c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis

Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.     

Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling

TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1-deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam)octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam(2)C-SK(4). Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system.     

Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study

Background

Information on the psychosexual outcome of individuals with disorders of sex development (DSDs) and intersex conditions is of great importance for sex assignment at birth of newborns with DSD.

Comparison of the lignin-degrading white rot fungi Phanerochaete chrysosporium and Sporotrichum pulverulentum at the DNA level

Summary DNA-hybridisation studies showed a close relationship between Phanerochaete chrysosporium ME446, most used in lignin degradation studies, and Sporotrichum pulverulentum Novobranova, the other standard lignin degrading strain. Two other strains of P. chrysosporium were both less related. We show that P. chrysosporium ME446 and S. pulverulentum Novobranova both have a GC-content of 59% for chromosomal DNA with the rRNA genes present as an AT-rich satellite; the mitochondrial DNA has a GC-content of 33%. The genome size estimated for P. chrysosporium ME446 is about 4–5 × 10⁷ bp.     

Short length of stay and the discharge process: Preparing breast cancer patients appropriately

ObjectiveBreast cancer is the most common cancer among women worldwide, increasing the relevance of an efficient and successful care process. As length of stay (LOS) in the hospital decreases, patients’ satisfaction with the LOS varies. We hypothesize that successful discharge planning can improve this evaluation.MethodsData of 4,390 female breast cancer patients from a cross-sectional survey was analyzed. The data was collected in 2017 in 86 German hospitals. Logistic regressions were used to test hypotheses.ResultsThe majority of included patients rated their LOS as appropriate. However, patients who felt better prepared for discharge were less likely to rate their stay as too short. A longer stay in the hospital further decreased this likelihood. The effect of LOS was moderated by patient experiences with preparation for discharge.ConclusionAs hospital LOS decreases, one challenge in allowing patients to feel sufficiently informed and ready to go home is the reduced time for face-to-face consultations. Our results indicate, however, that a strong and thorough discharge planning makes the actual number of days for LOS irrelevant for patient’s rating of LOS.Practice ImplicationsThe study results underscore the importance of ensuring the quality and thoroughness of the discharge process.     

Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury

BACKGROUND: Patients with Parkinson disease characteristically exhibit an increased echogenicity of the substantia nigra (SN) on transcranial sonography, a new neuroimaging technique. The same echo feature of the SN can be identified in 9% of healthy adults. OBJECTIVE: To evaluate the relevance of the echogenic SN in healthy adults. DESIGN: In the first part of the study, 10 healthy subjects younger than 40 years with a distinct SN hyperechogenicity underwent extensive neurological, motor, neuropsychological, and fluorine 18-dopa positron emission tomographic ([18F]-dopa PET) examinations. Results were compared with those of 10 subjects with a low echogenic SN. In the second part of the study, the postmortem brains of 20 patients without extrapyramidal disorders during their lifetime were sonographically examined with a particular focus on SN echogenicity. Subsequently, one half of the brain was prepared for heavy metal analysis, the other for a histological examination. RESULTS: Healthy subjects with SN hyperechogenicity exhibited a significant reduction of the [18F]-dopa uptake, especially in the putamen (Wilcoxon matched pair test: left side, P =.006; right side, P =.009), whereas their neuropsychological and motor performance were normal. Postmortem studies showed that the echogenicity of the SN correlated with its iron content. CONCLUSIONS: Increased echogenicity of the SN, characteristically seen in Parkinson disease, is related to a functional impairment of the nigrostriatal system (even in young healthy adults) that can be revealed by [18F]-dopa PET studies. Substantia nigra hyperechogenicity is related to a higher tissue iron level, which is known to enhance the cells' generation of reactive oxygen specimens. Therefore, we hypothesize that transcranial sonography may identify a susceptibility marker for the development of nigral injury that can be detected early in life, prior to the onset of Parkinson disease.     

Neoadjuvant endocrine therapy in primary breast cancer

Neoadjuvant chemotherapy has been employed increasingly in operable breast cancer during recent years. Several randomized trials showed that the chances of breast conserving therapy are being enhanced, and that survival was not compromised by primary systemic therapy compared to adjuvant treatment. Apart from the surgical advantages of tumor downstaging and breast conservation, therapy upfront might offer the chance to predict subsequent response of an individual patient to a given agent in the adjuvant setting. Furthermore, by investigating pre- and posttreatment tumor specimens, the neaodjuvant setting might help to evaluate new predictive biological markers, assess biologic effects of new treatments, and gain insight into molecular mechanisms. For postmenopausal patients with receptor-positive disease who cannot tolerate the toxicities of chemotherapy regimens or are not eligible for immediate surgery, endocrine treatment is emerging as an attractive alternative in the neoadjuvant setting. The new third-generation aromatase inhibitors letrozole and anastrozole have been compared to tamoxifen in 3 well-designed randomized neoadjuvant phase III trials (PO24, IMPACT, and PROACT). These studies showed significantly higher response rates for letrozole than for tamoxifen, and comparable ones for anastrozole. Thus, the primary use of an aromatase inhibitor seems a feasible and safe treatment option for postmenopausal women with early-stage breast cancer who do not wish to or are unable to undergo immediate surgery or preoperative chemotherapy. Further neoadjuvant endocrine trials should help us to elucidate the cross-talk between the different signal transduction pathways and their role in endocrine resistance.     

Subthalamic stimulation differentially modulates declarative and nondeclarative memory

Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.