THE INCIDENCE, CHARACTERISTICS, MANAGEMENT, PROGNOSIS, AND CLASSIFICATION OF BREAKTHROUGH VITREOUS HEMORRHAGE SECONDARY TO POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To describe breakthrough vitreous hemorrhage secondary to polypoidal choroidal vasculopathy (PCV). METHODS: Patients with the diagnosis of PCV from January 2005 to March 2020 at Peking Union Medical College Hospital were retrospectively reviewed, cases with breakthrough vitreous hemorrhage were analyzed. Subgroup analysis was conducted regarding pachychoroid PCV and nonpachychoroid PCV. RESULTS: Among 722 PCV patients (834 eyes), 103 eyes with breakthrough vitreous hemorrhage (12.4%) were included. Pars plana vitrectomy and proper further interventions could significantly improve the best-corrected visual acuity from logMAR 2.15 ± 0.48 (Snellen 20/2825) to 1.65 ± 0.67 (20/893). Hemorrhagic retinal detachment, baseline central macular thickness, and best-corrected visual acuity were factors associated with final best-corrected visual acuity (P < 0.05). In the pachychoroid PCV group, patients were younger, all had hemorrhagic pigment epithelial detachment, with a higher prevalence of choroidal vascular hyperpermeability and hemorrhagic retinal detachment, thicker subfoveal choroidal thickness, and thinner central macular thickness; besides, the initial pars plana vitrectomy were more complicated, more additional surgeries had to be performed. More eyes in the nonpachychoroid PCV group had received anti-vascular endothelial growth factor or photodynamic therapy, mostly fibrovascular pigment epithelial detachment, the best-corrected visual acuity and the status of the fellow eye were significantly worse. For the final ocular status, more eyes in nonpachychoroid PCV group were taking anti-vascular endothelial growth factor monotherapy, whereas more eyes in pachychoroid PCV group were stable. The choroidal parameters of these two groups were all significantly different. CONCLUSION: Breakthrough vitreous hemorrhage is a troublesome complication of PCV. Pars plana vitrectomy and additional interventions are required for better prognosis. Vitreous hemorrhage secondary to pachychoroid PCV or nonpachychoroid PCV have different characteristics and prognosis.

Ischemic Preconditioning-Induced SOCS-1 Protects Rat Intestinal Ischemia Reperfusion Injury via Degradation of TRAF6.

BACKGROUND: The inflammatory immune response plays an important role in mesenteric ischemia and ischemia-reperfusion injury. Toll-like receptor 4 (TLR4) is a critical receptor in transduction of the inflammatory response and plays an important role in intestinal homeostasis. Tumor necrosis factor receptor-associated factor 6 (TRAF6), known as a key adaptor protein downstream of TLR4, is involved in the inflammatory response by activating multiple apoptotic signaling pathways. However, mechanisms of the suppressor of cytokine signaling-1 (SOCS-1) in regulating cell inflammation and apoptosis are still obscure. OBJECTIVES: To investigate the TLR4-TRAF6 signaling pathway in intestinal ischemia and reperfusion injury, as well as SOCS-1 expression after ischemic preconditioning in the rat intestine. METHODS: The small bowel ischemia, ischemia-reperfusion, and preconditioning models were induced using ligation of the superior mesenteric artery in male Sprague-Dawley rats; then, the mRNA and protein levels of TLR4, TRAF6, and SOCS-1 were analyzed using real-time PCR, Western blot, and immunohistochemistry, respectively. RESULTS: The expression of TLR4 and TRAF6 was gradually increased with increasing intestinal ischemia duration, but increased substantially after ischemia-reperfusion injury. After ischemic preconditioning, TLR4 and TRAF6 expressions decreased; however, expression of SOCS-1 and the TLR4-TRAF6 pathway inhibitor was increased. CONCLUSION: These data show that ischemic preconditioning may induce the activation of SOCS-1 to inhibit the TLR4-TRAF6 signaling pathway, thereby playing a protective role in ischemia-reperfusion injury.

Sumoylation of the Tumor Suppressor Promyelocytic Leukemia Protein Regulates Arsenic Trioxide-Induced Collagen Synthesis in Osteoblasts.

