Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infi<em>lt</em>ration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore su<em>b</em>type was characterized <em>b</em>y immune activation and response to virus and IFNγ. Activation of transforming growth factor <em>β</em>, epithelial-mesenchymal transition, and angiogenesis pathways were o<em>b</em>served in the low TMEscore su<em>b</em>type, which are considered T-cell suppressive and may <em>b</em>e responsi<em>b</em>le for significantly worse prognosis in gastric cancer [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33(<em>b</em>)-</<em>b</em>)0.54; <i>P</i> &<em>lt</em>; 0.001]. Mu<em>lt</em>ivariate analysis revealed that the TMEscore was an independent prognostic <em>b</em>iomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46-0.89; <i>P</i> = 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07-0.89; <i>P</i> = 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.

<A<em>b</em>stractText>Mu<em>lt</em>iple loss-of-function a<em>lt</em>erations in genes that are involved in DNA repair, including homologous recom<em>b</em>ination repair, are associated with response to poly(adenosine diphosphate-ri<em>b</em>ose) polymerase (PARP) inhi<em>b</em>ition in patients with prostate and other cancers.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We conducted a randomized, open-la<em>b</em>el, phase 3 trial evaluating the PARP inhi<em>b</em>itor olapari<em>b</em> in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or a<em>b</em>iraterone). All the men had a qualifying a<em>lt</em>eration in prespecified genes with a direct or indirect role in homologous recom<em>b</em>ination repair. Cohort A (245 patients) had at least one a<em>lt</em>eration in <i><em>B</em>RCA1</i>, <i><em>B</em>RCA2</i>, or <i>ATM</i>; cohort <em>B</em> (142 patients) had a<em>lt</em>erations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olapari<em>b</em> or the physician's choice of enzalutamide or a<em>b</em>iraterone (control). The primary end point was imaging-<em>b</em>ased progression-free survival in cohort A according to <em>b</em>linded independent central review.</p><A<em>b</em>stractText>In cohort A, imaging-<em>b</em>ased progression-free survival was significantly longer in the olapari<em>b</em> group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P&<em>lt</em>;0.001); a significant <em>b</em>enefit was also o<em>b</em>served with respect to the confirmed o<em>b</em>jective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olapari<em>b</em> group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olapari<em>b</em>. A significant <em>b</em>enefit for olapari<em>b</em> was also seen for imaging-<em>b</em>ased progression-free survival in the overall population (cohorts A and <em>B</em>). Anemia and nausea were the main toxic effects in patients who received olapari<em>b</em>.</A<em>b</em>stractText><A<em>b</em>stractText>In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or a<em>b</em>iraterone and who had a<em>lt</em>erations in genes with a role in homologous recom<em>b</em>ination repair, olapari<em>b</em> was associated with longer progression-free survival and <em>b</em>etter measures of response and patient-reported end points than either enzalutamide or a<em>b</em>iraterone. (Funded <em>b</em>y AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov num<em>b</em>er, NCT02987543.).</A<em>b</em>stractText>

Using a mouse model recapitulating the main features of human chronic myelogenous leukemia (CML), we uncover the hierarchy of leukemic stem and progenitor cells contributing to disease pathogenesis. We refine the characterization of CML leukemic stem cells (LSCs) to the most immature long-term hematopoietic stem cells (LT-HSCs) and identify some important molecular deregulations underlying their aberrant behavior. We find that CML multipotent progenitors (MPPs) exhibit an aberrant B-lymphoid potential but are redirected toward the myeloid lineage by the action of the proinflammatory cytokine IL-6. We show that BCR/ABL activity controls Il-6 expression thereby establishing a paracrine feedback loop that sustains CML development. These results describe how proinflammatory tumor environment affects leukemic progenitor cell fate and contributes to CML pathogenesis.

BACKGROUND

Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications.

OBJECTIVE

We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT(4)) treatment exerts beneficial effects.

METHODS

This was a prospective study.

METHODS

The study was conducted in the Department of Obstetrics and Gynecology.

METHODS

A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb(+)).

METHODS

TPOAb(+) patients were divided into two groups: group A (n = 57) was treated with LT(4), and group B (n = 58) was not treated. The 869 TPOAb(-) patients (group C) served as a normal population control group.

METHODS

Rates of obstetrical complications in treated and untreated groups were measured.

RESULTS

At baseline, TPOAb(+) had higher TSH compared with TPOAb(-); TSH remained higher in group B compared with groups A and C throughout gestation. Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59-9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18-2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93-18.7).

CONCLUSIONS

Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery.

