Significant Systemic Effects Research Articles

Clinical Experience of Using 0.2 % Olopatadin in the Allergic Conjunctivitis Treatment

Purpose:to evaluate the efficacy and safety of complex therapy of allergic conjunctivitis, including 0.2 % olopatodin.Patients and methods:In 40 allergic conjunctivitis (AK) patients were performed: assessment of the intensity of itching and tearing, as well as conjunctival hyperemia and folliculosis (points); Schirmer’s test (SHT; mm); tear film break up time (TFBUT, s); assessment of the lid wiper epitheliopathy symptom (LWES, points); calculation of the xerosis indicator (XI; points, according to Bijsterveld). In the 1 group (20 pollen AK patients) were given: 0.2 % olopatadine instillations (1 time per day); preservative free polyvinylpyrrolidone and polyvinyl alcohol fixed combination (2–3 times a day, from 7 days of therapy). Control points: 7 and 30 days of therapy. Patients of 2 group with pollen AK and chronic blepharitis (saprophytic flora and Demodex) were performed: 0.2 % olopatadine instillations (1 time per day); eyelid hygiene (poloxamer 188 and PEG-90 gel; 2 times per day); ointment containing gentamicin and dexamethasone (application on the eyelids margins, 2 times a day, 14 days); acaricidal gel (based on preparations of sulfur, sodium hyaluronate and aloe extract; 2 times a day, from 15 days of therapy); preservative free polyvinylpyrrolidone and polyvinyl alcohol fixed combination (2–3 times a day, from 15 days of therapy). Control points: 14 and 30 days of treatment. Statistical analysis included: calculation of an average and its standard deviation (М ± s); evaluation of reliability of differences in control points (Wilcoxon’s T-criterion; χ2 criterion). Statistically significant was p < 0,05.Results:Patients of both groups had good tolerability of the treatment; no significant systemic and local side effects of treatment were noted. In 1 group patients by the 7th and 30th day of therapy, a significant decrease in the severity of itching, tearing and conjunctival hyperemia was observed. By the 30th day of observation, the complete absence of itching was noted in 85 % of individuals, the absence of hyperemia — in 80 %. The rest of the observed severity of these signs did not exceed the level of one point, and their manifestations were non-permanent. Conjunctival follicular response significantly decreased by 30 days of observation. SHT showed a significant decrease in all control points, remaining within normal limits. Dynamics of TFBUT and XI by 7 days of therapy was unreliable. By the 30th day of treatment, there was a significant positive dynamics of TFBUT and XI, compared with the state before the therapy and 7 days of observation. At the same time, TFBUT and XI have reached values close to normal. In 2 group patients by the 14th and 30th day of therapy, a significant decrease in the severity of itching, tearing, hyperemia and follicular conjunctival reaction was recorded (by 1–2 points). The value of SHT showed a significant decrease in all control points (within the normal values of the indicator). By the 14th day of therapy, a significant decrease of LWES was noted; the NT and XI the dynamics were statistically insignificant. By the 30th day of observation, significant positive dynamics of NT, XI, and LWES were noted, compared with the state before the start of treatment and 14 days of therapy. Despite the almost complete relief of symptoms and signs of allergy and ocular surface condition improvement, by 30 days of observation, the magnitudes of NT, XI and LWES still did not reach the normal state, which determined the need for further artificial tear therapy, eyelid hygiene and acaricide treatment.Conclusion:Combined therapy, including 0.2 % olopatadin instillation, demonstrated high efficacy in relieving symptoms (itching, tearing) and signs (hyperemia and follicular conjunctival reaction) of allergic conjunctivitis, as well as a good safety profile.

11\u03b2-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy

BackgroundDespite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11β-HSD1 to GIOP.MethodsWild type (WT) and 11β-HSD1 knockout (KO) mice were treated with corticosterone (100 μg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR.ResultsWild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11β-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone.ConclusionsThis study demonstrates that 11β-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11β-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids.

A Peptide Probe Enables Photoacoustic-Guided Imaging and Drug Delivery to Lung Tumors in K-rasLA2 Mutant Mice.

