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Ischemic stroke (IS) accounts for most of the cases of stroke onset, and due to short therapeutic time window for thrombolysis and numerous limited treatment measures and contraindications, lots of patients cannot receive satisfying therapeutic effects resulting in high disability and mortality worldly. In recent years, extracellular vesicles (EVs), as nanosized membrane-structured vesicles secreted from almost all cells, especially from stem/progenitor cells, have been reported to exert significant beneficial effects on IS from multiple approaches and notably ameliorate neurological outcome. Moreover, based on nano-size and lipid bilayer structure, EVs can easily penetrate the blood-brain barrier and migrate into the brain. In this review, we mainly systematically summarize the therapeutic effects of EVs on IS and explore their potential applications. Simultaneously, we also discuss administration routines, dosages, experimental observation time, and some key issues of EV application during IS treatment. It contributes to a comprehensive understanding of the progress of EV treatment for IS and providing confident evidence for further EV clinical application widely.

Convenient transportation and the large flow of residents in the city give rise to the wide spread of COVID-19. Data collection plays a crucial role in determining the effectiveness of the control of the pandemic. The pandemic is not only a serious problem in large cities, but also hitting medium-sized cities. Macau is a typical medium-sized city where the pandemic has been under effective control with comprehensive data collection. This thesis will conduct in-depth research on the collection and application of the statistics about COVID-19 in Macau. Macau collects data through the border, incorporating NAT (nucleic acid testing) data and health codes into daily-used mobile applications, which features a network with real-time updates and sharing. This thesis will connect to the construction of smart cities to provide ideas for handling large-scale public health issues in medium-sized cities.

This report summarizes the outcome of a workshop, “Multimodal Synchrotron Approach—Research Needs and Scientific Vision,” held during the National Synchrotron Light Source–II (NSLS-II)/Center for F...

Traumatic osteonecrosis of femoral head (TONFH) is a common orthopedic disease caused by physical injury in hip. However, the unclear pathogenesis mechanism of TONFH and lacking of simple noninvasive early diagnosis method cause the necessity of hip replacement for most patients with TONFH. In this study, we aimed to identify circulating microRNAs (miRNAs) by integrated bioinformatics analyses as potential biomarker of TONFH. mRNA expression profiles were downloaded from the Gene Expression Omnibus database. Then we combined two miRNA screen methods: Weighted gene co-expression network analysis and fold change based differentially expressed miRNAs analysis. As a result, we identified 14 key miRNAs as potential biomarkers for TONFH. Besides, 302 target genes of these miRNAs were obtained and the miRNA-mRNA interaction network was constructed. Furthermore, the results of Kyoto Encyclopedia of Gene and Genome pathway analysis, Gene Ontology function analysis, protein-protein interaction (PPI) network analysis and PPI network module analysis showed close correlation between these 14 key miRNAs and TONFH. Then we established receiver operating characteristic curves and identified 6-miRNA signature with highly diagnosis value including miR-93-5p (area under the curve [AUC] = 0.93), miR-1324 (AUC = 0.92), miR-4666a-3p (AUC = 0.92), miR-5011-3p (AUC = 0.92), and miR-320a (AUC = 0.89), miR-185-5p (AUC = 0.89). Finally, the results of quantitative real-time polymerase chain reaction confirmed the significantly higher expression of miR-93-5p and miR-320a in the serum of patients with ONFH. These circulating miRNAs could serve as candidate early diagnosis markers and potential treatment targets of TONFH.

Rationale: Autophagy in Schwann cells (SCs) is crucial for myelin debris degradation and clearance following peripheral nerve injury (PNI). Nerve growth factor (NGF) plays an important role in reconstructing peripheral nerve fibers and promoting axonal regeneration. However, it remains unclear if NGF effect in enhancing nerve regeneration is mediated through autophagic clearance of myelin debris in SCs. Methods: In vivo, free NGF solution plus with/without pharmacological inhibitors were administered to a rat sciatic nerve crush injury model. In vitro, the primary Schwann cells (SCs) and its cell line were cultured in normal medium containing NGF, their capable of swallowing or clearing degenerated myelin was evaluated through supplement of homogenized myelin fractions. Results: Administration of exogenous NGF could activate autophagy in dedifferentiated SCs, accelerate myelin debris clearance and phagocytosis, as well as promote axon and myelin regeneration at early stage of PNI. These NGF effects were effectively blocked by autophagy inhibitors. In addition, inhibition of the p75 kD neurotrophin receptor (p75NTR) signal or inactivation of the AMP-activated protein kinase (AMPK) also inhibited the NGF effect as well. Conclusions: NGF effect on promoting early nerve regeneration is closely associated with its accelerating autophagic clearance of myelin debris in SCs, which probably regulated by the p75NTR/AMPK/mTOR axis. Our studies thus provide strong support that NGF may serve as a powerful pharmacological therapy for peripheral nerve injuries.

Background Qingwei San (QWS), one of classic Chinese Medicine prescripts, has been widely used to treat stomach heat syndrome which manifests oral ulcer (OU), periodontitis and upper gastrointestinal bleeding for seven hundred years. However, the therapeutic effects of QWS on diabetic OU subjected to stomach heat syndrome are still ambiguous. In the study, we investigated the pharmacological mechanisms. Methods The main components of QWS aqueous extract were analyzed by LC–MS, and potential pathways of QWS targeting OU were predicted by network pharmacology. The db/db mice were administered with the decoction of dried Zingiber officinale Rosc. rhizome combined with NaOH cauterization to establish the model of diabetic OU subjected to stomach heat syndrome. Subsequently, the model mice were treated with QWS, and OU wound healing status were recorded. The pathological changes of gastric tissue and oral mucosa were evaluated using hematoxylin–eosin staining, and the morphology of collagen fibers in oral mucosa was assessed by Masson staining. The levels of thromboxane B2 (TXB2), 6-Keto-prostaglandin F1α (6-keto-PGF1α), interleukin-1 β (IL-1β), IL-2, IL-6, tumor necrosis factor-α (TNF-α), β-endorphin (β-EP) and 5-Hydroxytryptamine (5-HT) were determined by ELISA assay. The protein expressions of Toll-like receptor 4 (TLR4), TNF receptor associated factor 6 (TRAF6), myeloid differentiation factor 88 (MyD88), inhibitor of NF-κB alpha (IκΒα), p-IκΒα and nuclear factor kappa-B (NF-κB) p65 were measured by Western Blotting. Results A total of 183 compounds in QWS were identified by LC–MS, and identified 79 bioactive compounds corresponded to 269 targets and 59 pathways. QWS high-dose treatment significantly reduced the level of TXB2 and the ratio of TXB2/6-keto-PGF1α. Meanwhile, it improved mucosal pathological morphology, and reduced the area of OU and local edema. Simultaneously, the levels of TNF-α, IL-1β, IL-6, IL-2 and 5-HT, and the expressions of TLR4, TRAF6, MyD88, p-IκΒα and NF-κB p65 were decreased. Conclusion QWS treatment facilitates the healing of OU, ameliorates pathological morphologies of gastric and oral mucosa and decreases the levels of pro-inflammatory cytokines in db/db mice subjected to stomach heat syndrome, whose mechanism may be associated with the inhibition of TLR4/MyD88/NF-κB signaling pathway to exert anti-inflammatory effects.