NOD-like receptor (NLR) proteins (Nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. Their activation in response to a wide range of intracellular danger signals leads to formation of the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) and maturation of IL-1β and IL-18. Anthrax lethal toxin (LT) induces the caspase-1-dependent pyroptosis of mouse and rat macrophages isolated from certain inbred rodent strains through activation of the NOD-like receptor (NLR) Nlrp1 inflammasome. Here we show that LT cleaves rat Nlrp1 and this cleavage is required for toxin-induced inflammasome activation, IL-1 β release, and macrophage pyroptosis. These results identify both a previously unrecognized mechanism of activation of an NLR and a new, physiologically relevant protein substrate of LT.

<A<em>b</em>stractText>Dia<em>b</em>etes has emerged as an important risk factor for severe illness and death from COVID-19. There is a paucity of information on glycemic control among hospitalized COVID-19 patients with dia<em>b</em>etes and acute hyperglycemia.</A<em>b</em>stractText><A<em>b</em>stractText>This retrospective o<em>b</em>servational study of la<em>b</em>oratory-confirmed COVID-19 adu<em>lt</em>s evaluated glycemic and clinical outcomes in patients with and without dia<em>b</em>etes and/or acutely uncontrolled hyperglycemia hospitalized March 1 to April 6, 2020. Dia<em>b</em>etes was defined as A1C ≥6.5%. Uncontrolled hyperglycemia was defined as ≥2 <em>b</em>lood glucoses (BGs) > 180 mg/dL within any 24-hour period. Data were a<em>b</em>stracted from Glytec's data warehouse.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Among 1122 patients in 88 U.S. hospitals, 451 patients with dia<em>b</em>etes and/or uncontrolled hyperglycemia spent 37.8% of patient days having a mean BG > 180 mg/dL. Among 570 patients who died or were discharged, the mortality rate was 28.8% in 184 dia<em>b</em>etes and/or uncontrolled hyperglycemia patients, compared with 6.2% of 386 patients without dia<em>b</em>etes or hyperglycemia (<i>P</i> &<em>lt</em>; .001). Among the 184 patients with dia<em>b</em>etes and/or hyperglycemia who died or were discharged, 40 of 96 uncontrolled hyperglycemia patients (41.7%) died compared with 13 of 88 patients with dia<em>b</em>etes (14.8%, <i>P</i> &<em>lt</em>; .001). Among 493 discharged survivors, median length of stay (LOS) was longer in 184 patients with dia<em>b</em>etes and/or uncontrolled hyperglycemia compared with 386 patients without dia<em>b</em>etes or hyperglycemia (5.7 vs 4.3 days, <i>P</i> &<em>lt</em>; .001).</p><A<em>b</em>stractText>Among hospitalized patients with COVID-19, dia<em>b</em>etes and/or uncontrolled hyperglycemia occurred frequently. These COVID-19 patients with dia<em>b</em>etes and/or uncontrolled hyperglycemia had a longer LOS and markedly higher mortality than patients without dia<em>b</em>etes or uncontrolled hyperglycemia. Patients with uncontrolled hyperglycemia had a particularly high mortality rate. We recommend hea<em>lt</em>h systems which ensure that inpatient hyperglycemia is safely and effectively treated.</A<em>b</em>stractText>

Recombinant human lymphotoxin (LT) was compared with recombinant human tumor necrosis factor (TNF) for direct actions on cultured human endothelial cells (HEC). At equivalent half-maximal concentrations (based on L929 cytotoxicity units) LT and TNF each caused rapid and transient induction (peak 4 to 6 hr) of an antigen associated with leukocyte adhesion (detected by monoclonal antibody H4/18), a rapid but sustained increased expression (plateau 24 hr) of a lymphocyte adhesion structure (ICAM-1), a gradual (plateau 4 to 6 days) increase in expression of HLA-A,B antigens, and gradual (4 to 6 days) conversion of HEC culture morphology from epithelioid to fibroblastoid, an effect enhanced by immune interferon (IFN-gamma). Induction of H4/18 binding by maximal concentrations of LT or TNF could not be augmented by addition of the other cytokine, and 24 hr pretreatment with LT or TNF produced hyporesponsiveness to both mediators for reinduction. H4/18 binding can be transiently induced by tumor-promoting phorbol esters. Pretreatment with either LT or TNF also fully inhibited induction of H4/18 binding by phorbol ester, whereas phorbol ester pretreatment only variably and partially inhibited reinduction by LT or TNF. These actions of LT on endothelium shared with TNF may serve in vivo to promote lymphocyte and inflammatory leukocyte adhesion and transendothelial migration. Recombinant human interleukin 1 species (IL 1 alpha and IL 1 beta) shared many of the actions of LT and TNF and were indistinguishable from each other. However, IL 1 species could be distinguished from LT/TNF by their relative inability to enhance HLA-A,B expression, by their ability to augment H4/18 binding caused by maximally effective concentrations of LT or TNF, and by their inability to inhibit reinduction of H4/18 binding by LT or TNF. In contrast to the actions of LT or TNF, pretreatment with IL 1 alpha or IL 1 beta only partially inhibited induction of H4/18 binding by phorbol ester, and phorbol ester pretreatment consistently, albeit partially, inhibited induction by IL 1 species. These studies suggest that activated T cells through the secretion of LT can in turn activate the local endothelial lining so as to promote homing and extravasation of inflammatory cells. Furthermore, these LT actions can be augmented or complemented by other locally produced mediators such as IFN-gamma or IL 1.