The lack of molecular targets and targeting probes remains a major drawback for targeted imaging and drug delivery in lung cancer. In this study, we exploited in vivo phage display to identify a novel targeting probe that homes to the tumor in a K-rasLA2 mutant mouse lung cancer model. Compared with other candidate peptides selected from 5 rounds of phage display, the CRQTKN peptide homed to tumor nodules in the lung of mutant mice at higher levels. Photoacoustic tomography of mutant mice detected lung tumors via tumor homing of the near-infrared fluorescence dye-labeled CRQTKN peptide. Ex vivo photoacoustic images of isolated organs further demonstrated tumor homing of the CRQTKN peptide, whereas minimal accumulation was observed in control organs, such as the liver. Compared with untargeted liposomes and doxorubicin, doxorubicin-loaded liposomes whose surface was modified with the CRQTKN peptide more efficiently delivered doxorubicin and reduced the number or size of tumor lesions in K-rasLA2 mutant mice. Analysis of hematologic parameters and liver and kidney function showed no significant systemic side effects by the treatments. Affinity-based identification was used to detect TNF receptor superfamily member 19L (TNFRSF19L), which was upregulated in lung tumors of mutant mice, as the receptor for the CRQTKN peptide. In conclusion, these results suggest that the CRQTKN peptide is a promising targeting probe for photoacoustic-guided detection and drug delivery to lung cancer, and acts by binding to TNFRSF19L. SIGNIFICANCE: These findings present a new tumor-targeting probe for photoacoustic-guided detection and drug delivery.

Comparative Radioimmunotherapy of Experimental Melanoma with Novel Humanized Antibody to Melanin Labeled with 213Bismuth and 177Lutetium.

Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a beta emitter, 177Lu, and an alpha-emitter, 213Bi, as well as biodistribution, microSPECT/CT imaging, and mouse and human dosimetry calculations. microSPECT/CT imaging showed that a humanized antibody that targets “free” melanin in the tumor microenvironment had high tumor uptake in B16F10 murine melanoma in C57Bl/6 mice, with little to no uptake in naturally melanized tissues. Extrapolation of the mouse dosimetry data to an adult human demonstrated that doses delivered to major organs and the whole body by 177Lu-h8C3 would be approximately two times higher than those delivered by 213Bi-h8C3, while the doses to the tumor would be almost similar. RIT results indicated that 213Bi-h8C3 was more effective in slowing down the tumor growth than 177Lu-h8C3, while both radiolabeled antibodies did not produce significant hematologic or systemic side effects. We concluded that h8C3 antibody labeled with 213Bi is a promising reagent for translation into a clinical trial in patients with metastatic melanoma.

Abstract 5024: Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model

Abstract RIG-I is a highly important cytosolic pattern recognition receptor (PRR) involved in sensing RNA virus infection and inducing interferon (IFN) production. RIG-I’s natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. This study validates the use of intratumoral treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Firstly, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Secondly, cellular models of human melanoma confirm susceptibility of cancer cells to ppp-RNA treatment, revealing unexpected heterogeneity between cell lines in their selectivity for RNA features, including sequence, secondary structures and presence of triphosphate. Cellular RNA treatment responses (type I IFN, FasR, MHC-I, cytotoxicity) were demonstrated to be RIG-I dependent using RIG-I KO cells. Thirdly, we show that ppp-RNA treatment of a mouse melanoma tumor model, leads to significant local and systemic anti-tumor effects and survival benefits, associated with a type I IFN response, tumor cell apoptosis and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen specific CTLs following treatment with RIG-I agonist. Overall our study demonstrates that ppp-RNA or analogs thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy. However, potential challenges in the generation and formulation of potent RIG-I agonists remain to be solved. Citation Format: Mike W. Helms, Eric Parmantier, Kerstin Jahn-Hofmann, Felix Gnerlich, Lars König, Christiane Metz-Weidmann, Monika Braun, Gabriele Dietert, Kaj Grandien, Joachim Theilhaber, Hui Cao, Tim Wagenaar, Max Schnurr, Stefan Endres, Dmitri Wiederschain, Sabine Scheidler, Simon Rothenfusser, Bodo Brunner. Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5024.

