The Effect of Rho Kinase Inhibitors on In Vitro Human Orbital Preadipocytes.

PURPOSE: To identify the effects of Rho Kinase (ROCK) inhibitor medications on human orbital adipogenesis, fibroblast proliferation, and fibrosis. METHODS: Orbital adipose tissue was obtained from patients with Graves' ophthalmopathy (GO) as well as controls (non-GO or normal) after informed consent was done. These tissue samples were cultured and adipogenesis was initiated. Levels of Rho Kinase as well as cellular mediators of orbital inflammation and fibrosis. The same cultures and measurements were then repeated with the use of a ROCK inhibitor (KD025-ROCK2) to assess for changes in adipogenesis as well as markers associated with inflammation and fibrosis. RESULTS: Rho Kinase levels in GO tissue were more highly expressed than in controls. These levels were suppressed with the use of the ROCK inhibitor KD025. There was a dose-dependent reduction in differentiation of orbital adipocytes with the use of KD025. KD025 reduced the levels of fibrosis-related gene expression. Finally, there was a significant reduction of transforming growth factor beta mediated phosphorylation signaling pathways in the KD025-treated GO tissue. CONCLUSION: This study shows that the ROCK inhibitor, KD025, helps to reduce the expression of ROCK in GO tissue along with reducing orbital adipocyte differentiation as well as cell mediators involved in fibrosis that occurs in GO.

Quantification of collagen content and stromal cellularity within reactive stroma is predictive of prostate cancer biochemical recurrence and specific death.

Semiquantitative reactive stromal grading has been shown to be a predictor of biochemical recurrence and prostate cancer (PCa) specific death. It has been extensively validated. In this study we tested novel technologies to introduce quantitative measures of host response, in particular collagen content and stromal cellularity. We use 3 large retrospective cohorts, the Baylor College of Medicine cohort, the Brady cohort and the Pound cohort. Slides were stained and digitized using image deconvolution and analyzed using image segmentation and image analyses. PicroSirius red stain histochemical stains were used for collagen quantification. Area of cancer and stroma were measured independently, without regard to quality of stroma. Cellularity, in each compartment, was measured using image deconvolution, image segmentation and image analysis. Two biomarkers were tested in 3 independent cohorts with two endpoints, biochemical recurrence and prostate cancer specific death. Stromal cellularity (qCollCell) and stromal collagen area (qCollArea) are independently predictive biochemical recurrence in the Hopkins Brady cohort, particularly in Gleason 6-7 patients. Multivariate analysis demonstrated that increased stroma cellularity (qCollCell) was a significant predictor of PCa specific death, when compared to an established model of PCa, in the Baylor cohort. Stromal collagen (qCollArea) independently predicts PCa-specific death in the Hopkins Pound cohort. The introduction of a computerized quantitative test of the host response increases the probability that this test will be reproducible in other cohorts. The ability to improve prediction of prostate cancer specific death might lie in the study of the host and its response.

Kaempferol Protects Against Retinal Photoreceptor Degeneration in a Mouse Model of Light-Induced Retinal Injury.

Purpose: Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries with little in the way of treatment that prevents progression to end-stage disease. Kaempferol (KF) is a plant-derived dietary flavonoid that has demonstrated as a strong antioxidant showing neuroprotection in stroke models. We hypothesize that KF has protective effects against retinal degeneration and may serve as a therapeutic agent against AMD. Methods: BALB/c albino mice were assigned to 1 of 2 groups: control-treated or KF-treated retinal light injury mice. Mice were exposed to 8,000 lux cool white fluorescent light for 2 h to induce light injury. Control or KF was injected intraperitoneally after light injury for 5 days. Scotopic electroretinography (ERG) was recorded before light injury and 7 days after light injury. The retinal morphology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed after light injury. Results: ERG a- and b-wave amplitudes were significantly reduced in the retinal light injury group compared with the nonretinal light injury group. Retinal light injury produced markedly thinning of the outer nuclear layer along with significant TUNEL-positive signals. In contrast KF treatments significantly attenuated reduction of ERG a- and b- wave amplitudes and the loss of the outer nuclear layer. Conclusions: KF protects retinal photoreceptors and preserves retinal function against retinal degeneration caused by light injury. These initial findings suggest that KF may represent a novel therapy for retinal degenerative conditions such as AMD.

