<A<em>b</em>stractText>Recent therapeutic advances in cardiovascular disease, thanks to the discovery of endothelial progenitor cells (EPCs). Stromal cell-derived factor-1α (SDF-1α), platelet-derived growth factor (PDGF), <em>b</em>asic fi<em>b</em>ro<em>b</em>last growth factor (<em>b</em>FGF), and nitric oxide (NO) play a role in migration, homing, and differentiation of EPCs into mature endothelial cells. The incidence of cardiovascular disease is higher in men than in women. This fact suggests the influence of sex hormones on incidence of cardiovascular disease.</A<em>b</em>stractText><p><div>(<em>b</em>)Methods</<em>b</em>)</div>Twenty-four female wistar rats weighing 160-180 g were randomly divided into four groups (<i>N</i> = 6): 1. sham-treated <em>b</em>y sesame oil, 2. ovariectomized (OVX)-treated <em>b</em>y sesame oil, 3. OVX-treated <em>b</em>y 10 μg/kg/day testosterone, and 4. OVX-treated <em>b</em>y 100 μg/kg/day testosterone. After 21 days, the animals were euthanized and <em>b</em>lood samples were saved for determination of EPC count and serum levels of SDF-1α, PDGF, <em>b</em>FGF, and NO production.</p><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>High-dose testosterone induced significant increase in EPC count in OVX rats (<i>P</i> &<em>lt</em>; 0.05). Also 100 μg/kg/day testosterone increased serum level of SDF-1α more than OVX-treated <em>b</em>y 10 μg/kg/day testosterone (<i>P</i> &<em>lt</em>; 0.05). But 10 μg/kg/day testosterone increased significantly the serum level of PDGF >100 μg/kg/day testosterone-treated group (<i>P</i> &<em>lt</em>; 0.05). The serum level of <em>b</em>FGF in sham-treated <em>b</em>y sesame oil was equal with its concentration in OVX-treated <em>b</em>y 100 μg/kg/day testosterone. And the serum concentration of NO production in testosterone-treated groups were significantly less than other groups (<i>P</i> &<em>lt</em>; 0.05).</p><A<em>b</em>stractText>This study suggests that testosterone might <em>b</em>e effective on cardiovascular disease in females <em>b</em>y increasing EPC count through SDF-1α and PDGF mechanisms which are some of the vascular healing factors.</A<em>b</em>stractText>

Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B(4) biosynthesis, or LTB(4) receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB(4) biosynthesis, and an autocrine activation loop involving LTB(4) receptor 1.

The effect of viral suppression on long-term disease outcome after decompensation in patients with hepatitis B virus (HBV)-related cirrhosis has not been established. The aim of this study was to determine the long-term effect of antiviral therapy (AVT) in patients with HBV-related decompensated cirrhosis. This was a multicenter, prospective, inception cohort study of 707 patients who presented with first-onset decompensated complications, including 284 untreated and 423 antiviral-treated patients (58 previously treated, 253 with early treatment, and 112 with delayed treatment). The primary endpoint was 5-year liver transplantation (LT)-free survival. Secondary endpoints included virological response (VR) and serological response and improvement in liver function. Despite baseline high HBV activity and worse liver function, antiviral-treated patients had significantly better transplant-free survival than untreated patients (5-year survival rates of 59.7% vs. 46.0%, respectively), with more apparent benefits from antivirals in Child-Turcotte-Pugh class B/C and high-viremia groups. The rate of VR and hepatitis B e antigen seroconversion at 5 years in antiviral-treated patients was 14.2% and 49.1%, respectively. A significant improvement in liver function was observed in treated versus untreated patients, with 33.9% of treated patients delisted for LT. Patients with early treatment had better clinical outcomes than those with delayed treatment. Survival was dependent on antiviral response, being significantly better in responders than in nonresponders or untreated cases. The initial benefit of AVT was negated over time in nonresponders. Antiviral treatment and maintained VR remained independently predictive of survival. The study results were corroborated by propensity score-matching analysis.

