Tumor-associated stromal cells as key contributors to the tumor microenvironment.

The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells

ESPEN guideline on nutritional support for polymorbid medical inpatients.

BACKGROUND Disease-related malnutrition in polymorbid medical inpatients is a highly prevalent syndrome associated with significantly increased morbidity, disability, short- and long-term mortality, impaired recovery from illness, and cost of care. AIM As there are uncertainties in applying disease-specific guidelines to patients with multiple conditions, our aim was to provide evidence-based recommendations on nutritional support for the polymorbid patient population hospitalized in medical wards. METHODS This update adheres to the standard operating procedures for ESPEN guidelines. We did a systematic literature search for 15 clinical questions in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g. published guidelines), until July 12th. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations (incl. SIGN grading), which was followed by submission to Delphi voting. RESULTS From a total of 3527 retrieved abstracts, 60 new relevant studies were analyzed and used to generate a guideline draft that proposed 32 recommendations (7x A, 11x B, 10x O and 4x GPP), which encompass different aspects of nutritional support including indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. The results of the first online voting showed a strong consensus (agreement of >90%) on 100% of the recommendations. Therefore, no final consensus conference was needed. CONCLUSIONS Recent high-quality trials have provided increasing evidence that nutritional support can reduce morbidity and other complications associated with malnutrition in polymorbid patients. The timely screening of patients for risk of malnutrition at hospital admission followed by individualized nutritional support interventions for at-risk patients should be part of routine clinical care and multimodal treatment in hospitals worldwide. Use of this updated guideline offers an evidence-based nutritional approach to the polymorbid medical inpatients and may improve their outcomes

Near Infrared Fluorescent Nanoparticles Derived from Hyaluronic Acid Improve Tumor Contrast for Image-Guided Surgery.

Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or covalently conjugated Cy7.5. Using orthotopic human breast cancer MDA-MB-231 xenografts in nude mice we identified two lead formulations. One, NanoICGPBA, with physicochemically entrapped ICG, showed 2.3-fold greater tumor contrast than ICG alone at 24 h (p \u3c 0.01), and another, NanoCy7.5100-H, with covalently conjugated Cy7.5, showed 74-fold greater tumor contrast than Cy7.5 alone at 24 h (p \u3c 0.0001). These two lead formulations were then tested in immune competent BALB/c mice bearing orthotopic 4T1 breast cancer tumors. NanoICGPBA showed 2.2-fold greater contrast than ICG alone (p \u3c 0.0001), and NanoCy7.5100-H showed 14.8-fold greater contrast than Cy7.5 alone (p \u3c 0.0001). Furthermore, both NanoICGPBA and NanoCy7.5100-H provided strong tumor enhancement using image-guided surgery in mice bearing 4T1 tumors. These studies demonstrate the efficacy of a panel of HA-derived NPs in delineating tumors in vivo, and identifies promising formulations that can be used for future in vivo tumor removal efficacy studies

vPIF-1 is an insulin-like antiferroptotic viral peptide

Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone-releasing hormone antagonist-induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms

Signatures of technetium oxidation states: a new approach

A general strategy for the determination of Tc oxidation state by new approach involving X-ray absorption near edge spectroscopy (XANES) at the Tc L-3 edge is shown. A comprehensive series of Tc-99 compounds, ranging from oxidation states I to VII, was measured and subsequently simulated within the framework of crystal-field multiplet theory. The observable trends in the absorption edge energy shift in combination with the spectral shape allow for a deeper understanding of complicated Tc coordination chemistry. This approach can be extended to numerous studies of Tc systems as this method is one of the most sensitive methods for accurate Tc oxidation state and ligand characterization

Pathological consequences of VCP mutations on human striated muscle

*These authors have contributed equally to this work. Mutations in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). We report on the pathological consequences of three heterozygous VCP (R93C, R155H, R155C) mutations on human striated muscle. IBMPFD skeletal muscle pathology is characterized by degenerative changes and filamentous VCP-and ubiquitin-positive cytoplasmic and nuclear protein aggregates. Furthermore, this is the first report demonstrating that mutant VCP leads to a novel form of dilatative cardiomyopathy with inclusion bodies. In contrast to post-mitotic striated muscle cells and neurons of IBMPFD patients, evidence of protein aggregate pathology was not detected in primary IBMPFD myoblasts or in transient and stable transfected cells using wild-type-VCP and R93C-, R155H-, R155C-VCP mutants. Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3. Structural analysis demonstrated that R93 and R155 are both surface-accessible residues located in the centre of cavities that may enable ligand-binding. Mutations at R93 and R155 are predicted to induce changes in the tertiary structure of the VCP protein. The search for putative ligands to the R93 and R155 cavities resulted in the identification of cyclic sugar compounds with high binding scores. The latter findings provide a novel link to VCP carbohydrate interactions in the complex pathology of IBMPFD. Keywords: VCP; p97; myopathy; cardiomyopathy; IBMPFD Abbreviations: GST = glutathione S-transferase; IBMPFD = inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia; PBS = phosphate-buffered saline; SDS = sodium dodecyl sulphate; VCP = valosin-containing protei

Insights into the Electronic Structure of a U(IV) Amido and U(V) Imido Complex

Reaction of the N-heterocylic carbene ligand (i)PrIm (L-1) and lithium bis(trimethylsilyl)amide (TMSA) as a base with UCl4 resulted in U(IV) and U(V) complexes. Uranium's +V oxidation state in (HL1)(2)[U(V)(TMSI)Cl-5] (TMSI=trimethylsilylimido) (2) was confirmed by HERFD-XANES measurements. Solid state characterization by SC-XRD and geometry optimisation of [U(IV)(L-1)(2)(TMSA)Cl-3] (1) indicated a silylamido ligand mediated inverse trans influence (ITI). The ITI was examined regarding different metal oxidation states and was compared to transition metal analogues by theoretical calculations

Data publication: Insights into the Electronic Structure of a U(IV) Amido and U(V) Imido Complex

This set includes single-crystal X-ray diffraction, IR, HERFD XANES and quantumchemical calculation data for the characterization of the synthesized U(IV) amido and U(V) imido complexes. Furthermore with this the inverse trans influence can be evaluated

Data publication: Presence of uranium(V) during uranium(VI) reduction by Desulfosporosinus hippei DSM 8344T

The stored data sets represent both the raw data and the evaluated data that were used for the publication about uranium(VI) reduction by a sulfate-reducing bacterium