Comprehensive Analysis of Ferroptosis- and Immune-Related Signatures to Improve the Prognosis and Diagnosis of Kidney Renal Clear Cell Carcinoma.

Background: Almost 40% of patients with kidney renal clear cell carcinoma (KIRC) with advanced cancers eventually develop to metastases, and their 5-year survival rates are approximately 10%. Aberrant DNA methylations are significantly associated with the development of KIRC. The aim of our present study was to identify suitable ferroptosis- and immune-related (FI) biomarkers correlated with aberrant methylations to improve the prognosis and diagnosis of KIRC. Methods: ChAMP and DESeq2 in R (3.6.2) were used to screen the differentially expressed methylation probes and differentially expressed genes, respectively. Univariate and multivariate Cox regression were used to identify the overall survival (OS)-related biomarkers. Results: We finally identified five FI biomarkers (CCR4, CMTM3, IFITM1, MX2, and NR3C2) that were independently correlated with the OS of KIRC. The area under the curve value of the receiver operating characteristic value of prognosis model was 0.74, 0.68, and 0.72 in the training, validation, and entire cohorts, respectively. The sensitivity and specificity of the diagnosis model were 0.8698 and 0.9722, respectively. In addition, the prognosis model was also significantly correlated with several immune cells and factors. Conclusion: Our present study suggested that these five FI-DEGs (CCR4, CMTM3, IFITM1, MX2, and NR3C2) could be used as prognosis and diagnosis biomarkers for patients with KIRC, but further cross-validation clinical studies are still needed to confirm them.

Development and validation of a quantitative reactive stroma biomarker (qRS) for prostate cancer prognosis.

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

[Prostatitis studies in China from 2000 to 2020: A Knowledge Atlas-based study on the development trend of contemporary disciplines].

OBJECTIVE: To review and analyze the trend of researches on prostatitis in China in the past two decades. METHODS: We searched the core collection of China National Knowledge Infrastructure (CNKI) for studies on prostatitis, and analyzed the data obtained using Excel, Citespace and VOSviewer. RESULTS: Totally, 1 216 original articles were identified, with 3 271 keywords, ≥3-time high-frequency keywords accounting for 12.9%, with "", "", "chronic prostatitis", "prostatitis", and "" as the top 5 ones, each with a centrality higher than 300. Major prostatitis-related studies focused on the 8 keywords, namely, prostatitis, prostatic fluid, rats, prostate, syndromes, efficacy observation, compound (in traditional Chinese medicine, TCM), and therapeutic application. The included literature involved 2 808 authors, with 402 involved more than twice and most of them in a scattered manner. The major topics of prostatitis studies varied in the past two decades, focusing on TCM therapies, promotion of blood circulation and stasis and comprehensive nursing in 2000－2001, on animal models, CD4+ lymphocytes and other experimental molecules in 2007－2010, on urodynamics, risk factors and specific antigens in 2013－2016, and on literature information resources in 2016. CONCLUSIONS: The immune mechanism remains a hot topic in the future researches on prostatitis. In terms of treatment of the disease, TCM has a potential value, and more practice and studies are required for an optimal combination of TCM and Western medicine. Strengthened collaborative efforts are needed to establish an authoritative source channel for the keywords, and incorporate it into the national standard system, and above all, to integrate the prostatitis study into multi-disciplinary researches, eliminate academic barriers, encourage collaborative innovation with multiple parties, and promote the exchanges and development in this field.

Protection of Retinal Function by Nucleoside Reverse Transcriptase Inhibitors Following Retinal Ischemia/Reperfusion Injury.

