The Role of the TGF-beta Coreceptor Endoglin in Cancer

Endoglin (CD105) is an auxiliary membrane receptor of transforming growth factor beta (TGF-beta) that interacts with type I and type II TGF-beta receptors and modulates TGF-beta signaling. Endoglin is overexpressed in the tumor-associated vascular endothelium, where it modulates angiogenesis. This feature makes endoglin a promising target for antiangiogenic cancer therapy. In addition, recent studies on human and experimental models of carcinogenesis point to an important tumor cell-autonomous role of endoglin by regulating proliferation, migration, invasion, and metastasis. These studies suggest that endoglin behaves as a suppressor of malignancy in experimental and human epithelial carcinogenesis, although it can also promote metastasis in other types of cancer. In this review, we evaluate the implication of endoglin in tumor development underlying studies developed in our laboratories in recent years

Role of biomarkers in early infectious complications after lung transplantation

Background Infections and primary graft dysfunction are devastating complications in the immediate postoperative period following lung transplantation. Nowadays, reliable diagnostic tools are not available. Biomarkers could improve early infection diagnosis. Methods Multicentre prospective observational study that included all centres authorized to perform lung transplantation in Spain. Lung infection and/or primary graft dysfunction presentation during study period (first postoperative week) was determined. Biomarkers were measured on ICU admission and daily till ICU discharge or for the following 6 consecutive postoperative days. Results We included 233 patients. Median PCT levels were significantly lower in patients with no infection than in patients with Infection on all follow up days. PCT levels were similar for PGD grades 1 and 2 and increased significantly in grade 3. CRP levels were similar in all groups, and no significant differences were observed at any study time point. In the absence of PGD grade 3, PCT levels above median (0.50 ng/ml on admission or 1.17 ng/ml on day 1) were significantly associated with more than two- and three-fold increase in the risk of infection (adjusted Odds Ratio 2.37, 95% confidence interval 1.06 to 5.30 and 3.44, 95% confidence interval 1.52 to 7.78, respectively). Conclusions In the absence of severe primary graft dysfunction, procalcitonin can be useful in detecting infections during the first postoperative week. PGD grade 3 significantly increases PCT levels and interferes with the capacity of PCT as a marker of infection. PCT was superior to CRP in the diagnosis of infection during the study period

A novel panel of short mononucleotide repeats linked to informative polymorphisms enabling effective high volume low cost discrimination between mismatch repair deficient and proficient tumours

<div><p>Somatic mutations in mononucleotide repeats are commonly used to assess the mismatch repair status of tumours. Current tests focus on repeats with a length above 15bp, which tend to be somatically more unstable than shorter ones. These longer repeats also have a substantially higher PCR error rate, and tests that use capillary electrophoresis for fragment size analysis often require expert interpretation. In this communication, we present a panel of 17 short repeats (length 7–12bp) for sequence-based microsatellite instability (MSI) testing. Using a simple scoring procedure that incorporates the allelic distribution of the mutant repeats, and analysis of two cohort of tumours totalling 209 samples, we show that this panel is able to discriminate between MMR proficient and deficient tumours, even when constitutional DNA is not available. In the training cohort, the method achieved 100% concordance with fragment analysis, while in the testing cohort, 4 discordant samples were observed (corresponding to 97% concordance). Of these, 2 showed discrepancies between fragment analysis and immunohistochemistry and one was reclassified after re-testing using fragment analysis. These results indicate that our approach offers the option of a reliable, scalable routine test for MSI.</p></div

A de novo paradigm for male infertility

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p -value = 1.00 × 10 −5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p -value = 5.01 × 10 −4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p -value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility. Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