CONCLUSIONS

AVT significantly modifies the natural history of decompensated cirrhosis, improving liver function and increasing survival. The results underscore the importance of promptly administering potent antiviral drugs to patients under consideration for LT.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To analyze the clinical characteristics of the severe or critically ill patients with novel coronavirus pneumonia (COVID-19), and evaluate the impact of complicated myocardial injury on the prognosis of these patients. (<em>b</em>)Methods:</<em>b</em>) A retrospective study was conducted in 54 patients who admitted to Tongji hospital from Fe<em>b</em>ruary 3, 2020 to Fe<em>b</em>ruary 24, 2020 and met the criteria of severe or critical conditions of COVID-19. The clinical characteristics and hospital mortality rate were analyzed and compared <em>b</em>etween the patients with or without myocardial injury, which was defined with 3 times higher serum cardiac troponin value. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) The median age of the 54 patients was 68 (59.8, 74.3) years. Among all the patients, 24 (44.4%) patients were complicated with hypertension, 13 (24.1%) with dia<em>b</em>etes, 8 (14.8%) with coronary heart disease, and 3 (5.6%) with previous cere<em>b</em>ral infarction. During hospitalization, 24 (44.4%) of the patients were complicated with myocardial injury and 26 (48.1%) patients died in hospital. In-hospital mortality was significantly higher in patients with myocardial injury than in patients without myocardial injury (14 (60.9%) vs. 8 (25.8%), <i>P</i>=0.013). Moreover, the levels of C-reactive protein (153.6 (80.3, 240.7) ng/L vs. 49.8 (15.9, 101.9) ng/L) and N-terminal pro-<em>B</em>-type natriuretic peptide (852.0 (400.0, 2 315.3) ng/L vs. 197.0 (115.3, 631.0) ng/L) were significantly higher than patients without myocardial injury (all <i>P</i>&<em>lt</em>;0.01). (<em>b</em>)Conclusions:</<em>b</em>) Prevalence of myocardial injury is high among severe or critically ill COVID-19 patients. Severe or critically ill COVID-19 patients with myocardial injury face a significantly higher risk of in-hospital mortality. The study suggests that it is important to monitor and manage the myocardial injury during hospitalization for severe or critically ill COVID-19 patients.

OBJECTIVE

We assessed the short-term antihypertensive effects of soluble fiber-rich whole oat cereals when added to a standard American diet. In addition, multiple assessments of insulin sensitivity were conducted.

METHODS

This was a randomized, controlled, parallel-group pilot study designed to compare an oat cereal group (standardized to 5.52 g/day beta-glucan) to a low-fiber cereal control group (less than 1.0 g/day total fiber) over 6 weeks.

METHODS

A total of 18 hypertensive and hyperinsulinemic (= 10 U/mL or more) men and women completed the trial.

METHODS

Primary study outcomes were changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Secondary outcomes included blood lipid, fasting glucose, and insulin levels and side effects related to elevated blood pressure and increased dietary fiber intake.

RESULTS

The oat cereal group experienced a 7.5 mm Hg reduction in SBP (P <.01) and a 5.5 mm Hg reduction in DBP (P <.02), while there was virtually no change in either SBP or DBP in the control group. In the oat cereal group, a trend was observed for a lower total insulin response to a glucose load, suggesting improved insulin sensitivity. However, this could not be confirmed using estimates from the Bergman Minimal Model, perhaps because of our small sample size. The oats group experienced a significant reduction in both total cholesterol (9%) and low-density lipoprotein cholesterol (14%).

CONCLUSIONS

The addition of oat cereals to the normal diet of patients with hypertension significantly reduces both SBP and DBP. Soluble fiber-rich whole oats may be an effective dietary therapy in the prevention and adjunct treatment of hypertension.