Tacrolimus (FK506) and rapamycin (RAPA) are widely used to maintain long‐term immunosuppression after organ transplantation. However, the impact of accumulative drug administration on the recipients’ immune systems remains unclear. We investigated the impact of 3‐year FK506 or RAPA treatment after renal transplantation on the human immune systems. A discovery cohort of 30 patients was first recruited, and we discovered two distinctive T lineage suppressive regulatory patterns induced by chronic treatment of FK506 and RAPA. The increased percentage of senescent CD8+CD57+ T lineages and less responsive T cell receptor (TCR) pathway in the FK506 group indicate better graft acceptance. Meanwhile, percentages of regulatory T cells (Tregs) and expression of CTLA‐4 were both up to two‐fold higher in the RAPA group, suggesting the inconsistent reactivation potential of the FK506 and RAPA groups when an anti‐tumour or anti‐infection immune response is concerned. Additionally, up‐regulation of phosphorylated signaling proteins in T lineages after in vitro CD3/CD28 stimulation suggested more sensitive TCR‐signaling pathways reserved in the RAPA group. An independent validation cohort of 100 renal transplantation patients was further investigated for the hypothesis that long‐term RAPA administration mitigates the development of tumours and infections during long‐term intake of immunosuppressants. Our results indicate that RAPA administration indeed results in less clinical oncogenesis and infection. The deep phenotyping of T‐cell lineages, as educated by the long‐term treatment of different immunosuppressants, provides new evidence for personalized precision medicine after renal transplantations., Graphical Highlights 1. Different impacts of FK506 and RAPA on immune systems of renal transplantation recipients lead to different cell subsets involved in immunosuppression. 2. The suppressive subsets in the FK506 group are mainly CD57+ senescent T cells, percentage of which was about half in the RAPA group, and TCR signaling pathway is less likely to be activated under CD3/CD28 stimulation. 3. Meanwhile, the percentage of regulatory T cells and the expression of CTLA‐4 were more abundant in the RAPA group.

Background Our objective was to obtain normal patellofemoral measurements to analyse sex and individual differences. In addition, the absolute values and indices of tibial tuberosity-trochlear groove (TT-TG) distances are still controversial in clinical application. A better method to enable precise prediction is still needed. Methods Seventy-eight knees of 78 participants without knee pathologies were included in this cross-sectional study. A CT scan was conducted for all participants and three-dimensional knee models were constructed using Mimics and SolidWorks software. We measured and analysed 19 parameters including the TT-TG distance and dimensions and shapes of the patella, femur, tibia, and trochlea. LASSO regression was used to predict the normal TT-TG distances. Results The dimensional parameters, TT-TG distance, and femoral aspect ratio of the men were significantly larger than those of women (all p values p values > 0.05). The Pearson correlation coefficients between the anterior femoral offset and other indexes were consistently below 0.3, indicating no relationship or a weak relationship. Similar results were observed for the sulcus angle and the Wiberg index. Using LASSO regression, we obtained four parameters to predict the TT-TG distance (R2 = 0.5612, p Conclusions Normative data of patellofemoral morphology were provided for the Chinese population. The anterior-posterior dimensions of the women were thicker than those of men for the same medial-lateral dimensions. More attention should be paid to not only sex differences but also individual differences, especially the anterior condyle and trochlea. In addition, this study provided a new method to predict TT-TG distances accurately.

Background The leakage of blood-brain barrier (BBB) is main pathophysiological change in acute stage of ischemic stroke, which not only deteriorates neurological function, but also increases the risk of hemorrhagic transformation after thrombolysis. Purpose/Study Design This article investigates the efficacy of Notoginsenoside R1, an active ingredient of Panax notoginseng, on BBB permeability and explores related mechanisms after acute ischemic stroke. Methods In vivo, male Sprague-Dawley rats (260–280 g) were selected and randomly divided into 6 groups: sham group, model group, low, middle and high doses of Notoginsenoside R1 groups and positive drug Dl-3-n-Butylphthalide group. Except for sham group, rats were performed with permanent middle cerebral artery occlusion model in each group. Twelve hours later, rats were evaluated for Bederson neurological function, and BBB integrity by Evans blue leak imaging; Triphenyltetrazolium chloride staining was used to detect the volume of cerebral infarction. Frozen sections of rats’ brain tissue were prepared for detection of MMPs activity in situ zymography. Peripheral tissue of cerebral infarction was collected and tested the expression of MMP2, 9 and tight junction proteins (zo1, claudin5, occludin) by western blot. In vitro, transwell endothelial barrier model was established by bEnd.3 cells. Oxygen glucose deprivation (OGD) was chosen to simulate the hypoxic environment. Suitable OGD stimulation time as well as Notoginsenoside R1 and Dl-3-n-Butylphthalide optimal dose concentrations were determined through transwell leakage and CCK8 assay. Furthermore, endothelial subcellular component proteins were extracted. The change of zo1, claudin5, occludin and caveolin1 was detected by western blot. Results Notoginsenoside R1 treatment significantly reduced BBB leakage and cerebral infarction volume, weakened neurological deficits in post-stroke rats. Moreover, it inhibited the activity of MMPs in infarcted cortex and striatum, down-regulated MMP2, 9 and up-regulated zo1 and claudin5 expressions in penumbra. In vitro, Notoginsenoside R1 treatment decreased OGD-induced endothelial barrier permeability, restored expressions of zo1, claudin5 on cellular membrane and cytoplasm, as well as mediated membrane redistribution of occludin and caveolin1 from actin cytoskeletal fraction. Conclusions Notoginsenoside R1 treatment attenuates BBB permeability, cerebral infarction volume and neurological impairments in rats with acute cerebral ischemia. The mechanisms might be related to intervening degradation and redistribution of zo1, caludin5 and occludin by caveolin1/ MMP2/9 pathway. More effects and mechanisms of Notoginsenoside R1 on rehabilitation of stroke are worthy to be explored in the future.

