NKG2D ligands mediate immunosurveillance of senescent cells

Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.     

Two synchronous somatostatinomas of the duodenum and pancreatic head in one patient

Somatostatinomas are extremely rare neuroendocrine tumors of the gastrointestinal tract, first described in the pancreas in 1977 and in the duodenum in 1979. They may be functional and cause somatostatinoma or inhibitory syndrome, but more frequently are non-functioning pancreatic endocrine tumors that produce somatostatin alone. They are usually single, malignant, large lesions, frequently associated with metastases, and generally with poor prognosis. We present the unique case of a 57-year-old woman with two synchronous non-functioning somatostatinomas, one solid duodenal lesion and one cystic lesion within the head of the pancreas, that were successfully resected with a pylorus-preserving Whipple's procedure. No secondaries were found in the liver, or in any of the removed regional lymph nodes. The patient had an uneventful recovery, and remains well and symptom-free at 18 mo postoperatively. This is an extremely rare case of a patient with two synchronous somatostatinomas of the duodenum and the pancreas. The condition is discussed with reference to the literature.     

How αβ T cells deal with induced TCRα ablation

On deletion of the gene encoding the constant region of the T cell antigen receptor (TCR)alpha chain in mature T cells by induced Cre-mediated recombination, the cells lose most of their TCR from the cell surface within 7--10 days, but minute amounts of surface-bound TCR beta chains are retained for long periods of time. In a situation in which cellular influx from the thymus is blocked, TCR-deficient naive T cells decay over time, the decay rates being faster for CD8(+) cells (t(1/2) approximately 16 days) than for CD4(+) cells (t(1/2) approximately 46 days). TCR(+) na?ve cells are either maintained (CD8(+)) or decay more slowly (CD4(+); t(1/2) approximately 78 days.) Numbers of TCR-deficient memory T cells decline very slowly (CD8(+) cells; t(1/2) approximately 52 days) or not at all (CD4(+) cells), but at the population level, these cells fail to expand as their TCR(+) counterparts do. Together with earlier data on T cell maintenance in environments lacking appropriate major histocompatibility complex antigens, these data argue against the possibility that spontaneous ligand-independent signaling by the alpha beta TCR contributes significantly to T-cell homeostasis.     

Beitrag zur Frage der neurohumoralen Regulation der Entzündungen

Ohne Zusammenfassung     

Persistent influence of a narrative educational program on physician attitudes regarding patient care

Purpose: Educational approaches involving patient stories aim at enhancing empathy and patient-centered care; however, it is not known whether the influence of such programs on physician attitudes persists beyond medical school.

Materials and methods: The Family Centered Experience (FCE) paired preclinical medical students with patient families over two years and engaged students in reflective dialogs about the volunteers’ stories. This study examined possible long-term influences on attitudes toward medicine and doctoring. Interviews were conducted with former students at the end of or after post-graduate training. All had completed the FCE between 4 and 10 years before the study. Thematic analysis was informed by a constructivist Grounded Theory approach.

Results: Several themes were identified. The FCE made graduates aware of the patients’ perspectives and impacted their clinical practice in specific ways, such as developing collaborative partnerships, conducting family meetings, and breaking bad news. The course had influenced career choices and interest in teaching. Finally, the FCE enhanced appreciation of the human dimensions of medicine, which graduates had drawn upon in subsequent years.

Conclusions: A program based on longitudinal interactions with individuals with chronic illness can have persistent influence by stimulating reflection on the patient’s perspective and humanistic approaches to patient care.     

Yield of the PMP22 deletion analysis in patients with compression neuropathies

Journal of Neurology - Hereditary neuropathy with liability to pressure palsies (HNPP) is a rare neuromuscular disorder, mostly caused by PMP22 deletion. To determine a yield of the genetic...     

Searching for the physiological function of 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus: studies of substrate specificity and expression analysis

17beta-hydroxysteroid dehydrogenase from the filamentous fungus Cochliobolus lunatus (17beta-HSDcl) has recently been characterized. Since its function is still unclear, we performed substrate specificity studies to obtain some indications about its physiological function. Different steroids were studied as putative substrates of recombinant 17beta-HSDcl, androgens and estrogens, brassinosteroids, and the fungal steroid herbarulid. Among these androgens and estrogens were most efficiently converted. The following substrates in decreasing order were best reduced: 4-estrene-3,17-dione, 5alpha-androstane-3,17-dione, 4-androstene-3,17-dione and estrone. Two typical inhibitors were tested: carbenoxolone--a representative inhibitor of the SDR family and quercetin--a diagnostic inhibitor of carbonyl reductases. Among these two quercetin was more efficient. Expression studies revealed that 17beta-HSDcl is mainly expressed in the stationary phase of growth indicating its possible involvement in secondary metabolism.