CD209/CD14+ Dendritic Cells Characterization in Rheumatoid and Psoriatic Arthritis Patients: Activation, Synovial Infiltration, and Therapeutic Targeting

Dendritic cells (DC) have a key role in the initiation and progression of inflammatory arthritis (IA). In this study, we identified a DC population that derive from monocytes, characterized as CD209/CD14+ DC, expressing classical DC markers (HLADR, CD11c) and the Mo-DC marker (CD209), while also retaining the monocytic marker CD14. This CD209/CD14+ DC population is present in the circulation of Healthy Control (HC), with increased frequency in Rheumatoid Arthritis (RA) and Psoriatic arthritic (PsA) patients. We demonstrate, for the first time, that circulatory IA CD209/CD14+ DC express more cytokines (IL1β/IL6/IL12/TNFα) and display a unique chemokine receptor expression and co-expression profiles compared to HC. We demonstrated that CD209/CD14+ DC are enriched in the inflamed joint where they display a unique inflammatory and maturation phenotype, with increased CD40 and CD80 and co-expression of specific chemokine receptors, displaying unique patterns between PsA and RA. We developed a new protocol of magnetic isolation and expansion for CD209+ DC from blood and identified transcriptional differences involved in endocytosis/antigen presentation between RA and PsA CD209+ DC. In addition, we observed that culture of healthy CD209+ DC with IA synovial fluid (SF), but not Osteoarthritis (OA) SF, was sufficient to induce the development of CD209/CD14+ DC, leading to a poly-mature DC phenotype. In addition, differential effects were observed in terms of chemokine receptor and chemokine expression, with healthy CD209+ DC displaying increased expression/co-expression of CCR6, CCR7, CXCR3, CXCR4 and CXCR5 when cultured with RA SF, while an increase in the chemokines CCR3, CXCL10 and CXCL11 was observed when cultured with PsA SF. This effect may be mediated in part by the observed differential increase in chemokines expressed in RA vs PsA SF. Finally, we observed that the JAK/STAT pathway, but not the NF-κB pathway (driven by TNFα), regulated CD209/CD14+ DC function in terms of activation, inflammatory state, and migratory capacity. In conclusion, we identified a novel CD209/CD14+ DC population, which is active in the circulation of RA and PsA, an effect potentiated once they enter the joint. Furthermore, we demonstrated that JAK/STAT inhibition can be used as a therapeutic strategy to decrease the inflammatory state of the pathogenic CD209/CD14+ DC.

526 Removal of soluble tumor necrosis factors receptors 1/2 in patients with metastatic solid tumors using immune apheresis

BackgroundTNFα is a cytokine produced by immune cells and by tumor cells. The soluble forms of membrane TNF receptors 1/2 (sTNF-R1/2) act as decoy to neutralize TNFα, and are highly abundant in cancer patients. Elimination of sTNF-R1/2 may therefore unmask endogenous TNFα, to presumably exert anti-neoplastic effects and reverse resistance to immune checkpoint inhibitors. Immune Apheresis (IA) is a procedure designed to specifically capture sTNF-R1/2 from plasma by passing it over an affinity column. Here we employed Immunicom’s LW-02 Immunopheresis® device for removal of sTNF-R1/2 from plasma of cancer patients.MethodsIn cohort A, patients with melanoma, RCC, NSCLC or TNBC refractory to standard therapy were treated with IA only. IA treatment of 2 plasma volumes was done x3/week, for three treatment cycles (4 weeks each) up to a total of 36 treatments. Cohort B patients currently receive concurrent IA and Nivolumab therapy (240mg q2 weeks starting on week 5). sTNF-Rs removal and circulating inflammatory biomarkers were measured by immuno-assays, such as multiplex cytokine detection and mass cytometry. Pre- and post-treatment tumor biopsies were analyzed for tumor markers and TILs by immunohistochemistry.ResultsCohort A included six patients (3 Melanoma and 3 TNBC): three patients completed full study regimen, and three others were withdrawn due to clinical progression. AEs included chills (4/6), fever (2/6), anemia (6/6), central line thrombosis (1/6) and pulmonary embolism (1/6) All were Grade 2 except G3 anemia (1/6). There were no treatment related SAE’s. sTNF-Rs levels were significantly reduced, followed by enhanced detection of TNFα, and IFNγ in some cases. In two patients, CD8 counts and PD-1 and PD-L1 expression were increased. Congruently, blood mass cytometry showed reduction in Treg subsets and differential increase of CD8 subsets following treatment.ConclusionsThe use of Immunicom’s LW-02 Immunopheresis® device in combination with Terumo BCT Spectra Optia Apheresis System is safe and efficient in the removal of sTNF-Rs from blood plasma. Subsequent immuno-assay analyses indicated formation of inflammatory response which may facilitate effects of immunotherapy, yet to be investigated in cohort B.Trial RegistrationNCT04142931Ethics ApprovalSheba Medical Center Ethics Committee, 6136-19ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