By differentiating into and the balance being regulated between M1 (pro-inflammatory) and M2 (anti-inflammatory) heterogeneous populations, macrophages play critical roles during the host immune response in various physiological contexts in both health and diseases. Besides regulating innate and adaptive immune capacity, macrophages are also decisively involved in tissue homeostasis. However, how resident macrophages are regulated after tissue damages is still far from elucidation. In the present study, we found that adipose-derived stem cells (ADSCs) apparently promote bone defect rehabilitation in vivo via skewing differentiation of bone marrow-derived macrophage (BMDMs) towards anti-inflammatory M2 macrophages. In vitro data demonstrated that although ADSCs have the potential to differentiate to osteoblasts and adipose cells by using standard tissue culture-differentiating conditions, these mesenchymal progenitors are mainly regulated to differentiate into osteoblasts with overexpressed runt-related transcription factor 2, osteoprotegerin, osterix, and downregulated receptor activator of nuclear factor κB ligand in the presence of BMDMs-conditioned medium. Whereas BMDMs are polarized toward M2 macrophages with higher levels of arginase 1 and mannose receptor, but lower levels of inducible nitric oxide synthase and tumor necrosis factor-α when cocultured with ADSCs. In short, all these findings collectively demonstrated that ADSCs and resident host cells can synergistically contribute to the bony repair through mutual regulation of their differentiation and cytokine secretion.

Seeking for effective drugs which are beneficial to facilitating axonal regrowth and elongation after peripheral nerve injury (PNI) has gained extensive attention. Fibroblast growth factor 21 (FGF21) is a metabolic factor that regulates blood glucose and lipid homeostasis. However, there is little concern for the potential protective effect of FGF21 on nerve regeneration after PNI and revealing related molecular mechanisms. Here, we firstly found that exogenous FGF21 administration remarkably promoted functional and morphologic recovery in a rat model of sciatic crush injury, manifesting as persistently improved motor and sensory function, enhanced axonal remyelination and regrowth and accelerated Schwann cells (SCs) proliferation. Furthermore, local FGF21 application attenuated the excessive activation of oxidative stress, which was accompanied with the activation of nuclear factor erythroid‐2‐related factor 2 (Nrf‐2) transcription and extracellular regulated protein kinases (ERK) phosphorylation. We detected FGF21 also suppressed autophagic cell death in SCs. Additionally, treatment with the ERK inhibitor U0126 or autophagy inhibitor 3‐MA partially abolishes anti‐oxidant effect and reduces SCs death. Taken together, these results indicated that the role of FGF21 in remyelination and nerve regeneration after PNI was probably related to inhibit the excessive activation of ERK/Nrf‐2 signalling‐regulated oxidative stress and autophagy‐induced cell death. Overall, our work suggests that FGF21 administration may provide a new therapy for PNI.

Diabetic nephropathy (DN) is one of general and common complication of diabetes, which severely affects the physical and mental health of diabetic patients. Fibroblast growth factor 1 (FGF1), an effective control agent of blood glucose, plays an effective treatment role on diabetes‐induced renal injury. But the specific molecule mechanism underlying it is still unclear. Since induction of cellular stress is the main and common mechanism of diabetes‐induced complication, we hypothesized that reduction of cellular stress is also the molecular mechanism of FGF1 treatment for DN. Here, we have further confirmed that FGF1 significantly ameliorated the diabetes‐induced renal interstitial fibrosis and glomerular damage. The expression levels of collagen and α‐smooth muscle actin (α‐SMA) also dramatically induced in kidney from db/db mice, but these effects were blocked by FGF1 administration. Our mechanistic investigation had further revealed that diabetes significantly induced oxidative stress, nitrosative stress, and endoplasmic reticulum (ER) stress with upregulation of malondialdehyde (MDA), nitrotyrosine level, ER stress makers and downregulation of antioxidant capacity (AOC). FGF1 treatment significantly attenuated the effect of diabetes on cellular stress. We conclude that FGF1‐associated glucose decreases and subsequent reduction of cellular stress is the another potential molecule mechanism underlying FGF1 treatment for DN.

Long non-coding RNA (lncRNA) TTN antisense RNA 1 (TTN-AS1) was reported to be crucial modulators in the tumorigenesis of several types of cancers. However, it is unclear whether TTN-AS1 can regulate the progression of ovarian cancer (OC). The present study aimed to explore functional roles and molecular mechanism of TTN-AS1 in OC. Quantitative reverse transcriptase-polymerase chain reaction assay (qRT-PCR) was used to detect the expression of TTN-AS1 in OC tissues and cell lines. The biological function of TTN-AS1 in OC was identified by a series of in vitro and in vivo assays. Bioinformatics analysis and mechanism experiments were used to analyze and identify the molecular mechanism of TTN-AS1 in OC progression. A high level of TTN-AS1 was found in OC tissues and cell lines. High TTN-AS1 was positively associated with advanced FIGO stage, lymph node metastasis, and poorer overall survival of OC patients. Functionally, knockdown of TTN-AS1 inhibited cell proliferation, colony formation, invasion and migration of OC cells in vitro, and suppressed tumor formation in vivo. Mechanistically, TTN-AS1 functioned as a competing endogenous RNA by sponging microRNA-139-5p (miR-139-5p) to elevate Rho-associated coiled-coil containing protein kinase 2 (ROCK2). Downregulation of miR-139-5p or upregulation of ROCK2 partially rescued the inhibitory impact of TTN-AS1 knockdown on OC cells. These results obtained in the present study suggested that TTN-AS1 promoted the progression of OC by regulating the miR-139-5p/ROCK2 axis.

