A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response.

Immune checkpoint blockade (ICB) with antibodies has shown durable clinical responses in a wide range of cancer types, but the overall response rate is still limited. Other effective therapeutic modalities to increase the ICB response rates are urgently needed. New bispecific antibody (bsAb) formats combining the ICB effect and a direct action on cancer cells could improve the efficacy of current immunotherapies. Here, we report the development of a PD-L1/EGFR symmetric bsAb by fusing a dual-targeting tandem trimmer body with the human IgG1 hinge and Fc regions. The bsAb was characterized in vitro and the antitumor efficacy was evaluated in humanized mice bearing xenografts of aggressive triple-negative breast cancer and lung cancer. The IgG-like hexavalent bsAb, designated IgTT-1E, was able to simultaneously bind both EGFR and PD-L1 antigens, inhibit EGF-mediated proliferation, effectively block PD-1/PD-L1 interaction, and induce strong antigen-specific antibody-dependent cellular cytotoxicity activity in vitro. Potent therapeutic efficacies of IgTT-1E in two different humanized mouse models were observed, where tumor growth control was associated with a significantly increased proportion of CD8+ T cells. These results support the development of IgTT-1E for the treatment of EGFR+ cancers.post-print3,06 M

S194-P-FADD as a marker of aggressiveness and poor prognosis in human T-cell lymphoblastic lymphoma

T-cell lymphoblastic lymphoma is a haematological disease with an urgent need for reliable prognostic biomarkers that allow therapeutic stratification and dose adjustment. The scarcity of human samples is responsible for the delayed progress in the study and the clinical management of this disease, especially compared with T-cell acute lymphoblastic leukaemia, its leukemic counterpart. In the present work, we have determined by immunohistochemistry that S194-P-FADD protein is significantly reduced in a cohort of 22 samples from human T-cell lymphoblastic lymphoma. Notably, the extent of such reduction varies significantly among samples and has revealed determinant for the outcome of the tumour. We demonstrate that Fas-associated protein with death domain (FADD) phosphorylation status affects protein stability, subcellular localization and non-apoptotic functions, specifically cell proliferation. Phosphorylated FADD would be more stable and preferentially localized to the cell nucleus; there, it would favour cell proliferation. We show that patients with higher levels of S194-P-FADD exhibit more proliferative tumours and that they present worse clinical characteristics and a significant enrichment to an oncogenic signature. This supports that FADD phosphorylation may serve as a predictor for T-cell lymphoblastic lymphoma aggressiveness and clinical status. In summary, we propose FADD phosphorylation as a new biomarker with prognostic value in T-cell lymphoblastic lymphoma

Expression of p53 Protein and Tumor Angiogenesis as Prognostic Factors in Nasopharyngeal Carcinoma Patients.

The objective of this study was to evaluate the possible prognostic significance of p53 protein overexpression and tumor angiogenesis (TA) in nasopharyngeal carcinoma (NPC) patients, together with other clinicopathological variables. Forty-two NPC patients were evaluated in relation to survival. Nuclear p53 overexpression in neoplastic and endothelial cells was detected by immunohistochemistry (IHC) with the monoclonal antibody DO-7 and the polyclonal antibody against factor VIII-related antigen, respectively. Thereafter, we evaluated p53 cases in order to determine their nuclear immunoreactivity from negative (-) to positive (+, ++, +++). In addition, microvessels were counted in the most active areas of tumor neovascularization or hotspots using an image computer analyzer (MicroImage®). A Cox multiple regression survival analysis was used to determine the best prognostic indicators in NPC patients. As a result, tumor microvessel count, considered as a continuous variable, was the most important independent prognostic indicator in relation to survival (p = 0.0273), with a relative risk of death of 2,4399 [95% confidence interval = 1.1051 ; 5.3871] associated with the highest microvessel counts. Moreover, the only clinicopathological variable that demonstrated prognostic value in a Cox multiple regression survival analysis was histological type (p = 0.05). In addition, we did not observe any statistical association between intratumoral microvessel density (IMD), clinicopathological variables and p53 protein expression. Key words: p53 protein - Angiogenesis - Morphometry - Prognosis - Nasopharyngeal carcinom

Using Process Mining to Analyze Time-Distribution of Self-Assessment and Formative Assessment Exercises on an Online Learning Tool

