Soft tissue sarcomas are rare entities with over 50 histological subtypes. Liposarcoma (LS) is the most common neoplasm in this group; it is a complex neoplasm that is divided into different ...histological subtypes. Different therapy options, such as surgical resection, radiation, and chemotherapy, are available. Depending on the subtype, location, status of the resection margins and metastatic status, different therapy options are used. Therefore, the aim of this study was to determine the prognostic factors influencing the survival of patients affected by LS with consideration for the grading, histological subtype, state of the resection margin, size, location, metastases and local recurrence in a retrospective, single-centre analysis over 15 years.
We included 133 patients (male/female = 67/66) in this study. We recorded the histologic subtype, grade, TNM classification, localization, biopsy technique, tumour margins, number of operations, complications, radiation and dose, chemotherapy, survival, recrudescence, metastases and follow-up. Survivorship analysis was performed.
We detected 56 (43%; 95%-CI 34.6-51.6%) atypical LS cases, 21 (16.2%; 95%-CI 9.8-22.5) dedifferentiated LS cases, 40 (30.8%; 95%-CI 22.8-38.7) myxoid LS cases and 12 (9.2%; 95%-CI 4.3-14.2) pleomorphic LS cases. G1 was the most common grade, which was followed by G3. Negative margins (R0) were detected in 67 cases (53.6%; 95%-CI 44.9-62.3) after surgical resection. Local recurrence was detected in 23.6% of cases. The presence of metastases and dedifferentiated LS subtype as well as negative margins, grade and tumour size are significant prognostic factors of the survival rates (p < 0.015).
Grading, LS subtype, negative margins after surgery, metastases and tumour size are independently associated with disease-specific survival, and patients with local recurrence had lower survival rates. We hope our investigation may facilitate a further prospective study and clinical decision-making in LS.
Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The ...randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.
The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the ...critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health.
We study sequences of scaled edge-corrected empirical (generalized) K-functions (modifying Ripley's K-function) each of them constructed from a single observation of a d-dimensional fourth-order ...stationary point process in a sampling window
which grows together with some scaling rate unboundedly as
. Under some natural assumptions it is shown that the normalized difference between scaled empirical and scaled theoretical K-function converges weakly to a mean zero Gaussian process with simple covariance function. This result suggests discrepancy measures between empirical and theoretical K-function with known limit distribution which allow to perform goodness-of-fit tests for checking a hypothesized point process based only on its intensity and (generalized) K-function. Similar test statistics are derived for testing the hypothesis that two independent point processes in
have the same distribution without explicit knowledge of their intensities and K-functions.
Diagnosis of a low-grade periprosthetic joint infection (PJI) prior to revision surgery can be challenging, despite paramount importance for further treatment. Arthroscopic biopsy of synovial and ...periprosthetic tissue with subsequent microbiological and histological examination can be beneficial but its specific diagnostic value has not been clearly defined.
20 consecutive patients who underwent percutaneous synovial fluid aspiration as well as arthroscopic biopsy due to suspected PJI of the hip and subsequent one- or two-stage revision surgery at our institution between January 2012 and May 2015 were enrolled. Indication was based on the criteria (1) history of PJI and increased levels of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), (2) suspicious cell count and differential but negative bacterial culture in synovial aspirate, (3) early loosening (<less than 2 years), or (4) persisting pain without loosening but history of a PJI. At least two criteria had to be fulfilled in order to perform an arthroscopic biopsy.
Best overall diagnostic value was identified for arthroscopic biopsy and a combination of bacteriological and histological analysis with a sensitivity of 87.5%, specificity of 100% and accuracy of 95%. Bacteriological assessment of synovial aspirate revealed a sensitivity of 50.0%, specificity of 91.7%, and accuracy of 75%. ESR and CRP yielded a sensitivity of 75.0% for either hematologic test and specificities of 87.5 and 66.7%, respectively.
In conclusion, our data indicate that arthroscopic biopsy is superior to ESR and CRP as well as joint aspiration and their combinations. Concurrent microbiological and histological examination of the biopsy specimens allows for identification of the causative pathogen and its susceptibility pattern in order to preoperatively plan the surgical strategy as well as the antibiotic regimen. Moreover, intraarticular mechanical failure can be detected during hip arthroscopy emphasizing its diagnostic value. Level II diagnostic study.
There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal ...antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.
Previously assumed to be a select ligand for chemokine receptor CXCR4, chemokine CXCL12 is now known to activate both CXCR4 and CXCR7. However, very little is known about the co-expression of these ...receptors in cancer cells.