<A<em>b</em>stractText>This study presents a preliminary report on the chest radiographic and computed tomography (CT) findings of the 2019 novel coronavirus disease (COVID-19) pneumonia in Korea.</A<em>b</em>stractText><A<em>b</em>stractText>As part of a mu<em>lt</em>i-institutional colla<em>b</em>oration coordinated <em>b</em>y the Korean Society of Thoracic Radiology, we collected nine patients with COVID-19 infections who had undergone chest radiography and CT scans. We analyzed the radiographic and CT findings of COVID-19 pneumonia at <em>b</em>aseline. Fisher's exact test was used to compare CT findings depending on the shape of pulmonary lesions.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Three of the nine patients (33.3%) had parenchymal a<em>b</em>normalities detected <em>b</em>y chest radiography, and most of the a<em>b</em>normalities were peripheral consolidations. Chest CT images showed <em>b</em>ilateral involvement in eight of the nine patients, and a unilo<em>b</em>ar reversed halo sign in the other patient. In total, 77 pulmonary lesions were found, including patchy lesions (39%), large confluent lesions (13%), and small nodular lesions (48%). The peripheral and posterior lung fields were involved in 78% and 67% of the lesions, respectively. The lesions were typically ill-defined and were composed of mixed ground-glass opacities and consolidation or pure ground-glass opacities. Patchy to confluent lesions were primarily distri<em>b</em>uted in the lower lo<em>b</em>es (<i>p</i> = 0.040) and along the pleura (<i>p</i> &<em>lt</em>; 0.001), whereas nodular lesions were primarily distri<em>b</em>uted along the <em>b</em>ronchovascular <em>b</em>undles (<i>p</i> = 0.006).</p><A<em>b</em>stractText>COVID-19 pneumonia in Korea primarily manifested as pure to mixed ground-glass opacities with a patchy to confluent or nodular shape in the <em>b</em>ilateral peripheral posterior lungs. A considera<em>b</em>le proportion of patients with COVID-19 pneumonia had normal chest radiographs.</A<em>b</em>stractText>

Exposure of bone marrow-derived macrophages (BMDMs) to low concentrations of Bacillus anthracis lethal toxin (LT), whose catalytic subunit is lethal factor (LF), results in induction of a robust apoptotic response dependent on activation of Toll-like receptor (TLR)4. A similar TLR4-dependent apoptotic response is observed when BMDMs are infected with live B. anthracis (Sterne strain). However, TLR4 is considered to be a specific signaling receptor for lipopolysaccharide (LPS), a typical product of gram-negative bacteria, whereas B. anthracis is gram-positive. To understand how B. anthracis can activate TLR4, we analyzed its culture supernatants and found them to contain a potent TLR4-stimulating activity that can also induce apoptosis in macrophages in which the antiapoptotic p38 MAP kinase (whose activation is prevented by LF) was inhibited. Purification of this activity suggested it consists of anthrolysin O (ALO), a member of the cholesterol-dependent cytolysin (CDC) family. We show that recombinant ALO can activate TLR4 in a manner independent of LPS contamination and, together with LT, can induce macrophage apoptosis. We also provide genetic evidence that ALO is required for induction of macrophage apoptosis in response to infection with live B. anthracis and that other CDC family members share the ability to activate TLR4.