<A<em>b</em>stractText>While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without dia<em>b</em>etes, information on patients with type 2 dia<em>b</em>etes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or com<em>b</em>ined with pioglitazone, improves histology in patients with T2DM and NASH.</A<em>b</em>stractText><p><div>(<em>b</em>)RESEARCH DESIGN AND METHODS</<em>b</em>)</div>This was a proof-of-concept, randomized, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled trial conducted from 2010 to 2016. Patients with T2DM and <em>b</em>iopsy-proven NASH (<i>n</i> = 105) were randomized to vitamin E 400 IU <em>b</em>.i.d., vitamin E 400 IU <em>b</em>.i.d. plus pioglitazone 45 mg/day, or place<em>b</em>o. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fi<em>b</em>rosis. Secondary outcomes were resolution of NASH without worsening of fi<em>b</em>rosis, individual histological scores, and meta<em>b</em>olic parameters.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>More patients on com<em>b</em>ination therapy achieved the primary outcome versus place<em>b</em>o (54% vs. 19%, <i>P</i> = 0.003) <em>b</em>ut not with vitamin E alone (31% vs. 19%, <i>P</i> = 0.26). Both groups showed improvements in resolution of NASH compared with place<em>b</em>o (com<em>b</em>ination group: 43% vs. 12%, <i>P</i> = 0.005; vitamin E alone: 33% vs. 12%, <i>P</i> = 0.04). While steatosis assessed <em>b</em>y histology improved with com<em>b</em>ination therapy (<i>P</i> &<em>lt</em>; 0.001) and vitamin E alone (<i>P</i> = 0.018), inflammation (<i>P</i> = 0.018) and <em>b</em>allooning (<i>P</i> = 0.022) only improved with com<em>b</em>ination therapy. No improvement in fi<em>b</em>rosis was o<em>b</em>served in any group.</p><A<em>b</em>stractText>In this proof-of-concept study, com<em>b</em>ination therapy was <em>b</em>etter than place<em>b</em>o in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.</A<em>b</em>stractText>