BACKGROUND/AIMS: Promyelocytic leukemia (PML) protein is a tumor suppressor that fuses with retinoic acid receptor-α (PML-RARα) to contribute to the initiation of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) upregulates expression of TGF-ß1, promoting collagen synthesis in osteoblasts, and ATO binds directly to PML to induce oligomerization, sumoylation, and ubiquitination. However, how ATO upregulates TGF-ß1 expression is uncertain. Thus, we suggested that PML sumoylation is responsible for regulation of TGF-ß1 protein expression. METHODS: Kunming mice were treated with ATO, and osteoblasts were counted under scanning electron microscopy. Masson's staining was used to quantify collagen content. hFOB1.19 cells were transfected with siRNA against UBC9 or RNF4, and then treated with ATO or FBS. TGF-ß1, PML expression, and sumoylation were quantified with Western blot, and collagen quantified via immunocytochemistry. RESULTS: ATO enhanced osteoblast accumulation, collagen synthesis, and PML-NB formation in vivo. Knocking down UBC9 in hFOB1.19 cells inhibited ATO- and FBS-induced PML sumoylation, TGF-ß1 expression, and collagen synthesis. Conversely, knocking down RNF4 enhanced ATO- and FBS-induced PML sumoylation, TGF-ß1 expression, and collagen synthesis. CONCLUSION: These data suggest that PML sumoylation is required for ATO-induced collagen synthesis in osteoblasts.

Efficacy and safety of different agents, dosages and strategies of anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration: a network meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the efficacy and safety of different agents, dosages and strategies of anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (nAMD) by network meta-analysis. METHODS: Electronic database searches were conducted on PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 December 2019 to `identify relevant randomized controlled trials (RCTs). The standardized mean difference (SMD), odds ratios (OR), 95% confidence intervals (CI), the surface under the cumulative ranking curves and the mean ranks of each outcome were estimated by Stata 14.0. RESULTS: Forty-seven RCTs encompassing 17 872 nAMD patients randomly assigned to 36 regimens of anti-VEGF agents or sham treatment were included. T&E strategy shows top-level effect both in BCVA changes and the percentage of patients with a gain of 3 lines or more of BCVA. When taking the same strategy, there is no significant difference of efficacy among ranibizumab, bevacizumab and aflibercept (p > 0.05); The combination of radiation, topical NSAIDs and photodynamic therapy (PDT) might provide additional benefit in central retinal thickness (CRT) reduction; all these therapeutic regimens of different anti-VEGF agents do not significantly increase the risk of severe ocular or cardiocerebral vascular adverse events (ADEs) compared with sham treatment (p > 0.05). CONCLUSIONS: T&E strategy showed a satisfactory effect in visual improvement and there is no significant difference in efficacy or safety among ranibizumab, bevacizumab and aflibercept. All the included regimens have an acceptable risk of ADEs.

CXCL13 in Cancer and Other Diseases: Biological Functions, Clinical Significance, and Therapeutic Opportunities.

The development of cancer is a multistep and complex process involving interactions between tumor cells and the tumor microenvironment (TME). C-X-C chemokine ligand 13 (CXCL13) and its receptor, CXCR5, make crucial contributions to this process by triggering intracellular signaling cascades in malignant cells and modulating the sophisticated TME in an autocrine or paracrine fashion. The CXCL13/CXCR5 axis has a dominant role in B cell recruitment and tertiary lymphoid structure formation, which activate immune responses against some tumors. In most cancer types, the CXCL13/CXCR5 axis mediates pro-neoplastic immune reactions by recruiting suppressive immune cells into tumor tissues. Tobacco smoke and haze (smohaze) and the carcinogen benzo(a)pyrene induce the secretion of CXCL13 by lung epithelial cells, which contributes to environmental lung carcinogenesis. Interestingly, the knockout of CXCL13 inhibits benzo(a)pyrene-induced lung cancer and azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Thus, a better understanding of the context-dependent functions of the CXCL13/CXCR5 axis in tumor tissue and the TME is required to design an efficient immune-based therapy. In this review, we summarize the molecular events and TME alterations caused by CXCL13/CXCR5 and briefly discuss the potentials of agents targeting this axis in different malignant tumors.

Altered Plasma MicroRNAs as Novel Biomarkers for Arteriosclerosis Obliterans.