<A<em>b</em>stractText>A<em>lt</em>hough non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and NASH with advanced fi<em>b</em>rosis are closely associated with type 2 dia<em>b</em>etes mellitus (T2DM), their glo<em>b</em>al prevalence rates have not <em>b</em>een well descri<em>b</em>ed. Our aim was to estimate the prevalence of NAFLD, NASH, and advanced fi<em>b</em>rosis among patients with T2DM, <em>b</em>y regions of the world.</A<em>b</em>stractText><A<em>b</em>stractText>We searched for terms including NAFLD, NASH and T2DM in studies pu<em>b</em>lished from January 1989 to Septem<em>b</em>er 2018, using Pu<em>b</em>Med, Ovid MEDLINE®, EMBASE and We<em>b</em> of Science. Strict exclusion criteria were applied. Regional and glo<em>b</em>al mean prevalence weighted <em>b</em>y population size in each country were estimated and pooled using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Among 80 studies from 20 countries that met our inclusion criteria, there were 49,419 individuals with T2DM (mean age 58.5 years, mean <em>b</em>ody mass index 27.9 kg/m², and males 52.9%). The glo<em>b</em>al prevalence of NAFLD among patients with T2DM was 55.5% (95% CI 47.3-63.7). Studies from Europe reported the highest prevalence (68.0% [62.1-73.0%]). Among 10 studies that estimated the prevalence of NASH, the glo<em>b</em>al prevalence of NASH among individuals with T2DM was 37.3% (95% CI 24.7-50.0%). Seven studies estimated the prevalence of advanced fi<em>b</em>rosis in patients with NAFLD and T2DM to <em>b</em>e 17.0% (95% CI 7.2-34.8). Meta-regression models showed that geographic region and mean age (p &<em>lt</em>;0.5) were associated with the prevalence of NAFLD, jointly accounting for 63.9% of the heterogeneity.</p><A<em>b</em>stractText>This study provides the glo<em>b</em>al prevalence rates for NAFLD, NASH, and advanced fi<em>b</em>rosis in patients with T2DM. These data can <em>b</em>e used to estimate the clinical and economic <em>b</em>urden of NASH in patients with T2DM around the world.</A<em>b</em>stractText><A<em>b</em>stractText>Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent chronic liver disease worldwide. Type 2 dia<em>b</em>etes mellitus (T2DM) is an important risk factor for NAFLD. Additionally, T2DM seems to accelerate the progression of liver disease in NAFLD. Despite the high prevalence and serious clinical implications of NAFLD in patients with T2DM, it is usually overlooked in clinical practice. This meta-analysis provides evidence of the high prevalence of NAFLD and NASH in patients with T2DM. In this context, increasing awareness a<em>b</em>out the importance of NAFLD in patients with T2DM among all important stakeholders (primary care physicians, specialists, and hea<em>lt</em>h policy makers) must <em>b</em>e prioritized.</A<em>b</em>stractText>

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Nirapari<em>b</em>, an inhi<em>b</em>itor of poly(adenosine diphosphate [ADP]-ri<em>b</em>ose) polymerase (PARP), has <em>b</em>een associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-<em>b</em>ased chemotherapy, regardless of the presence or a<em>b</em>sence of <i>BRCA</i> mutations. The efficacy of nirapari<em>b</em> in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-<em>b</em>ased chemotherapy is unknown.</p><A<em>b</em>stractText>In this randomized, dou<em>b</em>le-<em>b</em>lind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive nirapari<em>b</em> or place<em>b</em>o once daily after a response to platinum-<em>b</em>ased chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recom<em>b</em>ination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival.</A<em>b</em>stractText><A<em>b</em>stractText>Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recom<em>b</em>ination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the nirapari<em>b</em> group than in the place<em>b</em>o group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P&<em>lt</em>;0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P&<em>lt</em>;0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the nirapari<em>b</em> group and 77% in the place<em>b</em>o group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), throm<em>b</em>ocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred.</A<em>b</em>stractText><A<em>b</em>stractText>Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-<em>b</em>ased chemotherapy, those who received nirapari<em>b</em> had significantly longer progression-free survival than those who received place<em>b</em>o, regardless of the presence or a<em>b</em>sence of homologous-recom<em>b</em>ination deficiency. (Funded <em>b</em>y GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov num<em>b</em>er, NCT02655016.).</A<em>b</em>stractText>

Insulin-dependent diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas. The results described here indicate that a beta-cell target antigen in non-obese diabetic (NOD/Lt) mice is a molecule cross-reactive with the 65-kDa heat shock protein (hsp65) of Mycobacterium tuberculosis. The onset of beta-cell destruction is associated with the spontaneous development of anti-hsp65 T lymphocytes. Subsequently hsp65 cross-reactive antigen becomes detectable in the sera of the prediabetic mice and some weeks later anti-hsp65 antibodies, anti-insulin antibodies, and anti-idiotypic antibodies to insulin antibodies become detectable. The hsp65-cross-reactive antigen, the autoantibodies, and the T-cell reactivity then decline with the development of overt insulin-dependent diabetes. The importance of hsp65 in the pathogenesis of insulin-dependent diabetes was confirmed by the ability of clones of anti-hsp65 T cells to cause insulitis and hyperglycemia in young NOD/Lt mice. Moreover, hsp65 antigen could be used either to induce diabetes or to vaccinate against diabetes, depending on the form of its administration to prediabetic NOD/Lt mice. Other antigens such as the 70-kDa heat shock protein (hsp70) had no effect on the development of diabetes.