Transverse Growth of the Maxillo-Mandibular Complex in Untreated Children: A Longitudinal Cone Beam Computed Tomography Study

The aim of this study is to evaluate the longitudinal transverse growth of the maxillo-mandibular complex in untreated children using the Cone Beam Computed Tomography (CBCT). Two sets of scans on 12 males (mean 8.75 years at T1 and 11.52 years at T2) and 18 females (mean 9.09 years at T1 and 10.80 years at T2) were analyzed using Dolphin 3D imaging. The transverse widths of various maxillary and mandibular skeletal landmarks and the dentoalveolar and dental landmarks at the level of first molars were measured. Overall, there were greater increases in the transverse dimension in the posterior than anterior portions of the maxilla and mandible. The increase in intergonial width of the mandible seems to be primarily due to the lengthening of the mandibular body. The dentoalveolar process at the first molar level increases at an equal rate corono-apically and is independent to the changes in molar inclination. When comparing maxillary dentoalveolar changes with that of the mandible, greater increases were noticed in the maxilla, which might be explained by the presence of sutural growth in the maxilla. Moreover, the first molars maintain their coordination with each other despite the differential increase in the maxillary and mandibular dentoalveolar processes.

Evaluating the association between COVID-19 and psychiatric presentations, suicidal ideation in an emergency department

Objective To estimate the association between COVID-19 and Emergency Department (ED) psychiatric presentations, including suicidal ideation. Methods Using an interrupted time series design, we analyzed psychiatric presentations using electronic health record data in an academic medical center ED between 2018 and 2020. We used regression models to assess the association between the onset of the COVID-19 outbreak and certain psychiatric presentations. The period February 26–March 6, 2020 was used to define patterns in psychiatric presentations before and after the coronavirus outbreak. Results We found a 36.2% decrease (unadjusted) in ED psychiatric consults following the coronavirus outbreak, as compared to the previous year. After accounting for underlying trends, our results estimate significant differential change associated with suicidal ideation and substance use disorder (SUD) presentations following the outbreak. Specifically, we noted a significant differential increase in presentations with suicidal ideation six weeks after the outbreak (36.4 percentage points change; 95% CI: 5.3, 67.6). For presentations with SUD, we found a differential increase in the COVID-19 time series relative to the comparison time series at all post-outbreak time points and this differential increase was significant three weeks (32.8 percentage points; 95% CI: 4.0, 61.6) following the outbreak. Our results estimate no differential changes significant at the P value < 0.05 level associated with affective disorder or psychotic disorder presentations in the COVID-19 time series relative to the comparator time series. Conclusions The COVID-19 outbreak in Boston was associated with significant differential increases in ED presentations with suicidal ideation and SUD.

Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression

Dose of Trp53, the main keeper of genome stability, influences tumorigenesis; however, the causes underlying and driving tumorigenesis over time by the loss of a single p53 allele are still poorly characterized. Here, we found that single p53 allele loss specifically impacted the oxidative, DNA damage and inflammatory status of hematopoietic lineages. In particular, single Trp53 allele loss in mice triggered oxidative stress in peripheral blood granulocytes and spleenocytes, whereas lack of two Trp53 alleles produced enhanced oxidative stress in thymus cells, resulting in a higher incidence of lymphomas in the Trp53 knockout (KO) mice compared with hemizygous (HEM). In addition, single or complete loss of Trp53 alleles, as well as p53 downregulation, led to a differential increase in basal, LPS- and UVB-induced expression of a plethora of pro-inflammatory cytokine, such as interleukin-12 (Il-12a), TNFα (Tnfa) and interleukin (Il-23a) in bone marrow-derived macrophage cells (BMDMs) compared to WT cells. Interestingly, p53-dependent increased inflammatory gene expression correlated with deregulated expression of the NF-κB pathway inhibitor IκBα. Chromatin immunoprecipitation data revealed decreased p65 binding to Nfkbia in the absence of p53 and p53 binding to Nfkbia promoter, uncovering a novel crosstalk mechanism between p53 and NF-κB transcription factors. Overall, our data suggest that single Trp53 allele loss can drive a sustained inflammatory, DNA damage and oxidative stress response that, over time, facilitate and support carcinogenesis.

Britain’s Empire Marketing Board and the failure of soft trade policy, 1926–33

Before 1932, Britain’s essentially free-trade policy left barely any scope for reciprocating the preferential tariffs that the Dominions applied to Britain’s exports. Thus, Britain attempted to reciprocate by means of a “soft” trade policy aimed at increasing Britain’s imports from the empire through wide-reaching publicity coordinated by the Empire Marketing Board (EMB). This article, the first econometric assessment of the EMB, argues that there was not a differential increase in the volume of those imports advertised by the EMB. Principal arguments for this failure are that British consumers were frequently unaware of the geographic origin of many commodities and that they tended to identify company brand more than country of origin.

Implications of a Narrow Automated Vehicle-Exclusive Lane on Interstate 15 Express Lanes

The main objective of this study is to evaluate the safety and operational impacts of an innovative infrastructure solution for safe and efficient integration of Automated Vehicle (AV) as an emerging technology into an existing transportation system. Filling the gap in the limited research on the effect of AV technology on infrastructure standards, this study investigates implications of adding a narrow reversible AV-exclusive lane to the existing configuration of I-15 expressway in San Diego, resulting in a 9 ft AV reversible lane and, in both directions, two 12-feet lanes for HOV and FasTrak vehicles. Given the difference between the operation of AVs and human-driven vehicles and reliance of AVs on sensors as opposed to human capabilities, the question is should we provide narrower AV-exclusive roadways assuming AVs are more precise in lateral and longitudinal lane keeping behaviour? To accomplish the goal of the project, a historical crash data analysis and a traffic simulation analysis were conducted. Crash data analysis revealed that unsafe speed, improper turning, and unsafe lane change are the most recurring primary collision factors on I-15 ELs. AVs’ automated longitudinal and lateral control systems could potentially reduce these types of collisions on an AV-exclusive lane with proper infrastructure features for AV sensor operation (e.g., distinct lane marking). Microsimulation findings indicated an AV-exclusive lane may increase traffic flow and density by up to 14% and 24%, respectively. It also showed that average speed is reduced. However, this could lead to the speed differential increase between the exclusive lane and adjacent lane requiring careful consideration if additional treatments or barriers are needed. The results of this study contribute to infrastructure adaptation to AV technology and future AV-exclusive lanes implementations.