Purpose: Retinal ischemia/reperfusion (I/R) injury is a common cause of visual impairment and blindness for which there remain limited treatment options. Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT), have been shown to block the NLRP3 inflammasome and prevent retinal degeneration in a mouse model of age-related macular degeneration. The NLRP3 inflammasome has also been shown to be triggered in I/R injury. Therefore, we studied the neuroprotective effects of AZT using a pressure-induced retinal ischemia mouse model. Methods: C57BL/6J mice were randomly assigned to 1 of 2 treatment groups: vehicle-treated retinal I/R injury (n = 6) or AZT-treated retinal I/R injury (n = 6). Vehicle (1% dimethyl sulfoxide [DMSO] in phosphate-buffered saline [PBS]) or AZT 50 mg/kg in 1% DMSO in PBS were injected intraperitoneally twice daily for 5 days. On day 2 of treatment, retinal ischemia was induced by transient elevation of intraocular pressure for 45 min. Scotopic electroretinography (ERG) was used to quantify retinal function before and 1 week after retinal ischemic insult. Retinal morphology was examined 1 week after ischemic insult. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and caspase 1 immunostaining was performed 24 h after retinal I/R injury. Results: Following I/R injury, ERG a- and b-wave amplitudes were significantly reduced in the vehicle-treated mice. AZT treatment significantly attenuated I/R-induced loss of retinal function as compared with vehicle-treated mice. Additionally, AZT-treated mice experienced significantly less inner retinal thinning as compared with vehicle-treated mice. TUNEL-positive cells were prevalent in the vehicle-treated I/R injury mouse retinas compared with the AZT-treated I/R injury mouse retinas. More caspase-1 immunoreactivity was detected in ganglion cell layer and inner nuclear layer (INL) in vehicle-treated I/R injury group than in AZT-treated I/R injury group. Conclusion: AZT treatment resulted in relative preservation of retinal structure and function following ischemic insult as compared with controls. This suggests AZT may have therapeutic value in the management of retinal ischemic diseases.

[Therapeutic effect of acupuncture combined with medication on chronic prostatitis of damp and heat stasis].

OBJECTIVE: To observe the clinical therapeutic effect of electroacupuncture (EA) combined with tamsulosin hydrochloride sustained release capsule on chronic prostatitis (CP) of damp and heat stasis. METHODS: A total of 70 patients with CP of damp and heat stasis were randomized into an acupuncture plus medication group (35 cases, 4 cases dropped off) and a medication group (35 cases, 5 cases dropped off). In the medication group, tamsulosin hydrochloride sustained release capsule was given orally, 0.2 mg a time, once each night. On the basis of treatment in the medication group, EA was applied at Guanyuan (CV 4), Sanyinjiao (SP 6) and Yinglingquan (SP 9), with disperse-dense wave, 5 mA in intensity for 30 min. Treatment for 30 days was as one course, and totally 3 courses were required in both groups. Before treatment, 1, 2, 3 months into treatment and at the follow-up of 2 months after treatment, the TCM syndrome score and National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) score were observed, and the clinical efficacy was evaluated in both groups. RESULTS: Compared before treatment, the TCM syndrome scores of 3 months into treatment and follow-up were decreased in the acupuncture plus medication group (P<0.01), and were lower than those in the medication group (P<0.05). Compared before treatment, the NIH-CPSI scores of 3 months into treatment and follow-up were decreased in both groups (P<0.01), and those in the acupuncture plus medication group were lower than the medication group (P<0.05). The total effective rate was 90.3% (28/31) in the acupuncture plus medication group, which was superior to 80.0% (24/30) in the medication group (P<0.05). CONCLUSION: Acupuncture combined with medication can improve the clinical symptoms in patients with CP of damp and heat stasis, and its therapeutic effect is superior to simple western medication.

Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance.

BACKGROUND: Nerves are key factors in prostate cancer (PCa) progression. Here, we propose that neuropeptide Y (NPY) nerves are key regulators of cancer-nerve interaction. METHODS: We used in vitro models for NPY inhibition studies and subsequent metabolomics, apoptotic and migration assays, and nuclear transcription factor-κB (NF-κB) translocation studies. Human naïve and radiated PCa tissues were used for NPY nerve density biomarker studies. Tissues derived from a Botox denervation clinical trial were used to corroborate metabolomic changes in humans. RESULTS: Cancer cells increase NPY positive nerves in vitro and in preneoplastic human tissues. NPY-specific inhibition resulted in increased cancer apoptosis, decreased motility, and energetic metabolic pathway changes. A comparison of metabolomic response in NPY-inhibited cells with the transcriptome response in human PCa patients treated with Botox showed shared 13 pathways, including the tricarboxylic acid cycle. We identified that NF-κB is a potential NPY downstream mediator. Using in vitro models and tissues derived from a previous human chemical denervation study, we show that Botox specifically, but not exclusively, inhibits NPY in cancer. Quantification of NPY nerves is independently predictive of PCa-specific death. Finally, NPY nerves might be involved in radiation therapy (RT) resistance, as radiation-induced apoptosis is reduced when PCa cells are cocultured with dorsal root ganglia/nerves and NPY positive nerves are increased in prostates of patients that failed RT. CONCLUSION: These data suggest that targeting the NPY neural microenvironment may represent a therapeutic approach for the treatment of PCa and resistance through the regulation of multiple oncogenic mechanisms.

