Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma.

Background: Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.

Methods: By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.

Therapeutic efficacy and safety of a human fusion construct targeting the TWEAK receptor Fn14 and containing a modified granzyme B.

Background: Antibody-drug conjugates are an exceptional and useful therapeutic tool for multiple diseases, particularly for cancer treatment. We previously showed that the fusion of the serine protease granzyme B (GrB), the effector molecule or T and B cells, to a binding domain allows the controlled and effective delivery of the cytotoxic payload into the target cell. The production of these constructs induced the formation of high molecular aggregates with a potential impact on the efficacy and safety of the protein.

Production of Recombinant Gelonin Using an Automated Liquid Chromatography System.

Advances in recombinant DNA technology have opened up new possibilities of exploiting toxic proteins for therapeutic purposes. Bringing forth these protein toxins from the bench to the bedside strongly depends on the availability of production methods that are reproducible, scalable and comply with good manufacturing practice (GMP). The type I ribosome-inhibiting protein, gelonin, has great potential as an anticancer drug, but is sequestrated in endosomes and lysosomes.

A novel in vivo model using immunotoxin in the absence of p-glycoprotein to achieve ultra selective depletion of target cells: Applications in trogocytosis and beyond.

A commonly employed method to determine the function of a particular cell population and to assess its contribution to the overall system in vivo is to selectively deplete that population and observe the effects. Using monoclonal antibodies to deliver toxins to target cells can achieve this with a high degree of efficiency. Here, we describe an in vivo model combining the use of immunotoxins and multidrug resistant (MDR) gene deficient mice so that only MDR deficient cells expressing the target molecule would be depleted while target molecule expressing, but MDR sufficient, cells are spared.

Identification of the cis‑molecular neighbours of the immune checkpoint protein B7‑H4 in the breast cancer cell‑line SK‑BR‑3 by proteomic proximity labelling.

The immune checkpoint protein B7‑H4 plays an important role in the positive as well as the negative regulation of immune T‑cell responses. When expressed on cancer cells, B7‑H4 inhibits T‑cell activity, and numerous types of cancer cells use upregulation of B7‑H4 as a survival strategy. Thus, B7‑H4 is a potential target for anticancer drug therapy.

CMOS-based bio-image sensor spatially resolves neural activity-dependent proton dynamics in the living brain.

Recent studies have shown that protons can function as neurotransmitters in cultured neurons. To further investigate regional and neural activity-dependent proton dynamics in the brain, the development of a device with both wide-area detectability and high spatial-ltemporal resolution is necessary. Therefore, we develop an image sensor with a high spatial-temporal resolution specifically designed for measuring protons in vivo.

Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization.

The objective of this study was to develop and explore a novel CD133-targeting immunotoxin (IT) for use in combination with the endosomal escape method photochemical internalization (PCI). scFvCD133/rGelonin was recombinantly constructed by fusing a gene (scFvCD133) encoding the scFv that targets both non-glycosylated and glycosylated forms of both human and murine CD133/prominin-1 to a gene encoding the ribosome-inactivating protein (RIP) gelonin (rGelonin). RIP-activity was assessed in a cell-free translation assay.

Development of a human immuno-oncology therapeutic agent targeting HER2: targeted delivery of granzyme B.

Background: Immunotherapeutic approaches designed to augment T and B cell mediated killing of tumor cells has met with clinical success in recent years suggesting tremendous potential for treatment in a broad spectrum of tumor types. After complex recognition of target cells by T and B cells, delivery of the serine protease granzyme B (GrB) to tumor cells comprises the cytotoxic insult resulting in a well-characterized, multimodal apoptotic cascade.

Methods: We designed a recombinant fusion construct, GrB-Fc-4D5, composed of a humanized anti-HER2 scFv fused to active GrB for recognition of tumor cells and internal delivery of GrB, simulating T and B cell therapy.

Advancing scholarship by publishing curriculum as an e-book.