<A<em>b</em>stractText>258 million people reside outside their country of <em>b</em>irth; however, to date no glo<em>b</em>al systematic reviews or meta-analyses of mortality data for these international migrants have <em>b</em>een done. We aimed to review and synthesise availa<em>b</em>le mortality data on international migrants.</A<em>b</em>stractText><A<em>b</em>stractText>In this systematic review and meta-analysis, we searched MEDLINE, Em<em>b</em>ase, the Cochrane Li<em>b</em>rary, and Google Scholar data<em>b</em>ases for o<em>b</em>servational studies, systematic reviews, and randomised controlled trials pu<em>b</em>lished <em>b</em>etween Jan 1, 2001, and March 31, 2017, without language restrictions. We included studies reporting mortality outcomes for international migrants of any age residing outside their country of <em>b</em>irth. Studies that recruited participants exclusively from intensive care or high dependency hospital units, with an existing hea<em>lt</em>h condition or status, or a particular hea<em>lt</em>h exposure were excluded. We also excluded studies limited to maternal or perinatal outcomes. We screened studies using systematic review software and extracted data from pu<em>b</em>lished reports. The main outcomes were all-cause and International Classification of Diseases, tenth revision (ICD-10) cause-specific standardised mortality ratios (SMRs) and a<em>b</em>solute mortality rates. We calculated summary estimates using random-effects models. This study is registered with PROSPERO, num<em>b</em>er CRD42017073608.</A<em>b</em>stractText><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Of the 12 480 articles identified <em>b</em>y our search, 96 studies were eligi<em>b</em>le for inclusion. The studies were geographically diverse and included data from all glo<em>b</em>al regions and for 92 countries. 5464 mortality estimates for more than 15·2 million migrants were included, of which 5327 (97%) were from high-income countries, 115 (2%) were from middle-income countries, and 22 (&<em>lt</em>;1%) were from low-income countries. Few studies included mortality estimates for refugees (110 estimates), asylum seekers (144 estimates), or la<em>b</em>our migrants (six estimates). The summary estimate of all-cause SMR for international migrants was lower than one when compared with the general population in destination countries (0·70 [95% CI 0·65-0·76]; I²=99·8%). All-cause SMR was lower in <em>b</em>oth male migrants (0·72 [0·63-0·81]; I²=99·8%) and female migrants (0·75 [0·67-0·84]; I²=99·8%) compared with the general population. A mortality advantage was evident for refugees (SMR 0·50 [0·46-0·54]; I²=89·8%), <em>b</em>ut not for asylum seekers (1·05 [0·89-1·24]; I²=54·4%), a<em>lt</em>hough limited data was availa<em>b</em>le on these groups. SMRs for all causes of death were lower in migrants compared with the general populations in the destination country across all 13 ICD-10 categories analysed, with the exception of infectious diseases and external causes. Heterogeneity was high across the majority of analyses. Point estimates of all-cause age-standardised mortality in migrants ranged from 420 to 874 per 100 000 population.</p><A<em>b</em>stractText>Our study showed that international migrants have a mortality advantage compared with general populations, and that this advantage persisted across the majority of ICD-10 disease categories. The mortality advantage identified will <em>b</em>e representative of international migrants in high-income countries who are studying, working, or have joined family mem<em>b</em>ers in these countries. However, our resu<em>lt</em>s might not reflect the hea<em>lt</em>h outcomes of more marginalised groups in low-income and middle-income countries <em>b</em>ecause little data were availa<em>b</em>le for these groups, highlighting an important gap in existing research. Our resu<em>lt</em>s present an opportunity to reframe the pu<em>b</em>lic discourse on international migration and hea<em>lt</em>h in high-income countries.</A<em>b</em>stractText><A<em>b</em>stractText>Wellcome Trust, National Institute for Hea<em>lt</em>h Research, Medical Research Council, Alliance for Hea<em>lt</em>h Policy and Systems Research, Department for International Development, Fogarty International Center, Grand Challenges Canada, International Development Research Centre Canada, Inter-American Institute for Glo<em>b</em>al Change Research, National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Mental Hea<em>lt</em>h, Swiss National Science Foundation, World Dia<em>b</em>etes Foundation, UK National Institute for Hea<em>lt</em>h Research Imperial Biomedical Research Centre, Imperial College Hea<em>lt</em>hcare Charity, and European Society for Clinical Micro<em>b</em>iology and Infectious Diseases (ESCMID) Study Group Research Funding for the ESCMID Study Group for Infections in Travellers and Migrants.</A<em>b</em>stractText>

<A<em>b</em>stractText>High tumor mutation <em>b</em>urden (TMB) can <em>b</em>enefit immunotherapy for mu<em>lt</em>iple tumor types, <em>b</em>ut the prevalence of hypermutated <em>b</em>reast cancer is not well descri<em>b</em>ed. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated <em>b</em>reast cancer.</A<em>b</em>stractText><A<em>b</em>stractText>We used de-identified data from individuals with primary or metastatic <em>b</em>reast cancer from six different pu<em>b</em>licly availa<em>b</em>le genomic studies. The prevalence of hypermutated <em>b</em>reast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per mega<em>b</em>ase (mut/M<em>b</em>). An additional eight patients were identified from a Dana-Far<em>b</em>er Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A su<em>b</em>set of patients was treated with regimens containing PD-1 inhi<em>b</em>itors.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The median TMB was 2.63 mut/M<em>b</em>. The median TMB significantly varied according to the tumor su<em>b</em>type (HR-/HER2- >HER2+ >HR+/HER2-, P &<em>lt</em>; 0.05) and sample type (metastatic > primary, P = 2.2 × 10^-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10^-14). APOBEC activity (59.2%), followed <em>b</em>y mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated <em>b</em>reast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pem<em>b</em>rolizuma<em>b</em>-<em>b</em>ased therapies derived an o<em>b</em>jective and dura<em>b</em>le response to therapy.</p><A<em>b</em>stractText>Hypermutation occurs in 5% of all <em>b</em>reast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity <em>b</em>eing the most common dominant process. Preliminary data suggest that hypermutated <em>b</em>reast cancers are more likely to <em>b</em>enefit from PD-1 inhi<em>b</em>itors.</A<em>b</em>stractText>