Therapeutic effect of acupuncture combined with medication on chronic prostatitis of damp and heat stasis / 中国针灸

OBJECTIVE@#To observe the clinical therapeutic effect of electroacupuncture (EA) combined with tamsulosin hydrochloride sustained release capsule on chronic prostatitis (CP) of damp and heat stasis.@*METHODS@#A total of 70 patients with CP of damp and heat stasis were randomized into an acupuncture plus medication group (35 cases, 4 cases dropped off) and a medication group (35 cases, 5 cases dropped off). In the medication group, tamsulosin hydrochloride sustained release capsule was given orally, 0.2 mg a time, once each night. On the basis of treatment in the medication group, EA was applied at Guanyuan (CV 4), Sanyinjiao (SP 6) and Yinglingquan (SP 9), with disperse-dense wave, 5 mA in intensity for 30 min. Treatment for 30 days was as one course, and totally 3 courses were required in both groups. Before treatment, 1, 2, 3 months into treatment and at the follow-up of 2 months after treatment, the TCM syndrome score and National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) score were observed, and the clinical efficacy was evaluated in both groups.@*RESULTS@#Compared before treatment, the TCM syndrome scores of 3 months into treatment and follow-up were decreased in the acupuncture plus medication group (@*CONCLUSION@#Acupuncture combined with medication can improve the clinical symptoms in patients with CP of damp and heat stasis, and its therapeutic effect is superior to simple western medication.

Inflammation and oxidative stress induced by lipid peroxidation metabolite 4-hydroxynonenal in human corneal epithelial cells.

PURPOSE: Oxidative stress is widely known to be a major contributor in the pathogenesis of dry eye disease (DED). 4-Hydroxynonenal (4-HNE), a well-known byproduct frequently measured as an indicator of oxidative stress-induced lipid peroxidation, has been shown to be elevated in both human and murine corneal DED samples. This study aims to investigate if 4-HNE is responsible for the oxidative stress in human corneal epithelial cells (HCECs) and explores the underlying mechanism by which it confers its effects. METHODS: SV40-immortalized HCECs were cultured in minimum essential media (MEM) with 1% penicillin/streptomycin and 10% fetal bovine serum. HCECs were exposed to media with or without 4-HNE and cell culture supernatants were collected at 4 and 24 h. Cellular reactive oxygen species (ROS) measurement was performed using a 2',7'-dichlorofluorescein diacetate (DCFDA) assay kit according to the manufacturer's instructions. Protein levels of antioxidant enzymes copper/zinc superoxide dismutase 1 (SOD1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were analyzed by Western blot. NF-κB activation and expression of IL-6 and IL-8 were measured using an NF-κB p65 Total SimpleStep ELISA Kit and Proteome Profiler Human Cytokine Array Kit. Cell viability was evaluated by LDH cytotoxicity assay. RESULTS: Treatment with 4-HNE decreased cell viability of HCECs. Band intensities corresponding to levels of ROS production showed a significant increase in ROS generation after treatment with 4-HNE. 4-HNE decreased SOD1 levels and upregulated NQO1 expression in HCECs. A significant increase in activation of NF-κB and production of pro-inflammatory cytokines IL-6 and IL-8 was observed after treatment with 4-HNE. Exposure to N-acetylcysteine (NAC), an antioxidant and ROS scavenger, antagonized the oxidative effects of 4-HNE on HCECs. CONCLUSION: 4-HNE induces oxidative stress in corneal epithelial cells by increasing levels of ROS generation and modifying the expression of antioxidant enzyme levels, decreasing cell viability of HCECs in vitro. This study demonstrates a potential pathway by which 4-HNE functions to confer its detrimental effects and provides a new therapeutic target for the treatment of DED.

Recurrent thrombosis in the lower extremities after thrombectomy in a patient with polycythemia vera: A case report.