The lymphokine tumor necrosis factor (TNF) has a well-defined role as an inducer of inflammatory responses; however, the function of the structurally related molecule lymphotoxin (LT alpha) is unknown. LT alpha is present on the surface of activated T, B, and LAK cells as a complex with a 33 kd glycoprotein, and cloning of the cDNA encoding the associated protein, called lymphotoxin beta (LT beta), revealed it to be a type II membrane protein with significant homology to TNF, LT alpha, and the ligand for the CD40 receptor. The gene for LT beta was found next to the TNF-LT locus in the major histocompatibility complex (MHC), a region of the MHC with possible linkage to autoimmune disease. These observations raise the possibility that a surface LT alpha-LT beta complex may have a specific role in immune regulation distinct from the functions ascribed to TNF.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Olapari<em>b</em> has shown significant clinical <em>b</em>enefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a <i>BRCA</i> mutation. The effect of com<em>b</em>ining maintenance olapari<em>b</em> and <em>b</em>evacizuma<em>b</em> in patients regardless of <i>BRCA</i> mutation status is unknown.</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We conducted a randomized, dou<em>b</em>le-<em>b</em>lind, international phase 3 trial. Eligi<em>b</em>le patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus <em>b</em>evacizuma<em>b</em>. Patients were eligi<em>b</em>le regardless of surgical outcome or <i>BRCA</i> mutation status. Patients were randomly assigned in a 2:1 ratio to receive olapari<em>b</em> ta<em>b</em>lets (300 mg twice daily) or place<em>b</em>o for up to 24 months; all the patients received <em>b</em>evacizuma<em>b</em> at a dose of 15 mg per kilogram of <em>b</em>ody weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Of the 806 patients who underwent randomization, 537 were assigned to receive olapari<em>b</em> and 269 to receive place<em>b</em>o. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olapari<em>b</em> plus <em>b</em>evacizuma<em>b</em> and 16.6 months with place<em>b</em>o plus <em>b</em>evacizuma<em>b</em> (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P&<em>lt</em>;0.001). The hazard ratio (olapari<em>b</em> group vs. place<em>b</em>o group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recom<em>b</em>ination deficiency (HRD), including tumors that had <i>BRCA</i> mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have <i>BRCA</i> mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the esta<em>b</em>lished safety profiles of olapari<em>b</em> and <em>b</em>evacizuma<em>b</em>.</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>In patients with advanced ovarian cancer receiving first-line standard therapy including <em>b</em>evacizuma<em>b</em>, the addition of maintenance olapari<em>b</em> provided a significant progression-free survival <em>b</em>enefit, which was su<em>b</em>stantial in patients with HRD-positive tumors, including those without a <i>BRCA</i> mutation. (Funded <em>b</em>y ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov num<em>b</em>er, NCT02477644.).</p>

<A<em>b</em>stractText>Patients with o<em>b</em>esity are at increased risk of exacer<em>b</em>ations from viral respiratory infections. However, the association of o<em>b</em>esity with the severity of coronavirus disease 2019 (COVID-19) is unclear. We examined this association using data from the only referral hospital in Shenzhen, China.</A<em>b</em>stractText><p><div>(<em>b</em>)RESEARCH DESIGN AND METHODS</<em>b</em>)</div>A total of 383 consecutively hospitalized patients with COVID-19 admitted from 11 January 2020 to 16 Fe<em>b</em>ruary 2020 and followed until 26 March 2020 at the Third People's Hospital of Shenzhen were included. Underweight was defined as a BMI &<em>lt</em>;18.5 kg/m², normal weight as 18.5-23.9 kg/m², overweight as 24.0-27.9 kg/m², and o<em>b</em>esity as ≥28 kg/m².</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Of the 383 patients, 53.1% were normal weight, 4.2% were underweight, 32.0% were overweight, and 10.7% were o<em>b</em>ese at admission. O<em>b</em>ese patients tended to have symptoms of cough (<i>P</i> = 0.03) and fever (<i>P</i> = 0.06) compared with patients who were not o<em>b</em>ese. Compared with normal weight patients, those who were overweight had 1.84-fold odds of developing severe COVID-19 (odds ratio [OR] 1.84, 95% CI 0.99-3.43, <i>P</i> = 0.05), while those who were o<em>b</em>ese were at 3.40-fold odds of developing severe disease (OR 3.40, 95% CI 1.40-2.86, <i>P</i> = 0.007), after adjusting for age, sex, epidemiological characteristics, days from disease onset to hospitalization, presence of hypertension, dia<em>b</em>etes, cardiovascular disease, chronic o<em>b</em>structive pulmonary disease, liver disease and cancer, and drug used for treatment. Additionally, after similar adjustment, men who were o<em>b</em>ese versus those who were normal weight were at increased odds of developing severe COVID-19 (OR 5.66, 95% CI 1.80-17.75, <i>P</i> = 0.003).</p><A<em>b</em>stractText>In this study, o<em>b</em>ese patients had increased odds of progressing to severe COVID-19. As the severe acute respiratory syndrome coronavirus 2 may continue to spread worldwide, clinicians should pay close attention to o<em>b</em>ese patients, who should <em>b</em>e carefully managed with prompt and aggressive treatment.</A<em>b</em>stractText>