<A<em>b</em>stractText>Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possi<em>b</em>le detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target <em>b</em>inding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells.</A<em>b</em>stractText><p><div>(<em>b</em>)EXPERIMENTAL DESIGN</<em>b</em>)</div>We used a series of single-chain varia<em>b</em>le fragments (scFv) with five different affinities targeting the same epitope of the mu<em>lt</em>iple myeloma-associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells <i>in vitro</i> and <i>in vivo</i>.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>We show that the inferior cytotoxicity and cytokine secretion mediated <em>b</em>y CD38 CARs of very low-affinity (<i>K</i><su<em>b</em>)d</su<em>b</em>) &<em>lt</em>; 1.9 × 10^-6 mol/L) <em>b</em>earing a 4-1BB intracellular domain can <em>b</em>e significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated <em>b</em>y the coexpression of 4-1BBL provided the CD28-<em>b</em>ased CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved <i>in vivo</i> antitumor function, while preserving their a<em>b</em>ility to discriminate target antigen density.</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>A com<em>b</em>inatorial costimulatory design allows the use of very low-affinity <em>b</em>inding domains (<i>K</i><su<em>b</em>)d</su<em>b</em>) &<em>lt</em>; 1 μmol/L) for the construction of safe <em>b</em>ut also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered <em>b</em>y selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.</p>

<p><div>(<em>b</em>)O<em>B</em>JECTIVE</<em>b</em>)</div>To determine the spectrum of phenotypes linked to the A<em>B</em>O <em>b</em>lood group system, using genetic determinants of the A<em>B</em>O <em>b</em>lood group system. Approach and Resu<em>lt</em>s: We assessed the risk of 41 hea<em>lt</em>h and disease outcomes, and 36 linear traits associated with the A<em>B</em>O <em>b</em>lood group system in the UK <em>B</em>io<em>b</em>ank cohort. A total of 406 755 unrelated individuals were included in this study. <em>B</em>lood groups A, <em>B</em>, and O were determined <em>b</em>ased on allele com<em>b</em>inations of previously esta<em>b</em>lished single-nucleotide polymorphisms rs8176746, rs8176719 in the A<em>B</em>O gene. Group A<em>B</em> was excluded <em>b</em>ecause of its relative small sample size. Overall, 187 387 (46%) were male with a mean (SD) age of 57±8.1 years and a median total exposure of 64 person-years (interquartile range, 57-70). Of 406 755 individuals, 182 621 (44.9%) participants had <em>b</em>lood group O, 182 786 (44.9%) had <em>b</em>lood group A, and 41 348 (10.2%) had <em>b</em>lood group <em>B</em>. A<em>B</em>O <em>b</em>lood groups were associated with 11 hea<em>lt</em>h and disease outcomes (<i>P</i>&<em>lt</em>;2.19×10^-4). A<em>B</em>O <em>b</em>lood groups were primarily associated with cardiovascular outcomes. Compared with individuals with <em>b</em>lood group O, <em>b</em>lood groups A and <em>B</em> were associated with increased odds of up to 1.56 (95% CI, 1.43-1.69) for throm<em>b</em>oem<em>b</em>olic events and decreased odds for hypertension (0.94 [95% CI, 0.92-0.97]).</p><A<em>b</em>stractText>The A<em>B</em>O <em>b</em>lood group system is associated with several parameters of hea<em>lt</em>hy aging and disease development. Knowledge of A<em>B</em>O <em>b</em>lood groups might <em>b</em>e of interest for more personalized approaches towards hea<em>lt</em>h maintenance and the prevention of diseases.</A<em>b</em>stractText>