AIM: Arteriosclerosis obliterans (ASO) of the lower extremities is a major cause of adult limb loss worldwide. A timely diagnosis in the early stages of the disease determines the clinical outcomes, however lacking of palpable symptoms remains the biggest obstacle. This study aimed to screen a cluster of microRNAs (miRNAs) that can be used as biomarker for the ASO in the earlier stages. METHODS: Plasma from 3 patients with ASO and 3 healthy controls were profiled to screen altered miRNAs by microarray, then Real time PCR was further used to confirm the changes in 55 ASO patients and 54 controls.We also analyzed the correlation of miRNAs level with Fontaine stages and the influence of T2DM which is a common complication with ASO on the level of miRNAs. RESULT: Twenty-four aberrantly expressed miRNAs were screened in the plasma of ASO patients. Real time PCR verified that the level of miR-4284 was significantly increased, while levels of miR-4463, miR-4306 and miR-221-3p were significantly decreased both in the plasma and in the sclerotic samples compared with the controls. Interestingly, we revealed a time and stage specific expression manner, as shown that expression of miR-4284 increased at the stage I of ASO and maintained the tendency to stage IV, while miR-4463 expression decreased at every stage of ASO; however, the expression of miR-4463 showed opposite changes in ASO patients with or without T2DM. CONCLUSION: Altered expressions of miR-4284 and miR-4463 are novel characteristics and may serve as potential biomarkers for the early diagnosis of ASO.

Ketamine-mediated afferent-specific presynaptic transmission blocks in low-threshold and sex-specific subpopulation of myelinated Ah-type baroreceptor neurons of rats.

BACKGROUND: Ketamine enhances autonomic activity, and unmyelinated C-type baroreceptor afferents are more susceptible to be blocked by ketamine than myelinated A-types. However, the presynaptic transmission block in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons (BRNs) is not elucidated.  METHODS: Action potentials (APs) and excitatory post-synaptic currents (EPSCs) were investigated in BRNs/barosensitive neurons identified by conduction velocity (CV), capsaicin-conjugated with Iberiotoxin-sensitivity and fluorescent dye using intact nodose slice and brainstem slice in adult female rats. The expression of mRNA and targeted protein for NMDAR1 was also evaluated.  RESULTS: Ketamine time-dependently blocked afferent CV in Ah-types in nodose slice with significant changes in AP discharge. The concentration-dependent inhibition of ketamine on AP discharge profiles were also assessed and observed using isolated Ah-type BRNs with dramatic reduction in neuroexcitability. In brainstem slice, the 2nd-order capsaicin-resistant EPSCs were identified and ~50% of them were blocked by ketamine concentration-dependently with IC50 estimated at 84.4 µM compared with the rest (708.2 µM). Interestingly, the peak, decay time constant, and area under curve of EPSCs were significantly enhanced by 100 nM iberiotoxin in ketamine-more sensitive myelinated NTS neurons (most likely Ah-types), rather than ketamine-less sensitive ones (A-types).  CONCLUSIONS: These data have demonstrated, for the first time, that low-threshold and sex-specific myelinated Ah-type BRNs in nodose and Ah-type barosensitive neurons in NTS are more susceptible to ketamine and may play crucial roles in not only mean blood pressure regulation but also buffering dynamic changes in pressure, as well as the ketamine-mediated cardiovascular dysfunction through sexual-dimorphic baroreflex afferent pathway.

Arsenic trioxide exerts a double effect on osteoblast growth in vitro.

Arsenic trioxide (ATO) is a promising antitumor agent used to treat acute promyelocytic leukemia (APL) and, recently solid tumor. The present study was designed to evaluate the effect of ATO proliferation of osteoblast that plays very important roles in maintaining the structure integrity and function of bone. Cell survives, apoptosis, collagen, and molecular targets were identified by multiple detecting techniques, including MTT assay, electron microscopy, collagen detecting kit, TUNEL kit, and western blot in hFOB1.19 human osteoblasts cell line. The results showed that low dose of ATO (0.25, 0.5, and 1µM) remarkably enhanced the viability of cultured osteoblasts in a concentration- and time-dependent manner. Intriguingly, a dual effect of high dose of ATO (5, 10, and 20µM) was also observed showing significant reduction in viability of culture osteoblasts at concentration- and time-dependent fashion. Moreover, low dose of ATO promoted secretion and synthesis of collagen, whereas high dose of ATO induced typical morphological characteristics of apoptosis in osteoblasts. Mechanically, western blot results demonstrated that low dose of ATO dramatically up-regulated TGF-ß1 protein and activated p-AKT proliferative signaling. And, high dose of ATO increased Bax/Bcl-2 ratio in a time-dependent fashion and activated caspase-3 apoptotic signaling. These results demonstrate at the first time that ATO exerts a double effect on osteoblast function depending upon the concentration and provide a clue to rationally use ATO for clinicians to pay more attention to protect bone from the adverse effects of therapeutic dose of ATO during tumor therapy.