Non-Agonistic Bivalent Antibodies That Promote c-MET Degradation and Inhibit Tumor Growth and Others Specific for Tumor Related c-MET

The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519–561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies

Distinguishing Characteristics between Pandemic 2009–2010 Influenza A (H1N1) and Other Viruses in Patients Hospitalized with Respiratory Illness

BACKGROUND: Differences in clinical presentation and outcomes among patients infected with pandemic 2009 influenza A H1N1 (pH1N1) compared to other respiratory viruses have not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study was performed of all hospitalized patients at the peak of the pH1N1 season in whom a single respiratory virus was detected by a molecular assay targeting 18 viruses/subtypes (RVP, Luminex xTAG). Fifty-two percent (615/1192) of patients from October, 2009 to December, 2009 had a single respiratory virus (291 pH1N1; 207 rhinovirus; 45 RSV A/B; 37 parainfluenza; 27 adenovirus; 6 coronavirus; and 2 metapneumovirus). No seasonal influenza A or B was detected. Individuals with pH1N1, compared to other viruses, were more likely to present with fever (92% & 70%), cough (92% & 86%), sore throat (32% & 16%), nausea (31% & 8%), vomiting (39% & 30%), abdominal pain (14% & 7%), and a lower white blood count (8,500/L & 13,600/L, all p-values<0.05). In patients with cough and gastrointestinal complaints, the presence of subjective fever/chills independently raised the likelihood of pH1N1 (OR 10). Fifty-five percent (336/615) of our cohort received antibacterial agents, 63% (385/615) received oseltamivir, and 41% (252/615) received steroids. The mortality rate of our cohort was 1% (7/615) and was higher in individuals with pH1N1 compared to other viruses (2.1% & 0.3%, respectively; p = 0.04). CONCLUSIONS/SIGNIFICANCE: During the peak pandemic 2009-2010 influenza season in Rhode Island, nearly half of patients admitted with influenza-like symptoms had respiratory viruses other than influenza A. A high proportion of patients were treated with antibiotics and pH1N1 infection had higher mortality compared to other respiratory viruses

The other Higgses, at resonance, in the Lee-Wick extension of the Standard Model

Within the framework of the Lee Wick Standard Model (LWSM) we investigate Higgs pair production $gg \to h_0 h_0$, $gg \to h_0 \tilde p_0$ and top pair production $gg \to \bar tt$ at the Large Hadron Collider (LHC), where the neutral particles from the Higgs sector ($h_0$, $\tilde h_0$ and $\tilde p_0$) appear as possible resonant intermediate states. We investigate the signal $gg \to h_0 h_0 \to \bar b b \gamma \gamma$ and we find that the LW Higgs, depending on its mass-range, can be seen not long after the LHC upgrade in 2012. More precisely this happens when the new LW Higgs states are below the top pair threshold. In $gg \to \bar tt$ the LW states, due to the wrong-sign propagator and negative width, lead to a dip-peak structure instead of the usual peak-dip structure which gives a characteristic signal especially for low-lying LW Higgs states. We comment on the LWSM and the forward-backward asymmetry in view of the measurement at the TeVatron. Furthermore, we present a technique which reduces the hyperbolic diagonalization to standard diagonalization methods. We clarify issues of spurious phases in the Yukawa sector.Comment: 36 pages, 16 figures, 3 table

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

Understanding needs: facilitating faculty support for formal assessment processes in higher education

Prior literature discusses how conflicting beliefs regarding assessment, competing workloads, and a lack of formal assessment resources may contribute to faculty reluctance to engage with formal assessment processes. There is a gap in research on exploring assessment leader-faculty relationships through the lens of Leader-Member Exchange Theory and how that may affect participation in formal assessment processes. To address this gap, the researcher implemented a qualitative, phenomenological study to interview faculty about their lived experiences in working with formal assessment processes and interacting with assessment leaders. The goal was to discover emerging thematic categories regarding faculty perceptions of formal assessment processes and working relationships with assessment leaders that inform strategies for addressing resistance to formal assessment. The sample consisted of 13 faculty members representing 3 divisions within a private accredited institution of higher education in California. Interview transcripts were redacted and qualitatively coded through a priori and emergent approaches. The results showed that faculty participants were knowledgeable about formal assessment processes, though there was a learning curve in understanding assessment-related tasks and disproportionate opportunities for participation. Participants also displayed awareness of whether assessment work reflected a culture of student learning or a culture of compliance; emphasis was placed on framing the benefits of assessment for not only student learning but also performance at the programmatic or institutional levels. Lastly, participants indicated that they trusted their assessment leaders through moments of conflict and resistance; tensions were instead directed toward the nature of formal assessment processes