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div><i>Helico<em>b</em>acter pylori</i> infection and a family history of gastric cancer are the main risk factors for gastric cancer. Whether treatment to eradicate <i>H. pylori</i> can reduce the risk of gastric cancer in persons with a family history of gastric cancer in first-degree relatives is unknown.</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this single-center, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled trial, we screened 3100 first-degree relatives of patients with gastric cancer. We randomly assigned 1838 participants with <i>H. pylori</i> infection to receive either eradication therapy (lansoprazole [30 mg], amoxicillin [1000 mg], and clarithromycin [500 mg], each taken twice daily for 7 days) or place<em>b</em>o. The primary outcome was development of gastric cancer. A prespecified secondary outcome was development of gastric cancer according to <i>H. pylori</i> eradication status, assessed during the follow-up period.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 1676 participants were included in the modified intention-to-treat population for the analysis of the primary outcome (832 in the treatment group and 844 in the place<em>b</em>o group). During a median follow-up of 9.2 years, gastric cancer developed in 10 participants (1.2%) in the treatment group and in 23 (2.7%) in the place<em>b</em>o group (hazard ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.94; P = 0.03 <em>b</em>y log-rank test). Among the 10 participants in the treatment group in whom gastric cancer developed, 5 (50.0%) had persistent <i>H. pylori</i> infection. Gastric cancer developed in 0.8% of participants (5 of 608) in whom <i>H. pylori</i> infection was eradicated and in 2.9% of participants (28 of 979) who had persistent infection (hazard ratio, 0.27; 95% CI, 0.10 to 0.70). Adverse events were mild and were more common in the treatment group than in the place<em>b</em>o group (53.0% vs. 19.1%; P&<em>lt</em>;0.001).</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>Among persons with <i>H. pylori</i> infection who had a family history of gastric cancer in first-degree relatives, <i>H. pylori</i> eradication treatment reduced the risk of gastric cancer. (Funded <em>b</em>y the National Cancer Center, South Korea; ClinicalTrials.gov num<em>b</em>er, NCT01678027.).</p>

<A<em>b</em>stractText>Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituxima<em>b</em> is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituxima<em>b</em>.</A<em>b</em>stractText><A<em>b</em>stractText>A phase III, mu<em>lt</em>icenter, randomized trial of lenalidomide plus rituxima<em>b</em> versus place<em>b</em>o plus rituxima<em>b</em> was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or place<em>b</em>o for 12 cycles plus rituxima<em>b</em> once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 358 patients were randomly assigned to lenalidomide plus rituxima<em>b</em> (n = 178) or place<em>b</em>o plus rituxima<em>b</em> (n = 180). Infections (63% <i>v</i> 49%), neutropenia (58% <i>v</i> 23%), and cutaneous reactions (32% <i>v</i> 12%) were more common with lenalidomide plus rituxima<em>b</em>. Grade 3 or 4 neutropenia (50% <i>v</i> 13%) and leukopenia (7% <i>v</i> 2%) were higher with lenalidomide plus rituxima<em>b</em>; no other grade 3 or 4 adverse event differed <em>b</em>y 5% or more <em>b</em>etween groups. Progression-free survival was significantly improved for lenalidomide plus rituxima<em>b</em> versus place<em>b</em>o plus rituxima<em>b</em>, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; <i>P</i> &<em>lt</em>; .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.</p><A<em>b</em>stractText>Lenalidomide improved efficacy of rituxima<em>b</em> in patients with recurrent indolent lymphoma, with an accepta<em>b</em>le safety profile.</A<em>b</em>stractText>

<A<em>b</em>stractText>In the KEYNOTE-010 study, pem<em>b</em>rolizuma<em>b</em> improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pem<em>b</em>rolizuma<em>b</em>.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pem<em>b</em>rolizuma<em>b</em> 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m² every 3 weeks. Eligi<em>b</em>le patients with disease progression after 35 cycles/2 years of pem<em>b</em>rolizuma<em>b</em> could receive second-course treatment (up to 17 cycles). Pem<em>b</em>rolizuma<em>b</em> doses were pooled <em>b</em>ecause no <em>b</em>etween-dose difference was o<em>b</em>served at primary analysis.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Pem<em>b</em>rolizuma<em>b</em> continued to improve OS over docetaxel in the PD-L1 TPS ≥ 50% and ≥ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; <i>P</i> &<em>lt</em>; .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; <i>P &<em>lt</em>;</i> .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pem<em>b</em>rolizuma<em>b</em>; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had o<em>b</em>jective response (RECIST v1.1, <em>b</em>linded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pem<em>b</em>rolizuma<em>b</em>: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had sta<em>b</em>le disease.</p><A<em>b</em>stractText>Pem<em>b</em>rolizuma<em>b</em> provided long-term OS <em>b</em>enefit over docetaxel, with managea<em>b</em>le safety, dura<em>b</em>le responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pem<em>b</em>rolizuma<em>b</em> for previously treated, PD-L1‒expressing advanced NSCLC.</A<em>b</em>stractText>