Biodegradable polymerized simvastatin stimulates bone formation

Previous research from our labs demonstrated the synthesis of polymerized simvastatin by ring-opening polymerization and slow degradation with controlled release of simvastatin in vitro. The objective of the present study was to evaluate the degradation and intramembranous bone-forming potential of simvastatin-containing polyprodrugs in vivo using a rat calvarial onlay model. Poly(ethylene glycol)-block-poly(simvastatin) and poly(ethylene glycol)-block-poly(simvastatin)-ran-poly(glycolide) were compared with simvastatin conventionally encapsulated in poly(lactic-co-glycolic acid) (PLGA) and pure PLGA. The rate of degradation was higher for PLGA with and without simvastatin relative to the simvastatin polyprodrugs. Significant new bone growth at the circumference of poly(ethylene glycol)-block-poly(simvastatin) disks was observed beginning at 4 weeks, whereas severe bone resorption (4 weeks) and bone loss (8 weeks) were observed for PLGA loaded with simvastatin. No significant systemic effects were observed for serum total cholesterol and body weight. Increased expression of osteogenic (BMP-2, Runx2, and ALP), angiogenic (VEGF), and inflammatory cytokines (IL-6 and NF-ĸB) genes was seen with all polymers at the end of 8 weeks. Poly(ethylene glycol)-block-poly(simvastatin), with slow degradation and drug release, controlled inflammation, and significant osteogenic effect, is a candidate for use in bone regeneration applications. Statement of SignificanceTraditional drug delivery systems, e.g., drug encapsulated in poly(lactic-co-glycolic acid) (PLGA), are typically passive and have limited drug payload. As an alternative, we polymerized the drug simvastatin, which has multiple physiological effects, into macromolecules (“polysimvastatin”) via ring-opening polymerization. We previously demonstrated that the rate of degradation and drug (simvastatin) release can be adjusted by copolymerizing it with other monomers. The present results demonstrate significant new bone growth around polysimvastatin, whereas severe bone loss occurred for PLGA loaded with simvastatin. This degradable biomaterial with biofunctionality integrated into the polymeric backbone is a useful candidate for bone regeneration applications.

Main features and applications of organogels in cosmetics.

Cosmetic treatments aim at improving skin appearance through vehicles of good sensory properties. Those vehicles are mainly emulsions and gels designed to deliver safe and effective compounds to skin. Creams and serums are widely used to achieve these goals, but recently a new type of formulation known as organogels triggered scientific attention, particularly in the design of both topical and cosmetic formulations. It has been established that the lipophilic nature of organogels makes it an excellent candidate for the delivery of cosmetic molecules through skin. In this review, we discuss the properties and characteristics of organogels and present the advantages of the application of these systems in cosmetics.

Results of Intralesional Bleomycin Sclerotherapy for Treatment of Orbital Lymphangiomas at a Tertiary Eye Care Centre in Bangladesh

Purpose: The purpose of our study was to evaluate the role of intralesional bleomycin injection for the treatment of orbital lymphangiomas. Methods: This was a prospective interventional case study. Twelve patients diagnosed with orbital lymphangiomas received intralesional bleomycin injection at a dose of 0.5 mg/kg body weight (maximum 15 mg) along with lignocaine 2%. Those who required retreatment were injected at intervals of 4 weeks. The outcome was reviewed radiologically and using serial photographic comparison. Result: Proptosis and lid swelling were the most frequent presentations. The number of injections ranged from 1 to 3. Fifty percent of our patients showed complete resolution, and the other 50% showed more than 70% resolution as evidenced radiologically and on digital photography. Conclusion: No significant ophthalmic or systemic side effect was noticed in our study group. Therefore, intralesional bleomycin injection can be considered as first-line therapy for treatment of orbital lymphangiomas.

A Novel, Low-Cost, Wide-Field, Infant Retinal Camera, "Neo": Technical and Safety Report for the Use on Premature Infants.

