A Systematic Review and Meta-Analysis of Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections in Type-2 Diabetes.

Diabetes mellitus (DM) has a growing prevalence worldwide, even in developing countries. Many antidiabetic agents are used to improve glycemic control; however, in cases of an insufficient outcome, insulin is administered. Yet, the timing of proper insulin administration is still a subject of intense research. To date, there have been no recommendations or guidelines for the use of continuous subcutaneous insulin infusion (CSII) in Type 2 Diabetes Mellitus (T2DM). In the present study, we have performed a meta-analysis to evaluate the use of CSII in patients with T2DM. An extensive literature search was conducted through the electronic databases Pubmed, Clinicaltrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) from October 2019-May 2022, for interventional studies related to T2DMI and CSII versus multiple daily injections (MDI). We included articles published in the English language only, yielding a total of thirteen studies. We found better outcomes in patients receiving CSII, in regard to glycated hemoglobin (HbA1c) and total insulin dose. In contrast, fasting plasma glucose and body weight did not show statistically significant differences between the two groups. Our analyses showed that CSII could be beneficial in patients with T2DM in order to achieve their glucose targets.

Cytotoxic Effect of Rosmarinus officinalis Extract on Glioblastoma and Rhabdomyosarcoma Cell Lines.

Rosmarinus officinalis is a well-studied plant, known for its therapeutic properties. However, its biological activity against several diseases is not known in detail. The aim of this study is to present new data regarding the cytotoxic activity of a hydroethanolic extract of Rosmarinus officinalis on glioblastoma (A172) and rhabdomyosarcoma (TE671) cancer cell lines. The chemical composition of the extract is evaluated using liquid chromatography combined with time-of-flight mass spectrometry, alongside its total phenolic content and antioxidant activity. The extract showed a promising time- and dose-dependent cytotoxic activity against both cell lines. The lowest IC50 values for both cell lines were calculated at 72 h after treatment and correspond to 0.249 ± 1.09 mg/mL for TE671 cell line and 0.577 ± 0.98 mg/mL for A172 cell line. The extract presented high phenolic content, equal to 35.65 ± 0.03 mg GAE/g of dry material as well as a strong antioxidant activity. The IC50 values for the antioxidant assays were estimated at 12.8 ± 2.7 µg/mL (DPPH assay) and 6.98 ± 1.9 µg/mL (ABTS assay). The compound detected in abundance was carnosol, a phenolic diterpene, followed by the polyphenol rosmarinic acid, while the presence of phenolic compounds such as rhamnetin glucoside, hesperidin, cirsimaritin was notable. These preliminary results suggest that R. officinalis is a potential, alternative source of bioactive compounds to further examine for abilities against glioblastoma and rhabdomyosarcoma.

The Impact of GLP1 Agonists on Bone Metabolism: A Systematic Review.

Background and Objectives: The association between diabetes mellitus and increased risk of bone fractures has led to the investigation of the impact of antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP1RAs) are a relatively novel and promising class of anti-hyperglycemic drugs. In addition to their blood glucose lowering action, GLP1RAs seem to have additional pleiotropic properties such as a beneficial skeletal effect; although the underlying mechanisms are not completely understood. The present systematic review summarizes current evidence about GLP1RAs and their effects on bone metabolism and fracture. Methods: An extensive literature search was conducted based on electronic databases namely, PubMed, Google Scholar and Cochrane Central Register of Controlled Trials (CENTRAL) through October 2019 to January 2020 for articles related to bone mineral density, diabetes mellitus and GLP1RAs. We included articles published in English. Finally, we included four randomized controlled trials, three meta-analyses, a case-control study and a population-based cohort analysis. Results: Based on the articles included, the animal studies indicated the salutary skeletal effects of GLP1RAs in opposition to what has been commonly observed in human studies, showing that these agents have no impact on bone mineral density (BMD) and the turnover markers. Moreover, it was demonstrated that GLP1 was not associated with fracture risk as compared to other anti-hyperglycemic drugs. Conclusions: Findings from this systematic review have demonstrated the neutral impact of GLP1RAs on BMD. Moreover, further double-blind randomized controlled trials are needed to draw more meaningful and significant conclusions on the efficacy of GLP1RAs on BMD.

