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Introduction Intervertebral disc (IVD) degeneration is often associated with low back pain and radiating leg pain. The purpose of this study is to develop a reproducible and standardized preclinical model of painful lumbar IVD degeneration by evaluation of structural and behavioral changes in response to IVD injury with increasing needle sizes. This model can be used to develop new therapies for IVD degeneration. Methods Forty‐five female Sprague Dawley rats underwent anterior lumbar disc needle puncture at levels L4‐5 and L5‐6 under fluoroscopic guidance. Animals were randomly assigned to four different experimental groups: needle sizes of 18 Gauge (G), 21G, 23G, and sham control. To monitor the progression of IVD degeneration and pain, the following methods were employed: μMRI, qRT‐PCR, histology, and biobehavioral analysis. Results T1‐ and T2‐weighted μMRI analysis showed a correlation between the degree of IVD degeneration and needle diameter, with the most severe degeneration in the 18G group. mRNA expression of markers for IVD degeneration markers were dysregulated in the 18G and 21G groups, while pro‐nociceptive markers were increased in the 18G group only. Hematoxylin and Eosin (H&E) and Alcian Blue/Picrosirius Red staining confirmed the most pronounced IVD degeneration in the 18G group. Randall‐Selitto and von Frey tests showed increased hindpaw sensitivity in the 18G group. Conclusion Our findings demonstrate that anterior disc injury with an 18G needle creates severe IVD degeneration and mechanical hypersensitivity, while the 21G needle results in moderate degeneration with no increased pain sensitivity. Therefore, needle sizes should be selected depending on the desired phenotype for the pre‐clinical model. Study Design Overview This study establishes and validates a rat model for lumbar IVD degeneration that is reflected in painful behavior. Based on our findings we conclude that annular disc injury with a 18G needle creates severe, painful IVD degeneration, while 21G needle injury results in moderate degeneration.

Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM.

D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II–IIIB gastric cancer. The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II–IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4–41·7) in the chemotherapy and surgery group and 34·3 months (25·6–41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy and surgery group and 59% (53–64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44–0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. F Hoffmann-La Roche and Sanofi-Aventis.

Bone consists of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of cells owing to physical separation by the bone cortex. The skeletal stem cell that gives rise to endosteal osteoblasts has been extensively studied; however, the identity of periosteal stem cells remains unclear 1 – 5 . Here we identify a periosteal stem cell (PSC) that is present in the long bones and calvarium of mice, displays clonal multipotency and self-renewal, and sits at the apex of a differentiation hierarchy. Single-cell and bulk transcriptional profiling show that PSCs display transcriptional signatures that are distinct from those of other skeletal stem cells and mature mesenchymal cells. Whereas other skeletal stem cells form bone via an initial cartilage template using the endochondral pathway 4 , PSCs form bone via a direct intramembranous route, providing a cellular basis for the divergence between intramembranous versus endochondral developmental pathways. However, there is plasticity in this division, as PSCs acquire endochondral bone formation capacity in response to injury. Genetic blockade of the ability of PSCs to give rise to bone-forming osteoblasts results in selective impairments in cortical bone architecture and defects in fracture healing. A cell analogous to mouse PSCs is present in the human periosteum, raising the possibility that PSCs are attractive targets for drug and cellular therapy for skeletal disorders. The identification of PSCs provides evidence that bone contains multiple pools of stem cells, each with distinct physiologic functions. A periosteal stem cell specialized in intramembranous bone formation has been identified and was found to be essential for normal bone development and fracture healing.

PDZ domain‐containing proteins (PDZ proteins) act as scaffolds for protein–protein interactions and are crucial for a variety of signal transduction processes. However, the role of PDZ proteins in organismal lifespan and aging remains poorly understood. Here, we demonstrate that KIN‐4, a PDZ domain‐containing microtubule‐associated serine‐threonine (MAST) protein kinase, is a key longevity factor acting through binding PTEN phosphatase in Caenorhabditis elegans. Through a targeted genetic screen for PDZ proteins, we find that kin‐4 is required for the long lifespan of daf‐2/insulin/IGF‐1 receptor mutants. We then show that neurons are crucial tissues for the longevity‐promoting role of kin‐4. We find that the PDZ domain of KIN‐4 binds PTEN, a key factor for the longevity of daf‐2 mutants. Moreover, the interaction between KIN‐4 and PTEN is essential for the extended lifespan of daf‐2 mutants. As many aspects of lifespan regulation in C. elegans are evolutionarily conserved, MAST family kinases may regulate aging and/or age‐related diseases in mammals through their interaction with PTEN.

Most data on the clinical epidemiology of atrial fibrillation (AF) are reported from Western populations, and data for Asians are limited. We aimed to investigate the 10-year trends of the prevalence and incidence of non-valvular AF and provide prevalence projections till 2060 in Korea. We also investigated the annual risks of adverse outcomes among patients with AF. Using the Korean National Health Insurance Service database involving the entire Korean population, a total of 679,416 adults with newly diagnosed AF were identified from 2006 to 2015. The incidence and prevalence of AF and risk of adverse outcomes following AF onset were assessed. The prevalence of AF progressively increased by 2.10-fold from 0.73% in 2006 to 1.53% in 2015. The trend of its incidence was flat with a 10-year overall incidence of 1.77 per 1,000 person-years. The prevalence of AF is expected to reach 5.81% (2,290,591 patients with AF) in 2060. For a decade, the risk of all-cause mortality following AF declined by 30% (adjusted hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.68–0.72), heart failure by 52% (adjusted HR: 0.48, 95% CI: 0.44–0.51), and ischemic stroke by 9% (adjusted HR: 0.91, 95% CI: 0.88–0.93). The burden of AF among Asian patients is increasing. Although the overall risks of cardiovascular events and death following AF onset have decreased over a decade, the event rates are still high. Optimized management of any associated comorbidities should be part of the holistic management approach for patients with AF.

ObjectiveTemporal changes in the healthcare burden of atrial fibrillation (AF) are less well known in rapidly ageing Asian countries. We examined trends in hospitalisations, costs, treatment patterns and outcomes related to AF in Korea.MethodsUsing the National Health Insurance Service (NHIS) database involving the entire adult Korean population (n=41 701 269 in 2015), we analysed a nationwide AF cohort representing 931 138 patients with AF. We studied all hospitalisations due to AF from 2006 to 2015.ResultsOverall, hospitalisations for AF increased by 420% from 767 to 3986 per 1 million Korean population from 2006 to 2015. Most admissions occurred in patients aged ≥70 years, and the most frequent coexisting conditions were hypertension, heart failure and chronic obstructive pulmonary disease. Hospitalisations mainly due to major bleeding and AF control increased, whereas hospitalisations mainly due to ischaemic stroke and myocardial infarction decreased. The total cost of care increased even after adjustment for inflation from €68.4 million in 2006 to €388.4 million in 2015, equivalent to 0.78% of the Korean NHIS total expenditure. Overall in-hospital mortality decreased from 7.5% in 2006 to 4.3% in 2015. The in-hospital mortality was highest in patients ≥80 years of age (7.7%) and in patients with chronic kidney disease (7.4%).ConclusionsAF hospitalisations have increased exponentially over the past 10 years in Korea, in association with an increase in comorbid chronic diseases. Mortality associated with AF hospitalisations decreased during the last decade, but hospitalisation costs have markedly increased.

RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3–27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.

Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms. The current work reports the structure of the human organic cation transporter 3 (OCT3 / SLC22A3) and provides the structural basis of its inhibition by two specific inhibitors, decynium-22 and corticosterone.

NRC publication: Yes