PurposeTo report the technical aspects, systemic, and ocular safety of a novel, low-cost, wide-field, infant retinal camera for use on premature infants.MethodsThe device, the “3nethra Neo” (Neo) is a 120° portable, contact, wide-field, unibody camera, with a CMOS sensor (2040 × 2040 resolution) and a warm light-emitting diode (LED) illumination source. The Neo was used to image 140 awake, preterm infants between postmenstrual age (PMA) of 28 to 37 weeks, undergoing retinopathy of prematurity (ROP) screening. Baseline, ‘during procedure', at 5 minutes, and for 60 minutes postprocedure, readings of oxygen saturation and heart rate were recorded. The device design, optics, illumination, and software specifications were compared with the RetCam 3.ResultsStudy defined bradycardia (9 infants, 6.4%), tachycardia (3 infants, 2.1%), and hypoxia (2 infants, 1.4%) were observed but there were no clinically significant systemic changes that required intervention during or following any of the study time intervals. There was a transient increase in heart rate by 9.68 (7.53–11.83; P < 0.0001) and marginal decrease in oxygen saturation (−1.94 [−1.60 to −2.28], P < 0.0001), which started to return to baseline 5 minutes after the procedure. Transient redness was seen in two eyes (0.7%) of two infants. No other ocular adverse effects were observed.ConclusionsThe Neo is easy to use in preterm infants and being compact was readily portable. There were no significant ocular or systemic adverse effects, potentially allowing it to be a viable low-cost device for ROP screening in low resource settings.Translational RelevanceThe camera provides a safe and affordable alternative to image the retina of infants by using novel illumination and lens mechanics and has the potential of worldwide acceptance.

03:09 PM Abstract No. 219 Local immunotherapy: Intra-arterial liver tumor vaccination in a pig model of metastatic pancreatic cancer

Locoregional therapy lacks the ability to treat systemic disease. Systemic chemotherapy or immunotherapy has significant systemic side effects. Here, we present a proof-of-concept of intra-arterial immunotherapy using saponins (a vaccine adjuvant) in a pig tumor model. Liver and peripancreatic tumors were induced in an Oncopig (a transgenic pig with Cre-inducible p53 and Kras mutations) using an adenoviral vector carrying the Cre recombinase gene. A lipiodol/saponin emulsion was injected selectively into a branch of the hepatic artery through a 4 F catheter. Response to therapy was evaluated on contrast-enhanced CT and necropsy. As a negative control, selective hepatic artery embolization using 100-300 micron Embospheres was performed in a different pig. After selective hepatic artery immunoembolization using the lipiodol/saponin emulsion, CT performed 3 days later showed 19% decrease in size of the embolized liver tumors (n=2), 71% decrease in size of an unembolized liver tumor (n=1), and 25% decrease in size of peripancreatic tumors (n=2). On histology, tumor-infiltrating lymphocytes were seen in the necrotic liver tumors, and no viable tumor cells were seen in the liver or peripancreatic tumors. In the negative control pig (n=1), selective hepatic artery embolization using Embospheres resulted in tissue necrosis without a detectable local immune response on histology. In a pig model, intra-arterial tumor vaccination using lipiodol/saponin emulsion resulted in tumor-infiltrating lymphocytes, tumor necrosis, and regression of both intrahepatic and extrahepatic tumors. Additional experiments are necessary to confirm these encouraging preliminary results.

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.

Effect of Intra-arterial Nimodipine on Cerebral Oxygen Saturation and Systemic Hemodynamic Indices in Patients With Cerebral Vasospasm: A Prospective Cohort Study.

Intra-arterial nimodipine (IaN) is used in the management of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The impact of IaN therapy on regional cerebral oxygen saturation (rScO2) assessed by near infra-red spectroscopy, and dynamic cardiac indices, is currently unknown. This study assessed the effect of IaN on rScO2 and systemic hemodynamic indices during IaN therapy for cerebral vasospasm after aSAH. This prospective cohort study was conducted in 20 patients over sixteen month period after ethics committee approval and informed consent. Patients with angiographic evidence of vasospasm received IaN 3mg over 30 minutes in the spastic vessels. Data regarding rScO2 heart rate (HR), mean blood pressure (MBP) cardiac index (CI), stroke volume index (SVI), stroke volume variation (SVV), and total peripheral resistance index (TPRI) were collected during IaN treatment. The primary outcome measure was change in rScO2 after IaN therapy. There was no significant change from baseline in ipsilateral and contralateral rScO2 after IaN administration (mean difference [MD], 0.2; 95% confidence interval [CI], -2.1 to 1.6; P=0.804, and 1.3; -1.1 to 3.8; P=0.276, respectively). There was a significant decrease in MBP and TPRI (MD, -12.4; 95% CI, -6.6 to -18.2; P<0.001, and -674.3; -374.9 to -973.7; P<0.001, respectively) and increase in SVI and CI (MD, 7.5; 95% CI, 14.4 to 0.6; P=0.035 and 0.7; 0.9 to 0.4; P<0.001, respectively) after IaN therapy. HR and SVV were unchanged. IaN for aSAH-related cerebral vasospasm did not improve rScO2 but was associated with significant systemic hemodynamic effects, including a decrease in MBP and TPRI. These hemodynamic changes might offset any potential effects of IaN to improve rScO2.

