Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11DS) is associated with learning and cognitive dysfunctions and a high risk of developing schizophrenia. It has become increasingly clear that dendritic spine plasticity is tightly linked to cognition. Thus, understanding how genes involved in cognitive disorders affect synaptic networks is a major challenge of modern biology. Several studies have pointed to a spine density deficit in 22q11DS transgenic mice models. Using the LgDel mouse model, we first quantified spine deficit at different stages using electron microscopy. Next we performed repetitive confocal imaging over several days on hippocampal organotypic cultures of LgDel mice. We show no imbalanced ratio between daily spine formation and spine elimination, but a decreased spine life expectancy. We corrected this impaired spine stabilization process by overexpressing ZDHHC8 palmitoyltransferase, whose gene belongs to the LgDel microdeletion. Overexpression of one of its substrates, the cdc42 brain-specific variant, under a constitutively active form (cdc42-palm-CA) led to the same result. Finally, we could rescue spine density in vivo, in adult LgDel mice, by injecting pups with a vector expressing cdc42-palm-CA. This study reveals a new role of ZDHHC8-cdc42-palm molecular pathway in postsynaptic structural plasticity and provides new evidence in favor of the dysconnectivity hypothesis for schizophrenia.

Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

The effect of experimental balancing interferences on masticatory performance.

Immediate adaptation to experimental-balancing interferences is known to affect jaw kinematics and electromyographic activity (EMG). However, little is known about the influence on masticatory performance parameters. This study hypothesises that balancing-side interferences significantly reduce the performance of the masticatory system. Twenty-one healthy subjects (eleven female, mean age: 24.1 ± 1.2 years) chewed standardised silicone cubes performing 15 masticatory cycles on the right side under three experimental conditions: (i) natural dentition (ND), (ii) splints with structured occlusal profiles (SS) (iii) splints with balancing interferences in the left molar region (OI). The particle size distribution was determined by a validated scanning procedure and curve fitted with the Rosin-Rammler function to determine X(50)-values. The EMG of both temporalis and masseter muscles was recorded simultaneously, and the total muscle work (TMW) was calculated. A jaw-tracking device recorded the incisal movement path (IMP). The functional parameters under the experimental conditions were compared by repeated-measures analysis of variance. The findings confirm our hypothesis. The X(50)-values differed significantly (P < 0.01) between ND and OI (4.34 vs. 4.60 mm), and between SS and OI (4.34 vs. 4.60 mm), respectively. In contrast, no significant differences (P > 0.05) were observed between SS and ND. There was no significant difference in both TMW (1269.0 vs. 1284.9 vs. 1193.9 µV*s) and IMP (720.2 vs. 735.3 vs. 723.1 mm) amongst the three conditions (P > 0.05). These findings confirm the assumption that the disturbance of the habitual chewing cycles by balancing-side interferences significantly reduces the masticatory performance in the short term. Occlusal balancing-side interferences are common technical failures of dental restorations. Simulation of this condition caused deterioration of masticatory performance in healthy young adults. Further studies should be carried out, on whether the observed effect is long-term and whether masticatory performance decreases even more in patients with reduced adaptive capacity.

Limited role for surveillance PET-CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy.

BACKGROUND: The usefulness of positron emission tomography with computed tomography (PET-CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. METHODS: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET-CT after achieving complete metabolic response (CMR) following primary therapy. RESULTS: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8-133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI ≥3. Including indeterminate scans, PET-CT retained high sensitivity 95% and specificity 97% for relapse. CONCLUSION: Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ≥3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.

Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre, International Extranodal Lymphoma Study Group study.