Background: In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC.

Methods: Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes.

<strong class="sub-title"> Resu<em>lt</em>s: </strong> Four genes (A<em>B</em>C<em>B</em>6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P &<em>lt</em>; 0.001, HR = 0.27) and test cohort (P &<em>lt</em>; 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TM<em>B</em>; higher fractions of macrophages, follicular helper T cells, memory <em>B</em> cells, and neutrophils; and exhibited higher expression of CD83, <em>B</em>7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy.

Conclusions: The prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. Video Abstract.

Keywords: Ferroptosis; Hepatocellular carcinoma (HCC); Immune microenvironment; Prognosis; TMB.

<A<em>b</em>stractText>Baseline use of corticosteroids is associated with poor outcomes in patients with non-small-cell lung cancer (NSCLC) treated with programmed cell death-1 axis inhi<em>b</em>ition. To approach the question of causation versus correlation for this association, we examined outcomes in patients treated with immunotherapy depending on whether corticosteroids were administered for cancer-related palliative reasons or cancer-unrelated indications.</A<em>b</em>stractText><A<em>b</em>stractText>Clinical outcomes in patients with NSCLC treated with immunotherapy who received ≥ 10 mg prednisone were compared with outcomes in patients who received 0 to &<em>lt</em>; 10 mg of prednisone.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Of 650 patients, the 93 patients (14.3%) who received ≥ 10 mg of prednisone at the time of immunotherapy initiation had shorter median progression-free survival (mPFS) and median overall survival (mOS) times than patients who received 0 to &<em>lt</em>; 10 mg of prednisone (mPFS, 2.0 <i>v</i> 3.4 months, respectively; <i>P</i> = .01; mOS, 4.9 <i>v</i> 11.2 months, respectively; <i>P</i> &<em>lt</em>; .001). When analyzed <em>b</em>y reason for corticosteroid administration, mPFS and mOS were significantly shorter only among patients who received ≥ 10 mg prednisone for palliative indications compared with patients who received ≥ 10 mg prednisone for cancer-unrelated reasons and with patients receiving 0 to &<em>lt</em>; 10 mg of prednisone (mPFS, 1.4 <i>v</i> 4.6 <i>v</i> 3.4 months, respectively; log-rank <i>P</i> &<em>lt</em>; .001 across the three groups; mOS, 2.2 <i>v</i> 10.7 <i>v</i> 11.2 months, respectively; log-rank <i>P</i> &<em>lt</em>; .001 across the three groups). There was no significant difference in mPFS or mOS in patients receiving ≥ 10 mg of prednisone for cancer-unrelated indications compared with patients receiving 0 to &<em>lt</em>; 10 mg of prednisone.</p><A<em>b</em>stractText>A<em>lt</em>hough patients with NSCLC treated with ≥ 10 mg of prednisone at the time of immunotherapy initiation have worse outcomes than patients who received 0 to &<em>lt</em>; 10 mg of prednisone, this difference seems to <em>b</em>e driven <em>b</em>y a poor-prognosis su<em>b</em>group of patients who receive corticosteroids for palliative indications.</A<em>b</em>stractText>