Nanotechnology for the treatment of deep endometriosis: uptake of lipid core nanoparticles by LDL receptors in endometriotic foci

OBJECTIVE:Rapidly dividing cells in multiple types of cancer and inflammatory diseases undergo high low density lipoprotein (LDL) uptake for membrane synthesis, and coupling an LDL-like nanoemulsion, containing lipid nanoparticles (LDE) to a chemotherapeutic agent efficiently targets these cells without significant systemic effects. This was a prospective exploratory study that evaluated the uptake of a radioactively labeled LDE emulsion by receptors of endometriotic foci and the capacity of the LDE for cellular internalization.METHODS:The lipid profile of each patient was determined before surgery, and labeled LDE were injected into fourteen patients with intestinal or nonintestinal endometriosis. The radioactivity of each tissue sample (intestinal endometriosis, nonintestinal endometriosis, healthy peritoneum, or topical endometrium) was measured.RESULTS:The group with intestinal endometriosis presented higher levels of plasma LDL but lower LDE uptake by foci than the nonintestinal group, suggesting less cell division and more fibrosis. The uptake of LDE was highest in the topical endometrium, followed by the healthy peritoneum, and lowest in the endometriotic lesion. Since the endometriotic foci showed significant LDE uptake, there was likely increased consumption of LDL by these cells, similar to cells in cancers and inflammatory diseases. Plasma cholesterol levels had no influence on LDE uptake, which showed that the direct delivery of the nanoemulsion to target tissues was independent of serum lipoproteins. There were no significant differences in the parameters (p>0.01) because of the small sample size, but the findings were similar to those of previous studies.CONCLUSION:Nanotechnology is a promising therapeutic option for surgery and hormonal blockage for deep endometriosis, with a lower complication rate and no systemic side effects.

Anti-tumour necrosis factor biological therapies for the treatment of uveitic macular oedema (UMO) for non-infectious uveitis.

Non-infectious uveitis describes a heterogenous group of ocular disorders characterised by intraocular inflammation in the absence of infection. Uveitis is a leading cause of visual loss, most commonly due to uveitic macular oedema (UMO). Treatment is aimed at reducing disease activity by suppression of the intraocular inflammatory response. In the case of macular oedema, the aim is to restore macular architecture as quickly as possible, in order to prevent irreversible photoreceptor damage in this area. Acute exacerbations are typically managed with corticosteroids, which may be administered topically, locally or systemically. Whilst these are often rapidly effective in achieving disease control, long-term use is associated with significant local and systemic side effects, and 'steroid sparing agents' are typically used to achieve prolonged control in severe or recalcitrant disease. Anti-tumour necrosis factor (TNF) drugs block a critical cytokine in the inflammatory signalling process, and have emerged as effective steroid-sparing immunomodulatory agents in a wide range of non-ocular conditions. There is mechanistic data to suggest that they may provide a more targeted approach to disease control in UMO than other agents, but to date, these agents have predominantly been used 'off label' as the majority are not licensed for ocular use. This review aims to summarise the available literature reporting the use of anti-TNF therapy in UMO, thus developing the evidence-base on which to make future treatment decisions and develop clinical guidelines in this area. To assess the efficacy of anti-TNF therapy in treatment of UMO. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Ovid Embase; LILACS; Web of Science Conference Proceedings Citation Index- Science (CPCI-S); System for Information on Grey Literature in Europe (OpenGrey); the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 29 March 2018. We planned to include all relevant randomised controlled trials assessing the use of anti-TNF agents in treatment of UMO. No limits were applied to participant age, gender or ethnicity. The primary comparisons of this review were: anti-TNF versus no treatment or placebo; anti-TNF versus another pharmacological agent; comparison of different anti-TNF drugs; comparison of different doses and routes of administration of the same anti-TNF drug. The primary outcome measure that we assessed for this review was best-corrected visual acuity (BCVA) in the treated eye. Secondary outcome measures were anatomical macular change, clinical estimation of vitreous haze and health-related quality of life. Two review authors independently screened titles and abstracts retrieved through the database searches. We retrieved full-text reports of studies categorised as 'unsure' or 'include' after we had reviewed the abstracts. Two review authors independently reviewed each full-text report for eligibility. We resolved discrepancies through discussion. We identified no completed or ongoing trial that was eligible for this Cochrane Review. Our review did not identify any evidence from randomised controlled trials for or against the role of anti-TNF agents in the management of UMO. Although there are a number of high-quality randomised controlled trials that demonstrate the efficacy of anti-TNF agents in preventing recurrence of inflammation in uveitis, the reported study outcomes do not include changes in UMO. As a result, there were insufficient data to conclude whether there was a significant treatment effect specifically for UMO. Future trials should be designed to include quantitative measures of UMO as primary study outcomes, for example by reporting the presence or absence of UMO, or by measuring central macular thickness for study participants. Furthermore, whilst UMO is an important complication of uveitis, we acknowledge that uveitis is associated with many significant structural and functional complications. It is not possible to determine treatment efficacy based on a single outcome measure. We recommend that future reviews of therapeutic interventions in uveitis should use composite measures of treatment response comprising a range of potential complications of disease.