The study of the relationships between self-regulated learning and formative assessment is an active line of research in the educational community. A recent review of the literature highlights that the study of these connections has been mainly unidirectional, focusing on how formative assessment helps students to self-regulate their learning, being much less explored the effect of self-regulated learning strategies on formative assessment. In this context, analyzing automatically captured students’ activities within online learning tools can provide us further insights on the interactions between these two topics. More specifically, this article examines the activity traces of 382 students who used an online tool to learn a programming language. The tool incorporates review exercises for promoting self-assessment (an important self-regulated learning strategy). Furthermore, the tool is used in supervised laboratories where students receive formative assessment. This study uses process mining techniques to analyze the temporal component of student behavior in both types of activities, their interaction, and how self-assessment relates to formative assessment. Some key lessons are learned: activities promoting self-assessment significantly improved students’ involvement in formative assessment activities; increasing selfassessment cannot compensate for a lack of effort in formative assessment. We also underline that, to the best of our knowledge, to date no research has used process mining to consider the time component in the analysis of the relationships between formative assessment and self-assessment

An HST/NICMOS view of the prototypical giant HII region NGC604 in M33

We present the first high-spatial resolution near-infrared (NIR) imaging of NGC 604, obtained with the NICMOS camera aboard the Hubble Space Telescope (HST). These NICMOS broadband images reveal new NIR point sources, clusters, and diffuse structures. We found an excellent spatial correlation between the 8.4 GHz radio continuum and the 2.2mu-m nebular emission. Moreover, massive young stellar object candidates appear aligned with these radio peaks, reinforcing the idea that those areas are star-forming regions. Three different scaled OB associations are recognized in the NICMOS images. The brightest NIR sources in our images have properties that suggest that they are red supergiant stars, of which one of them was previously known. This preliminary analysis of the NICMOS images shows the complexity of the stellar content of the NGC 604 nebula.Comment: Paper presented in the Workshop "Young massive star clusters: initial conditions and environments" (Granada, Spain - Sept 2007). Astrophysics & Space Science in press, 7 pages, 4 figure

The Fanconi Anemia Pathway Protects Genome Integrity from R-loops

Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops

Awareness of Practice and Comparison with Best Evidence in Surgical Site Infection Prevention in Colorectal Surgery

Background: The use of mechanical bowel preparation and prophylaxis with oral antimicrobial agents can prevent surgical site infection (SSI) in colorectal surgical procedures, but routine adoption of these and other practices by surgeons has been limited. The aim of this study was to determine the actual practice and surgeon beliefs about preventative measures in elective colorectal operations and to compare them with established recommendations. Methods: Web-based survey was sent to colorectal surgeons assessing knowledge, beliefs, and practices regarding the use of preventative measures for SSI. Results: Of 355 surgeons, 33% had no feedback of SSI rate; 60% believed in evidence for normothermia, wound edge protection, and use of alcohol solution, and reported use of these strategies. There was a discrepancy in the assumed evidence and use of hyperoxia, glove replacement after anastomosis, surgical tools replacement, and saline surgical site lavage. Most of respondents believe that oral antibiotic prophylaxis diminishes infection, but is indicated only by one third of them. Few surgeons believe in MBP, but many actually use it. Most surgeons believe that there is a discrepancy between published guidelines and actual clinical practice. As proper means to implement guidelines, checklists, standardized orders, surveillance, feedback of SSI rates, and educational programs are rated most highly by surgeons, but few of these are in place at their institutions. Conclusions: Gaps in the translation of evidence into practice remain in the prevention of SSI in colorectal surgical procedures. Several areas for improvement have been identified. Specific implementation strategies should be addressed in colorectal units

Effect of diacutaneous fibrolysis on the muscular properties of gastrocnemius muscle

Diacutaneous fibrolysis is a noninvasive technique that has been shown to be effective in the treatment of musculoskeletal disorders such as shoulder pain, lateral epicondylalgia, patellofemoral pain syndrome and carpal tunnel syndrome. However, while diacutaneous fibrolysis is applied to soft tissue, its effects on muscular properties are unknown. The purpose of the present study was to evaluate the effects of diacutaneous fibrolysis on muscle properties as measured by tensiomyography and myotonometry in asymptomatic subjects. An analytical descriptive study was performed. A single session of diacutaneous fibrolysis on the gastrocnemius muscle was applied to one limb (treated limb group) and the other limb was the control (control limb group). Subjects were assessed with tensiomyography and myotonometry before treatment (T0), after treatment (T1) and 30 minutes later (T2). The primary outcomes were tensiomyography and myotonometry variables. The treated limb group showed a statistically significant increase (p<0.05) in tensiomyography parameters. A decrease in rigidity and increase in relaxation was also observed on myotonometry at T1, with some of the effects being maintained at T2. Rigidity and relaxation at T1 were statistically significant between groups (p<0.05). A single session of diacutaneous fibrolysis to the gastrocnemius muscle of asymptomatic subjects produced immediate changes in muscle properties. These changes were maintained 30 minutes after the application of the technique