Hepatocellular carcinoma (HCC) is increasingly reported in patients with nonalcoholic fatty liver disease (NAFLD). Our aim was to assess the prevalence and mortality of patients with NAFLD-HCC. We examined Surveillance, Epidemiology and End Results (SEER) registries (2004-2009) with Medicare-linkage files for HCC, which was identified by the International Classification of Diseases for Oncology, third edition codes using topography and morphology codes 8170-8175. Medicare-linked data was used to identify NAFLD, hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease (ALD), and other liver disease using International Classification of Diseases, Ninth Revision, Clinical Modification codes. NAFLD was also defined by clinical diagnosis (cryptogenic cirrhosis, obese-diabetics with cryptogenic liver disease). A logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HCC. In addition, adjusted hazard ratios for 1-year mortality were estimated by Cox's proportional hazard regression. A total of 4,929 HCC cases and 14,937 controls without HCC were included. Of the HCC cases, 54.9% were related to HCV, 16.4% to ALD, 14.1% to NAFLD, and 9.5% to HBV. Across the 6-year period (2004 to 2009), the number of NAFLD-HCC showed a 9% annual increase. NAFLD-HCC were older, had shorter survival time, more heart disease, and were more likely to die from their primary liver cancer (all P < 0.0001). Of those who received a transplant after HCC (n = 488), only 5% were related to NAFLD-HCC. In multivariate analysis, NAFLD increased the risk of 1-year mortality (OR, 1.21; 95% CI: 1.01-1.45). Additionally, older age, lower income, unstaged HCC increased risk of 1-year mortality while receiving a liver transplant (LT), and having localized tumor stage were protective (all P < 0.05).

CONCLUSIONS

NAFLD is becoming a major cause of HCC in the United States. NAFLD HCC is associated with shorter survival time, more advanced tumor stage, and lower possibility of receiving a LT.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Patients with metastatic colorectal cancer with the <i>BRAF</i> V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhi<em>b</em>ition of BRAF alone has limited activity <em>b</em>ecause of pathway reactivation through epidermal growth factor receptor signaling.</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this open-la<em>b</em>el, phase 3 trial, we enrolled 665 patients with <i>BRAF</i> V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafeni<em>b</em>, <em>b</em>inimetini<em>b</em>, and cetuxima<em>b</em> (triplet-therapy group); encorafeni<em>b</em> and cetuxima<em>b</em> (dou<em>b</em>let-therapy group); or the investigators' choice of either cetuxima<em>b</em> and irinotecan or cetuxima<em>b</em> and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and o<em>b</em>jective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the dou<em>b</em>let-therapy group as compared with the control group. We report here the resu<em>lt</em>s of a prespecified interim analysis.</p><A<em>b</em>stractText>The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P&<em>lt</em>;0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P&<em>lt</em>;0.001). The median overall survival in the dou<em>b</em>let-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P&<em>lt</em>;0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the dou<em>b</em>let-therapy group, and in 61% in the control group.</A<em>b</em>stractText><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>A com<em>b</em>ination of encorafeni<em>b</em>, cetuxima<em>b</em>, and <em>b</em>inimetini<em>b</em> resu<em>lt</em>ed in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the <i>BRAF</i> V600E mutation. (Funded <em>b</em>y Array BioPharma and others; BEACON CRC ClinicalTrials.gov num<em>b</em>er, NCT02928224; EudraCT num<em>b</em>er, 2015-005805-35.).</p>