Attenuating MKRN1 E3 ligase-mediated AMPKα suppression increases tolerance against metabolic stresses in mice.

The 5' adenosine monophosphate-activated protein kinase (AMPK) is an essential energy sensor in the cell, which, at low energy levels, instigates the cellular energy-generating systems along with suppression of the anabolic signaling pathways. The activation of AMPK through phosphorylation is a well-known process; however, activation alone is not sufficient, and knowledge about the other regulatory networks of post-translational modifications connecting the activities of AMPK to systemic metabolic syndromes is important, which is still lacking. The recent studies on Makorin Ring Finger Protein 1 (MKRN1) mediating the ubiquitination and proteasome-dependent degradation of AMPK( implicate that the post-translational modification of AMPK, regulating its protein homeostasis, could impose significant systemic metabolic effects (Lee et al. Nat Commun 9:3404). In this study, MKRN1 was identified as a novel E3 ligase for both AMPKα1 and α2. Mouse embryonic fibroblasts, genetically deleted for Mkrmn1, and Ampkα1 and α2, became stabilized with the suppression of lipogenesis pathways and an increase in nutrient consumption and mitochondria regeneration. Of note, the Mkrn1 knockout mice fed normal chow displayed no obvious phenotypic defects or abnormality, whereas the Mkrn1-null mice exhibited strong tolerance to metabolic stresses induced by high-fat diet (HFD). Thus, these mice, when compared with the HFD-induced wild type, were resistant to obesity, diabetes, and non-alcoholic fatty liver disease. Interestingly, in whole-body Mkrn1 knockout mouse, only the liver and white and brown adipose tissues displayed anincrease in the active phosphorylated AMPK levels, but no other organs, such as the hypothalamus, skeletal muscles, or pancreas, displayed such increases. Specific ablation of MKRN1 in the mouse liver using adenovirus prevented HFD-induced lipid accumulation in the liver and blood, implicating MKRN1 as a possible therapeutic target for metabolic syndromes, such as obesity, type II diabetes, and fat liver diseases. This study would provide a crucial perspective on the importance of post-translational regulation of AMPK in metabolic pathways and will help researchers develop novel therapeutic strategies that target not only AMPK but also its regulators.

Injectable Hydrogels as Unique Platforms for Local Chemotherapeutics-Based Combination Antitumor Therapy.

Different strategies of chemotherapeutics-based combination cancer therapy have presented enhanced antitumor efficiency and are widely used in clinical cancer treatments. However, several drawbacks of the systems for systemic administration, including low drug accumulation at tumor sites and significant systemic side effects limit their efficacy and application in the clinic. Local drug co-delivery systems based on injectable hydrogels may have considerable advantages, such as a facile drug-delivery procedure, targeted delivery of antitumor agents to tumor sites in a sustained manner, and markedly reduced systemic toxicities. Thus, in recent years, these systems have received increasing attention and consequently various injectable hydrogels have been tested as platforms for local chemotherapeutics-based combination antitumor therapy. In this review, the focus is on recent advances in injectable hydrogel-based drug co-delivery systems for local combination antitumor therapy, including multiple chemotherapeutics combination therapy, chemo-immunotherapy, chemo-radiotherapy, and hyperthermia-chemotherapy. Moreover, the rationale and preparation of local co-delivery systems are summarized and discussed.

