Bispecific designed ankyrin repeat proteins (DARPins) targeting epidermal growth factor receptor inhibit A431 cell proliferation and receptor recycling.

The EGF receptor (EGFR) has been implicated in the development and progression of many tumors. Although monoclonal antibodies directed against EGFR have been approved for the treatment of cancer in combination with chemotherapy, there are limitations in their clinical efficacy, necessitating the search for robust targeting molecules that can be equipped with new effector functions or show a new mechanism of action. Designed ankyrin repeat proteins (DARPins) may provide the targeting component for such novel reagents.

Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study.

Context: This article presents the results of a pivotal Phase 3 study that assesses a new treatment for the management of chronic low back pain: a transdermal patch containing the opioid buprenorphine. In this randomized, placebo-controlled study with an enriched enrollment design, the buprenorphine transdermal system (BTDS) was found to be efficacious and generally well tolerated.

Objectives: This enriched, multicenter, randomized, double-blind study evaluated the efficacy, tolerability, and safety of BTDS in opioid-naïve patients who had moderate to severe chronic low back pain.

Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model.

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [(18)F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [(18)F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33-35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes.

MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells.

MicroRNA (miRNA)-deficient helper T cells exhibit abnormal IFN-γ production and decreased proliferation. However, the contributions of individual miRNAs to this phenotype remain poorly understood. We conducted a screen for miRNA function in primary T cells and identified individual miRNAs that rescue the defects associated with miRNA deficiency.

Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study.

Unlabelled: In this enriched design study, 1,160 opioid-experienced patients with chronic, moderate to severe low back pain entered an open-label run-in period; 660 demonstrated analgesic benefit from and tolerability to buprenorphine transdermal system 20 mcg/hour (BTDS 20) treatment and were randomized to receive either BTDS 20, BTDS 5 mcg/hour (BTDS 5), or the active control (immediate release oxycodone 40-mg/day) during an 84-day double-blind phase. The primary endpoint, "average pain in the last 24 hours" during double-blind weeks 4, 8, and 12, was significantly lower for patients receiving BTDS 20 compared with patients receiving BTDS 5 (P < .001, treatment difference of -.

On the discovery of precursor processing.

Studies of the biosynthesis of insulin in a human insulinoma beginning in 1965 provided the first evidence for a precursor of insulin, the first such prohormone to be identified. Further studies with isolated rat islets then confirmed that the precursor became labeled more rapidly than insulin and later was converted to insulin by a proteolytic processing system located mainly within the secretory granules of the beta cell and was then stored or secreted. The precursor was designated "proinsulin" in 1967 and was isolated and sequenced from beef and pork sources.

Ex vivo graft purging and expansion of autologous blood progenitor cell products from patients with multiple myeloma.

Autologous peripheral blood progenitor cell (PBPC) transplantation is the treatment of choice for selected myeloma patients. However, tumor cells contaminating the apheresis product are a potential source of relapse. Here we report a sequential purging strategy targeting mature and immature clonogenic myeloma cell populations in the autograft.

A synthetic HIV-1 subtype C backbone generates comparable PR and RT resistance profiles to a subtype B backbone in a recombinant virus assay.

In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C) viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT) fragments from 8 HIV-1 subtype C-infected patient samples were RT-PCR-amplified and cloned into the HIV-1-C backbone (deleted for GPRT) using In-Fusion reagents.

Calculation of binding free energies of inhibitors to plasmepsin II.

An understanding at the atomic level of the driving forces of inhibitor binding to the protein plasmepsin (PM) II would be of interest to the development of drugs against malaria. To this end, three state of the art computational techniques to compute relative free energies-thermodynamic integration (TI), Hamiltonian replica-exchange (H-RE) TI, and comparison of bound versus unbound ligand energy and entropy-were applied to a protein-ligand system of PM II and several exo-3-amino-7-azabicyclo[2.2.

Adventures with insulin in the islets of Langerhans.

Insulin is a small but beautifully organized protein with a unique two-chain structure, the first protein to be sequenced. The mechanism of its biosynthesis invited much initial speculation but was finally clarified by the discovery of proinsulin, its single-chain precursor. The rich present-day field of protein precursor processing via post-translational proteolysis within the secretory pathway arose in the early 1970s as an offshoot of studies on insulin biosynthesis, which provided a novel paradigm for the generation of many other small neuroendocrine peptides.

Do you know this syndrome? Becker nevus syndrome.

Becker nevus syndrome is the association of Becker's nevus with breast hypoplasia and other ipsilateral bone or muscle changes. It is considered to be a hormone-dependent disorder caused by a disturbance in the activity of the androgen receptor that appears to be increased in Becker's nevus, which may influence the development of associated lesions. We present a relevant case of this syndrome due to the rare systematization of the lesions in addition to the exuberant extracutaneous involvement in this case.

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1).