Anti-VEGF intravitreal injections in the era of COVID-19: responding to different levels of epidemic pressure.

PURPOSE: Following the first wave of the COVID-19 pandemic in early 2020, the easing of strict measures to reduce its spread has led to a resurgence of cases in many countries at both the national and local level. This article addresses how guidance for ophthalmologists on managing patients with retinal disease receiving intravitreal injections of anti-vascular endothelial growth factor (VEGF) during the pandemic should be adapted to the local epidemic pressure, with more or less stringent measures implemented according to the ebb and flow of the pandemic. METHODS: The Vision Academy's membership of international retinal disease experts analyzed guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic and graded the recommendations according to three levels of increasing epidemic pressure. The revised recommendations were discussed, refined, and voted on by the 14-member Vision Academy Steering Committee for consensus. RESULTS: Protocols to minimize the exposure of patients and healthcare staff to COVID-19, including use of personal protective equipment, physical distancing, and hygiene measures, should be routinely implemented and intensified according to local infection rates and pressure on the hospital/clinic or healthcare system. In areas with many COVID-19-positive clusters, additional measures including pre-screening of patients, postponement of non-urgent appointments, and simplification of complex intravitreal anti-VEGF regimens should be considered. Treatment prioritization for those at greatest risk of irreversible vision loss should be implemented in areas where COVID-19 cases are increasing exponentially and healthcare resources are strained. CONCLUSION: Consistency in monitoring of local infection rates and adjustment of clinical practice accordingly will be required as we move forward through the COVID-19 era. Ophthalmologists must continue to carefully weigh the risk-benefits to minimize the exposure of patients and healthcare staff to COVID-19, ensure that patients receive sight-saving treatment, and avoid the potential long-term impact of prolonged treatment postponement.

EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT USING A TREAT-AND-EXTEND REGIMEN FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: The ARIES Study: A Randomized Clinical Trial.

BACKGROUND/PURPOSE: Treating neovascular age-related macular degeneration with intravitreal aflibercept treat-and-extend (T&E) can reduce treatment burden. ARIES assessed whether intravitreal aflibercept early-start T&E was noninferior to late-start T&E. METHODS: A randomized, open-label, Phase 3b/4 study that included treatment-naïve patients aged ≥50 years with the best-corrected visual acuity 73-25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg intravitreal aflibercept at Week (W) 0, W4, W8, and W16. At W16, patients were randomized 1:1 to early-start (2W interval adjustments) or late-start T&E (8W intervals until W48 then 2W interval adjustments). Primary endpoint: the best-corrected visual acuity change from randomization to W104. RESULTS: Two-hundred seventy-one patients were randomized. The mean (SD) best-corrected visual acuity at baseline was 60.2 (12.1; early-T&E) and 61.3 (10.8; late-T&E) letters. The mean (SD) best-corrected visual acuity change (W16-104) was -2.1 (11.4) versus -0.4 (8.4) letters (early-T&E vs. late-T&E; least-squares mean difference: -2.0; 95% confidence interval: -4.75 to 0.71; P = 0.0162 for noninferior); +4.3 (13.4) versus +7.9 (11.9) letters (W0-104). The mean (SD) number of injections was 12.0 (2.3) versus 13.0 (1.8). From baseline to W104, 93.4% and 96.2% maintained best-corrected visual acuity; the mean (SD) central retinal thickness change was -161.6 (135.6) µm and -158.6 (125.1) µm. The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients. CONCLUSION: Outcomes were similar between patients with neovascular age-related macular degeneration treated with an intravitreal aflibercept early-T&E or late-T&E regimen after initial dosing, with one injection difference over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02581891 https://clinicaltrials.gov/ct2/show/NCT02581891. Supplemental Digital Contents (files 1 http://links.lww.com/IAE/B419).

