Autophagy in cancer: having your cake and eating it

Autophagy, one of two major intracellular degradation pathways, plays a critical role in energy homeostasis and the quality control of macromolecules and intracellular organelles. Previous work has demonstrated the importance of autophagy in maintaining cellular fitness, both in healthy and stressful conditions, revealing the complex interplay between autophagy and other stress-responsive phenotypes. The complex outcomes of stress-responsive autophagy confer on it both pro- and anti-tumourigenic roles, depending on the cellular and environmental context. Furthermore, recent findings that functionally link autophagy to the tumour suppressor mechanism, cellular senescence, have revealed a new role of autophagy in cancer biology. In this review we summarise the current evidence on the relationship between autophagy and cancer, with a focus on its role in senescence.     

CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A-HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a "lock and key" interaction is typical of innate receptor-ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.     

Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.     

Sifting,sorting and saturating data in a grounded theory study of information use by practice nurses: A worked example

The terminology used to analyse data in a grounded theory study can be confusing. Different grounded theorists use a variety of terms which all have similar meanings. In the following study, we use terms adopted by Charmaz including: initial, focused and axial coding. Initial codes are used to analyse data with an emphasis on identifying gerunds, a verb acting as a noun. If initial codes are relevant to the developing theory, they are grouped with similar codes into categories. Categories become saturated when there are no new codes identified in the data. Axial codes are used to link categories together into a grounded theory process. Memo writing accompanies this data sifting and sorting. The following article explains how one initial code became a category providing a worked example of the grounded theory method of constant comparative analysis. The interplay between coding and categorization is facilitated by the constant comparative method.     

Outcomes from homeopathic prescribing in veterinary practice: a prospective, research-targeted, pilot study

BACKGROUND AND AIMS: Targeted research development in veterinary homeopathy is properly informed by the systematic collection and analysis of relevant clinical data obtained by its practitioners. We organised a pilot data collection study, in which 8 Faculty of Homeopathy veterinarians collected practice-based clinical and outcomes data over a 6-month period. METHODS: A specifically designed Excel spreadsheet enabled recording of consecutive clinical appointments under the following headings: date; identity of patient and owner (anonymised); age, sex and species of patient; medical condition/complaint treated; whether confirmed diagnosis, chronic or acute, new or follow-up case; owner-assessed outcome (7-point Likert scale: -3 to +3) compared with first appointment; homeopathic medicine/s prescribed; other medication/s for the condition/complaint. Spreadsheets were submitted monthly by e-mail to the project organisers for data checking, synthesis and analysis. RESULTS: Practitioners submitted data regularly and punctually, and most data cells were completed. 767 individual patients were treated (547 dogs, 155 cats, 50 horses, 5 rabbits, 4 guinea-pigs, 2 birds, 2 goats, 1 cow, and 1 tortoise). Outcome from two or more homeopathic appointments per patient condition was obtained in 539 cases (79.8% showing improvement, 6.1% deterioration, 11.7% no change; outcome not recorded in 2.4% of follow-ups). Strongly positive outcomes (scores of +2 or +3) were achieved in: arthritis and epilepsy in dogs and, in smaller numbers, in atopic dermatitis, gingivitis and hyperthyroidism in cats. CONCLUSIONS: Systematic recording of data by veterinarians in clinical practice is feasible and capable of informing future research in veterinary homeopathy. A refined version of the spreadsheet can be used in larger-scale research-targeted veterinary data collection.     

Clinical Effects of Lactobacillus rhamnosus in Non‐Surgical Treatment of Chronic Periodontitis: A Randomized Placebo‐Controlled Trial With 1‐Year Follow‐Up

Background: Probiotics are living microorganisms that provide beneficial effects for the host when administered in proper quantities. The aim of this double‐masked placebo‐controlled parallel‐arm randomized clinical trial is to evaluate the clinical effects of a Lactobacillus rhamnosus SP1‐containing probiotic sachet as an adjunct to non‐surgical therapy. Methods: Twenty‐eight systemically healthy volunteers with chronic periodontitis were recruited and monitored clinically at baseline and 3, 6, 9, and 12 months after therapy. Clinical parameters measured included plaque accumulation, bleeding on probing, probing depths (PDs), and clinical attachment loss. Patients received non‐surgical therapy, including scaling and root planing (SRP), and were assigned randomly to a test (SRP + probiotic, n = 14) or control (SRP + placebo, n = 14) group. The intake, once a day for 3 months, of an L. rhamnosus SP1 probiotic sachet commenced after the last session of SRP. Results: Both test and control groups showed improvements in clinical parameters at all time points evaluated. However, the test group showed greater reductions in PD than the control. Also, at initial visits and after 1‐year follow‐up, the test group showed a statistically significant reduction in the number of participants with PD ≥6 mm, indicating a reduced need for surgery, in contrast to the placebo group. Conclusion: The results of this trial indicate that oral administration of L. rhamnosus SP1 resulted in similar clinical improvements compared with SRP alone.     

Detection of laryngeal cancer--the case for early specialist assessment.

The first 300 patients referred from 11 participating general practices (GPs) to the Hoarse Voice Clinic, Queen Elizabeth Hospital, Birmingham, were studied prospectively to estimate the accuracy of GPs' diagnosis of laryngeal symptoms and to assess whether the provision of a direct referral immediate access service for the assessment of persistent laryngeal symptoms is an effective way of ensuring early referral and detection of laryngeal cancer. The GPs' assessment of laryngeal symptoms was inaccurate. Diagnosis after the initial clinic visit was accurate, predicting all histological cases of cancer. Laryngoscopy was possible in all patients at the first clinic visit. Disease requiring admission for direct laryngoscopy and biopsy was found in 39 patients (14%). Ten (3.3%) were found to have laryngeal cancer, of which eight were early lesions. When seen in the clinic 102 (34%) had normal voices and larynxes. A hoarse voice is a symptom requiring specialist assessment. By using the flexible fibreoptic nasendoscope all patients larynxes can be seen in clinic, an accurate diagnosis quickly made and the appropriate management instigated. It is feasible to offer this service without appointments to patients with persistent hoarseness.