BACKGROUND: Acute arterial embolism of the extremities is a surgical emergency. Atrial fibrillation is the major etiology of acute arterial embolism of the extremities. Emergency femoral artery thrombectomy can successfully treat this issue. However, polycythemia vera (PV) may sometimes explain this medical emergency. Recurrent thrombosis in the lower extremities after thrombectomy can be found in patients with PV, and reoperation is needed for this condition. CASE SUMMARY: A 68-year-old man in China suffered from sudden pain in the left lower extremity for 14 h. The examination in the emergency department showed a diagnosis of acute arterial embolism of the extremities combined with PV. The patient's complaint disappeared after repeat emergency thrombectomy. CONCLUSION: Patients with acute arterial embolism of the extremities should be treated carefully, especially those who have recurrent thrombosis after emergency thrombectomy. Clinicians should be aware of PV, a rare cause of acute arterial embolism of the extremities. The combination of thrombectomy, phlebotomy, and antiplatelet and anticoagulant drugs may be a suitable therapeutic regimen for these patients.

Group cognitive behavioural therapy can reduce stigma and improve treatment compliance in major depressive disorder patients.

AIM: The stigma of mental disorders and poor treatment compliance can deprive patients with major depressive disorder (MDD) of receiving standard treatment. This study aimed to clarify whether MDD patients' stigma and treatment non-compliance issues can be mitigated using group cognitive behavioural therapy (GCBT). METHODS: Eighty-eight participants with first-episode MDD were randomly divided into GCBT groups (GCBTs) and control groups (Cs). The Hamilton Rating Scale for Depression (HRSD-24), Morisky Medication Adherence Scale (MMAS-8™) and Stigma Scale (SS) were used to evaluate the therapeutic effect on all participants before and after receiving GCBT. Data were assessed at baseline and post-treatment. RESULTS: At the baseline, there were no significant differences (in terms of the demographic data of the participants and the scores on HRSD-24, MMAS-8™ and SS) between the two groups. After 8 weeks of GCBT, there were significant differences in HRSD-24 (P < .01), MMAS-8™ (P < .01), SS (P < .01), treatment compliance (P < .01) and therapeutic effect evaluation based on rate of deduction (P < .05) between the two groups. CONCLUSION: GCBT can reduce patients' sense of stigma, improve treatment compliance, effectively alleviate depressive symptoms and promote the recovery of MDD patients.

Infectious interface keratitis (IIK) following lamellar keratoplasty: A literature review.

