Improved prediction of mortality by combinations of inflammatory markers and standard clinical scores in patients with acute-on-chronic liver failure and acute decompensation

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) as a sinister prognosis and there is a need for accurate biomarkers and scoring systems to better characterize ACLF patients and predict prognosis. Systemic inflammation and renal failure are hallmarks in ACLF disease development and progression. We hypothesized that the combination of specific inflammatory markers in combination with clinical scores are better predictors of survival than the originally developed CLIF-C acute decompensation (AD) and CLIF-C ACLF scores. METHODS: We re-evaluated all previously measured inflammatory markers in 522 patients from the CANONIC study, 342 without and 180 with ACLF. We used the Harrell's C-index to determine the best marker alone or in combination with the original scores and calculated new scores for prediction of mortality in the original CANONIC cohort. RESULTS: The best markers to predict 90-day mortality in patients without ACLF were the plasma macrophage activation markers soluble (s)CD163 and mannose receptor (sMR). Urinary neutrophil gelatinase associated lipocalin (UNGAL) and sCD163 were predictors for 28-day mortality in patients with ACLF. The new developed CLIF-C AD+sMR score in patients without ACLF improved 90-days mortality prediction compared to the original CLIF-C AD score (C-index 0.82(0.78-0.86) vs. 0.74(0.70-0.78, P=0.004). Further, the new CLIF-C ACLF+sCD163+UNGAL improved the original CLIF-C ACLF score for 28-days mortality (0.85(0.79-0.91) vs. 0.75(0.70-0.80), P=0.039). CONCLUSIONS: The capability of these inflammatory markers to improve the original prognostic scores in cirrhosis patients without and with ACLF points to a key role of macrophage activation and inflammation in the development and progression of AD and ACLF

Association of Common Variants in TNFRSF13B, TNFSF13, and ANXA3 with Serum Levels of Non-Albumin Protein and Immunoglobulin Isotypes in Japanese

We performed a genome-wide association study (GWAS) on levels of serum total protein (TP), albumin (ALB), and non-albumin protein (NAP). We analyzed SNPs on autosomal chromosomes using data from 9,103 Japanese individuals, followed by a replication study of 1,600 additional individuals. We confirmed the previously- reported association of GCKR on chromosome 2p23.3 with serum ALB (rs1260326, Pmeta = 3.1×10−9), and additionally identified the significant genome-wide association of rs4985726 in TNFRSF13B on 17p11.2 with both TP and NAP (Pmeta = 1.2×10−14 and 7.1×10−24, respectively). For NAP, rs3803800 and rs11552708 in TNFSF13 on 17p13.1 (Pmeta = 7.2×10−15 and 7.5×10−10, respectively) as well as rs10007186 on 4q21.2 near ANXA3 (Pmeta = 1.3×10−9) also indicated significant associations. Interestingly, TNFRSF13B and TNFSF13 encode a tumor necrosis factor (TNF) receptor and its ligand, which together constitute an important receptor-ligand axis for B-cell homeostasis and immunoglobulin production. Furthermore, three SNPs, rs4985726, rs3803800, and rs11552708 in TNFRSF13B and TNFSF13, were indicated to be associated with serum levels of IgG (P<2.3×10−3) and IgM (P<0.018), while rs3803800 and rs11552708 were associated with IgA (P<0.013). Rs10007186 in 4q21.2 was associated with serum levels of IgA (P = 0.036), IgM (P = 0.019), and IgE (P = 4.9×10−4). Our results should add interesting knowledge about the regulation of major serum components

Capmatinib in MET exon 14-mutated non-small-cell lung cancer:final results from the open-label, phase 2 GEOMETRY mono-1 trial

Background: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib. Methods: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1–7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1–7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed. Findings: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8–65·4) for the treatment-naïve patients and 66·9 months (56·7–73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0–79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1–54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3–4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported. Interpretation: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC. </p

