HDAC6 Inhibition Alleviates Anesthesia and Surgery-Induced Less Medial Prefrontal-Dorsal Hippocampus Connectivity and Cognitive Impairment in Aged Rats.

To investigate the underlying mechanisms of postoperative cognitive dysfunction and the impairment of medial prefrontal cortex-hippocampus connectivity. Postoperative cognitive dysfunction frequently affects elderly following surgery. The role of inter-brain-region connectivity abnormality after anesthesia and surgery on postoperative cognitive dysfunction development remains unclear. Medial prefrontal cortex-hippocampus connectivity of aged and adult rats was evaluated by injecting neurotracer biotinylated dextranamine (BDA) into bilateral hippocampus 3 days before partial hepatectomy, and biotinylated dextranamine positive cells of medial prefrontal cortex 2 days after hepatectomy were counted. HDAC6 shRNA was injected into medial prefrontal cortex and hippocampus bilaterally before hepatectomy or an HDAC6 activity inhibitor Tubastatin A was administered systemically after hepatectomy. Neuroinflammation and HDAC6 down-target ac-tubulin in medial prefrontal cortex and hippocampus were detected. Learning and memory of rats were evaluated by Barnes Maze task during 2-5 days after surgery and delayed matching-to-place water maze task during 10-23 days after surgery. Compared to the age-matched normal controls, anesthesia and surgery significantly decreased BDA-positive neurons in medial prefrontal cortex of aged rats, but not young adult rats. Local HDAC6 knockdown and systemic HDAC6 inhibition both increased BDA-positive neurons number of medial prefrontal cortex, alleviated learning and memory impairment in the Barnes Maze task and water maze task, decreased HDAC6 expression, inflammatory cytokines, astrocyte and microglial activation, and increased ac-tubulin expression in aged rats which received surgery. Our data indicated that anesthesia and surgery impaired medial prefrontal cortex-hippocampus connectivity and cognition which was associated with HDAC6 overexpression.

Technology-enhanced AcceleRation of Germline Evaluation for Therapy (TARGET): A randomized controlled trial of a pretest patient-driven webtool vs. genetic counseling for prostate cancer germline testing.

BACKGROUND: Germline testing has an increasingly important role in prostate cancer care. However, a relative shortage of genetic counselors necessitates alternate strategies for delivery of pre-test education for germline testing. This study, funded by the Prostate Cancer Foundation, seeks to address the need for novel methods of delivery of pre-test germline education beyond traditional germline counseling to facilitate informed patient decision-making for germline testing. METHODS: This is a two-armed randomized controlled trial (RCT) with a target enrollment of 173 participants with prostate cancer per study arm (total anticipated n = 346). Patients who meet criteria for germline testing based on tumor features, family history or Ashkenazi Jewish ancestry are being recruited from 5 US sites including academic, private practice and Veterans healthcare settings. Consenting participants are randomized to the interactive pretest webtool or germline counseling with assessment of key patient-reported outcomes involved in informed decision-making for germline testing. RESULTS: Participants complete surveys at baseline, after pretest education/counseling, and following disclosure of germline results. The primary outcome of the study is decisional conflict for germline testing. Secondary outcomes include genetic knowledge, satisfaction, uptake of germline testing, and understanding of results. CONCLUSION: Our hypothesis is that the web-based genetic education tool is non-inferior to traditional genetic counseling regarding key patient-reported outcomes involved in informed decision-making for germline testing. If proven, the results would support deploying the webtool across various practice settings to facilitate pre-test genetic education for individuals with prostate cancer and developing collaborative care strategies with genetic counseling. CLINICALTRIALS: gov Identifier: NCT04447703.

Clinical Potential of Nerve Input to Tumors: A Bioelectricity Perspective.

We support the notion that the neural connections of the tumor microenvironment (TME) and the associated 'bioelectricity' play significant role in the pathophysiology of cancer. In several cancers, the nerve input promotes the cancer process. While straightforward surgical denervation of tumors, therefore, could improve prognosis, resulting side effects of such a procedure would be unpredictable and irreversible. On the other hand, tumor innervation can be manipulated effectively for therapeutic purposes by alternative novel approaches broadly termed "electroceuticals." In this perspective, we evaluate the clinical potential of targeting the TME first through manipulation of the nerve input itself and second by application of electric fields directly to the tumor. The former encompasses several different biophysical and biochemical approaches. These include implantable devices, nanoparticles, and electroactive polymers, as well as optogenetics and chemogenetics. As regard bioelectrical manipulation of the tumor itself, the "tumor-treating field" technique, applied to gliomas commonly in combination with chemotherapy, is evaluated. Also, as electroceuticals, drugs acting on ion channels and neurotransmitter receptors are highlighted for completeness. It is concluded, first, that electroceuticals comprise a broad range of biomedical tools. Second, such electroceuticals present significant clinical potential for exploiting the neural component of the TME as a strategy against cancer. Finally, the inherent bioelectric characteristics of tumors themselves are also amenable to complementary approaches. Collectively, these represent an evolving, dynamic field and further progress and applications can be expected to follow both conceptually and technically.