The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) alpha and LTbeta form heterotrimers that are expressed on the surface of activated lymphocytes and natural killer cells; LTalpha homotrimers can be secreted as well. Mice with a disrupted LTalpha gene lack lymph nodes (LN), Peyer's patches (PP), and follicular dendritic cell (FDC) networks and reveal profound defects of the splenic architecture. However, it is unclear which of these abnormalities is the result of the absence in LTalpha homotrimers or LTalphabeta heterotrimers. To distinguish between these two possibilities, a mouse strain deficient in LTbeta was created employing Cre/loxP-mediated gene targeting. Mice deficient in LTbeta reveal severe defects in organogenesis of the lymphoid system similar to those of LTalpha-/- mice, except that mesenteric and cervical LN are present in most LTbeta-deficient mice. Both LTbeta- and LTalpha-deficient mice show significant lymphocytosis in the circulation and peritoneal cavity and lymphocytic infiltrations in lungs and liver. After immunization, PNA-positive B cell clusters were detected in the splenic white pulp of LTbeta-deficient mice, but FDC networks were severely underdeveloped. Collectively, these results indicate that LTalpha can signal independently from LTbeta in the formation of PNA-positive foci in the spleen, and especially in the development of mesenteric and cervical LN.

The binding subunit of Escherichia coli heat-labile enterotoxin (LT-B) is a highly active oral immunogen. Transgenic tobacco and potato plants were made with the use of genes encoding LT-B or an LT-B fusion protein with a microsomal retention sequence. The plants expressed the foreign peptides, both of which formed oligomers that bound the natural ligand. Mice immunized by gavage produced serum and gut mucosal anti-LT-B immunoglobulins that neutralized the enterotoxin in cell protection assays. Feeding mice fresh transgenic potato tubers also caused oral immunization.

<A<em>b</em>stractText>The out<em>b</em>reak of the 2019 novel coronavirus disease (COVID-19) not only caused particularly large pu<em>b</em>lic hea<em>lt</em>h pro<em>b</em>lems, <em>b</em>ut also caused great psychological distress, especially for medical staff. We aimed to investigate the prevalence rate of insomnia and to confirm the related social psychological factors among medical staff in hospitals during the COVID-19 out<em>b</em>reak.</A<em>b</em>stractText><A<em>b</em>stractText>Medical staff mem<em>b</em>ers in China were recruited, including frontline medical workers. The questionnaire, administered through the WeChat program, o<em>b</em>tained demographic data and asked self-design questions related to the COVID-19 out<em>b</em>reak, insomnia/depressive/anxiety symptoms, and stress-related symptoms. We used a logistic regression analysis to examine the associations <em>b</em>etween sociodemographic factors and insomnia symptoms.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em></<em>b</em>)</div>There were a total of 1,563 participants in our study. Five-hundred-and-sixty-four (36.1%) participants had insomnia symptoms according to the Insomnia Severity Index (ISI) (total score ≥ 8). A mu<em>lt</em>iple <em>b</em>inary logistic regression model revealed that insomnia symptoms were associated with an education level of high school or <em>b</em>elow (OR = 2.69, <i>p</i> = 0.042, 95% CI = 1.0-7.0), <em>b</em>eing a doctor (OR = 0.44, <i>p</i> = 0.007, 95% CI = 0.2-0.8), currently working in an isolation unit (OR = 1.71, <i>p</i> = 0.038, 95% CI = 1.0-2.8), is worried a<em>b</em>out <em>b</em>eing infected (OR = 2.30, p &<em>lt</em>; 0.001, 95% CI = 1.6-3.4), perceived lack of helpfulness in terms of psychological support from news or social media with regard to COVID-19 (OR = 2.10, <i>p</i> = 0.001, 95% CI = 1.3-3.3), and having very strong uncertainty regarding effective disease control (OR = 3.30, <i>p</i> = 0.013, 95% CI = 1.3-8.5).</p><A<em>b</em>stractText>Our study found that more than one-third of the medical staff suffered insomnia symptoms during the COVID-19 out<em>b</em>reak. The related factors included education level, an isolation environment, psychological worries a<em>b</em>out the COVID-19 out<em>b</em>reak, and <em>b</em>eing a doctor. Interventions for insomnia among medical staff are needed considering the various sociopsychological factors at play in this situation.</A<em>b</em>stractText>

The clinical manifestations of cholera are largely attributable to the actions of a secreted hexameric ABLT) with which it shares 80% sequence homology. In both cases, the wedge-shaped A subunit is loosely held high above the plane of the pentameric B subunits by the tethering A2 chain. The most striking difference between the two toxins occurs at the carboxyl terminus of the A2 chain. Whereas the last 14 residues of the A2 chain of LT threading through the central pore of the BLT, are clearly visible in choleragen's electron-density map. In the accompanying article we describe the three-dimensional structure of the isolated B pentamer of cholera toxin (choleragenoid). Comparison of the crystalline coordinates of choleragen, choleragenoid, and LT provides a solid three-dimensional foundation for further experimental investigation. These structures, along with those of related toxins from Shigella dysenteria and Bordetella pertussis, offer a first step towards the rational design of new vaccines and anti-microbial agents.