The Edar subfamily in feather placode formation

AbstractA subgroup of the TNF receptor family, composed of Edar, Troy and Xedar, are implicated in the development of ectodermal appendages, such as hair follicles, teeth and sweat glands. We have isolated chicken orthologues of these three receptors and analysed their roles in early feather development. Conservation of protein sequences between mammalian and avian proteins is variable, with avian Edar showing the greatest degree of sequence identity. cXedar differs from its mammalian orthologue in that it contains an intracellular death domain. All three receptors are expressed during early feather morphogenesis and dominant negative forms of each receptor impair the epithelial contribution to feather bud morphogenesis, while the dermal contribution appears unaffected. Hyperactivation of each receptor leads to more widespread assumption of placode fate, though in different regions of the skin. Receptor signaling converges on NF-κB, and inhibiting this transcription factor alters feather bud number and size in a stage-specific manner. Our findings illustrate the roles of these three receptors during avian skin morphogenesis and also suggest that activators of feather placode fate undergo mutual regulation to reach a decision on skin appendage location and size

Methods to identify, study and understand End-user participation in HIT development

<p>Abstract</p> <p>Background</p> <p>Experience has shown that for new health-information-technology (HIT) to be suc-cessful clinicians must obtain <it>positive clinical benefits </it>as a result of its implementation and <it>joint-ownership </it>of the decisions made during the development process. A prerequisite for achieving both success criteria is <it>real </it>end-user-participation. Experience has also shown that further research into developing improved methods to collect more detailed information on social groups participating in HIT development is needed in order to support, facilitate and improve real end-user participation.</p> <p>Methods</p> <p>A case study of an EHR planning-process in a Danish county from October 2003 until April 2006 was conducted using process-analysis. Three social groups (physicians, IT-professionals and administrators) were identified and studied in the <it>local, present </it>perspective. In order to understand the interactions between the three groups, the <it>national, historic </it>perspective was included through a literature-study. Data were collected through observations, interviews, insight gathered from documents and relevant literature.</p> <p>Results</p> <p>In the local, present perspective, the administrator's strategy for the EHR planning process meant that there was no clinical workload-reduction. This was seen as one of the main barriers to the physicians to achieving real influence. In the national, historic perspective, physicians and administrators have had/have different perceptions of the purpose of the patient record and they have both struggled to influence this definition. To date, the administrators have won the battle. This explains the conditions made available for the physicians' participation in this case, which led to their role being reduced to that of clinical consultants - rather than real participants.</p> <p>Conclusion</p> <p>In HIT-development the interests of and the balance of power between the different social groups involved are decisive in determining whether or not the end-users become real participants in the development process. Real end-user-participation is essential for the successful outcome of the process. By combining and developing existing theories and methods, this paper presents an improved method to collect more detailed information on social groups participating in HIT-development and their interaction during the development. This allows HIT management to explore new avenues during the HIT development process in order to support, facilitate and improve real end-user participation.</p

Expression of TNF-superfamily members BAFF and APRIL in breast cancer: Immunohistochemical study in 52 invasive ductal breast carcinomas

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest an association between chronic inflammation, modulating the tissue microenvironment, and tumor biology. Tumor environment consists of tumor, stromal and endothelial cells and infiltrating macrophages, T lymphocytes, and dendritic cells, producing an array of cytokines, chemokines and growth factors, accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of tumor and surrounding cells, responsible for tumor progression and spreading or induction of antitumor immune responses and rejection. Tumor Necrosis Factor (TNF) family members (19 ligands and 29 receptors) represent a pleiotropic family of agents, related to a plethora of cellular events from proliferation and differentiation to apoptosis and tumor reduction. Among these members, BAFF and APRIL (CD257 and CD256 respectively) gained an increased interest, in view of their role in cell protection, differentiation and growth, in a number of lymphocyte, epithelial and mesenchymal structures.</p> <p>Methods</p> <p>We have assayed by immunohistochemistry 52 human breast cancer biopsies for the expression of BAFF and APRIL and correlated our findings with clinicopathological data and the evolution of the disease.</p> <p>Results</p> <p>BAFF was ubiquitely expressed in breast carcinoma cells, DCIS, normal-appearing glands and ducts and peritumoral adipocytes. In contrast, APRIL immunoreactive expression was higher in non-malignant as compared to malignant breast structures. APRIL but not BAFF immunoreactivity was higher in N+ tumors, and was inversely related with the grade of the tumors. Neither parameter was related to DFS or the OS of patients.</p> <p>Conclusion</p> <p>Our data show, for the first time, an autocrine secretion of BAFF and APRIL from breast cancer cells, offering new perspectives for their role in neoplastic and normal breast cell biology and offering new perspectives for possible selective intervention in breast cancer.</p