Molecular characterisation and expression analysis of SEREX-defined antigen NUCB2 in gastric epithelium, gastritis and gastric cancer

NUCB2 is an EF-hand Ca2+ binding protein that has been implicated in various physiological processes like calcium homeostasis, hypothalamic regulation of feeding and TNF receptor shedding. In our previous study we identified NUCB2 as a potential tumour antigen eliciting autoantibody responses in 5.4% of gastric cancer patients but not in the healthy individuals. The current study aimed to elucidate the molecular mechanism underlying NUCB2 immunogenicity and to gain an insight into the physiological functions of NUCB2 in the stomach. mRNA expression analysis demonstrated that NUCB2 is ubiquitously expressed in normal tissues, including lymphoid tissues, and downregulated in gastric tumours when compared with the adjacent relatively normal stomach tissues. The search for molecular alterations resulted in the identification of novel mRNA variants transcribed from an alternative promoter and expressed predominantly in gastric cancers. Western blot analysis demonstrated that the protein levels correspond to mRNA levels and revealed that NUCB2 is phosphorylated in gastric mucosa. Furthermore, a 55 kDa isoform, generated presumably by yet an unidentified post-translational modification was detected in gastric tumours and AGS gastric cancer cells but was absent in the relatively normal gastric mucosa and thereby might have served as a trigger for the immune response against NUCB2. Staining of stomach tissue microarray with anti-NUCB2 antibody revealed that it is expressed in the secretory granules of chief cells and in the cytoplasm of parietal cells in the functioning gastric glands which are lost in atrophic glands and tumour cells. Hence we propose that NUCB2 may be implicated in gastric secretion by establishing an agonist-releasable Ca2+ store in ER or Golgi apparatus, signalling via heterotrimeric Gα proteins and/or mediating the exocytosis of the secretory granules

Serological identification and expression analysis of gastric cancer-associated genes

Serological identification of tumour antigens by recombinant expression cloning has proved to be an effective strategy for the identification of cancer-associated genes having a relevance to cancer aetiology and progression, and for defining possible targets for immunotherapeutic intervention. In the present study we applied this technique to identify immunogenic proteins for gastric cancer that resulted in isolation of 14 distinct serum-reactive antigens. In order to evaluate their role in tumourigenesis and assess the immunogenicity of the identified antigens, we characterised each cDNA clone by DNA sequence analysis, mRNA tissue distribution, comparison of mRNA levels in cancerous and adjacent non-cancerous tissues and the frequency of antibody responses in allogeneic patient and control sera. Previously unknown splice variants of TACC1 and an uncharacterised gene Ga50 were identified. The expression of a newly identified TACC1 isoform is restricted to brain and gastric cancer tissues. Comparison of mRNA levels by semi-quantitative RT–PCR revealed a relative overexpression of three genes in cancer tissues, including growth factor granulin and Tbdn-1 – an orthologue of the mouse acetyltransferase gene which is associated with blood vessel development. An unusual DNA polymorphism – a three-nucleotide deletion was found in NUCB2 cDNA but its mRNA level was consistently decreased in gastric tumours compared with that in the adjacent non-cancerous tissues. This study has revealed several new gastric cancer candidate genes; additional studies are required to gain a deeper insight into their role in the tumorigenesis and their potential as therapeutic targets

Psychosoziale Unterstützung während der COVID-19-Pandemie: interdisziplinäres Versorgungskonzept an einem Universitätsklinikum

BACKGROUND Since the beginning of the outbreak, the COVID-19 pandemic has caused an increased demand for psychosocial support for patients, their family members, and healthcare workers. Concurrently, possibilities to provide this support have been hindered. Quarantine, social isolation, and SARS-CoV\hbox-2 infections represent new and severe stressors that have to be addressed with innovative psychosocial care. OBJECTIVE AND METHOD This article describes the COVID-19 psychosocial first aid concept at the University Hospital Munich (LMU Klinikum) developed by an interdisciplinary team of psychiatric, psychological, spiritual care, psycho-oncological, and palliative care specialists. RESULTS A~new psychosocial first aid model has been implemented for COVID-19 inpatients, family members, and hospital staff consisting of five elements. CONCLUSION The concept integrates innovative and sustainable ideas, e.g. telemedicine-based approaches and highlights the importance of multidisciplinary collaboration to cope with challenges in the healthcare system.Hintergrund Die COVID-19-Pandemie hat seit ihrem Beginn zu einem erhöhten psychosozialen Unterstützungsbedarf bei Patient*innen, Angehörigen und Mitarbeiter*innen geführt und übliche Wege klinischer Versorgung erschwert. Sowohl Quarantäne- und Isolationsmaßnahmen als auch SARS-CoV-2-Infektionen und -Erkrankungen sind zu neuen und erheblichen Belastungsfaktoren geworden, die in neuen Ansätzen der Versorgung adressiert werden müssen. Ziel der Arbeit und Methode Dieser Beitrag beschreibt die Entwicklung des Konzeptes Psychosoziale Versorgung COVID-19 am LMU-Klinikum in München durch ein interdisziplinäres Team von Psychiater*innen, Psycholog*innen, Seelsorger*innen, Psychoonkolog*innen und Palliativmediziner*innen. Ergebnis Das neue Versorgungsmodell zur psychosozialen Unterstützung wurde für stationäre COVID-19-Patient*innen des Klinikums, deren Angehörige und Mitarbeiter*innen bestehend aus fünf Elementen implementiert. Diskussion Das Angebot integriert innovative und nachhaltige Ansätze, wie den Einsatz telemedizinischer Interventionen, und unterstreicht den Wert interdisziplinärer Zusammenarbeit zur Bewältigung von Herausforderungen im Gesundheitswesen