BUILDING AN ARTIFICIAL CEREBELLUM USING A SYSTEM OF DISTRIBUTED Q-LEARNING AGENTS

About 400 million years ago sharks developed a separate co-processor in their brains that not only made them faster but also more precisely coordinated. This co-processor, which is nowadays called cerebellum, allowed sharks to outperform their peers and survive as one of the fittest. For the last 40 years or so, researchers have been attempting to provide robots and other machines with this type of capability. This thesis discusses currently used methods to create artificial cerebellums and points out two main shortcomings: 1) framework usability issues and 2) building blocks incompatibility issues. This research argues that the framework usability issues hinder the production of good quality artificial cerebellums for a large number of applications. Furthermore, this study argues that the building blocks incompatibility issues make artificial cerebellums less efficient that they could be, given our current technology. To tackle the framework usability issues, this thesis research proposes the use of a new framework, which formalizes the task of creating artificial cerebellums and offers a list of simple steps to accomplish this task. Furthermore, to tackle the building blocks incompatibility issues, this research proposes thinking of artificial cerebellums as a set of cooperating q-learning agents, which utilize a new technique called Moving Prototypes to make better use of the available memory and computational resources. Furthermore, this work describes a set of general guidelines that can be applied to accelerate the training of this type of system. Simulation is used to show examples of the performance improvements resulting from the use of these guidelines. To illustrate the theory developed in this dissertation, this paper implements a cerebellum for a real life application, namely, a cerebellum capable of controlling a type of mining equipment called front-end loader. Finally, this thesis proposes the creation of a development tool based on this formalization. This research argues that such a development tool would allow engineers, scientists and technicians to quickly build customized cerebellums for a wide range of applications without the need of becoming experts on the area of Artificial Intelligence, Neuroscience or Machine Learning

TGF-β and MMPs: A complex regulatory loop involved in tumor progression

Transforming growth factor-β (TGF-β) has a dual and contradictory role in cancer. It is a tumor suppressor at early stages of tumor formation by virtue of its growth inhibitory and pro-apoptotic functions. However, at later stages of tumor progression, tumor cells lose their sensitivity to be growth inhibited by this cytokine, and, then, TGF-β facilitates tumor invasion and metastasis by diverse mechanisms, including the induction of an epithelial-mesenchymal transition, the suppression of the immune system and the stimulation of angiogenesis. Matrix metalloproteinases (MMPs) have also been shown to play a pivotal function in tumor cell migration, invasion and angiogenesis. MMPs and TGF-β form an interplay loop that may attenuate or promote tumor progression. On one hand, latent TGF-β, an inactive TGF-β precursor that is sequestered by the extracellular matrix, is proteolytically activated by MMPs; the released active cytokine may, then, suppress or promote tumor cell growth and invasiveness depending on the tumor stage. On the other hand, TGF-β regulates the expression of MMPs and their tissue inhibitors TIMPs in both tumor and stromal cells. MMPs in the tumor microenvironment are involved in the control of tumor cell growth and survival by modulating the bioavailability of growth factors and chemokines, and they also influence inflammation and angiogenesis. Thus, by modulating the net balance of MMPs and TIMPs in both compartments: the tumor and stroma, TGF-β regulates malignant progression

Caveolin-1 interacts and cooperates with the transforming growth factor-β type I receptor ALK1 in endothelial caveolae

Aims: Activin receptor-like kinase (ALK)1 is a transforming growth factor (TGF)-β type I membrane receptor restricted almost entirely to endothelial cells (ECs) and involved in vascular remodelling and angiogenesis. Previous reports have shown that the ubiquitous TGF-β type I receptor ALK5 and the type II receptor are located in cholesterol-rich membrane microdomains named caveolae. The aim of this work was to assess the location of ALK1 in endothelial caveolae as well as to study the role of caveolin-1 on the TGF-β/ALK1 signalling pathway. Methods and results: The subcellular distribution of ALK1 was analysed by confocal microscopy and co-fractionation experiments in human ECs. The association between human ALK1 and caveolin-1 was studied in caveolin-1-deficient human epithelial cells by co-immunoprecipitation. The functional role of caveolin-1 on the ALK1-mediated TGF-β signalling was elucidated using ALK1-specific luciferase reporters in human ECs, caveolin-1-/-mouse embryonic fibr