PURPOSE: The purpose of this study was to review the published incidence, etiology, clinical features and management of patients who developed infectious interface keratitis (IIK) following lamellar keratoplasty. DESIGN: This study is a systematic literature review. METHODS: We conducted a systematic review of published Chinese and English report through a PubMed search with the medical subject headings using the following terms: corneal transplantation, keratoplasty, anterior lamellar keratoplasty (ALK), deep anterior lamellar keratoplasty (DALK), deep lamellar endothelial keratoplasty (DLEK), Descemet membrane endothelial keratoplasty (DMEK), Descemet stripping endothelial keratoplasty (DSEK), Descemet stripping automated endothelial keratoplasty (DSAEK), infectious interface keratitis (IIK), fungal keratitis, and bacterial keratitis. Data collected included patient demographics, surgical technique, clinical signs, treatment, outcomes, and donor rim cultures. A review of the relevant literatures was also undertaken. RESULTS: From 2007 to Feb. 2018, we identified 62 cases of IIK following lamellar corneal surgery. The mean age was 26.95 ±â€¯8.80 years with a male/female ratio of 11:8 in DALK/ALK group and 69.65 ±â€¯8.00 years with a male/female ratio of 17:16 in DSAEK/DSEK/DMEK group (no gender information for 10 cases). Of the 62 cases, 46 cases (75.41%) were fungal, 9 cases (14.75%) were bacterial, 2 cases (3.28%) were Actinomyces species, 1 case (1.64%) was acanthamoeba, and 4 cases (6.56%) were indeterminant. The mean onset of symptoms was postoperative day (POD) 49.47 ±â€¯48.56 in DALK/ALK group, and 53 ±â€¯112.01 in EK group, and 62.44 ±â€¯50.07 for the bacterial keratitis, and 51.5 ±â€¯102.42 for fungal keratitis. The mean postoperative follow-up period was 10.10 ±â€¯9.36 months in DALK/ALK group and 12.37 ±â€¯12.28 months in DSAEK/DSEK/DMEK group. Of the total 62 cases, 1 case (1.61%) with a Klebsiella pneumoniae positive donor rim cultures was associated with the same pathogen in the IIK, and 16 cases (25.81%) of fungal positive donor rim cultures were associated with the same pathogen in the IIK. Clinical signs included conjunctival injection, interface opacity, stromal edema for bacterial keratitis, and dense white infiltrates at the interface with endothelial plaques in some cases of fungal keratitis. Medical treatment included topical and oral antimicrobial agents. Surgical interventions included therapeutic keratoplasty. In 15 cases (24.19%), medical management was successful. Of the remaining 47 cases, 8 (12.90%) were managed with a repeat lamellar keratoplasty (LK) and 39 (62.90%) were unresponsive to conservative medical treatment and underwent a therapeutic keratoplasty (TKP). Post infectious best corrected visual acuity (BCVA) was logMAR 0 in 7 eyes (11.29%), better than or equal to logMAR 0.4 in 20 eyes (32.26%), less than logMAR 0.4 in 22 eyes (35.48%) and logMAR 0.7 or worse in 13 eyes (20.97%). In the rim culture negative group(n = 19), the average BCVA was logMAR 0.59 ±â€¯0.68, with was logMAR 0.44 ±â€¯0.74 in rim culture positive group (n = 15). There were three recurrence cases were reported after DMEK during the postoperative follow-up period. CONCLUSIONS: Infectious interface keratitis (IIK) is an uncommon complication of lamellar keratoplasty, but it can result in a substantial loss of vision or permanent blindness. Although graft infection can occur at any time following surgery, it most commonly (87%) occurred during the first 3 months postoperatively (54/62 cases). The most commonly reported causative organism of IIK following lamellar keratoplasty was C. albicans. Positive rim culture results can provide more rapid and appropriate treatment directed to the identified organism. Therapeutic keratoplasty (TKP) was the most common surgical procedure for the management of IIK. Visual outcomes post TKP are fair with 32.26% (20/62) of patients obtaining LogMAR 0.4 or better.

Moving Beyond Gleason Scoring.

CONTEXT.­: The combination of grading and staging is the basis of current standard of care for prediction for most cancers. D. F. Gleason created the current prostate cancer (PCa) grading system. This system has been modified several times. Molecular data have been added. Currently, all grading systems are cancer-cell based. OBJECTIVE.­: To review the literature available on host response measures as reactive stroma grading and stromogenic carcinoma, and their predictive ability for PCa biochemical recurrence and PCa-specific death. DATA SOURCES.­: Our own experience has shown that reactive stroma grading and the subsequently binarized system (stromogenic carcinoma) can independently predict biochemical recurrence and/or PCa-specific death, particularly in patients with a Gleason score of 6 or 7. Stromogenic carcinoma has been validated by 4 other independent groups in at least 3 continents. CONCLUSIONS.­: Broders grading and Dukes staging have been combined to form the most powerful prognostic tools in standard of care. The time has come for us to incorporate measures of host response (stromogenic carcinoma) into the arsenal of elements we use to predict cancer survival, without abandoning what we know works. These data also suggest that our current definition of PCa might need some revision.

Comparative Genomics Reveals the Genetic Mechanisms of Musk Secretion and Adaptive Immunity in Chinese Forest Musk Deer.

The Chinese forest musk deer (Moschus berezovskii; FMD) is an artiodactyl mammal and is both economically valuable and highly endangered. To investigate the genetic mechanisms of musk secretion and adaptive immunity in FMD, we compared its genome to nine other artiodactyl genomes. Comparative genomics demonstrated that eight positively selected genes (PSGs) in FMD were annotated in three KEGG pathways that were related to metabolic and synthetic activity of musk, similar to previous transcriptome studies. Functional enrichment analysis indicated that many PSGs were involved in the regulation of immune system processes, implying important reorganization of the immune system in FMD. FMD-specific missense mutations were found in two PSGs (MHC class II antigen DRA and ADA) that were classified as deleterious by PolyPhen-2, possibly contributing to immune adaptation to infectious diseases. Functional assessment showed that the FMD-specific mutation enhanced the ADA activity, which was likely to strengthen the immune defense against pathogenic invasion. Single nucleotide polymorphism-based inference showed the recent demographic trajectory for FMD. Our data and findings provide valuable genomic resources not only for studying the genetic mechanisms of musk secretion and adaptive immunity, but also for facilitating more effective management of the captive breeding programs for this endangered species.