Long-lasting desynchronization in rat hippocampal slice induced by coordinated reset stimulation.

In computational models it has been shown that appropriate stimulation protocols may reshape the connectivity pattern of neural or oscillator networks with synaptic plasticity in a way that the network learns or unlearns strong synchronization. The underlying mechanism is that a network is shifted from one attractor to another, so that long-lasting stimulation effects are caused which persist after the cessation of stimulation. Here we study long-lasting effects of multisite electrical stimulation in a rat hippocampal slice rendered epileptic by magnesium withdrawal. We show that desynchronizing coordinated reset stimulation causes a long-lasting desynchronization between hippocampal neuronal populations together with a widespread decrease in the amplitude of the epileptiform activity. In contrast, periodic stimulation induces a long-lasting increase in both synchronization and amplitude

Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study.

The discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinson's disease (PD) has prompted the development of novel neuromodulation paradigms. Coordinated reset neuromodulation intends to specifically counteract excessive synchronization and to induce cumulative unlearning of pathological synaptic connectivity and neuronal synchrony.In this prospective case series, six PD patients were evaluated before and after coordinated reset neuromodulation according to a standardized protocol that included both electrophysiological recordings and clinical assessments.Coordinated reset neuromodulation of the subthalamic nucleus (STN) applied to six PD patients in an externalized setting during three stimulation days induced a significant and cumulative reduction of beta band activity that correlated with a significant improvement of motor function.These results highlight the potential effects of coordinated reset neuromodulation of the STN in PD patients and encourage further development of this approach as an alternative to conventional high-frequency deep brain stimulation in PD

The causal relationship between subcortical oscillations and parkinsonian resting tremor.

To study the dynamical mechanism which generates Parkinsonian resting tremor, we apply coupling directionality analysis to local field potentials (LFP) and accelerometer signals recorded in an ensemble of 48 tremor epochs in four Parkinsonian patients with depth electrodes implanted in the ventro-intermediate nucleus of the thalamus (VIM) or the subthalmic nucleus (STN). Apart from the traditional linear Granger causality method we use two nonlinear techniques: phase dynamics modelling and nonlinear Granger causality. We detect a bidirectional coupling between the subcortical (VIM or STN) oscillation and the tremor, in the theta range (around 5 Hz) as well as broadband (>2 Hz). In particular, we show that the theta band LFP oscillations definitely play an efferent role in tremor generation, while beta band LFP oscillations might additionally contribute. The brain-->tremor driving is a complex, nonlinear mechanism, which is reliably detected with the two nonlinear techniques only. In contrast, the tremor-->brain driving is detected with any of the techniques including the linear one, though the latter is less sensitive. The phase dynamics modelling (applied to theta band oscillations) consistently reveals a long delay in the order of 1-2 mean tremor periods for the brain-->tremor driving and a small delay, compatible with the neural transmission time, for the proprioceptive feedback. Granger causality estimation (applied to broadband signals) does not provide reliable estimates of the delay times, but is even more sensitive to detect the brain-->tremor influence than the phase dynamics modelling

The generation of Parkinsonian tremor as revealed by directional coupling analysis

To reveal the dynamic mechanism underlying Parkinsonian resting tremor, we applied a phase dynamics modelling technique to local field potentials and accelerometer signals recorded in three Parkinsonian patients with implanted depth electrodes. We detect a bidirectional coupling between the subcortical oscillation and the tremor. The tremor $\rightarrow$ brain driving is a linear effect with a small delay corresponding to the neural transmission time. In contrast, the brain $\rightarrow$ tremor driving is a nonlinear effect with a long delay in the order of 1-2 mean tremor periods. Our results are well reproduced for an ensemble of 41 tremor epochs in three Parkinsonian patients and confirmed by surrogate data tests and model simulations. The uncovered mechanism of tremor generation suggests to specifically counteract tremor by desynchronizing the subcortical oscillatory neural activity