Effects of Hochuekkito combined with pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) has significant systemic effects, such as weight loss, which affects exercise capacity, health-related quality of life (HRQOL) and survival. The traditional herbal medicine, Hochuekkito (TJ-41), improves the nutritional status and decreases systemic inflammation in patients with COPD. However, to date, the additive effect of TJ-41 on pulmonary rehabilitation (PR) in patients with COPD has not been researched comprehensively. The purpose of the present study was to investigate the efficacy and safety of adding TJ-41 to PR for patients with COPD. Thirty-three malnourished patients with COPD were randomly assigned to receive low-intensity exercise with (TJ-41 group) or without (control group) TJ-41 treatment for 12 weeks. The primary outcome was the change in the 6-min walk distance (6MWD). Secondary outcomes included changes in the body composition, peripheral muscle strength, modified Medical Research Council dyspnea score, visual analog scale (VAS) score for dyspnea, VAS score for fatigue and COPD assessment test (CAT) score. After the 12-week treatment, body weight and percent ideal body weight were significantly increased in the TJ-41 group (P<0.05), but not in the control group. After the 12-week treatment, the modified Medical Research Council dyspnea score, VAS score for dyspnea, VAS score for fatigue and total CAT score decreased significantly in the TJ-41 group (all P<0.05), but not in the control group. There were no significant differences in the 6MWD and peripheral muscle strength between baseline and after 12 weeks of treatment in either group. No adverse effects were noted with the use of TJ-41. It was concluded that the addition of TJ-41 to PR may benefit malnourished patients with COPD with respect to dyspnea and HRQOL.

Hepatitis E Virus infection seroprevalence and the associated risk factors in animals raised in Ibadan, Nigeria

ABSTRACTHepatitis E (HE) is an important viral hepatitis of global public and livestock health, and food security significance due to the ubiquitous distribution, multiple transmission route and zoonotic potentials. HE is also endemic in most developing countries including Nigeria. This study therefore investigates the seroprevalence and associated risk factors of HEV infection in pigs raised in Ibadan, Nigeria. Taking an analytical cross-sectional study design, 176 animals (comprising 120 pigs, 26 goats, and 30 cattle) were randomly sampled at the Bodija Municipal abattoir, Ibadan. Serum samples and demographic information were collected for HEV antibody detection (using a commercial recombinant genotype-3 antigen ELISA kit) and risk factors, respectively. A 57.5% (69/120) HEV seroprevalence was reported in the pigs while 0% prevalence was reported in the goats and cattle. In the pigs, a significant age-based HEV seropositivity difference (χ2 = 5.30; OR = 0.20–0.89; p = 0.02) with a higher seroprevalence in the < 6 months (68.42%; 39/57) compared to the > 6 months age group (47.62%; 20/63) was reported. No significant sex, breed and husbandry system effect on HEV seroprevalence was detected in the pigs. This study therefore underscores the high HEV seroprevalence and age-based odds of HEV-exposure in pigs in Ibadan, Nigeria.

In Vivo Translation of Peptide-Targeted Drug Delivery Systems Discovered by Phage Display

Therapeutic compounds with narrow therapeutic windows and significant systemic side effects benefit from targeted drug delivery strategies. Peptide-protein interactions are often exploited for targeting, with phage display a primary method to identify high-affinity peptide ligands that bind cell surface and matrix bound receptors preferentially expressed in target tissues. After isolating and sequencing high-binding phages, peptides are easily synthesized and chemically modified for incorporation into drug delivery systems, including peptide-drug conjugates, polymers, and nanoparticles. This review describes the phage display methodology to identify targeting peptide sequences, strategies to functionalize drug carriers with phage-derived peptides, specific examples of drug carriers with in vivo translation, and limitations and future applications of phage display to drug delivery.

This issue of ACTA

This issue of <i>ACTA</i>