Fractal Dynamics in the RR Interval of Craniopharyngioma and Adrenal Tumor in Adolescence.

Heart rate variability (HRV) is the physiological phenomenon of variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval and/or RR variability (where R is a point corresponding to the peak of the QRS complex of the ECG wave and RR is the interval between successive Rs) and other components extracted from these. HRV is a field of research interest in pathophysiology (in general) and cancer prognosis (more specifically). Adolescents with adrenal tumor or craniopharyngioma were investigated, herein. Αutonomic nervous system recordings were performed with Task Force® Monitor (gold standard of the Task Force of the European Society of Cardiology and the North American Society of Electrophysiology). The RR interval (RRI) time series calculations were performed with the MatLab® computational environment and included the estimation of fractal dimension and Lyapunov exponent. Fractal dimensions were calculated by estimating N and R, where N represents the number of "squares" needed for a fractal shape to be completed and their respective "square size" R. By definition, if the first derivative of d ln N/d ln R remains constant for a space of R, this is the fractal dimension of the shape, in the present case of the time series trajectory. We found that RRI manifested different fractal dynamics, thus, a complex pattern of progression in these two morbid entities, suggesting the need for further investigation in ANS contribution to tumor pathophysiology.

Adults' Stress Response to Unexpected Oral and Arithmetic Tasks in Supine Position.

To study the autonomic nervous system (ANS) and hypothalamus pituitary adrenal axis (HPA) response before and after mental stress test in healthy adolescents and adults, is the aim of this study. Twenty healthy adults (aged 23-46 years) entered the Trier Social Stress Test (TSST), after informed consent signing. The procedure was modified: (a) the participants' position was supine as ANS system changes were to be assessed, (b) the interviewers were entering and departing from the session room. Salivary cortisol (marker of HPA axis response) samples were collected at the end of the baseline and 20 min after TSST. ANS of the heart was measured with CNS Task Force Monitor in supine position and was recorded during relaxation (15 min) and after TSST. The sympathovagal balance (LF/HF ratio) for each phase was computed. Evaluations were conducted with R. The HPA axis disturbance between baseline and 20 min after TSST was significant (g = 0.545 [0.092, 0.999]) and in adolescents (whereas, the mean intervals of the sinus rhythm RR parameter were found largely changed (g = 0.834 [0.340, 1.327]). The sympathovagal balance component of heart rate variability LF/HF ratio was founded unchanged (g = 0.215 [-0.211, 0.641]). RR changes were not correlated to salivary cortisol concentrations at any phase. Mean RRIs and salivary cortisol levels were significantly increased, although HPA axis showed medium size effect. However, the systems effectively counterbalance the perturbation, since the LF/HF ratio does not change. Our findings suggest further research in stress effect on HPA and ANS cross-talk and dynamics.

Kisspeptin and the Genetic Obesity Interactome.

BACKGROUND: Kisspeptin (encoded by the KISS1 gene in humans) is an excitatory neuromodulatory peptide implicated in multiple homeostatic systems, including anti-oxidation, glucose homeostasis, nutrition, locomotion, etc. Therefore, in the current obesity epidemic, kisspeptin is gaining increasing interest as a research objective. AIM: To construct an updated interactome of genetic obesity, including the kisspeptin signal transduction pathway. METHODS: Kisspeptin and obesity-related genes or gene products were extracted from the biomedical literature, and a network of functional associations was created. RESULTS: The generated network contains 101 nodes corresponding to gene/gene products with known and/or predicted interactions. In this interactome, KISS1 and KISS1R are connected directly to the luteinizing hormone receptor (LHCGR), gonadotropin-releasing hormone receptor (GNRH1), and indirectly, through the latter, to proopiomelanocortin (POMC), glucagon, leptin (LEP), and/or pro-protein convertase subtilisin/kexin-type 1 (PCSK1), all of which are critically implicated in obesity disorders. CONCLUSIONS: Our updated obesidome includes kisspeptin and its connections to the genetic obesity signalosome with 12 major hubs: glucagon (GCG), insulin (INS), arginine vasopressin (AVP), G protein subunit beta 1 (GNB1) and proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), gonadotropin-releasing hormone 1 (GNRH1), adrenoceptor beta 2 and 3 (ADRB2-3), glucagon-like peptide 1 receptor (GLP1R), and melanocortin 3 receptor (MC3R) genes were identified as major "hubs" for genetic obesity, providing novel insight into the body's energy homeostasis.

