em>b</em>les (BDI-II for depression, GAD-7 for anxiety, and PSQI for sleep) to PwE and people without epilepsy (PwoE). Regression analysis identified predictors of seizure worsening. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) We collected responses from 456 PwE (344 females) and 472 PwoE (347 females). Outpatient examinations of PwE were postponed in 95% of cases. One-third of PwE complained of issues with epilepsy management, <em>b</em>ut only 71% of them reached the treating physician and solved their pro<em>b</em>lems. PwE had worse depressive and anxiety symptoms (higher BDI-II and GAD-7 scores; <i>p</i> &<em>lt</em>; 0.001) than PwoE. Sleep quality was equally compromised in <em>b</em>oth groups (47 and 42%). Sixty-seven PwE (18%) reported seizure worsening, which was <em>b</em>est explained <em>b</em>y the num<em>b</em>er of anti-seizure medications (ASM) of chronic therapy and the severity of sleep disorder. (<em>b</em>)Conclusions:</<em>b</em>) During the current COVID-19 pandemic, a significant percentage of PwE experienced difficu<em>lt</em>ies in follow-up and a seizure num<em>b</em>er increase, in particular those chronically taking more ASMs and with poor sleep quality. This dramatic experience outlines the urgent need for validation and implementation of telemedicine services for epileptic patients in order to provide regular follow-up.

Keywords: COVID-19; anxiety; depression; epilepsy; sleep.