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Research has failed to consistently show that therapists facilitate better client outcomes as they gain more experience. The present study was designed to examine changes in early client retention over the course of extended periods of time among 2591 therapists in private practice. Naturalistic data collected between 2018 and 2022 was extracted from a technology‐enabled practice‐research group (PRG). Therapists displayed an increase in client dropout rates as they gained more experience on the PRG. Additionally, larger caseloads on the PRG were associated with lower increases in client dropout over time. Finally, therapists working with clients paying higher out‐of‐pocket fees (e.g., co‐pays) had higher increases in client dropout over time. These findings provide additional evidence supporting the distinction between clinical experience and expertise. [ABSTRACT FROM AUTHOR]

Engagement in measurement‐based care (MBC) has been shown to be an effective practice for optimizing psychotherapy outcomes. Best practices for MBC suggest that it is crucial for therapists to consistently review scores. However, the exact impact of this practice on MBC's effectiveness has yet to be fully elucidated. The current study examined the association between the frequency of therapists reviewing clients' depression scores and client psychotherapy outcomes. The sample consisted of 6182 clients diagnosed with depression who sought treatment from 2248 therapists through a practice research group. Patient Health Questionnaire‐9 (PHQ‐9) was administered prior to sessions, and therapists could access the scores via their therapist portal. The results based on multilevel modelling revealed that how often therapists view their clients' PHQ‐9 results was not a significant predictor of therapy outcomes. However, therapists who, across their caseloads, viewed client PHQ‐9 scores more frequently facilitated better treatment outcomes. These results suggest that therapists who routinely engage in MBC facilitate better therapy outcomes. Implications for practice and research are provided. [ABSTRACT FROM AUTHOR]

Organocatalytic asymmetric transformation of common aromatic heterocycles via in situ formation of highly reactive dearomatized ortho‐quinodimethane diene species and subsequent [4+2] cycloaddition with suitable dienophiles has become a powerful tool to enter cyclohexane‐fused heterocycles. Most of these reactions were previously applied to benzo‐fused heterocycles or poorly aromatic rings. Herein, we disclose how previously intractable aromatic imidazole rings, equipped with removable methylidene malononitrile activating handle, could be involved as competent cycloaddends with β‐aryl enals in efficient eliminative [4+2] cycloadditions under mild organocatalytic conditions. This method allowed the efficient and direct preparation of scantly represented 6,7‐dihydrobenzo[d]imidazoles with optimal enantio‐ and regioselectivities. Post‐cycloaddition chemical editing provided imidazole‐based ring systems with diverse oxidation state and functional groups. [ABSTRACT FROM AUTHOR]

This article introduces an alternative and less conservative ℋ∞$$ {\mathscr{H}}_{\infty } $$ filter design procedure applied to continuous time uncertain systems. In order to provide a reduction in conservatism and an ℋ∞$$ {\mathscr{H}}_{\infty } $$ norm improvement, the proposed technique avoids the conventional convexification procedure—which uses structure restrictions and slack variables. Instead, it defines an unconstrained structure. The proposed technique consists of a hybrid procedure, combining the application of linear matrix inequalities (LMIs) with heuristic optimization algorithms (HOAs). The HOAs, specifically genetic algorithms, are used to optimize terms that could cause bilinearities, subsequently evaluated by LMIs and generating the desired filter. Numerical examples and a comparison with other methodologies are presented, testifying to the proposed method's efficacy and the performance. [ABSTRACT FROM AUTHOR]

Objective: Early diagnosis and tight control improve outcomes of rheumatoid arthritis (RA). However, whether establishing an early arthritis clinic (EAC) is sustainable for national health systems is not known. This analysis aimed to compare effectiveness and costs of an EAC compared to patients followed by the current standard of care. Methods: A retrospective study on administrative health databases of patients with a new diagnosis of RA was conducted: 430 patients followed in an EAC were enrolled, and 4 non‐EAC controls were randomly matched for each. During 2 years of follow‐up, the mean health care costs (outpatient, inpatient, pharmaceutical, and global) and 3 effectiveness measures (number and length of hospitalization and quality of care) of the EAC and non‐EAC were estimated. The incremental cost‐effectiveness ratio was calculated as well as the cost‐effectiveness acceptability curve. Results: The cohorts included patients with a mean age of 55.4 years, and 1,506 patients (70%) were female. The mean pharmaceutical (2,602 versus 1,945 euros) and outpatient (2,447 versus 1,778 euros) costs were higher in the EAC cohort. Conversely, a higher rate of non‐EAC patients had a low adherence to quality‐of‐care indicators. The expected number of hospitalizations and the length of stay were statistically significantly higher in the non‐EAC versus EAC. Conclusion: Despite an expected increase in outpatient costs (visits and diagnostic tests) and pharmaceutical costs, the reduction in terms of number and length of hospitalizations and the higher adherence to international quality‐of‐care guidelines support the effectiveness of the EAC model. [ABSTRACT FROM AUTHOR]

Objectives: Laryngeal squamous cell carcinomas (LSCCs) typically have an excellent prognosis for stage I tumors but a significant risk of locoregional and distant recurrence for intermediate to advanced disease. This study will investigate the clinical relevance of the tumor microenvironment in a large cohort of treatment‐naïve patients affected by stage II–IV LSCC. Methods: Whole slide‐based digital pathology analysis was applied to measure six immune cell populations identified by immunohistochemistry (IHC) staining for CD3, CD8, CD20, CD66b, CD163 and CD38. Survival analysis was performed by Cox proportional hazards models and unsupervised hierarchical clustering using the k‐means method. Double IHC staining and in‐situ hybridisation by RNAscope allowed further analysis of a protumoral B cell population. Results: A cohort of 98 patients was enrolled and analysed. The cluster of immune‐infiltrated LSCCs demonstrated a significantly worse disease‐specific survival rate. We also discovered a new association between high CD20+ B cells and a greater risk of distant recurrence. The phenotypic analysis of infiltrating CD20+ B cells showed a naïve (BCL6−CD27−Mum1−) regulatory phenotype, producing TGFβ but not IL10, according to an active TGFβ pathway, as proved by positive pSMAD2 staining. Conclusion: The identification of regulatory B cells in the context of LSCC, along with the activation of the TGFβ pathway, could provide the basis for new trials investigating the efficacy of already available molecules targeting the TGFβ pathway in the treatment of LSCC. [ABSTRACT FROM AUTHOR]

Melanoma is the deadliest form of skin cancer, and more than 150,000 cases are diagnosed every year in Europe. New strategies in treatment approved over the past decade, such as immunotherapy and targeted therapy, have prolonged life expectation even in stage IV melanoma patients. However, due to the increasing incidence of this cancer, the development of new therapeutic strategies remains urgent. Recent studies revealed the combination of nintedanib, a tyrosine kinase inhibitor approved as an antifibrotic drug, and immuno‐ and/or targeted therapy drugs to be promising. Here we present three new dual covalent conjugates, in which a nintedanib unit is permanently linked to a cyclopeptidomimetic ligand for the αVβ3 integrin, a transmembrane receptor involved in cell survival, proliferation and migration, which is overexpressed by tumour cells, and therefore recognized as marker for tumour targeting. In vitro assays on human melanoma tumour cells confirmed the high binding affinity of these conjugates for αVβ3 integrin‐positive melanoma cells, as well as their integrin‐mediated cell internalization. Two of these conjugates were efficient in inhibiting the mitogen activated protein kinase (MAPK) signalling pathway, common to both integrin‐ and growth factor‐ biological targets. Such targeted conjugates could therefore be of special interest in melanoma treatment alone or in combination with other anticancer drugs. [ABSTRACT FROM AUTHOR]

For high‐risk endometrial cancer (EC) patients, adjuvant chemotherapy is recommended to improve outcome. Yet, predictive biomarkers for response to platinum‐based chemotherapy (Pt‐aCT) are currently lacking. We tested expression of L1 cell‐adhesion molecule (L1CAM), a well‐recognised marker of poor prognosis in EC, in tumour samples from high‐risk EC patients, to explore its role as a predictive marker of Pt‐aCT response. L1CAM expression was determined using RT‐qPCR and immunohistochemistry in a cohort of high‐risk EC patients treated with Pt‐aCT and validated in a multicentric independent cohort. The association between L1CAM and clinicopathologic features and L1CAM additive value in predicting platinum response were determined. The effect of L1CAM gene silencing on response to carboplatin was functionally tested on primary L1CAM‐expressing cells. Increased L1CAM expression at both genetic and protein level correlated with high‐grade, non‐endometrioid histology and poor response to platinum treatment. A predictive model adding L1CAM to prognostic clinical variables significantly improved platinum response prediction (C‐index 78.1%, P =.012). In multivariate survival analysis, L1CAM expression was significantly associated with poor outcome (HR: 2.03, P =.019), potentially through an indirect effect, mediated by its influence on response to chemotherapy. In vitro, inhibition of L1CAM significantly increased cell sensitivity to carboplatin, supporting a mechanistic link between L1CAM expression and response to platinum in EC cells. In conclusion, we have demonstrated the role of L1CAM in the prediction of response to Pt‐aCT in two independent cohorts of high‐risk EC patients. L1CAM is a promising candidate biomarker to optimise decision making in high‐risk patients who are eligible for Pt‐aCT. [ABSTRACT FROM AUTHOR]

RNA virus in a single host consists of a heterogeneous population of replicating viruses designated as quasispecies.[1] Quasispecies dynamics during infection represent an adaptive strategy of the virus to evade immune responses.[2] Thus, in vaccinated immunocompetent individuals, the appearance of quasispecies is expected to inversely correlate with the level of master sequence adaptation to a hostile microenvironment. Emergence of S gene-based quasispecies explains an optimal adaptation of Omicron BA.5 subvariant in the immunocompetent vaccinated human host The low frequency of quasispecies observed in BA.2.3- and BA.5-infected patients supports the hypothesis that these omicron sub-lineages are adapted to vaccine-elicited immune responses. [Extracted from the article]

Chronic non‐scarring scalp folliculitis is a little‐known entity included within the spectrum of scalp folliculitis, a group of diseases sharing clinical features but with heterogeneity in terms of residual scarring (always absent in chronic non‐scarring scalp folliculitis), microbiology, and response to antibiotics. Chronic non‐scarring scalp folliculitis is most likely an inflammatory disease within the group of neutrophilic dermatoses. The recognition of the inflammatory nature of this disease may pave the way for the use of new therapies, directly targeting pathogenic molecules. Herein, we report the first case of chronic non‐scarring scalp folliculitis treated by adalimumab. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Dignass et al papers. To view these articles, visit https://doi.org/10.1111/apt.17622 and https://doi.org/10.1111/apt.17763 [ABSTRACT FROM AUTHOR]

Layered double hydroxide (LDH) as nano‐carrier of parahydroxybenzoate (listed in EC Directive 10/2011) was coated on a biodegradable film of cellulose acetate, coupled with compostable cellulose cardboard and trays realized. The sustained release of parahydroxybenzoate ionically intercalated into the LDH resulted significantly slower than the parahydroxybenzoate free dispersed into the coating medium. Such active packaging showed significant antimicrobial activity against Salmonella enterica Typhimurium, Escherichia coli, Listeria monocytogenes and Lactobacillus sakei. It was more than one in all cases, ranging from 1.1 for E. coli to 2.6 for S. enterica Typhimurium. Overall migration tests in ethanol at 50% (v/v), as food simulant, showed that the prepared packaging is suitable for food contact, being the migrated amount below the limits imposed by the EU regulation. Fresh‐cut iceberg lettuce was packed into the prepared active packaging and in a control packaging with no active coating and stored in condition of thermal stress (i.e. 10°C). Organoleptic characteristics and the evolution up to 14 days of mesophilic lactic bacteria, total bacteria count, yeasts and moulds showed a significant inhibition of such strains from the active filler. Comparing the lettuce packed in control and active packaging, for mesophilic lactic bacteria, it was found a delta log of 0.24 (CFU), and for the total bacteria count, a delta log of 1.63 (CFU). The most significant effects were observed respect to yeasts and moulds and yeasts counts. For yeasts, it was observed a delta log of 2.32 (CFU), and for yeasts and moulds, a delta log of 2.5 (CFU). The prediction of the shelf life of the lettuce was done following the growth of E. coli up to 30 days through the Gompertz equation. It was found a prolongation of the shelf life from 11 to 16 days [ABSTRACT FROM AUTHOR]

In recent years, targeted therapies have raised increasing interest as effective strategies to improve therapeutic efficiency, reduce the impact of adverse side effects, and overcome drug resistance, particularly in the field of cancer chemotherapeutics. Many examples of RGD (Arg-Gly-Asp) peptide-drug conjugates (PDCs) have been proposed as targeted drug delivery systems. These molecular hybrids embody high affinity ligands targeting disease signatures (overexpressed integrin receptors or specific integrin-related pathways within diseased cells/tissues) connected to recognized therapeutic units by means of carefully designed linker-spacer combinations, to ultimately control stability, physico-chemical properties, timing, and localization of drug release. This account has collected and critically surveyed relevant contributions from the period of 2015 to the present day, wishing to provide a window open on new synthesis strategies facing the challenging issues of site-selective drug delivery and dual drug targeting. [ABSTRACT FROM AUTHOR]

In early 2020 the new respiratory syndrome COVID‐19 (caused by the zoonotic SARS‐CoV‐2 virus) spread like a pandemic, starting from Wuhan, China, causing severe economic depression. Despite some advances in drug treatments of medical complications in the later stages of the disease, the pandemic's death toll is tragic, as no vaccine or specific antiviral treatment is currently available. By using a systems approach, we identify the host‐encoded pathway, which provides ribonucleotides to viral RNA synthesis, as a possible target. We show that methotrexate, an FDA‐approved inhibitor of purine biosynthesis, potently inhibits viral RNA replication, viral protein synthesis, and virus release. The effective antiviral methotrexate concentrations are similar to those used for established human therapies using the same drug. Methotrexate should be most effective in patients at the earliest appearance of symptoms to effectively prevent viral replication, diffusion of the infection, and possibly fatal complications. Highlights: The COVID‐19 pandemic caused by the SARS‐CoV‐2 virus is a global public health threat causing over 800000 deaths, millions of infected people, and severe economic depression.No vaccine or specific antiviral treatments are currently available.By inhibiting the host‐encoded pathway, which provides ribonucleotides to viral RNA synthesis, the FDA‐approved drug methotrexate efficiently blocks SARS‐CoV‐2 replication. [ABSTRACT FROM AUTHOR]

Objectives: The role of tumor‐associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs. Methods: The relevance, derivation, phenotype and interactions of nodal TANs were explored via a large immunohistochemical analysis of carcinoma‐draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor‐promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial‐to‐mesenchymal transition (EMT) signatures. Results: The pan‐carcinoma screening identified a consistent infiltration (59%) of CD66b+ TANs in tumor‐draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra‐lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. In vitro experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM‐CSF. Moreover, by retrospective analysis, a high CD66b+ TAN density in M‐TDLNs of OSCC (n = 182 patients) predicted a worse prognosis. The analysis of the OSCC‐TCGA dataset unveiled that the expression of a set of neutrophil‐specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66b+TANs co‐localised with PDPN+S100A9− EMT‐switched tumor cells in areas of lymphangiogenesis. The pro‐EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs. Conclusion: Our findings are consistent with a novel pro‐tumoral TAN compartment that may promote nodal spread via EMT, through the lymphatics. [ABSTRACT FROM AUTHOR]

In recognition of the key role played by integrins in several life‐threatening dysfunctions, the search for novel small‐molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)‐RGD based cyclopeptidomimetics with attracting αVβ3 integrin affinity and selectivity, the design and straightforward synthesis of 18 new AmpRGD chemotypes bearing additional structural variants were herein implemented, to shift toward peptide‐like αVβ6 integrin targeted binders. The ligand competence of the synthesized products toward αVβ6 was evaluated in competitive binding assays on isolated receptors, and αVβ6/αVβ3 selectivity was determined for a subgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity. [ABSTRACT FROM AUTHOR]

Objective: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). Methods: Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi‐IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0–9) and of CD20+ B cell infiltrate (on a scale of 0–4). B cell scores were validated by digital image analysis and B cell lineage–specific transcript analysis (RNA‐Seq) in the early RA (n = 91) and TNFi‐IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). Results: Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage–specific transcripts. B cell–rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi‐IR cohort (P = 0.025). B cell–rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti–citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell–rich patients were demonstrated in both cohorts. Conclusion: We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell–rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA. [ABSTRACT FROM AUTHOR]

B cell receptor (BCR) critically contributes to the growth of multiple types of mature B cell neoplasms, representing a preferred target of therapy. Strikingly, whereas IgH SP + sp DHL/THL GCB lymphomas retained IgM expression, IgH SP UND sp lymphomas systematically completed IgH class-switching, yet failed to assemble signaling-competent Ig/CD79B/A BCR complexes. IMMUNOGLOBULIN CLASS DICTATES TRANSFORMATION TRAJECTORY AND BCR STATUS OF MYC/BCL2 DOUBLE-HIT LYMPHOMA: BIOLOGY AND CLINICAL IMPLICATIONS. [Extracted from the article]

Background/Objectives: Little is known about the dermoscopic features of atypical fibroxanthoma. Methods: This was a case‐control study. Atypical fibroxanthoma lesions were compared with a control group with non‐melanoma skin cancer. Results: Altogether 40 atypical fibroxanthoma were collected. Most developed in men (93%), appearing mainly as nodular (63%), amelanotic (93%) and ulcerated (78%) lesions. Most lesions were located on the scalp (55%) and the ears (13%). Dermoscopically, most atypical fibroxanthoma displayed red (83%) and white (70%) structureless areas and irregular linear vessels (43%). A series of features achieved statistical significance when comparing atypical fibroxanthoma with non‐melanoma skin cancer. The presence of red and white structureless areas and white lines, and the absence of yellowish‐white opaque scales, hairpin vessels and arborising vessels were predictive of atypical fibroxanthoma in univariate analysis. However, when squamous cell carcinoma was excluded from the analysis, none of the criteria achieved statistical significance. When basal cell carcinoma was excluded, three variables achieved statistical significance in predicting atypical fibroxanthoma: red, structureless areas, the absence of opaque yellowish‐white scales and absence of white circles. Conclusions: Atypical fibroxanthomas seem to be barely distinguishable from basal cell carcinoma dermoscopically, but they are more easily distinguishable from a well to moderately differentiated squamous cell carcinoma. A histopathological examination is needed for the final diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether the choice of synovial biopsy technique (arthroscopy, blind needle [BN] biopsy, ultrasound [US]–guided portal and forceps [P&F], or US‐guided needle biopsy [NB]) translates to significant variation in synovial tissue quality and quantity, with the aim of informing recommendations for the choice of synovial sampling technique within clinical trials. Methods: In total, 159 procedures from 5 academic rheumatology centers were evaluated. Hematoxylin and eosin–stained, paraffin‐embedded synovial tissue sections from patients with inflammatory arthritis were assessed in order to determine the proportion of graded synovial fragments, total area of graded synovial tissue, and synovitis score per procedure. RNA quantity (μg of RNA) and quality (RNA integrity number) per procedure were also assessed in the synovial samples. Results: In this study, 84 of the 159 procedures performed on large joints at baseline (25 arthroscopic, 35 US‐P&F, 11 US‐NB, and 13 BN biopsies), 41 of the 159 procedures performed on small joints at baseline (11 US‐P&F, 20 US‐NB, and 10 BN biopsies), and 34 sequential biopsy procedures were evaluated. Compared to all other techniques evaluated in the small and large joints, fewer small joint BN biopsies and a significantly lower proportion of large joint BN biopsies yielded graded synovial tissue. No significant difference in either the proportion of graded tissue samples or total graded synovial tissue area between the US‐NB and arthroscopic large joint procedures was demonstrated. Among the sequential biopsy procedures evaluated (small joint US‐NB, large joint arthroscopy, US‐P&F biopsy, and BN biopsy), no significant difference in the proportion of graded synovial tissue or total graded synovial tissue area was demonstrated. All procedures yielded RNA of significant quality and quantity for subsequent transcriptomic analysis. Conclusion: These data support the integration of US‐guided methods along with arthroscopic biopsy for clinical trial protocols in which sequential sampling of synovium from the large and small joints is needed for both histologic and molecular analysis. BN biopsy may be considered if graded synovial tissue is not required for subsequent analyses. [ABSTRACT FROM AUTHOR]

In this work, some films of poly(ε-caprolactone) (PCL) containing lysozyme at 5% by weight are obtained. Lysozyme is a natural antimicrobial molecule. The films are submitted to cold drawing process at three different draw ratios, λ = 3, 4, and 5, where λ is the ratio between final and initial length. Morphology, physical and barrier properties of the drawn samples are studied and correlated to the release of lysozyme. Tests against Bacillus sp are performed and correlated to the material texture. The molecular orientation of uniaxially drawn lysozyme doped PCL films is demonstrated to be a significant parameter for controlled release monitoring of the active molecule and the antimicrobial activity. [ABSTRACT FROM AUTHOR]

IL-34 and colony-stimulating factor 1 (CSF1) are two alternative ligands for the CSF1 receptor that play nonredundant roles in the development, survival, and function of tissue macrophages and Langerhans cells (LCs). In this study, we investigated the spatio-temporal production of IL-34 and its impact on skin LCs in the developing embryo and adult mice in the steady state and during inflammation using Il34LacZ reporter mice and newly generated inducible Il34-knockout mice. We found that IL-34 is produced in the developing skin epidermis of the embryo, where it promotes the final differentiation of LC precursors. In adult life, LCs required IL-34 to continually self-renew in the steady state. However, during UV-induced skin damage, LC regeneration depended on neutrophils infiltrating the skin, which produced large amounts of CSF1. We conclude that LCs require IL-34 when residing in fully differentiated and anatomically intact skin epidermis, but rely on neutrophil-derived CSF1 during inflammation. Our demonstration that neutrophils are an important source of CSF1 during skin inflammation may exemplify a mechanism through which neutrophils promote their subsequent replacement with mononuclear phagocytes. [ABSTRACT FROM AUTHOR]

Objective. To examine in a cohort of rheumatoid arthritis (RA) patients undergoing serial ultrasound (US)–guided biopsies of small joints in the context of clinical trials whether sufficient synovial tissue could be obtained at both baseline and second biopsy to: 1) accurately evaluate the synovial immune phenotype, 2) permit adequate RNA extraction to determine molecular signatures, and 3) sensitively detect change in the number of synovial sublining macrophages (CD681) following effective therapy. Methods. Synovial samples from RA patients undergoing US-guided biopsy of small joints as part of 2 clinical trials (Barts Early Arthritis Cohort [n518] and the Clinical and Pathological Response to Certolizumab Pegol (CLIP-Cert) study [n517]) were examined, and the quality and quantity of histologic samples and RNA extracted per joint were determined and compared to synovial thickness and power Doppler scores determined by US before biopsy. Modulation of the number of CD681 sublining macrophages was correlated with clinical response to treatment. Results. Good quality synovial tissue that accurately reflected the synovial immune phenotype of the total joint was obtained in 80% of US-guided procedures when synovial thickness (higher than grade 2) was documented before biopsy. In 100% of the procedures, sufficient RNA was extracted to permit molecular analysis. There was a significant correlation between change in CD681 sublining macrophage number and clinical response to treatment. Conclusion. This study provides minimum standards for sample retrieval for small joint biopsy. Furthermore, our findings confirm the clinical utility of the procedure in the largest reported cohort of US-guided small joint biopsies. The demonstration that small joint synovial tissue can be readily accessed by a technically simple, minimally invasive procedure is likely to facilitate critical advancements in the knowledge of RA pathobiology and personalized health care. [ABSTRACT FROM AUTHOR]

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Å from the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules' effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which describes the development and pilot-testing of the Simple Psoriatic Arthritis Screening (SiPAS) questionnaire tool to screen psoriasis patients with psoriatic arthritis.

ABSTRACT Tako-Tsubo cardiomyopathy is a transient left ventricular apical ballooning syndrome also known as stress-induced cardiomyopathy. This reversible cardiomyopathy without epicardial coronary artery disease mimics acute myocardial infarction. Right ventricular involvement, which has been infrequently reported, is present in about a quarter of cases of Tako-Tsubo cardiomyopathy and is associated with a more severe clinical outcome. We report the case of a 55-year-old postmenopausal woman with transient biventricular apical ballooning. She recently had acute exacerbation of multiple sclerosis. Regional and global function of both ventricles was estimated using two-dimensional speckle tracking strain echocardiography. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound 42:121-124, 2014 [ABSTRACT FROM AUTHOR]

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α6 integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α6 integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α6 integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC. [ABSTRACT FROM AUTHOR]