We used immunohistochemistry to determine the extent of co-expression in pancreatic cancer tissue samples and immunoblotting to verify expression in pancreatic cancer cell lines. In cell culture studies, siRNA was used to knock down expression of CXCR4, CXCR7, K-Ras and β-arrestin -2 prior to stimulating the cells with CXCL12. Activation of the mitogen-activated protein kinase pathway (MAPK) was assessed using both a Raf-pull down assay and western blotting. The involvement of the receptors in CXCL12-mediated increases in cell proliferation was examined via an ATP-based proliferation assay.
First, we discovered frequent CXCR4/CXCR7 co-expression in human pancreatic cancer tissues and cell lines. Next, we observed consistent increases in ERK1/2 phosphorylation after exposure to CXCL12 or CXCL11, a CXCR7 agonist, in pancreatic cancer cell lines co-expressing CXCR4/CXCR7. To better characterize the receptor-mediated pathway(s), we knocked down CXCR4 or CXCR7, exposed the cells to CXCL12 and examined subsequent effects on ERK1/2. We observed that CXCR7 mediates the CXCL12-driven increase in ERK1/2 phosphorylation. Knockdown of CXCR4 expression however, decreased levels of K-Ras activity. Conversely, KRAS knockdown greatly reduced CXCL12-mediated increases in ERK1/2 phosphorylation. We then evaluated the role of β-arrestin-2, a protein directly recruited by chemokine receptors. We observed that β-arrestin-2 knockdown also inhibited increases in ERK1/2 phosphorylation mediated by both CXCR4 and CXCR7. Finally, we investigated the mechanism for CXCL12-enhanced cell proliferation and found that either receptor can modulate cell proliferation.
In summary, our data demonstrate that CXCR4 and CXCR7 are frequently co-expressed in human pancreatic cancer tissues and cell lines. We show that β-arrestin-2 and K-Ras dependent pathways coordinate the transduction of CXCL12 signals. Our results suggest that the development of therapies based on inhibiting CXCL12 signaling to halt the growth of pancreatic cancer should be focused at the ligand level in order to account for the contributions of both receptors to this signaling pathway.
Increasing rates of prosthetic joint infection (PJI) have presented challenges for general practitioners, orthopedic surgeons and the health care system in the recent years. The diagnosis of PJI is ...complex; multiple diagnostic tools are used in the attempt to correctly diagnose PJI. Evidence-based algorithms can help to identify PJI using standardized diagnostic steps.
We reviewed relevant publications between 1990 and 2015 using a systematic literature search in MEDLINE and PUBMED. The selected search results were then classified into levels of evidence. The keywords were prosthetic joint infection, biofilm, diagnosis, sonication, antibiotic treatment, implant-associated infection, Staph. aureus, rifampicin, implant retention, pcr, maldi-tof, serology, synovial fluid, c-reactive protein level, total hip arthroplasty (THA), total knee arthroplasty (TKA) and combinations of these terms.
From an initial 768 publications, 156 publications were stringently reviewed. Publications with class I-III recommendations (EAST) were considered. We developed an algorithm for the diagnostic approach to display the complex diagnosis of PJI in a clear and logically structured process according to ISO 5807.
The evidence-based standardized algorithm combines modern clinical requirements and evidence-based treatment principles. The algorithm provides a detailed transparent standard operating procedure (SOP) for diagnosing PJI. Thus, consistently high, examiner-independent process quality is assured to meet the demands of modern quality management in PJI diagnosis.
Polydimethylsiloxane (PDMS) has been the material of choice for microfluidic applications in cell biology for many years, with recent advances encompassing nano-scaffolds and surface modifications to ...enhance cell-surface interactions at nano-scale. However, PDMS has not previously been amenable to applications which require complex geometries in three dimensions for cell culture device fabrication in the absence of additional components. Further, PDMS microfluidic devices have limited capacity for cell retrieval following culture without severely compromising cell health. This study presents a designed and entirely 3D-printed microfluidic chip (8.8 mm × 8.2 mm × 3.6 mm) using two-photon polymerization (2PP). The 'nest' chip is composed of ten channels that deliver sub-microliter volume flowrates (to ~ 600 nL/min per channel) to 10 individual retrievable cell sample 'cradles' that interlock with the nest to create the microfluidic device. Computational fluid dynamics modelling predicted medium flow in the device, which was accurately validated by real-time microbead tracking. Functional capability of the device was assessed, and demonstrated the capability to deliver culture medium, dyes, and biological molecules to support cell growth, staining and cell phenotype changes, respectively. Therefore, 2PP 3D-printing provides the precision needed for nanoliter fluidic devices constructed from multiple interlocking parts for cell culture application.
The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations ...occurring in 17%-25% of all cancers. In particular, approximately 30%-40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.
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