Type-2 diabetes (T2D) is a common metabolic disorder, which causes several physiological and pathological complications. Spleen is regarded as an important organ, which regulates immune system and iron metabolism in the body. Precious few studies have been conducted to explore the pathological and deleterious roles of diabetes on spleen. In our current study, we have explored and confirmed the pathological effects of diabetes on spleen in db/db experimental mice model. In our current study, 0.5 mg/kg fibroblast growth factor 1 (FGF1) dose was intraperitoneally administrated to db/db mice. We found that diabetes evidently induced spleen enlargement and fibrosis progression in the db/db mice. Additionally, our studies demonstrate that iron has hugely deposited in the spleen in db/db mice. Several studies have documented that diabetes largely disrupts the inflammatory cells distribution, immune homeostasis, proliferation and oxidative stress with the down-regulation of anti-inflammatory cytokines and antioxidant activities. Moreover, we have observed that FGF1 administration significantly reversed the deleterious effect of diabetes on spleen enlargement and dysfunction. In summary, these substantial findings clearly demonstrate that diabetes plays deleterious roles in maintaining the spleen structure and functions. Therefore, our investigations suggest that FGF1 can effectively prevent diabetes-mediated splenomegaly progression.

Rationale: Dyke-Davidoff-Masson syndrome (DDMS) is a rare syndrome commonly occurring in children and characterized by cerebral hemiatrophy, hypertrophy of the skull, epilepsy, and mental retardation.[1,2] However, few have been reported in China, especially in teenagers. This case investigated its possible cause and explored a relative effective solution. Patient concerns: A 24-year-old female came to department having experienced recurrent seizures for 12 years. Diagnosis: DDMS was diagnosed from its manifestations, biochemistry indexes, and imaging (computed tomography angiography, magnetic resonance venography, and so on). Interventions: Several drugs are used to treat the disease, including valproate, carbamazepine, topiramate, and ginkgo biloba extract. Outcomes: Under the medicine treatment of magnesium valproate with carbamazepine, the patient experienced partial seizures approximately once per month that lasted 30 to 60 seconds each without any complications observed during a follow-up period of 24 months. Conclusion: The imaging and clinical features of DDMS in this teenager were similar to those in classic infantile-onset cases. A potential cause of the disease could be brain trauma, which impaired the middle cerebral artery and reduced cerebral blood supply, leading to epilepsy and hemiatrophy. Lessons: It was concluded early diagnosis and pharmacotherapy are the keys to preventing intellectual decline in DDMS patients. Moreover, the combination of magnesium valproate and carbamazepine could significantly reduce the frequency and duration of seizures, despite not eliminating them completely.

Mass cytometry, also called cytometry by time-of-flight (CyTOF), is an emerging powerful proteomic analysis technique that utilizes metal chelated polymer (MCP) as mass tags for interrogating high-dimensional biomarkers simultaneously on millions of individual cells. However, under the typical polymer-based mass tag system, the sensitivity and multiplexing detection ability has been highly restricted. Herein, a new structure mass tag based on a nanometal organic framework (NMOF) is reported for multiparameter and sensitive single-cell biomarker interrogating in CyTOF. A uniform-sized Zr-NMOF (33 nm) carrying 105 metal ions is synthesized under modulator/reaction time coregulation, which is monodispersed and colloidally stable in water for over one-year storage. On functionalization with an antibody, the Zr mass tag exhibits specific molecular recognition properties and minimal cross-reaction toward nontargeted cells. In addition, the Zr-mass tag is compatible with MCP mass tags in a multiparameter assay for mouse spleen cells staining, which exploits four additional channels, m/z = 90, 91, 92, 94, for single-cell immunoassays in CyTOF. Compared to the MCP mass tag, the Zr-mass tag provides an additional fivefold signal amplification. This work provides the fundamental technical capability for exploiting NMOF-based mass tags for CyTOF application, which opens up possibility of high-dimensional single-cell immune profiling, low abundant antigen detection, and development of new barcoding systems.

Diabetic peripheral neuropathy (DPN) is one of the most common and troublesome complications of diabetes mellitus. It has been demonstrated that nerve growth factor (NGF) exerts a pivotal role in the regulation of neuronal growth and the promotion of DPN recovery. However, the exact molecular mechanisms are not well understood. Recent studies have indicated that as a novel therapeutic target, endoplasmic reticulum (ER) stress participates in the onset and progression of DPN. In the present study, it has been demonstrated that NGF prevents the sciatic nerve from degeneration and demyelination in DPN rats. Thus, RSC 96 cells, which retain the characteristic features of Schwann cells (SCs), were cultured in medium containing 30 mM glucose (high glucose, HG) to mimic SCs in DPN mice. The 50-ng/ml dose of NGF was identified to be the optimal concentration for treating an excessive ER stress level under HG conditions for 24 h. We found that NGF treatment significantly inhibits HG-induced ER stress and subsequently suppresses ER-related apoptosis. Further, NGF administration also activates the upstream signaling pathway of ER stress, PI3K/Akt/GSK3β signaling and ERK1/2 signaling. Co-treatment with the PI3K inhibitor LY294002 or ERK1/2 inhibitor U0126 significantly reverses the protective role of NGF on HG-induced excessive ER stress and subsequent apoptosis. These observations suggest that the neuroprotective role of NGF in DPN is mediated by the inhibition of excessive ER stress via the activation of the PI3K/Akt/GSK3β and ERK1/2 signaling pathways.

Creating a microenvironment at the injury site that favors axonal regrowth and remyelinationis pivotal to the success of therapeutic reinnervation. The mature myelin sheath of the peripheral nervous system depends on active participation of Schwann cells to form new cytoskeletal components and tremendous amounts of relevant neurotrophic factors. In this study, we utilized a new biomaterial for growth factor delivery consisting of a biocompatible polycation, poly(ethylene argininylaspartatediglyceride) and heparin. It is capable of binding a variety of growth factors to deliver basic fibroblast growth factor (bFGF) through polyvalent ionic interactions for nerve repair. In vitro assays demonstrated that the bFGF loading efficiency reached 10 μg and this delivery vehicle could control the release of bFGF. In vivo, the coacervate enhanced bFGF bioavailability, which improved both motor and sensory function. It could also acceleratemyelinated fiber regeneration and remyelination and promote Schwann cells proliferation. Furthermore, the neuroprotective effect of bFGF-coacervate in sciatic nerve injury was associated with the alleviation of endoplasmic reticulum stress signal. This heparin-based delivery platform leads to increased bFGF loading efficiency and better controls its release, which will provide an effective strategy for peripheral nerve injury regeneration therapy.