Background: The ventricular myocardial performance index (MPI) is a feasible echocardiographic parameter for the evaluation of patients with chronic heart failure (CHF). The long-term prognostic role of right ventricular MPI (RV MPI) has been already assessed in patients with more advanced CHF but data are lacking in moderate CHF. The aim of the study is to evaluate the possible prognostic role of RV MPI in moderate CHF patients compared to others traditional RV parameters. Methods: From 2003 to 2004 we enrolled 95 consecutive NYHA class II CHF patients (65 males and 30 females), with the mean age of 66 ± 11 years with left ventricular ejection fraction (LVEF) <40%, on optimal medical treatment. All patients were evaluated clinically and by echocardiography with a follow-up of 5 years (combined end point: cardiovascular mortality and hospitalization for HF). Results: RV MPI was 0.45 ± 0.36, tricuspid annular plane systolic excursion was 21 ± 8 mm, RV fractional area change was 42 ± 12%, systolic pulmonary artery pressure was 33 ± 9 mmHg, and acceleration time of pulmonic flow was 115.5 + 22.62 msec. After the 5 year follow-up the total mortality was 24.2% and HF hospitalization rate was 33%. At Cox multivariate analysis only an RV MPI superior to median value (>0.38) and tricuspid annular plane systolic excursion inferior to median value (<18 mm) had shown a significant prognostic role. Conclusion: The RV MPI in a population of moderate CHF showed to have a more long-term powerful prognostic value than other conventional and traditional echocardiographic right ventricular functional parameters. [ABSTRACT FROM AUTHOR]

(Echocardiography 2011;28:E198-E201) [ABSTRACT FROM AUTHOR]

Fibroblast growth factor-2 (FGF2) plays a major role in angiogenesis. The pattern recognition receptor long-pentraxin 3 (PTX3) inhibits the angiogenic activity of FGF2. To identify novel FGF2-antagonistic peptide(s), four acetylated (Ac) synthetic peptides overlapping the FGF2-binding region PTX3-(97-110) were assessed for their FGF2-binding capacity. Among them, the shortest pentapeptide Ac-ARPCA-NH (PTX3-[100-104]) inhibits the interaction of FGF2 with PTX3 immobilized to a BIAcore sensorchip and suppresses FGF2-dependent proliferation in endothelial cells, without affecting the activity of unrelated mitogens. Also, Ac-ARPCA-NH inhibits angiogenesis triggered by FGF2 or by tumorigenic FGF2-overexpressing murine endothelial cells in chick and zebrafish embryos, respectively. Accordingly, the peptide hampers the binding of FGF2 to Chinese Hamster ovary cells overexpressing the tyrosine-kinase FGF receptor-1 (FGFR1) and to recombinant FGFR1 immobilized to a BIAcore sensorchip without affecting heparin interaction. In all the assays the mutated Ac-ARPA-NH peptide was ineffective. In keeping with the observation that hydrophobic interactions dominate the interface between FGF2 and the FGF-binding domain of the Ig-like loop D2 of FGFR1, amino acid substitutions in Ac-ARPCA-NH and saturation transfer difference-nuclear magnetic resonance analysis of its mode of interaction with FGF2 implicate the hydrophobic methyl groups of the pentapeptide in FGF2 binding. These results will provide the basis for the design of novel PTX3-derived anti-angiogenic FGF2 antagonists. [ABSTRACT FROM AUTHOR]

Background Excision of large tumours, particularly of the limbs, can be challenging because of problems related to wound repair. This is especially true of the lower legs, where skin is often tight and difficult to mobilize. Closure by flap, which would represent the first choice for defects usually between 12–15 mm to 38–40 mm diameter, is at risk of developing complications, such as end-flap necrosis or dehiscence due to skin tension. For larger defects, usually more than 40 to 45 mm diameter, grafting still remains the only realistic option in the majority of cases, with all the various problems associated with this procedure, such as lengthy healing times and the risk of developing leg ulcers, above all in elderly patients with impaired blood circulation. Second intention healing implies extraordinarily long healing times with often unacceptable delays in normal ambulation and activity. Objective To find an alternative to the usual repair techniques and to try to reduce the risk of complications. Conclusions We developed a relatively simple but effective technique for the closure of large wounds resulting from the excision of tumours. Our technique consists of two longitudinal, parallel, transposition flaps obtained from two opposite sides of the wound, with major axes orientated in the cephalic-caudal direction. The two flaps are then rotated around two fulcra placed at two extremes of the wound by approximately 90°. This relatively simple technique has never caused any of the ordinarily associated problems in terms of necrosis or ulcer development. In addition, dehiscence of sutures never occurred, given the fact that suture tension is minimal. Quick healing has resulted in the majority of cases, avoiding all the problems associated with grafting or other traditional flap techniques. [ABSTRACT FROM AUTHOR]

Abstract: Background: Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF). Methods and results: We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a ≥25% and a ≥0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%). Results: Patients were followed for 480±363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13–1.81; p =0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p =0.002), LV ejection fraction (p =0.012), furosemide daily dose (p =0.03) and NYHA class (p =0.05) on admission. Conclusion: WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF. [Copyright &y& Elsevier]

Background Lichen planus-like keratosis (LPLK) or benign lichenoid keratosis is an involuting cutaneous entity where regressing features are the histologic hallmark. Most authors consider LPLK as an heterogeneous spectrum of intraepithelial epidermal or melanocytic lesions, mainly pigmented, involuting by inflammatory regression. Objective The authors review the clinico-histologic definition and correlate with the dermoscopic features of LPLK. Methods Sixteen LPLK were clinically distributed into three types: plaque-like (PL), flat erythematous (FE) and flat pigmented (FP) type and evaluated with conventional dermoscopy. Dermoscopic features of regression were recorded as the presence of blue-white structures and vascular structures. The predominant distribution, size and colour of pigmented granules were also recorded. All cases were excised and submitted to histopathologic examination and subdivided into three groups according to the early, classic and atrophic subtypes. Results The FP (44%) and the FE (37%) types are diagnosed more frequently than the PL type (19%). PL type correlates better with the classic type. FE correlates mainly with early/atrophic types, while the FP nearly exclusively with the late atrophic type. Regressive features are present in all but one case with a predominance of blue areas (94%). Localized (55%) and diffuse (37.5%) granular pattern are presenting in all but one case. The diffuse granular pattern correlates with the FP type (5/6 cases), while the localized granular pattern is mainly present (6/9 cases) in the FE type. Vascular structures can be found in half of the cases and white scar-like depigmentation is just present in four cases. BWS and vascular structures present together are observed in four cases (25%). Conclusions Our results show a large correlation among clinical, histologic and dermoscopic aspects of LPLK may be interpreted as a spectrum of cutaneous lesions going into inflammatory regression, showing different clinical and dermoscopic patterns according to the involuting stage. The early type of LPLK (FE) shows a localized granular pattern where regression is at the very early stage. The classic dermoscopic features of regressing lesion for LPLK (pigmented granular pattern) apply to the most frequent encountered pigmented atrophic flat type or classic pigmented type, where sometimes regression is advanced or almost complete and no clear diagnosis of a previous benign/malignant - epithelial or melanocytic lesion can often be given. Regressive dermoscopic features must be evaluated in the context of global and clinical pattern of the lesion. Nonetheless dermoscopy can close correlate with clinical incipient or complete regression and must prompt the need for eventual prophylactic surgical removal. [ABSTRACT FROM AUTHOR]

The HIV-1 transactivating factor (Tat) acts as an extracellular cytokine on target cells, including endothelium. Here, we report about the Tat-antagonist capacity of chemically sulfated derivatives of the Escherichia coli K5 polysaccharide. O-sulfated K5 with high sulfation degree (K5-OS(H)) and N,O-sulfated K5 with high (K5-N,OS(H)) or low (K5-N,OS(L)) sulfation degree, but not unmodified K5, N-sulfated K5, and O-sulfated K5 with low sulfation degree, bind to Tat preventing its interaction with cell surface heparan sulfate proteoglycans, cell internalization, and consequent HIV-LTR-transactivation. Also, K5-OS(H) and K5-N,OS(H) prevent the interaction of Tat to the vascular endothelial growth factor receptor-2 on endothelial cell (EC) surface. Finally, K5-OS(H) inhibits αvβ3 integrin/Tat interaction and EC adhesion to immobilized Tat. Consequently, K5-OS(H) and K5-N,OS(H) inhibit the angiogenic activity of Tat in vivo. In conclusion, K5 derivatives with distinct sulfation patterns bind extracellular Tat and modulate its interaction with cell surface receptors and affect its biological activities. These findings provide the basis for the design of novel extracellular Tat antagonists with possible implications in anti-AIDS therapies. [Copyright &y& Elsevier]

HIV-1-transactivating factor Tat contributes to virus replication and to the onset of AIDS-associated pathologies by targeting different infected and uninfected cell types. We previously demonstrated that the B-oligomer of pertussis toxin (PTX-B) inhibits HIV infection and replication in primary T cells and macrophages and Tat-dependent HIV-1 long terminal repeat (LTR) transactivation inT lymphoid Jurkat cells. Here we demonstrate that PTX-B inhibits Tat-dependent NF-κB activation and HIV-1 LTR-transactivation in non-permissive epithelial HL3T1 cells in a phosphatidylinositol 3′-kinase-dependent way. PTX-B exerts its inhibition both when Tat is produced endogenously in transfected cells and in cells incubated with the extracellular Tat protein. In this latter case, PTX-B does not interfere with extracellular Tat uptake by cells. PTX-B inhibited also interleukin-8 secretion and virus expression stimulated in chronically infected U1 promonocytic cells by intra- and/or extracellular Tat. The genetically modified holotoxin PT-9 K/129G retains the capacity to inhibit Tat transactivating activity and HIV replication in both HIV-permissive and non-permissive cells. Inconclusion, PTX-B acts as a "pleiotropic" inhibitor of Tat, and this may significantly contribute to the broad spectrum of anti-HIV-1 effects exerted by PTX-B in different cell types, and suggests PTX-B and its derivatives as prototypic for the development of anti-Tat drugs. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Dermoscopy provides additional criteria for the diagnosis of skin lesions. Objective To investigate the dermoscopic aspect of clear cell acanthoma (CCA). Methods Six consecutive cases of CCAs were observed under conventional dermoscopy (Case 1–4) or videodermoscopy (Case 5–6). Results Common dermoscopic findings were: (i) squamous surface with translucid collarette; (ii) dilated capillary loops, mainly perpendicularly orientated to the skin surface, as dotted, pinpoint-like structures, regularly distributed in a reticular array over the surface. Conclusions The vascular psoriasis-like dermoscopic findings seem to be a clue for CCA and provide evidence of an inflammatory process for CCA formation. [ABSTRACT FROM AUTHOR]