Using a fixed dose of antigen, the immune response to detoxified mutants of LT-WT following intranasal (i.n.), subcutaneous (s.c.) and oral (i.g.) immunisation has been studied. When given i.n., both LT-WT and mutant toxin, K63, generated significant levels of toxin-specific IgG in the serum, and the levels of IgA in nasal and lung lavages were greater than those induced by rLT-B. In comparison, i.g. immunisation of mice with a similar quantity of either LT-WT or K63 toxin induced barely detectable levels of IgG in the sera. However, if the amount of protein used for i.g. immunisation was increased tenfold, relatively good levels of toxin-specific IgG were induced in the sera by both LT-WT or K63. Low levels of toxin-specific IgA were also observed in intestinal washes from these mice. Western blotting of the sera, using the native toxin as an antigen, demonstrated the presence of both anti-A and anti-B subunit antibodies. Most significantly, toxin-neutralising antibodies were induced in the serum, with the strongest activity being induced by the LT-WT, an intermediate activity induced by mutant K63 and a lower response by rLT-B. Together, these data show that ADP-ribosyltransferase is not necessary for mucosal immunogenicity of these proteins, and that the i.n. route of immunisation is more effective than the i.g. route of immunisation for the generation of both systemic (IgG) and mucosal (IgA) immune responses.

The efficacy of edible vaccines produced in potato tubers was examined in mice. Transgenic plants were developed by Agrobacterium tumefaciens-mediated transformation. The antigen selected was the non-toxic B subunit of the Escherichia coli enterotoxin (recLT-B). A synthetic gene coding for recLT-B was made and optimised for expression in potato tubers and accumulation in the endoplasmic reticulum. Introduction of this gene under control of the tuber-specific patatin promoter in potato plants resulted in the production of functional, i.e. Gm1-binding, recLT-B pentamers in tubers. Selected tubers containing about 13 microg of recLT-B per gram fresh weight were used for immunisation. Subcutaneous immunisation with an extract of recLT-B tubers yielded high antibody titres in serum that were similar to those obtained with bacterial recLT-B. The efficacy of oral administration of recLT-B tubers was determined by measuring mucosal and systemic immune responses in naive and primed mice. Animals were primed by subcutaneous injection of an extract of recLT-B tuber plus adjuvant. Naive and primed mice were fed 5 g of tubers ( approximately 65 microg of recLT-B) or were intubated intragastrically with 0.4 ml of tuber extract ( approximately 2 microg of recLT-B). In naive mice, feeding recLT-B tubers or intubation of tuber extract did not induce detectable anti-LT antibody titres. In primed animals, however, oral immunisation resulted in significant anti-LT IgA antibody responses in serum and faeces. Intragastric intubation of tuber extract revealed higher responses than feeding of tubers. These results indicate clearly that functional recLT-B can be produced in potato tubers, that this recombinant protein is immunogenic and that oral administration thereof elicits both systemic and local IgA responses in parentally primed, but not naive, animals.

Lymphotoxin (LT), a cytokine belonging to the TNF family, has established roles in the formation of secondary lymphoid structures and in the compartmentalization of T and B lymphocyte areas of the spleen. In this study, we examine the role of LT in directing the composition of intestinal lymphocytes. We report that mice deficient in LT have a normal composition of intestinal lamina propria (LP) T lymphocytes, and an absence of intestinal LP B lymphocytes. We further refine this observation to demonstrate that the interaction of LT with the LTbetaR is essential for the presence LP B lymphocytes. The LT/LTbetaR-dependent events relevant for the presence of LP B lymphocytes occur after birth, do not require the presence of Peyer's patches, lymph nodes, or the spleen; and therefore, are distinct and independent from the previously identified roles of LT/LTbetaR. The LT-dependent signal relevant for the presence of LP B lymphocytes is optimally supplied by a LT-sufficient B lymphocyte, and requires a LTbetaR-sufficient radio-resistant, non-bone marrow-derived cell. Based upon the severity of the deficit of LP B lymphocytes we observed, these novel LT/LTbetaR-dependent events are of primary importance in directing the entry and residence of LP B lymphocytes.

NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-γ production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non-toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-γ production by NK cells in response to B. anthracis spores was: i) contact-dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-γ production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-γ secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-γ secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms.