Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta-Analysis of 20 Prospective Studies.

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline.

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome.

PCR-Free Shallow Whole Genome Sequencing for Chromosomal Copy Number Detection from Plasma of Cancer Patients Is an Efficient Alternative to the Conventional PCR-Based Approach.

Somatic copy number alterations can be detected in cell-free DNA (cfDNA) by shallow whole genome sequencing (sWGS). PCR is typically included in library preparations, but a PCR-free method could serve as a high-throughput alternative. To evaluate a PCR-free method for research and diagnostics, archival peripheral blood or bone marrow plasma samples, collected in EDTA- or lithium-heparin-containing tubes, were collected from patients with non-small-cell lung cancer (n = 10 longitudinal samples; 4 patients), B-cell lymphoma (n = 31), and acute myeloid leukemia (n = 15), or from healthy donors (n = 14).

Course and predictors of upper leg muscle strength over 48 months in subjects with knee osteoarthritis: Data from the osteoarthritis initiative.

Objectives: Weakness of upper leg muscles has a negative impact on future disease and functional status in subjects with knee osteoarthritis (OA). The aims of the present study were to (i) describe the course of muscle strength over 48 months and (ii) identify baseline predictors for a decline in upper leg muscle strength over time in subjects with knee OA.

Methods: Data were obtained from the Osteoarthritis Initiative (OAI) database, a multicenter, observational study of knee OA.

Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.

Objective: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.

Design, Setting, And Participants: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo.

Dietary protein intake and upper leg muscle strength in subjects with knee osteoarthritis: data from the osteoarthritis initiative.

The aims of this study were (1) to describe dietary protein intake, and (2) to evaluate the association between dietary protein intake and upper leg muscle strength in subjects with knee osteoarthritis (OA). Baseline data from the OA was used, in a cross-sectional study. All subjects were diagnosed with symptomatic and radiographic knee OA.

Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study.

Objectives: Surveillance colonoscopy is thought to prevent colorectal cancer (CRC) in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk.

Design: A multicentre, multinational database of patients with long-standing IBD colitis without high-risk features and undergoing regular CRC surveillance was constructed.

Variation in the diagnosis and clinical management of lentigo maligna across Europe: a survey study among European Association of Dermatologists and Venereologists members.

Background: Lentigo maligna (LM), a form of melanoma in situ, is treated to prevent progression to lentigo maligna melanoma (LMM). Surgical treatment is the gold standard. However, treatment guidelines are based on expert opinion, and comparative studies are lacking.

High Risk of Advanced Colorectal Neoplasia in Patients With Primary Sclerosing Cholangitis Associated With Inflammatory Bowel Disease.

Background & Aims: Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC, termed PSC-IBD) are at increased risk for colorectal cancer, but their risk following a diagnosis of low-grade dysplasia (LGD) is not well described. We aimed to determine the rate of advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia and/or colorectal cancer, following a diagnosis of indefinite dysplasia or LGD in this population.

Methods: We performed a retrospective, longitudinal study of 1911 patients with colonic IBD (293 with PSC and 1618 without PSC) who underwent more than 2 surveillance colonoscopies from 2000 through 2015 in The Netherlands or the United States (9265 patient-years of follow-up evaluation).

The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.

Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress---- TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs).

Design Thinking as a Tool for Interdisciplinary Education in Health Care.

Problem: Grappling with complex structural health care issues requires medical professionals to have training in skills and knowledge that go beyond the basic and clinical sciences. It is also crucial for health care professionals to be able to work collaboratively. However, medical education has only limitedly institutionalized the teaching of these skills.

Incidence of Interval Colorectal Cancer Among Inflammatory Bowel Disease Patients Undergoing Regular Colonoscopic Surveillance.

Background & Aims: Surveillance is recommended for patients with long-term inflammatory bowel disease because they have an increased risk of colorectal cancer (CRC). To study the effectiveness of surveillance, we determined the incidence of CRC after negative findings from surveillance colonoscopies (interval CRC).

Methods: We collected data from 1273 patients with ulcerative colitis or Crohn's disease, enrolled in a surveillance program at 7 hospitals in The Netherlands, who underwent 4327 surveillance colonoscopies from January 1, 2000, through January 1, 2014.

Maternal Nodal inversely affects NODAL and STOX1 expression in the fetal placenta.

Nodal, a secreted signaling protein from the transforming growth factor beta (TGF-β)-super family plays a vital role during early embryonic development. Recently, it was found that maternal decidua-specific Nodal knockout mice show intrauterine growth restriction (IUGR) and preterm birth. The chromosomal location of NODAL is in the same linkage area as the placental (fetal) pre-eclampsia (PE) susceptibility gene STOX1, which is associated with the familial form of early-onset, IUGR-complicated PE.

Two way communication between neutrophils and dendritic cells.

Neutrophils are instrumental in innate immunity by mediating immediate removal of pathogens. Recent findings demonstrate that they are able to communicate with dendritic cells, which form a link between innate and adaptive immunity by stimulating long-term memory T cell responses. This communication occurs through the cell-surface receptors Mac-1 and carcinoembryonic antigen-related cellular adhesion molecule on neutrophils, which interact with C-type lectins such as dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN).

Viral piracy: HIV-1 targets dendritic cells for transmission.

Dendritic cells (DCs), the professional antigen presenting cells, are critical for host immunity by inducing specific immune responses against a broad variety of pathogens. Remarkably the human immunodeficiency virus-1 (HIV-1) subverts DC function leading to spread of the virus. At an early phase of HIV-1 transmission, DCs capture HIV-1 at mucosal surfaces and transmit the virus to T cells in secondary lymphoid tissues.

Recognition of tumor glycans by antigen-presenting cells.

C-type lectin receptors on antigen-presenting cells are potent antigen-uptake receptors with specificity for glycan structures. Glycosylation changes during malignant transformation create tumor-specific carbohydrate structures that interact with C-type lectins on dendritic cells. Recent findings revealed that tumor glycoproteins, such as carcinoembryonic antigen and MUC-1, indeed interact with the C-type lectins DC-SIGN and macrophage galactose-type lectin on antigen-presenting cells.

Potency of HIV-1 envelope glycoprotein gp120 antibodies to inhibit the interaction of DC-SIGN with HIV-1 gp120.

The interaction of DC-SIGN with gp120 provides an attractive target for intervention of HIV-1 transmission. Here, we have investigated the potency of gp120 antibodies to inhibit the DC-SIGN-gp120 interaction. We demonstrate that although the V3 loop is not essential for DC-SIGN binding, antibodies against the V3 loop partially inhibit DC-SIGN binding, suggesting that these antibodies sterically hinder DC-SIGN binding to gp120.

Cost-effectiveness of early intervention: comparison between intraluminal bronchoscopic treatment and surgical resection for T1N0 lung cancer patients.

Background: For patients with early-stage lung cancer (ESLC) and severe comorbidities, the cost-effectiveness of early intervention may be reduced by screening and treatment-related morbidity and mortality in addition to the risk for non-cancer-related deaths.

Objectives: The use of bronchoscopic treatment (BT) for centrally located ESLC as minimally invasive technique has raised questions whether this approach will be more cost-effective than standard surgical resection in the above-mentioned cohort of patients.

Methods: The cost-effectiveness of BT of 32 medically inoperable patients with intraluminal tumor has been compared to a matched control group of surgically treated stage IA cancer patients.

Pathogens use carbohydrates to escape immunity induced by dendritic cells.

Dendritic cells (DCs) play a central role in balancing immune responses between tolerance induction and immune activation. Under steady state conditions DCs continuously sample antigens, leading to tolerance, whereas inflammatory conditions activate DCs, inducing immune activation. DCs express C-type lectin receptors (CLRs) for antigen capture and presentation, whereas Toll-like receptors (TLRs) are involved in pathogen recognition and DC activation.

Self- and nonself-recognition by C-type lectins on dendritic cells.

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens.

Pathogens target DC-SIGN to influence their fate DC-SIGN functions as a pathogen receptor with broad specificity.

Dendritic cells (DC) are vital in the defense against pathogens. To sense pathogens DC express pathogen recognition receptors such as toll-like receptors (TLR) and C-type lectins that recognize different fragments of pathogens, and subsequently activate or present pathogen fragments to T cells. It is now becoming evident that some pathogens subvert DC functions to escape immune surveillance.

DC-SIGN: escape mechanism for pathogens.

Dendritic cells (DCs) are crucial in the defence against pathogens. Invading pathogens are recognized by Toll-like receptors (TLRs) and receptors such as C-type lectins expressed on the surface of DCs. However, it is becoming evident that some pathogens, including viruses, such as HIV-1, and non-viral pathogens, such as Mycobacterium tuberculosis, subvert DC functions to escape immune surveillance by targeting the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin).

DC-SIGN: a novel HIV receptor on DCs that mediates HIV-1 transmission.

The dendritic cell (DC)-specific HIV-1 receptor DC-SIGN plays a key-role in the dissemination of HIV-1 by DCs. DC-SIGN captures HIV-1 at sites of entry, enabling its transport to lymphoid tissues, where DC-SIGN efficiently transmits low amounts of HIV-1 to T cells. The expression pattern of DC-SIGN in mucosal tissue, lymph nodes, placenta and blood suggests a function for DC-SIGN in both horizontal and vertical transmission of HIV-1.

A fatal attraction: Mycobacterium tuberculosis and HIV-1 target DC-SIGN to escape immune surveillance.

Dendritic cells (DCs) are vital in the defense against pathogens. However, it is becoming increasingly clear that some pathogens subvert DC functions to escape immune surveillance. For example, HIV-1 targets the DC-specific C-type lectin DC-SIGN (DC-specific intercellular-adhesion-molecule-3-grabbing nonintegrin) to hijack DCs for viral dissemination.

ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study.

Background: The purpose of this study was to evaluate ALIMTA (pemetrexed disodium, LY231514), a multi-targeted antifolate with first-line activity against non-small-cell lung cancer (NSCLC), in a second-line setting.

Patients And Methods: Patients with NSCLC were eligible for this phase II study if they had progressive disease within 3 months after first-line chemotherapy or progression while being treated with first-line chemotherapy. In 81 patients studied, two cohorts of patients were assigned based on whether the first-line therapy had included a platinum regimen.