Nerve input to tumours: Pathophysiological consequences of a dynamic relationship.

It is well known that tumours arising in different organs are innervated and that 'perineural invasion' (cancer cells escaping from the tumour by following the nerve trunk) is a negative prognostic factor. More surprisingly, increasing evidence suggests that the nerves can provide active inputs to tumours and there is two-way communication between nerves and cancer cells within the tumour microenvironment. Cells of the immune system also interact with the nerves and cancer cells. Thus, the nerve connections can exert significant control over cancer progression and modulating these (physically or chemically) can affect significantly the cancer process. Nerve inputs to tumours are derived mainly from the sympathetic (adrenergic) and the parasympathetic (cholinergic) systems, which are interactive. An important component of the latter is the vagus nerve, the largest of the cranial nerves. Here, we present a two-part review of the nerve inputs to tumours and their effects on tumorigenesis. First, we review briefly some relevant general issues including ultrastructural aspects, stemness, interactions between neurones and primary tumours, and communication between neurones and metastasizing tumour cells. Ultrastructural characteristics include synaptic vesicles, tumour microtubes and gap junctions enabling formation of cellular networks. Second, we evaluate the pathophysiology of the nerve input to five major carcinomas: cancers of prostate, stomach, colon, lung and pancreas. For each cancer, we present (i) the nerve inputs normally present in the cancer organ and (ii) how these interact and influence the cancer process. The best clinical evidence for the role of nerves in promoting tumorigenesis comes from prostate cancer patients where metastatic progression has been shown to be suppressed significantly in cases of spinal cord injury. The balance of the sympathetic and parasympathetic contributions to early versus late tumorigenesis varies amongst the different cancers. Different branches of the vagus provide functional inputs to several of the carcinomas and, in two-way interaction with the sympathetic nervous system, affect different stages of the cancer process. Overall, the impact of the vagus nerve can be 'direct' or 'indirect'. Directly, the effect of the vagus is primarily to promote tumorigenesis and this is mediated through cholinergic receptor mechanisms. Indirectly, pro- and anti-tumour effects can occur by stimulation or inhibition of the sympathetic nervous system, respectively. Less well understood are the 'indirect' anti-tumour effect of the vagus nerve via immunomodulation/inflammation, and the role of sensory innervation. A frequent occurrence in the nerve-tumour interactions is the presence of positive feedback driven by agents like nerve growth factor. We conclude that the nerve inputs to tumours can actively and dynamically impact upon cancer progression and are open to clinical exploitation.

POLG mutations presenting as Charcot-Marie-Tooth disease.

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot-Marie-Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.

Genetic differentiation of Rubus chamaemorus populations in the Czech Republic and Norway after the last glacial period.

The population structure of cloudberry (Rubus chamaemorus L.), collected from Krkonose Mountains (the Czech Republic), continental Norway and Spitsbergen, was examined using microsatellite analyses (SSR). Among 184 individuals, 162 different genotypes were identified. The overall unbiased gene diversity was high ( h^=0.463 ). A high level of genetic differentiation among populations (FST = 0.45; p < .01) indicated restricted gene flow between populations. Using a Bayesian approach, six clusters were found which represented the genetic structure of the studied cloudberry populations. The value of correlation index between genetic and geographical distances (r = .44) indicates that gene flow, even over a long distance, could exist. An exact test of population differentiation showed that Rubus chamaemorus populations from regions (Krkonose Mountains, continental Norway and Spitsbergen) are differentiated although some individuals within populations share common alleles even among regions. These results were confirmed by AMOVA, where the highest level of diversity was found within populations (70.8%). There was no difference between 87 pairs of populations (18.7%) mostly within cloudberry populations from continental Norway and from Spitsbergen. Based on obtained results, it is possible to conclude that Czech and Norwegian cloudberry populations are undergoing differentiation, which preserves unique allele compositions most likely from original populations during the last glaciation period. This knowledge will be important for the creation and continuation of in situ and ex situ conservation of cloudberry populations within these areas.

Climate change and national crop wild relative conservation planning.

Climate change is likely to be one of the most important factors affecting our future food security. To mitigate negative impacts, we will require our crops to be more genetically diverse. Such diversity is available in crop wild relatives (CWRs), the wild taxa relatively closely related to crops and from which diverse traits can be transferred to the crop. Conservation of such genetic resources resides within the nation where they are found; therefore, national-level conservation recommendations are fundamental to global food security. We investigate the potential impact of climate change on CWR richness in Norway. The consequences of a 1.5 and 3.0 °C temperature rise were studied for the years 2030, 2050, 2070, 2080 and then compared to the present climate. The results indicate a pattern of shifting CWR richness from the south to the north, with increases in taxa turnover and in the numbers of threatened taxa. Recommendations for in situ and ex situ conservation actions over the short and long term for the priority CWRs in Norway are presented. The methods and recommendations developed here can be applied within other nations and at regional and global levels to improve the effectiveness of conservation actions and help ensure global food security.