OvCa-Chip microsystem recreates vascular endothelium–mediated platelet extravasation in ovarian cancer

In ovarian cancer, platelet extravasation into the tumor and resulting metastasis is thought to be regulated mostly by the vascular endothelium. Because it is difficult to dissect complex underlying events in murine models, organ-on-a-chip methodology is applied to model vascular and platelet functions in ovarian cancer. This system (OvCa-Chip) consists of microfluidic chambers that are lined by human ovarian tumor cells interfaced with a 3-dimensional endothelialized lumen. Subsequent perfusion with human platelets within the device’s vascular endothelial compartment under microvascular shear conditions for 5 days uncovered organ-to-molecular–level contributions of the endothelium to triggering platelet extravasation into tumors. Further, analysis of effluents available from the device’s individual tumor and endothelial chambers revealed temporal dynamics of vascular disintegration caused by cancer cells, a differential increase in cytokine expression, and an alteration of barrier maintenance genes in endothelial cells. These events, when analyzed within the device over time, made the vascular tissue leaky and promoted platelet extravasation. Atorvastatin treatment of the endothelial cells within the OvCa-Chip revealed improved endothelial barrier function, reduction in inflammatory cytokines and, eventually, arrest of platelet extravasation. These data were validated through corresponding observations in patient-derived tumor samples. The OvCa-Chip provides a novel in vitro dissectible platform to model the mechanisms of the cancer-vascular-hematology nexus and the analyses of potential therapeutics.

Los impactos de la nueva política de salario mínimo. El caso de Jalisco y Baja California

In 2019, a new minimum wage policy is promoted that configures two wage regions: the free zone of the northern border of Mexico and the rest of the country. For the first region an increase of 100 percent is authorized and for the second of 16.2 per-cent. Our objective is to analyze the impact that, in 2019, the differential increase of the minimum wage in the generation of new jobs of the salaried labor force (target population of the minimum wage) of Jalisco (emblematic entity of the rest of Mexico region) and of Baja California (entity of the region of the free zone of the northern border of Mexico) contrasting it with the national average in three levels: occupa-tional structure, sector and economic activity and by size of establishment, as well as by sex. The statistical evidence is processed by the national survey of occupation and employment (ineGi).

Comparative assessment of different radiological criteria to identify paradoxical hyperprogression (HPD) to IO drugs.

e15229 Background: HPD is a new pattern of response consisting of accelerated tumor growth due to immunotherapy (5%-20% of pts on IO drugs). The tumor growth rate (TGR, Champiat et al.) estimates the differential increase in tumor volume over time, pre- and on IO drugs, to assess for HPD, but it is not easily calculated in practice. A comparison of the different methods to identify HPD is missing. Methods: Retrospective study of 182 consecutive pts treated in Phase 1 studies of IO drugs at START Madrid-CIOCC in 2017-8, comparing 3 HPD measurement criteria (Champiat, Matos -which does not use pre-baseline CT scans-, and Saâda-Bouzid). Cohen’s Kappa index was calculated as a measure of the agreement between the 3 methods, being those values closer to 1 the more concordant ones. Overall survival (OS) rates were calculated by Kaplan-Meier (p < 0.05 to be significant). Results: 99 (54%) of 182 pts had progressive disease at cycle 1 of treatment and in 62 (34%) pre-baseline CT scans were available to calculate TGR. The Champiat method identified 18 (9.9%) pts with HPD. Of 61 cases validated to comparison, the Matos criteria labeled 27 pts (14.8% of 182) with HPD, of whom only 10 pts coincided with those identified by Champiat with a low agreement (Kappa: 0.140, p:0.251). No significant differences in OS between pts with non-HPD vs HPD by Matos criteria were seen (p = 0.16). With Saâda-Bouzid method, of 59 cases validated to comparison, 17 pts (9.3% of 182) were labeled with HPD and 13 of them coincided with those identified by Champiat method with a high agreement (Kappa:0.706, p:0.000). Differences in OS between non-HPD vs HPD pts were statistically significant (p = 0.038). Conclusions: HPD might have a detrimental effect to 10% of pts on IO drugs, also in our series. Every effort should be done to obtain pre-baseline CT scans to identify HPD response to IO drugs, based on differential TGR. The use of Saâda-Bouzid method is preferred due to its practical application and its correlation with survival. [Table: see text]