Diabetes triggers abnormal ovarian follicular development and consequently leads to infertility. Here, we established a type 2 diabetes mouse model by feeding with high fat diet (HFD) for 15/20 weeks and assessed the effect of diabetes on follicular development and ovarian angiogenesis. After fed with HFD for 15 weeks, mice had the characteristics of type 2 diabetes, which was much more serious after 20 weeks on HFD. After 20 weeks on HFD, the mice had shown abnormal ovarian morphology with hyaline appearance, much less blood vessel, follicular development arrest and less of granulosa cells (GCs) in mature follicles, but not in ovaries from 15 weeks on HFD. Elevated makers of DNA damage, ER stress and apoptosis of GCs were observed in ovaries from HFD for 20 weeks. Additionally, diabetes significantly suppressed ovarian angiogenesis with the evidence of down-regulation of CD31 via inhibiting HIF1α-VEGF signaling pathway in time-dependent. We concluded that diabetes triggers abnormal ovarian function via inducing GCs apoptosis and suppressing ovarian angiogenesis.

Diabetic neuropathy is a kind of insidious complications that impairs neural and vascular function and ultimately leads to somatic and visceral denervation. Basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) are important neurotrophic factors for stimulating angiogenesis and improving peripheral nerve function. Administrating a single factor has good therapeutic effect on diabetic peripheral neuropathy (DPN). However, the short half-life and rapid diffusion of growth factors under physiological conditions limits its clinical applications. Here, we used a biodegradable coacervate, composed of heparin and polycation, to dominate the combined release of bFGF and NGF in a steady fashion. We found this combined growth factors (GFs) coacervate, administered as a single injection, improved motor and sensory functions, restored morphometric structure and decreased apoptosis of Schwann cells in a rat model of prolonged DPN. Similarly the GFs coacervate, as compared with free bFGF and NGF combination, markedly reduced the apoptosis level of a rat Schwann cell line, RSC 96 cells in vitro. We also demonstrated that neuroprotective effects of the GFs coacervate in both rat DPN model and hyperglycemia-induced RSC 96 cell model is likely due to suppression of endocytoplasmic reticulum stress (ERS).

Introduction: It remains controversial on high risks for early breast cancer patients with one to three axillary nodes after mastectomy who is predisposition to locoregional recurrence. The present study is to investigate the relationship between primary tumor site and loco-regional recurrence (LRR) and explore the predictive value of clinicopathological characteristics in LRR for early breast cancer patients with one to three positive axillary lymph nodes after mastectomy. Methods: We reviewed the clinical data of 656 consecutively diagnosed patients with pT1-2N1M0 breast cancer who were treated in Sun Yat-sen University Cancer Center with radical operation without postoperative radiotherapy between March 1998 and December 2010. The primary tumor sites included outer quadrant in 455 patients (69.36%), inner quadrant in 156 patients (23.78%)and central quadrant in 45 patients (6.86%). LRR and LRR-free survival (LRFS) in combination with clinical and pathological features were analyzed to screen out patients with higher risk of LRR. Results: The median follow-up time was 64.9 months. The 5-, 10-year LRR for the cohort was 8.6% and 12.9%, respectively; the 5-, 10-year LRFS was 86.2% and 76.4%, respectively. Multivariate analyses showed that age of ≤35 years, inner quadrant tumor and non-luminal subtype were independent risk factors for LRR and LRFS. Patients with primary tumor in inner quadrant showed higher LRR and poorer LRFS when risk factors are ≥2 than those with tumors in other sites. Conclusions: Inner quadrant tumor was an independent predictor for LRR and LRFS in patients with early breast cancer and one to three positive axillary lymph nodes, which would be more accurate in combination with other prognostic indexes including patients' age, pathological T stage, Ki67 status, molecular subtypes.

s Background: Type 2 diabetes (T2D) is a metabolic dysfunction disease that causes several complications. Liver injury is one of these that severely affects patients with diabetes. Fibroblast growth factor 1 (FGF1) has glucose-lowering activity and plays a role in modulation of several liver injuries. Nevertheless, the effects and potential mechanisms of FGF1 against diabetes-induced liver injury are unknown. Methods: To further investigate the effect of FGF1 on diabetic liver injury, we divided db/db mice into two groups and intraperitoneally (i.p.) injected either with FGF1 at 0.5 mg/kg body weight or saline every other day for 4 weeks. Then body weights were measured. Serum and liver tissues were collected for biochemical and molecular analyses. Results: FGF1 significantly reduced blood glucose and ameliorated diabetes-induced liver steatosis, fibrosis and apoptosis. FGF1 also restored defective hepatic autophagy in db/db mice. Mechanistic investigations showed that diabetes markedly induced oxidative stress and endoplasmic reticulum stress and that FGF1 treatment significantly attenuated these effects. Conclusions: FGF1-associated glucose level reduction and amelioration of cellular stress are potential protective effects of FGF1 against diabetes-induced liver injury. Key words: Fibroblast growth factor 1 (FGF1); Diabetes; Liver injury; Oxidative stress; Endoplasmic reticulum (ER) stress

Colon cancer (CC) is one of the leading causes of cancer related mortality. Research over past decades have profoundly enhanced our understanding of immunotherapy, a major clinical accomplishment, and its potential role toward treating CC. However, studies investigating the expression of these immune checkpoints, such as epithelial cell adhesion molecule (EpCAM), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1), by peripheral blood mononuclear cells (PBMCs) is lacking. Here, high-dimensional mass cytometry (CyTOF) is used to investigate immune alterations and promising immunotherapeutic targets expression by PBMCs of CC patients. Results reveal that expression of EpCAM and PD-L1 on CD4+ T cells significantly increased in patients with CC, compared with age- and sex- matching healthy controls and patients with colonic polyps. These differences are also validated in an independent patient cohort using flow cytometry. Further analysis revealed that EpCAM+ CD4+ T cells are PD-L1+ CCR5+ CCR6+. Immunofluorescence staining results demonstrate that the increase of EpCAM+ CD4+ T cells is also observed in tumor tissues, rather than para-cancerous tissues. To ascertain the functional disorders of the identified cell subset, phosphorylated signaling protein levels are assessed using imaging mass cytometry. Increases in pp38 MAPK and pMAPKAPK2 are observable, indicating abnormal activation of pp38 MAPK-pMAPKAPK2 signaling pathway. Results in this study indicate that EpCAM+ CD4+ T cells may play a role in CC development. Detailed knowledge on the functionality of EpCAM+ CD4+ T cells is of high translational relevance.