Entropy in Cardiac Autonomic Nervous System of Adolescents with General Learning Disabilities or Dyslexia.

Heart rate variability (HRV) represents one of the two key markers of the autonomic nervous system. It is measured by the time variation in the beat-to-beat interval, while the period between successive beats is defined as the RR interval (RRI). Its components are classified as linear and non-linear. In the field of psychophysiology, HRV is investigated as a key player of possible predictive or diagnostic value. Female adolescents with general learning disabilities or dyslexia were recruited at the Center for Adolescent Medicine and UNESCO Chair on Adolescent Health Care of the National and Kapodistrian University of Athens. Adolescents were further assessed for HRV. Data were collected with the Task Force® Monitor at the Cardiovascular Laboratory of the Biomedical Research Foundation of the Academy of Athens. The RRI time-series were estimated for approximate entropy (AE), conditional entropy (CE), corrected conditional entropy (CCE), fuzzy entropy (FE), permutation entropy (PE), sample entropy (SE), and Shannon's entropy (ShE). RRI manifested complex dynamics, indicating a complex pattern of progression. This finding suggests that RRI conceals non-linear dynamics, which if investigated in depth could provide more knowledge on the relation between RRI and learning disorders.

Systems Approaches in the Common Metabolomics in Acute Lymphoblastic Leukemia and Rhabdomyosarcoma Cells: A Computational Approach.

Acute lymphoblastic leukemia is the most common childhood malignancy. Rhabdomyosarcoma, on the other hand, is a rare type of malignancy which belongs to the primitive neuroectodermal family of tumors. The aim of the present study was to use computational methods in order to examine the similarities and differences of the two different tumors using two cell lines as a model, the T-cell acute lymphoblastic leukemia CCRF-CEM and rhabdomyosarcoma TE-671, and, in particular, similarities of the metabolic pathways utilized by two different cell types in vitro. Both cell lines were studied using microarray technology. Differential expression profile has revealed genes with similar expression, suggesting that there are common mechanisms between the two cell types, where some of these mechanisms are preserved from their ancestor embryonic cells. Expression of identified species was modeled using known functions, in order to find common patterns in metabolism-related mechanisms. Species expression manifested very interesting dynamics, and we were able to model the system with elliptical/helical functions. We discuss the results of our analysis in the context of the commonly occurring genes between the two cell lines and the respective participating pathways as far as extracellular signaling and cell cycle regulation/proliferation are concerned. In the present study, we have developed a methodology, which was able to unravel some of the underlying dynamics of the metabolism-related species of two different cell types. Such approaches could prove useful in understanding the mechanisms of tumor ontogenesis, progression, and proliferation.

Bioinformatics Analyses of Spatial Peripheral Circadian Clock-Mediated Gene Expression of Glucocorticoid Receptor-Related Genes.

Glucocorticoids are ubiquitous, pleotropic steroid hormones secreted from the cortices of the adrenal glands in a circadian fashion under the strong influence of the central Clock center located in the suprachiasmatic nuclei (SCN) of the hypothalamus. In previous work, we reported that the circadian transcription factor CLOCK and its heterodimer partner BMAL1 suppress the transcriptional activity of the glucocorticoid receptor (GR) by acetylating a lysine cluster located in its hinge region between the DNA- and ligand-binding domains. This regulation of GR transcriptional activity by CLOCK/BMAL1 functions as a counter-regulatory loop against the diurnally fluctuating circulating glucocorticoids. Here, we have performed further analyses of our data using bioinformatics and computational methods. Gene expression data were analyzed using unsupervised machine learning methods, such as hierarchical clustering, k-means, Naïve Bayes classification, and polynomial regression analyses. We determined expression patterns of Clock-related genes, unraveled the dynamics of spatial data, and defined the temporal function of Clock-mediated GR-regulated genes. Gene expressions manifested nonlinear dynamics, possibly because we obtained dynamic results from stationary measurements. The mechanics of the circadian rhythms are still obscure, and more studies are required to understand how such rhythms influence mammalian physiology.