Background: Medical educators provide service by developing curricula and writing learning material. In addition, academic institutions expect medical educators to publish scholarship to be considered for promotion and academic advancement. Unfortunately, educators may receive limited time to execute these duties and expectations.

Light-enhanced VEGF/rGel: A tumor targeted modality with vascular and immune-mediated efficacy.

Interactions between stromal cells and tumor cells pay a major role in cancer growth and progression. This is reflected in the composition of anticancer drugs which includes compounds directed towards the immune system and tumor-vasculature in addition to drugs aimed at the cancer cells themselves. Drug-based treatment regimens are currently designed to include compounds targeting the tumor stroma in addition to the cancer cells.

CONTeMPLATE-a mnemonic to help medical educators infuse reflection into their residency curriculum.

Reflection, where clinical experiences are analyzed to gain greater understanding and meaning, is an important step in workplace learning. Residency programs must teach their residents the skills needed for deep reflection. Medical educators may find it difficult to construct a curriculum which includes the key elements needed to enable learners to attain these skills.

SAFE QI - a framework to overcome the challenges of implementing a quality improvement curriculum into a residency program.

Quality improvement (QI) is an essential component of medical practice. Medical students and residents must learn the skills to conduct clinical QI during their educational programs. Medical educators must create and implement a curriculum in QI to empower their students to develop this skill and knowledge.

Applying a reflexive framework to evaluate a communication skills curriculum.

After creating and delivering an educational curriculum, medical educators must ultimately evaluate the effectiveness of the implemented curriculum. Seasoned educators can benefit from using an established framework to help them structure a thorough, complete curricular evaluation; however, novice educators may have difficulty in transforming the concept of evaluation into a concrete process. The RUFDATA (Reasons and purpose, Uses, Focus, Data and evidence, Audience, Timing, and Agency) framework is one such paradigm.

Early Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Chain Molecular Testing.

When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT) lymphoma. We describe a patient with a history of Sjögren's syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP). However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH) polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.

Using an Instructional Design Model to Teach Medical Procedures.

Educators are often tasked with developing courses and curricula that teach learners how to perform medical procedures. This instruction must provide an optimal, uniform learning experience for all learners. If not well designed, this instruction risks being unstructured, informal, variable amongst learners, or incomplete.

Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68).

Coaching patients during pulmonary function testing: A practical guide.

Pulmonary function tests are an important tool to assist in the diagnosis and management of patients with respiratory disease. Ensuring that the tests are of acceptable quality is vital. Acceptable pulmonary function test quality requires, among others, optimal patient performance.

Correction: Chigrinova, M., et al. Kinugasa reactions in water: from green chemistry to bioorthogonal labelling. Molecules 2015, 20, 6959-6969.

The authors wish to make the following correction to this paper [1]: The author name "Paul Pezacki" should be "John Paul Pezacki". [..

Kinugasa reactions in water: from green chemistry to bioorthogonal labelling.

The Kinugasa reaction has become an efficient method for the direct synthesis of β-lactams from substituted nitrones and copper(I) acetylides. In recent years, the reaction scope has been expanded to include the use of water as the solvent, and with micelle-promoted [3+2] cycloadditions followed by rearrangement furnishing high yields of β-lactams. The high yields of stable products under aqueous conditions render the modified Kinugasa reaction amenable to metabolic labelling and bioorthogonal applications.

Development of human serine protease-based therapeutics targeting Fn14 and identification of Fn14 as a new target overexpressed in TNBC.

The cytokine TWEAK and its receptor, Fn14, have emerged as potentially valuable targets for cancer therapy. Granzyme B (GrB)-containing Fn14-targeted constructs were generated containing either the Fn14 ligand TWEAK (GrB-TWEAK) or an anti-Fn14 humanized single-chain antibody (GrB-Fc-IT4) as the targeting moieties. Both constructs showed high affinity and selective cytotoxicity against a panel of Fn14-expressing human tumor cells including triple-negative breast cancer (TNBC) lines.