Lymphotoxin (LT)alpha is expressed by activated T cells, especially CD4(+) T helper type 1 cells, and by activated B and natural killer cells, but the functions of this molecule in vivo are incompletely defined. We have previously shown that follicular dendritic cell (FDC) clusters and germinal centers (GCs) are absent from the peripheral lymphoid tissues of LTalpha-deficient (LTalpha-/-) mice. LTalpha-/- mice produce high levels of antigen-specific immunoglobulin (Ig)M, but very low levels of IgG after immunization with sheep red blood cells. We show here that LTalpha-expressing B cells are essential for the recovery of primary, secondary, and memory humoral immune responses in LTalpha-/- mice. It is not necessary for T cells to express LTalpha to support these immune functions. Importantly, LTalpha-expressing B cells alone are essential and sufficient for the formation of FDC clusters. Once these clusters are formed by LTalpha-expressing B cells, then LTalpha-deficient T cells can interact with B cells to generate GCs and productive class-switched antibody responses. Thus, B cells themselves provide an essential signal that induces and maintains the lymphoid microenvironment essential for GC formation and class-switched Ig responses.

Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia >> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance.

<A<em>b</em>stractText>The coronavirus disease 2019 (COVID-19) epidemic, caused <em>b</em>y severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), <em>b</em>egan in Wuhan city, Hu<em>b</em>ei province, in Decem<em>b</em>er, 2019, and has spread throughout China. Understanding the evolving epidemiology and transmission dynamics of the out<em>b</em>reak <em>b</em>eyond Hu<em>b</em>ei would provide timely information to guide intervention policy.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We collected individual information from official pu<em>b</em>lic sources on la<em>b</em>oratory-confirmed cases reported outside Hu<em>b</em>ei in mainland China for the period of Jan 19 to Fe<em>b</em> 17, 2020. We used the date of the fourth revision of the case definition (Jan 27) to divide the epidemic into two time periods (Dec 24 to Jan 27, and Jan 28 to Fe<em>b</em> 17) as the date of symptom onset. We estimated trends in the demographic characteristics of cases and key time-to-event intervals. We used a Bayesian approach to estimate the dynamics of the net reproduction num<em>b</em>er (R<su<em>b</em>)t</su<em>b</em>)) at the provincial level.</p><A<em>b</em>stractText>We collected data on 8579 cases from 30 provinces. The median age of cases was 44 years (33-56), with an increasing proportion of cases in younger age groups and in elderly people (ie, aged >64 years) as the epidemic progressed. The mean time from symptom onset to hospital admission decreased from 4·4 days (95% CI 0·0-14·0) for the period of Dec 24 to Jan 27, to 2·6 days (0·0-9·0) for the period of Jan 28 to Fe<em>b</em> 17. The mean incu<em>b</em>ation period for the entire period was estimated at 5·2 days (1·8-12·4) and the mean serial interval at 5·1 days (1·3-11·6). The epidemic dynamics in provinces outside Hu<em>b</em>ei were highly varia<em>b</em>le <em>b</em>ut consistently included a mixture of case importations and local transmission. We estimated that the epidemic was self-sustained for less than 3 weeks, with mean Rt reaching peaks <em>b</em>etween 1·08 (95% CI 0·74-1·54) in Shenzhen city of Guangdong province and 1·71 (1·32-2·17) in Shandong province. In all the locations for which we had sufficient data coverage of Rt, Rt was estimated to <em>b</em>e <em>b</em>elow the epidemic threshold (ie, &<em>lt</em>;1) after Jan 30.</A<em>b</em>stractText><A<em>b</em>stractText>Our estimates of the incu<em>b</em>ation period and serial interval were similar, suggesting an early peak of infectiousness, with possi<em>b</em>le transmission <em>b</em>efore the onset of symptoms. Our resu<em>lt</em>s also indicate that, as the epidemic progressed, infectious individuals were isolated more quickly, thus shortening the window of transmission in the community. Overall, our findings indicate that strict containment measures, movement restrictions, and increased awareness of the population might have contri<em>b</em>uted to interrupt local transmission of SARS-CoV-2 outside Hu<em>b</em>ei province.</A<em>b</em>stractText><A<em>b</em>stractText>National Science Fund for Distinguished Young Scholars, National Institute of General Medical Sciences, and European Commission Horizon 2020.</A<em>b</em>stractText>