Mutations in the “guardian of the genome” TP53 predominate in solid tumors. In addition to loss of tumor suppressor activity, a specific subset of missense mutations confers additional oncogenic properties. These “gain-of-function” (GOF) mutations portend poor prognosis across cancer types regardless of treatment. Our objective in this study was to identify novel therapeutic opportunities to overcome the deleterious effects of GOF TP53 mutants. Using gynecologic cancer cell lines with known TP53 mutational status, we established that treatment with a proteasome inhibitor induced cell death in cells with two recurrent GOF TP53 mutations (R175H and R248Q), and addition of a histone deacetylase inhibitor (HDACi) enhanced this effect. By contrast, p53-null cancer cells were relatively resistant to the combination. Towards understanding the mechanism, we found that proteasome inhibition promotes apoptosis of cells with TP53 GOF mutations, potentially through induction of the unfolded protein response. In line with the reported hyperstabilization of GOF p53 protein, cells treated with HDACi exhibited reduced levels of p53 protein. Together, these data form the basis for future clinical studies examining therapeutic efficacy in a preselected patient population with GOF TP53 mutations.

Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p < 0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.

Mutations in the “guardian of the genome” TP53 predominate in solid tumors. In addition to loss of tumor suppressor activity, a specific subset of missense mutations confers additional oncogenic properties. These “gain-of-function” (GOF) mutations portend poor prognosis across cancer types regardless of treatment. Our objective in this study was to identify novel therapeutic opportunities to overcome the deleterious effects of GOF TP53 mutants. Using gynecologic cancer cell lines with known TP53 mutational status, we established that treatment with a proteasome inhibitor induced cell death in cells with two recurrent GOF TP53 mutations (R175H and R248Q), and addition of a histone deacetylase inhibitor (HDACi) enhanced this effect. By contrast, p53-null cancer cells were relatively resistant to the combination. Proteasome inhibition promoted apoptosis of cells with TP53 GOF mutations, potentially through induction of the unfolded protein response. In line with the reported hyperstabilization of GOF p53 protein, cells treated with HDACi exhibited reduced levels of p53 protein. Together, these data form the basis for future clinical studies examining therapeutic efficacy in a preselected patient population with GOF TP53 mutations.

Background: A moderate dose of radiation is the recommended treatment for solitary plasmacytoma (SP), but there is controversy over the role of surgery. Our study aimed at comparing different treatment modalities in the management of SP. Materials and Methods: Data from 38 consecutive patients with solitary plasmacytoma, including 16 with bone plasmacytoma and 22 with extramedullary plasmacytoma, were retrospectively reviewed. 15 patients received radiotherapy alone; 11 received surgery alone, and 12 received both. The median radiation dose was 50Gy. All operations were performed as radical resections. Local progression-free survival (LPFS), multiple myeloma-free survival (MMFS), progression-free survival (PFS) and overall survival (OS) were calculated and outcomes of different therapies were compared. Results: The median follow-up time was 55 months. 5-year LPFS, MMFS, PFS and OS were 87.0%, 80.9%, 69.8% and 87.4%, respectively. Univariate analysis revealed, compared with surgery alone, radiotherapy alone was associated with significantly higher 5-year LPFS (100% vs 69.3%, p=0.016), MMFS (100% vs 51.4%, p=0.006), PFS (100% vs 33.7%, p=0.0004) and OS (100% vs 70%, p=0.041). Conclusions: Radiotherapy alone can be considered as a more effective treatment for SP over surgery. Whether a combination of radiotherapy and surgery improves outcomes requires further study.

Background The study compares the effectiveness of bupivacaine and fentanyl (BUPI-FEN) and ropivacaine and fentanyl (ROPI-EFN) in epidural analgesia for labor pain through a meta-analysis of relevant randomized clinical trials. Material/Methods Multiple electronic databases were searched using appropriate MeSH terms and keywords for original English language research papers published between 1990 and March 2014. Meta-analyses results were based on the mean differences between the groups as well as odds ratios where appropriate. Statistical heterogeneity amongst the included studies was tested by I2 index. Results Nine studies that met the inclusion criteria were selected for analysis which consisted of 556 parturient patients. The duration of the second stage of labor was significantly shorter in the BUPI-FEN group by a mean of −6.87 (−10.98, −2.77; P

Heatstroke is a big threat to human health; however, the characteristic of pathological changes of neurons during heatstroke development remains unclear. Here, using an in vitro model of primary cultured neurons from newborn Wistar rats, we investigated the effects of the different combinations of high temperature (37, 39, 41, 43, 45, and 47°C) and exposure time (45 min and 1 h) on the neurons. We found that, under the treatment of 45 min-heat, the neurons could resist high temperature up to 45°C, and under the treatment of 1 h-heat, the mortality of neurons increased as the temperature rises. After heating for 1 h, only a small minority of the neurons died under 41 and 43°C, which primarily occurred in the form of apoptosis. Up to 45°C for 1 h, most neurons occurred to necrosis. Meaningfully, some necrotic neurons expressed specific fried egg-like morphology. Our findings suggest that different high temperatures and exposure times were two key factors influencing the death of neurons. Under the high temperature (below 43°C for 1 h) similar to heatstroke, it just led a small percentage of neurons to apoptosis, and anti-apoptosis controls for preventing and treating heatstroke are promising.