BACKGROUND: We evaluated the long-term results of radiotherapy for patients with gastric marginal zone lymphoma (GMZL). PATIENTS AND METHODS: We carried out a retrospective, multi-centre study of patients with low-grade GMZL treated by radiotherapy between 17 July 1981 and 25 March 2004. RESULTS: There were 102 eligible patients. Fifty-eight patients were previously untreated and 44 had recurrent/residual disease after prior treatment (HP eradication, chemotherapy and surgery in 35, 9 and 8 patients, respectively, and 7 had >1 prior therapy). Radiation fields included the stomach /involved nodes in 61 patients and whole abdomen in 41. The median radiotherapy dose to stomach was 40 Gy (range 26-46 Gy) in a median 22 fractions. With a median follow-up after radiotherapy of 7.9 years (range 0.3-24 years), 10- and 15-year freedom from treatment failure (FFTF) was 88% (95% CI 82%-95%). Risk factors for TF were a large-cell component (P = 0.036) and an exophytic growth pattern (P = 0.042). Radiotherapy field size, radiotherapy dose, and failure of prior therapy were not associated with inferior FFTF. Ten-year overall survival was 70% (95% CI 60%-82%). CONCLUSIONS: Radiotherapy achieves cure for the majority of patients with low-grade GMZL, including patients who have had prior therapy. Several features may predict a poorer outcome.

Minimising critical organ irradiation in limited stage Hodgkin lymphoma: a dosimetric study of the benefit of involved node radiotherapy.

BACKGROUND: Chemotherapy plus radiotherapy is the standard of care for patients with limited stage Hodgkin lymphoma (HL). Radiotherapy is evolving from involved field radiotherapy (IFRT) to involved node radiotherapy (INRT) to decrease radiotherapy-related morbidity. In the absence of long-term toxicity data, dose-volume metrics of organs at risk (OAR) provide a surrogate measure of toxicity risk. PATIENTS AND METHODS: Ten female patients with stage I-IIA supradiaphragmatic HL were randomly selected. All patients had pre-chemotherapy computerised tomography (CT) and CT-positron emission tomography staging. Using CT planning, three radiotherapy plans were produced per patient: (i) IFRT, (ii) INRT using parallel-opposed beams and (iii) INRT using volumetric modulated arc therapy (VMAT). Radiotherapy dose was 30.6 Gy in 1.8 Gy fractions. OAR evaluated were lungs, breasts, thyroid, heart and coronary arteries. RESULTS: Compared with IFRT, INRT significantly reduced mean doses to lungs (P < 0.01), breasts (P < 0.01), thyroid (P < 0.01) and heart (P < 0.01), on Wilcoxon testing. Compared with conventional INRT, VMAT improved dose conformality but increased low-dose radiation exposure to lungs and breasts. VMAT reduced the heart volume receiving 30 Gy (V30) by 85%. CONCLUSIONS: Reduction from IFRT to INRT decreased the volumes of lungs, breasts and thyroid receiving high-dose radiation, suggesting the potential to reduce long-term second malignancy risks. VMAT may be useful for patients with pre-existing heart disease by minimising further cardiac toxicity risks.

Adjustment to cancer and the information needs of people with lung cancer.

OBJECTIVE: Although typically high, the need for information varies between cancer patients. Few studies, however, have examined the factors that predict patient information needs. This study investigated the influence of different styles of adjustment to cancer on information needs. It was proposed that adjustment styles can be defined in terms of goal pursuit and that adjustment influences information needs as these also arise from goal pursuit. METHOD: Seventy-three lung cancer patients were recruited at their first appointment with their radiation oncologist. Participants completed the Patient Information Needs Questionnaire measuring Disease Orientated (DO) information and Action Orientated (AO) information, the Mini-Mental Adjustment to Cancer Scale, and a purpose-built measure of cancer-related personal goals. RESULTS: High levels of the adjustment styles, Fighting Spirit and Anxious Preoccupation, were related to a high need for DO information (p=0.042 and 0.023, respectively). Conversely, high levels of the adjustment style Cognitive Avoidance was related to a low need for DO information (p=0.041). High levels of Anxious Preoccupation were also positively related to a high need for AO information (p=0.018). Support for the proposed theoretical model was also found: information goals predicted information needs and mediated the relationship between Fighting Spirit and DO information need. CONCLUSIONS: These findings suggest that information needs vary as a function of adjustment to cancer. Consequently information provision to cancer patients could be more appropriately tailored by attending to how a patient is adjusting to their diagnosis of cancer.