Diabetes (T1DM and T2DM) is characterized by a deficit in β-cell mass. A broader understanding of human β-cell replication mechanism is thus important to increase β-cell proliferation for future therapeutic interventions. Here, we show that p27 (Kip1), a CDK inhibitor, is expressed abundantly in isolated adult human islets and interacts with various positive cell cycle regulatory proteins including D-type cyclins (D1, D2 and D3) and their kinase partners, CDK4 and CDK6.

Pim3 negatively regulates glucose-stimulated insulin secretion.

Pancreatic β-cell response to glucose stimulation is governed by tightly regulated signaling pathways which have not been fully characterized. A screen for novel signaling intermediates identified Pim3 as a glucose-responsive gene in the β cell, and here, we characterize its role in the regulation of β-cell function. Pim3 expression in the β-cell was first observed through microarray analysis on glucose-stimulated murine insulinoma (MIN6) cells where expression was strongly and transiently induced.

European marrow donor information system: concept and praxis.

Hematopoietic stem cell transplantation is an increasingly used treatment option for patients with severe disorders of hematopoiesis. In roughly two thirds of the cases, an unrelated donor must be sought in international databases. These searches would nowadays be unimaginable without the support of information technologies.

Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene.

Over the last decade our insight into the causes of neonatal diabetes has greatly expanded. Neonatal diabetes was once considered a variant of type 1 diabetes that presented early in life. Recent advances in our understanding of this disorder have established that neonatal diabetes is not an autoimmune disease, but rather is a monogenic form of diabetes resulting from mutations in a number of different genes encoding proteins that play a key role in the normal function of the pancreatic beta-cell.

Distinct requirements of microRNAs in NK cell activation, survival, and function.

MicroRNAs (miRNAs) are small noncoding RNAs that have recently emerged as critical regulators of gene expression within the immune system. In this study, we used mice with conditional deletion of Dicer and DiGeorge syndrome critical region 8 (Dgcr8) to dissect the roles of miRNAs in NK cell activation, survival, and function during viral infection. We developed a system for deletion of either Dicer or Dgcr8 in peripheral NK cells via drug-induced Cre activity.

Minimally invasive sinus augmentation.

Sinus lift surgery has become more common as patients choose dental implants for tooth replacement. The recent development of a graft material that stimulates osteogenesis coupled with the application of tissue engineering principles has allowed for refinement of this surgical modality. A simple nontraumatic subantral sinus lift microsurgery is presented.

Cord blood natural killer cells exhibit impaired lytic immunological synapse formation that is reversed with IL-2 exvivo expansion.

Peripheral blood natural killer (NK) cell therapy for acute myeloid leukemia has shown promise in clinical trials after allogeneic stem cell transplantation. Cord blood (CB) is another potentially rich source of NK cells for adoptive immune therapy after stem cell transplantation. Tightly regulated receptor signaling between NK cells and susceptible tumor cells is essential for NK cell-mediated cytotoxicity.

Intraislet production of GLP-1 by activation of prohormone convertase 1/3 in pancreatic α-cells in mouse models of ß-cell regeneration.

The islet of Langerhans is a highly vascularized micro-organ consisting of not only ß-cells but multiple cell types such as α-, delta-, pancreatic polypeptide- and epsilon-cells that work together to regulate glucose homeostatis. We have recently proposed a new model of the neonatal islet formation in mice by a process of fission following contiguous endocrine cell proliferation in the form of branched cord-like structures in embryos and newborns. There exist large stretches of interconnected islet structures along large blood vessels in the neonatal pancreas, which, upon further development, segregate into smaller fragments (i.

Pancreatic islet plasticity: interspecies comparison of islet architecture and composition.

The pancreatic islet displays diverse patterns of endocrine cell arrangement. The prototypic islet, with insulin-secreting beta-cells forming the core surrounded by other endocrine cells in the periphery, is largely based on studies of normal rodent islets. Recent reports on large animals, including humans, show a difference in islet architecture, in which the endocrine cells are randomly distributed throughout the islet.

Elevated resource availability sufficient to turn opportunistic into virulent fish pathogens.

There is mounting evidence that organic or inorganic enrichment of aquatic environments increases the risk of infectious diseases, with disease agents ranging from helminth parasites to fungal, bacterial, and viral pathogens. The causal link between microbial resource availability and disease risk is thought to be complex and, in the case of so-called "opportunistic pathogens," to involve additional stressors that weaken host resistance (e.g.

Analysis of peptides in prohormone convertase 1/3 null mouse brain using quantitative peptidomics.

Neuropeptides are produced from larger precursors by limited proteolysis, first by endopeptidases and then by carboxypeptidases. Major endopeptidases required for these cleavages include prohormone convertase (PC) 1/3 and PC2. In this study, quantitative peptidomics analysis was used to characterize the specific role PC1/3 plays in this process.

Derivation, propagation and controlled differentiation of human embryonic stem cells in suspension.

Undifferentiated human embryonic stem cells (hESCs) are currently propagated on a relatively small scale as monolayer colonies. Culture of hESCs as floating aggregates is widely used for induction of differentiation into embryoid bodies. Here we show that hESC lines can be derived from floating inner cell masses in suspension culture conditions that do not involve feeder cells or microcarriers.