Background/Aims: Insulin-like growth factor-1 (IGF-1) has an important role in cells' proliferation, differentiation and apoptosis, and it may be involved in carcinogenesis. Several epidemiological studies assessed the association between circulating IGF-1 level and ovarian cancer risk, but there was still no conclusive finding. Methods: A meta-analysis of published studies was performed to assess the association between circulating IGF-1 level and ovarian cancer risk. The summary odds ratio (OR) with 95% confidence interval (95%CI) was calculated through meta-analysis to evaluate the strength of the association. Results: Five eligible studies were included into the meta-analysis, which involved a total of 2,028 cases of ovarian cancer and 4,625 controls. Meta-analysis of total 5 studies showed that high circulating IGF-1 level was correlated with decreased risk of ovarian cancer (OR = 0.84, 95%CI 0.74-0.97, P = 0.013). After adjusting for heterogeneity, high circulating IGF-1 level was still correlated with decreased risk of ovarian cancer (OR = 0.83, 95%CI 0.72-0.95, P = 0.007). Subgroup analysis by age showed that circulating IGF-1 level was not correlated with ovarian cancer risk in women both less than 55 years and more than 55 years. However, after adjusting for heterogeneity, high circulating IGF-1 level was correlated with decreased ovarian cancer risk in women less than 55 years (OR = 0.82, 95%CI 0.72-0.94, P = 0.004). Conclusion: Our meta-analysis suggests that high circulating IGF-1 level may be correlated with decreased ovarian cancer risk, especially in women less than 55 years. More studies are needed to further assess the association between circulating IGF-1 level and ovarian cancer risk in the future.

Because of scant availability of tissue samples, we did not perform elaborate examination of chromatin immunoprecipitation and specific binding of SET domain-containing proteins to the promoters of Rad51. These remain avenues for future investigations., In the present study, we aimed to examine whether SET domain-containing methyltransferases are up-regulated in different classes of renal cell carcinoma. We immunoblotted against SET domain and quantified the expression of these modular domains. Furthermore, we examined the expression of Rad51, the key protein that confers genomic stability. There was enhanced expression of SET domain-containing histone methyltransferases in whole lysates of all classes of renal carcinoma. In metastatic high grade clear cell carcinoma, this expression was more pronounced. Though we could not demonstrate direct correlation, we showed that epigenetic modification by methylation is associated with decreased genomic translation of Rad51.

Expression of progesterone receptor (PR) is a favorable prognostic marker for multiple solid tumors. However, PR expression is reduced or lost in malignant tumors which hinders response to progesterone therapy. Thus, monitoring and restoring functional PR expression is of utmost importance to sensitize progesterone therapy in endometrial cancer. We developed a stable cell line expressing the endogenous PR gene tagged a reporter gene (Hygromycin and mCherry) with CRISPR/Cas9-mediated genome editing. This allows efficient monitoring of PR expression in its native epigenetic landscape. The reporter gene expression faithfully reflects and amplifies PR expression following treatment with histone deacetylase inhibitor, romidepsin. This reporter gene transfected cells were successfully used to screen the FDA-approved 1018 library by high throughput screening in searching of potential novel drugs that increase PR expression. This strategy provides an efficient drug screening tool that can be used to screen novel PR inducers in multiple cancer cell lines. Citation Format: Yiyang Li, Xiangbing Meng, Kuo-kuang Wen, Meng Wu, Adam Dupuy, Kimberly Leslie, Shujie Yang. A novel tool for monitoring endogenous progesterone receptor expression by mCherry using CRISPR-Cas9 genome editing technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2494.

The homologous recombination repair (HRR) pathway is required for high-fidelity repair of double-strand DNA breaks. Cancer cells with HRR deficiency due to somatic BRCA1 or BRCA2 mutations are sensitive to platinum agents and targeted therapy with PARP inhibitors. Endometrial cancer is the most common cancer of the female reproductive system. DNA damage agents are commonly used in treatment but tumors often develop resistance. Metadherin (MTDH) has been shown to be amplified in a wide range of solid tumors as well as in leukemia and lymphoma. Overexpression of MTDH is correlated with angiogenesis, metastasis, and chemoresistance. Histone lysine N-methyl-transferase G9a catalyzes the demethylation of histone H3 at lysine residue 9 (H3K9) resulting in a repressive histone modification. The objective of this study is to validate the function of MTDH and G9a in HRR and test the potential to target MTDH or G9a to increase drug sensitivity. p21 expression was induced when G9a was depleted. DNA damage induced MTDH expression at 4 hours after 8Gy γ-irradiation in the well validated endometrial adenocarcinoma cell line Ishikawa H. However, induction of MTDH protein expression by the same radiation dosage was reduced when G9a was depleted. The G9a inhibitor UNC0642 itself can also induce the expression of MTDH after 24 hours treatment. Ishikawa parental cells and two Ishikawa sub-cell lines in which G9a was depleted by CRISPR were tested for the DNA damage biomarker γH2Ax and Rad51 foci formation at 4 hours following 8Gy irradiation. G9a depletion was shown to decrease Rad51 foci formation and to increase the formation of γH2Ax foci. Two natural products, Celastrol and Pristimerim were found to inhibit MTDH, FANCD2 and FANCI protein levels, which may be used to induce BRCA-ness in homologous recombination repair proficient cancer cells. G9a depletion results in the reduction of irradiation-induced Rad51 foci formation and an increase of irradiation-induced γH2Ax foci formation. We suggest that G9a depletion can increase cancer cell sensitivity to DNA damage agents. MTDH is induced by DNA damage and is a G9a inhibitor. MTDH depletion causes reduction of irradiation-induced Rad51 foci. This study is supported by the University of Iowa Department of Obstetrics and Gynecology Research Development Fund, NIH grant R01CA99908 and R01CA184101. Citation Format: Xiangbing Meng, Shujie Yang, Jianling Bi, Yiyang Li, Yuping Zhang, Sudartip Areecheewaku, Mary Li, Zihan Wang, Aliasger K. Salem, Kimberly K. Leslie. Induction of HRD by targeting G9a and MTDH in DNA repair proficient endometrial cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4852.

