Extent of radiological response does not reflect survival in primary central nervous system lymphoma

Background In primary central nervous system lymphoma (PCNSL), small enhancing lesions can persist after treatment. It is unknown whether a difference in response category (complete response [CR], complete response unconfirmed [CRu], or partial response [PR]) reflects survival. We aimed to determine the value of a central radiology review on response assessment and whether the extent of response influenced progression-free and/or overall survival. Methods All patients in the HOVON 105/ALLG NHL 24 study with at least a baseline MRI and one MRI made for response evaluation available for central review were included. Tumor measurements were done by 2 independent central reviewers, disagreements were adjudicated by a third reviewer. Crude agreement and interobserver agreement (Cohen's kappa) were calculated. Differences in progression-free and overall survival between different categories of response at the end-of-protocol-treatment were assessed by the log-rank test in a landmark survival-analysis. Results Agreement between the central reviewers was 61.7% and between local and central response assessment was 63.0%. Cohen's kappa's, which corrects for expected agreement, were 0.44 and 0.46 (moderate), respectively. Progression agreement or not was 93.3% (kappa 0.87) between local and central response assessment. There were no significant differences in progression-free and overall survival between patients with CR, CRu, or PR at the end-of-protocol-treatment, according to both local and central response assessment. Conclusions Reliability of response assessment (CR/CRu/PR) is moderate even by central radiology review and these response categories do not reliably predict survival. Therefore, primary outcome in PCNSL studies should be survival rather than CR or CR/CRu-rate.

Defective Autophagy in Sf1 Neurons Perturbs the Metabolic Response to Fasting and Causes Mitochondrial Dysfunction

ObjectiveThe ventromedial nucleus of the hypothalamus (VMH) is a critical component of the forebrain pathways that regulate energy homeostasis. It also plays an important role in the metabolic response to fasting. However, the mechanisms contributing to these physiological processes remain elusive. Autophagy is an evolutionarily conserved mechanism that maintains cellular homeostasis by turning over cellular components and providing nutrients to the cells during starvation. Here we investigated the importance of the autophagy-related gene Atg7 in Sf1-expressing neurons of the VMH in control and fasted conditions.MethodsWe generated Sf1-Cre; Atg7loxP/loxP mice and examined their metabolic and cellular response to fasting.ResultsFasting induces autophagy in the VMH, and mice lacking Atg7 in Sf1-expressing neurons display altered regulation in glucose and leptin homeostasis and impaired energy expenditure regulation in response to fasting. Moreover, loss of Atg7 in Sf1 neurons causes alterations in the central response to fasting. Furthermore, alterations in mitochondria morphology and activity are observed in mutant mice.ConclusionTogether, these data show that autophagy is nutritionally regulated in VMH neurons and that VMH autophagy participates in the control of energy homeostasis during fasting.

Complexity and Modularity

Modularity is the single most important concept related to software and digitalization, and one that every manager and many experts should understand. This chapter elaborates modularity as a central response to complexity that relates to the design, production, and operation of technological systems. Digital technologies increase modularity by facilitating the creation of clear interfaces between sub-systems and processes. This, in turn, allows complex systems to be split into autonomous parts that can be developed and installed independently. Modularity allows companies to scale up their activities more quickly and cheaply, while also facilitating innovation both within modules, by eliminating interdependencies that hamper development efforts, and at the architectural level, through the creative recombination of pre-existing modules.

The peripheral and central expression of CGRP and IB4 in chronic pain from MIA-induced TMJOA rats

Background Chronic pain is the prevalent symptom that drives temporomandibular joint osteoarthritis (TMJOA) patients to ask for medical care, yet present alleviator remain less effective. This study aimed to investigate the actual TMJOA related chronic pain and the peripheral and central response in a TMJOA animal model. Methods This study firstly determined appropriate MIA dose based on pain behavior assessment with automated electronic von frey in rats. TMJOA pain correlated condylar structure alteration was evaluated by histological staining and Micro-CT. Then, the period of TMJOA chronic pain was further explored by assessing the alteration of glial fibrillary acidic protein (GFAP) positive astrocytes and ionized calcium binding adaptor molecule 1 (Iba1) positive microglia numbers in trigeminal spinal nucleus (TSN) and carrying out non-steroidal anti-inflammatory drugs (NSAIDS) pharmacological efficacy experiment. Finally, expression of neurofilament 200 (NF200), calcitonin gene-related peptide (CGRP), isolectin B4 (IB4) in trigeminal ganglion (TG) and TSN was detected by immunofluorescence. Results 1 mg/50 µl of MIA was considered as an appropriate dose. MIA induced gradual alteration of condylar structure correlated to TMJ mechanical allodynia. GFAP and IBA-1 positive cell numbers upregulated on 2, 3, 4 weeks after MIA injection. NSAIDS pharmacological efficacy disappeared on 10 days post MIA injection. Up-regulation of CGRP and IB4 was found in TG and TSN on 2 and 4 weeks, while expression of NF200 remained unchanged. Conclusion MIA induced TMJOA related chronic pain period emerges on 2 weeks after MIA injection. CGRP, IB4 positive afferent in both peripheral and central nervous system may involve in TMJOA related chronic pain in rats.