FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin–dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP–patients. Studying the proteomic signature of VCP–mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP–patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP–patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro–survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts

Durchflusszytometrische Analysen des Liquor cerebrospinalis von Patienten mit primären ZNS-Lymphomen

Ziel der Arbeit war es, den Stellenwert der Durchflusszytometrie gegenüber der Zytomorphologie und der Magnetresonanztomographie für die Nachweisbarkeit einer Meningeosis lymphomatosa bei Patienten mit primären ZNS Lymphomen (PCNSL) zu ermitteln. Der Untersuchung lag ein Kollektiv (n = 30) mit PCNSL (Typ DLCBL) zugrunde. Durchflusszytometrisch sprachen eine aberrante Expression des Antigens CD45, eine übermäßige Expression des Antigens CD10 und/oder eine Leichtkettenrestriktion für Lymphomzellen im Liquor cerebrospinalis. Zytomorphologisch wurde bei 13,3%, magnetresonanztomographisch bei 6,7% und durchflusszytometrisch bei 23,3% eine meningeale Dissemination nachgewiesen. Wie für eine sekundäre meningeale Dissemination von aggressiven systemischen B-Zell-Lymphomen berichtet, bewies die Durchflusszytometrie verglichen mit der konventionellen Zytomorphologie und der Magnetresonanztomographie eine verbesserte Sensitivität zum Nachweis einer Meningeosis lymphomatosa bei PCNSL

Les problèmes complexes de Monsieur XL

Cas clinique de nodule pulmonair

Shoulder complaints and incidence of shoulder pathologies after contralateral major amputation in the mid and long-term

Introduction Amputations of the upper extremity are rare but present a life-altering event that is accompanied with considerable restrictions for the affected patients. Even with functional prosthesis, tasks of the amputated limb are usually transferred to the unaffected arm which could result in complaints of the unaffected shoulder in the mid and long term. We therefore aimed to investigate musculoskeletal pain and morphological degenerative changes of the shoulder following a contralateral amputation. Materials and methods We included all patients with a major amputation treated at our institution with a minimum of three years since the amputation. All patients received an MRI of both shoulders and were investigated using validated scores for the upper extremity and physical activity (SSV, ASES, DASH, GPAQ, SF-36). Results of the MRIs were investigated for morphological changes by two blinded investigators comparing the side of the amputation and the unharmed upper extremity and results were correlated to the time since amputation and their physical activity. Results A total of 20 patients with a mean age of 56 +/- 19.9 years (range, 23-82 years) could be included in the study. The mean time since the amputation was 26.3 +/- 19 years (range, 3-73 years). On the unharmed upper extremity, the mean SSV was 61.9 +/- 24.6, the mean ASES-Score 54.5 +/- 20.3, the Constant-score of 63.7 +/- 40.4 and a DASH-score of 47.6 +/- 23.8. The MRI of the unharmed shoulder showed significant more full-thickness rotator cuff tears and joint effusion compared to the side of the amputation. Significant differences in the degree of a glenohumeral arthritis, AC-joint arthritis, or partial rotator cuff tears could not be found between shoulders. Conclusion Amputations of the upper extremity are associated with a high disability of the unharmed upper extremity and more full thickness rotator cuff tears compared to the side of the amputation. However, the small number of patients and rotator cuff injuries should be kept in mind when interpreting the data

Diagnosis of leptomeningeal disease in diffuse large B-cell lymphomas of the central nervous system by flow cytometry and cytopathology

Reliable detection of leptomeningeal disease has the potential of facilitating the diagnosis of central nervous system (CNS) lymphoma and is important for therapeutic considerations. Currently, the standard diagnostic procedure for the detection of lymphoma in the cerebrospinal fluid is cytopathology. To improve the limited specificity and sensitivity of cytopathology, flow cytometry has been suggested as an alternative. Here, we evaluated multi-parameter flow cytometry in combination with conventional cytopathology in cerebrospinal fluid (CSF) samples from 30 patients with primary CNS lymphoma and seven patients with secondary CNS lymphoma. Overall, in 11 of 37 (29.7%) patients with CNS lymphoma, lymphoma cells were detected in CSF by flow cytometry, while cytopathology was less sensitive displaying unequivocally malignant CSF cells in only seven of all 37 (18.9%) patients. Six (16.2%) patients showed cytopathological results suspicious of lymphoma; however, in only one of these patients, the diagnosis of CSF lymphoma cells could be confirmed by flow cytometry. In primary CNS lymphomas (PCNSL), seven of 30 (23.3%) patients were positive for CSF lymphoma cells in flow cytometry, in contrast to four (13.3%) patients with PCNSL with definitely positive cytopathology. In summary, our results suggest that multi-parameter flow cytometry increases the sensitivity and specificity of leptomeningeal disease detection in CNS lymphomas. Both methods should be applied concurrently for complementary diagnostic assessment in patients with CNS lymphoma

A highly reliable convolutional neural network based soft tissue sarcoma metastasis detection from chest x-ray images

Introduction: soft tissue sarcomas are a subset of malignant tumors that are relatively rare and make up 1% of all malignant tumors in adulthood. Due to the rarity of these tumors, there are significant differences in quality in the diagnosis and treatment of these tumors. One paramount aspect is the diagnosis of hematogenous metastases in the lungs. Guidelines recommend routine lung imaging by means of X-rays. With the ever advancing AI-based diagnostic support, there has so far been no implementation for sarcomas. The aim of the study was to utilize AI to obtain analyzes regarding metastasis on lung X-rays in the most possible sensitive and specific manner in sarcoma patients. Methods: a Python script was created and trained using a set of lung X-rays with sarcoma metastases from a high-volume German-speaking sarcoma center. 26 patients with lung metastasis were included. For all patients chest X-ray with corresponding lung CT scans, and histological biopsies were available. The number of trainable images were expanded to 600. In order to evaluate the biological sensitivity and specificity, the script was tested on lung X-rays with a lung CT as control. Results: in this study we present a new type of convolutional neural network-based system with a precision of 71.2%, specificity of 90.5%, sensitivity of 94%, recall of 94% and accuracy of 91.2%. A good detection of even small findings was determined. Discussion: the created script establishes the option to check lung X-rays for metastases at a safe level, especially given this rare tumor entity