What is the central question of this study? What potential biochemical changes are associated with renal parenchyma 6-12 months after renal transplantation and delayed graft failure? What is the main finding and its importance? Tissue fibrosis, mediated by tissue ischaemia-induced induction of hypoxia-inducible factor-1α and fibronectin and consequent activation of lysyl oxidase, is a major underlying pathophysiological mechanism that contributes to delayed graft failure several months after renal transplantation. The present investigation was undertaken to evaluate the potential biochemical changes associated with renal parenchyma 6-12 months after renal transplantation and delayed graft failure. Serum concentrations of transforming growth factor-β in these subjects always remained elevated. In addition, examination of tissue from needle biopsies confirmed that there were consistent changes in the enzyme lysyl oxidase, which functions as an amine oxidase, modifies lysine residues on collagen and cross-links in a process of modulation of the extracellular matrix. Parenchymal levels of hypoxia-inducible factor-1α and fibronectin were elevated, as detected by Western blotting. These findings indicate an ongoing ischaemic insult, which might result from increased tissue fibrosis or, in some cases, might be additive with pre-existing pathophysiological factors that constrain proper renal haemodynamics. Thus, increased lysyl oxidase activity, which we assayed, is a potential unfavourable mechanism occurring in these kidneys that are undergoing failure and probably causes increased fibrosis within the organ and causes ischaemia, renovascular hypertension and a cascade leading to renal dysfunction and failure.

Background The metalloproteinase family of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) degrades extracellular matrix. However, the relevance of the ADAMTS family to cardiovascular diseases remains largely unknown. The study aimed to examine plasma ADAMTS-7 levels in patients with acute myocardial infarction (AMI) and the relationship between plasma ADAMTS-7 levels and heart function. Methods This was a prospective study performed in 84 patients with ST-elevation myocardial infarction (STEMI), 70 patients with non-STEMI (NSTEMI), and 38 controls. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma ADAMTS-7 levels. Cardiac structure and function were assessed using two-dimensional transthoracic echocardiography. Patients were stratified according to left ventricular ejection fraction (LVEF) ≤35% or >35%. Results Plasma ADAMTS-7 levels were higher in patients with LVEF ≤35% compared with those with LVEF >35% (6.73 ± 2.47 vs. 3.22 ± 2.05 ng/ml, P

Introduction: As a tumor suppressor in the endometrium, progesterone and its synthesized analogue progestin have a long history as a treatment for endometrial cancer. Loss of progesterone receptor (PR) in endometrial cancer leads to therapeutic failure, and our group has identified several mechanisms underlying PR loss, most notably epigenetic silencing of PR transcription. Recently, a Finnish group demonstrated that progestin therapy in premenopausal women is associated with a lower incidence of not only endometrial cancer, but also ovarian, pancreatic and lung cancers. This unexpected protective function of progestin in organs outside of the reproductive system led us to hypothesize that tumor progression effects in endometrial, ovarian, pancreatic and lung cancer is occurs due to the loss of progesterone’s protective effects. Methods and results: Supporting a potential protective role of progesterone, we discovered that PR is downregulated in multiple tumors, including breast, endometrial, ovarian, cervical, pancreatic and lung cancers, and loss of PR was consistently associated with a poor prognosis based on analysis of the Oncomine database. Similarly, PR expression was low in multiple ovarian, pancreatic and lung cancer cells. Mechanistic studies revealed that PR downregulation was mediated by the polycomb-repressor complex and DNA methylation, though the precise mechanism differed among cell lines and cancer types. Treatment with epigenetic modulators, which are FDA-approved for multiple myeloma, restored functional PR expression at both the mRNA and protein level and promoted marked cell death through induction of apoptosis. . Moreover, overexpression of PR or treatment with epigenetic modulators in combination with progesterone enhanced this effect, indicating a key protective role for progesterone signaling through PR. Conclusion: These data suggest loss of PR may be a general theme for tumorigenesis or disease progression in multiple tumor types beyond the classically studied endometrial cancer. In addition, the epigenetic mechanisms contributing to PR downregulation in endometrial tumors were recapitulated in other tumor types, including ovarian, pancreatic and lung tumors. These studies collectively set the stage for use of progestin therapy in combination with epigenetic modulators, a concept we term “molecularly enhanced progestin therapy,” as a novel therapeutic approach for many cancers. This combinatorial strategy has the power to revitalize the use of epigenetic modulators, which have proved disappointing in solid tumors, as an approach to resensitize cancer cells to a tumor suppressor. Citation Format: Yiyang Li, Tamar Kavlashvili, Cheng Huang, Yuping Zhang, Xiangbing Meng, Kristina Thiel, Kimberly Leslie, Shujie Yang. Loss of progesterone receptor through epigenetic regulation is associated with poor prognosis in multiple solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2556. doi:10.1158/1538-7445.AM2017-2556

Background Nasal-type extranodal natural killer/T-cell lymphoma (ENKTCL) originates primarily in the nasal cavity or extra-nasal sites within the upper aerodigestive tract. However, it is unclear whether the primary site can serve as an independent prognostic factor or whether the varying clinical outcomes observed with different primary sites can be attributed merely to their propensities of regional lymph node involvement. The aim of this study was to investigate the prognostic implications of the primary site and regional lymph node involvement in patients with early-stage nasal-type ENKTCL. Methods To develop a nomogram, we reviewed the clinical data of 215 consecutively diagnosed patients with early-stage nasal-type ENKTCL who were treated in Sun Yat-sen University Cancer Center with chemotherapy and radiotherapy between 2000 and 2011. The predictive accuracy and discriminative ability of the nomogram were determined using a concordance index (C-index) and calibration curve. Results The 5-year overall survival (OS) and progression-free survival (PFS) rates of patients with nasal ENKTCL were higher than those of patients with extra-nasal ENKTCL (OS: 68.2% vs. 46.0%, P = 0.030; PFS: 53.4% vs. 26.6%, P = 0.010). The 5-year OS and PFS rates of patients with Ann Arbor stage IE ENKTCL were higher than those of patients with Ann Arbor stage IIE ENKTCL (OS: 66.3% vs. 59.2%, P = 0.003; PFS: 51.4% vs. 40.3%, P = 0.009). Multivariate analysis showed that age >60 years, ECOG performance status score ≥2, elevated lactate dehydrogenase (LDH) level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year OS rate; age >60 years, elevated LDH level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year PFS rate. The nomogram included the primary site and regional lymph node involvement based on multivariate analysis. The calibration curve showed good agreement between the predicted and actual 5-year OS and PFS rates, and the C-indexes of the nomogram for the OS and PFS rates were 0.697 and 0.634, respectively. Conclusions The primary site and regional lymph node involvement are independent prognostic factors for early-stage ENKTCL treated with chemotherapy followed by definitive radiotherapy.