The draft genome sequence of forest musk deer (Moschus berezovskii).

Background: The forest musk deer, Moschus berezovskii, is one of seven musk deer (Moschus spp.) and is distributed in Southwest China. Akin to other musk deer, the forest musk deer has been traditionally and is currently hunted for its musk (i.e., global perfume industry). Considerable hunting pressure and habitat loss have caused significant population declines. Consequently, the Chinese government commenced captive breeding programs for musk harvesting in the 1950s. However, the prevalence of fatal diseases is considerably restricting population increases. Disease severity and extent are exacerbated by inbreeding and genetic diversity declines in captive musk deer populations. It is essential that knowledge of captive and wild forest musk deer populations' immune system and genome be gained in order to improve their physical and genetic health. We have thus sequenced the whole genome of the forest musk deer, completed the genomic assembly and annotation, and performed preliminary bioinformatic analyses. Findings: A total of 407 Gb raw reads from whole-genome sequencing were generated using the Illumina HiSeq 4000 platform. The final genome assembly is around 2.72 Gb, with a contig N50 length of 22.6 kb and a scaffold N50 length of 2.85 Mb. We identified 24,352 genes and found that 42.05% of the genome is composed of repetitive elements. We also detected 1,236 olfactory receptor genes. The genome-wide phylogenetic tree indicated that the forest musk deer was within the order Artiodactyla, and it appeared as the sister clade of four members of Bovidae. In total, 576 genes were under positive selection in the forest musk deer lineage. Conclusions: We provide the first genome sequence and gene annotation for the forest musk deer. The availability of these resources will be very useful for the conservation and captive breeding of this endangered and economically important species and for reconstructing the evolutionary history of the order Artiodactyla.

Zidovudine protects hyperosmolarity-stressed human corneal epithelial cells via antioxidant pathway.

Dry Eye Disease (DED) is a very common disorder that can result in severe disability and vision loss. Although the pathogenesis of DED is not fully understood, hyperosmolarity, inflammation, and tear film instability are recognized as hallmarks of DED. Recently, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), a class of medication used to treat HIV, have been shown to inhibit inflammation in a mouse model of retinal atrophy. In this study, we investigated whether Zidovudine (AZT) can inhibit human corneal epithelial cell (HCEC) inflammatory responses under hyperosmotic conditions. HCECs were cultured in hyperosmotic media containing AZT. Cell viability, cytokine production, and reactive oxygen species (ROS) production were measured. We found that AZT decreased nuclear factor kappa B (NF-κB) and Interleukin-6 (IL-6) levels, increased Superoxide Dismutase 1 (SOD1) production, decreased ROS production, and increased cell viability. These results support the novel use of AZT in the reduction of ocular surface inflammation and the promotion of corneal health in the context of DED.

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury.

Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE-/-) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE-/- mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE-/- mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE-/- mice. At 42days after injury, the inflammation was still robust in the injured spinal cord in apoE-/- but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE-/- mice. The spared white matter was significantly decreased in apoE-/- mice compared to wild type ones. Locomotor function was significantly decreased in apoE-/- mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE-/- mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE-/- mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.

Papilloma-pseudovirus eradicates intestinal tumours and triples the lifespan of ApcMin/+ mice.

Inducing tumour-specific adaptive immunity, such as cytotoxic T lymphocyte (CTL) response, can result in promising antitumour effect against several human malignancies, especially in combination with immune checkpoint blockade strategies. However, little is known whether activation of innate immunity can lead to direct tumoricidal effect. Here, we develop a papilloma pseudovirus-based oral immunotherapeutic approach that shows strong tumoricidal effects in the gut, resulting in an almost tripled lifespan of ApcMin/+ mice (an animal model of human intestinal tumorigenesis). Mechanistically, these pseudoviruses activate the NLRP3 and AIM2 inflammasomes, leading to caspase-1-mediated tumour regression that is dependent on neither cytotoxic T lymphocytes nor humoral immune response. Blocking caspase-1 activation abrogated the therapeutic effects of the pseudoviruses. Thus, targeting innate immune sensors in tumours by the pseudoviruses might represent a strategy to treat intestinal tumours.