Abstract Fatal calciphylaxis (CPX) occurred in two 71-year-old females both requiring haemodialysis for end-stage renal disease. Case 2 also had an associated follicular lymphoplasmocytoid lymphoma. Although laboratory tests disclosed normal coagulation parameters, this woman had a striking cutaneous histological picture of vessel thrombosis and finally died of disseminated intravascular coagulation. CPX is a rare but potentially life-threatening complication of renal failure. The clinical picture is primarily characterized by livedoid purpura with subsequent cutaneous ischaemia and painful ulcerations. Cutaneous ischaemic phenomena are sustained by a progressive process of vascular calcification and thrombosis involving small to medium size arteries of the dermis and subcutis. Although not yet clearly explained, the pathogenetic role of a predisposing hypercoagulability state is currently the most frequently considered hypothesis. [ABSTRACT FROM AUTHOR]

Background: Metalloproteinases (MMPs) are thought to be involved in the process of destruction of basement membranes and stromal invasion by neoplastic epithelial cells. Aims: In order to investigate the role of MMPs in cutaneous oncogenesis we studied the expression of MMP-2 and MMP-9 in 34 cases of epidermal preinvasive neoplastic lesions and invasive carcinomas. We also studied their relationship with the expression of tissue inhibitors of MMPs and with proliferative activity and p53 expression in neoplastic epithelial cells. Results: MMP-9 was found to be focally expressed by neoplastic epithelial cells at the infiltrative edges in microinvasive carcinomas and in dyskeratotic foci in Bowen’s disease and widely invasive carcinomas. Gradation of Mib-1 positivity and p53 expression was found with increasing abnormality in the spectrum of malignancy. Conclusions: Our results seem to suggest the involvement of MMPs in microinvasive carcinomas, which show also low proliferative activity and p53 expression, whether other factors seem to be more important in widely invasive carcinomas. [ABSTRACT FROM AUTHOR]

A case of acquired reactive perforating collagenosis in a 70-year old man with a long standing digitate parapsoriasis is reported. Multiple asymptomatic cutaneous hyperpigmented papules with a central adherent keratotic plug developed simultaneously with widespread purpuric eruption following a single i.m. diclofenac injection. Histologic examination of a keratotic lesion revealed an epidermal crater with centrally degenerated collagen and elastic fibre extrusion. This case is interesting for the lack of pruritus, the transepithelial elimination of both collagen and elastic fibres and the association with parapsoriasis. The etiologic role of diclofenac is discussed. The term acquired perforating dermatosis may be more suitable for this case. [ABSTRACT FROM AUTHOR]

Thysanoptera dermatitis is caused by the bite of small (1–2 mm) insects (generally thrips). Thrips usually feed on the juices of vegetables but if they reach human skin they can suck the epidermal lymph after biting. The cutaneous lesions formed are small pink and itchy papules localized mainly on the trunk and the arms. Diagnosis is only possible by demonstrating that the insect is present inside one of the lesions of the skin. Thysanoptera dermatitis is often misdiagnosed as mosquito bites. Although self-resolving in a few days, Thysanoptera dermatitis should be known not only for the cultural and scientific training of the dermatologist but also to add more detailed diagnostic information to the generic diagnosis of ‘entomodermatosis’ and to confirm the benign evolution of the bites. [ABSTRACT FROM AUTHOR]

In the literature no specific dermoscopic criteria have been described for the diagnosis of Bowen's disease (BD). To assess the morphological findings of BD seen under dermoscopic observation. Clinical and dermoscopic images of 14 patients affected by BD with various amount of pigmentation were obtained by means of Heine Dermaphot. Dermoscopic images were analysed by experienced observers applying the modified pattern analysis. The most frequently occurring dermoscopic features were found to be: multicomponent pattern (100%); atypical vascular structures (86.6%); absence of pigmented network (64.3%) or presence of pseudo-network (35.7%); irregular diffuse pigmentation or blotches of pigment (64.2%); irregularly distributed dots and globules (64.2%); focal/multifocal hypopigmentation (78.5%), scaly surface (64.2%) and haemorrages (26.6%). Dermoscopically, BD is mainly characterized by a multicomponent global pattern associated with a prominent vascular pattern (mainly dotted vessels) and a scaly surface. Although no specific dermoscopic criteria can be given for BD, epiluminescence can be a valuable aid in the diagnosis of such a mimicker lesion. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor related to lichen planus with plasm cell infiltrate, published in January 1997 issue of "Journal of the European Academy of Dermatology and Vernereology."

An abstract of the article "De novo acute heart failure and acutely decompensated chronic heart failure: one single syndrome or two different entities?," by S. Bugatti and colleagues is presented.

An abstract of the article "Prognostic Variables in Patients Hospitalised for Acute Heart Failure: A Single Center Experience," by M. Metra and colleagues is presented.