[Anti-diabetic drugs. Weight reduction as a favourable side effect]. / Antidiabetika. Gewichtsreduktion als wünschenswerter Begleiteffekt.

The increasing prevalence of type 2 diabetes mellitus in the last years is mainly attributable to an increase in life expectancy and the high incidence of obesity. Nearly 90% of all type 2 diabetic patients in Germany are overweight or obese. The attributable risk of obesity in the development of type 2 diabetes mellitus is approximately 70%. Oral anti-diabetic drugs like sulfonylurea, glinides, and glitazones as well as insulin increase body weight within years by up to 8 kg with damaging side effects on cardiovascular organs. Dipeptidylpeptidase 4 (DPP-4) inhibitors do not affect body weight and metformin as well as glucagon like peptid 1 (GLP-1) receptor agonists decrease it. A reduction in body weight by changes in life style is effective but only a few overweight patients achieve the therapeutic goals. By using anti-diabetic drugs as monotherapy or in combination with other anti-diabetic compounds body weight, glycemic control and other cardiovascular risk factors may be influenced favorably.

Long-term Survival with 18-Fluorodeoxyglucose Positron Emission Tomography-directed Therapy in Non-small Cell Lung Cancer with Synchronous Solitary Brain Metastasis.

AIMS: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease. MATERIALS AND METHODS: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors. RESULTS: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS. CONCLUSIONS: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease.

Assessment of trabecular and cortical architecture and mechanical competence of bone by high-resolution peripheral computed tomography: comparison with transiliac bone biopsy.

UNLABELLED: We compared microarchitecture and mechanical competence parameters measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite-element analysis of radius and tibia to those measured by histomorphometry, micro-CT, and finite-element analysis of transiliac bone biopsies. Correlations were weak to moderate between parameters measured on biopsies and scans. INTRODUCTION: HR-pQCT is a new imaging technique that assesses trabecular and cortical bone microarchitecture of the radius and tibia in vivo. The purpose of this study was to determine the extent to which microarchitectural variables measured by HR-pQCT reflect those measured by the "gold standard," transiliac bone biopsy. METHODS: HR-pQCT scans (Xtreme CT, Scanco Medical AG) and iliac crest bone biopsies were performed in 54 subjects (aged 39 +/- 10 years). Biopsies were analyzed by 2D quantitative histomorphometry and 3D microcomputed tomography (microCT). Apparent Young's modulus, an estimate of mechanical competence or strength, was determined by micro-finite-element analysis (microFE) of biopsy microCT and HR-pQCT images. RESULTS: The strongest correlations observed were between trabecular parameters (bone volume fraction, number, separation) measured by microCT of biopsies and HR-pQCT of the radius (R 0.365-0.522; P < 0.01). Cortical width of biopsies correlated with cortical thickness by HR-pQCT, but only at the tibia (R = 0.360, P < 0.01). Apparent Young's modulus calculated by microFE of biopsies correlated with that calculated for both radius (R = 0.442; P < 0.001) and tibia (R = 0.380; P < 0.001) HR-pQCT scans. CONCLUSIONS: The associations between peripheral (HR-pQCT) and axial (transiliac biopsy) measures of microarchitecture and estimated mechanical competence are significant but modest.

Computational analyses of small endosseous implants in osteoporotic bone.

For many years orthopedic implants were developed for patients with good bone stock. Recently it has become clear that these implants have a decreased performance when implanted in bone with low density, such as in osteoporosis. Reduced performance in osteoporotic bone is not unexpected because of the reduced quality of the peri-implant bone and the reduced bone-implant contact area. Nevertheless, the precise failure mechanisms are not well understood. Although experimental testing is considered the gold standard to determine implant fixation, it is hampered by many limitations. Computational models could potentially aid in obtaining a better understanding of implant fixation as they allow analyzing the mechanical interaction between implants and peri-implant tissues. This article provides a review of the existing finite element models of small endosseous implants in bone. The aim is to analyze the potential of such models to aid the understanding of implant failure mechanisms with the goal of improving implant performance in low quality bone.