Genotypic and Clinical Analysis of a Thalassemia Major Cohort: An Observational Study.

Thalassemia major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients are suffering from various health conditions, including endocrinopathies and low bone mineral density. The aim of the present study was to investigate the correlation between clinical and biochemical parameters as well as to identify possible relations in a genotype to phenotype pattern. Sixty-four patients with TM (32 men and 32 women) participated in a cross-sectional study design. The patients were recruited from "Aghia Sofia" Children's Hospital. Clinical and biochemical parameters were evaluated as well as specific mutations were identified. We have found significant correlations between biochemical parameters and iron chelation, hormone replacement treatment as well as TM genotype and hematocrit and T-score. To conclude, the current study showed that clinical parameters of TM patients correlate significantly with both biochemical factors and genotypical patient parameters. Our present study showed that there is a connection between genotype and phenotype as, for example, the identified relation between hematocrit and T-scores and TM-specific mutations. This connection indicates that there is still much more to learn about the role of mutations not only in the disease itself but also in the underlying comorbidities.

Urticaria from the Neurodermatological Perspective: A Temporal Analysis of Urticaria and Cognition.

Chronic spontaneous urticaria (CSU, or CU) is a disease that significantly affects the quality of life of patients. The connection between the cognitive state of an individual and dermatological diseases has been previously reported, and it is known, although not thoroughly investigated, that there is a cognitive and quality of life relation to dermal pathologies. Urticaria is a chronic disease that requires a specialized approach to diagnosis and treatment but also a holistic approach with respect to the consideration of both the pathophysiology of the disease and the cognition status of the patient. The present study aims at analyzing CU score and cognitive indexes with respect to time, as a time series and their subsequent interactions. We have attempted to model the investigated time series in order to unravel possible causative relationships between cognitive/quality of life factors and urticaria. One hundred and eleven patients (29 males/82 females) admitted to our department were diagnosed with CU. CU was estimated on UAS7 score basis, which was used in order to define disease severity. Indexes used for assessing the cognitive and quality of life of patients' status included the Urticaria Control Test (UCT) and Dermatology Life Quality Index (DLQI). Significant correlations were found between UAS7 score and the UCT and DLQI scores, respectively. Interestingly, each score time series was modelled by different sets of equations, indicating the unique effect each one has on the disease, as well as that each score probably is manifested by a different pathophysiological mechanism.

Dual Mechanisms of Metabolism and Gene Expression of the CCRF-CEM Leukemia Cells under Glucocorticoid Treatment.

BACKGROUND: Glucocorticoids play an essential part in anti-leukemic therapies, but resistance is a crucial event for the prognosis of the disease. Glucocorticoids influence the metabolic properties of leukemic cells. The inherent plasticity of clinically evolving cancer cells justifies the characterization of drug-induced early oncogenic pathways, which represent a likely source of detrimental secondary effects. AIM: The present work aims to investigate the effect of glucocorticoids in metabolic pathways in the CCRF-CEM leukemic cells. Metabolic factors and gene expression profiles were examined in order to unravel the possible mechanisms of the CCRF-CEM leukemic cell growth dynamics. METHODS: CCRF-CEM cells were used as a model. Cells were treated with prednisolone with concentrations 0-700 µM. Cell culture supernatants were used for glucose, lactic acid, LDH, Na+, K+ and Ca++ measurements. Cytotoxicity was determined with flow cytometry. Microarray analysis was performed using two different chips of 1.2 k and 4.8 k genes. Gene Ontology enrichment analysis was applied to find metabolism- and GC-related genes. RESULTS: Higher prednisolone concentrations inhibited glucose uptake, without exhibiting any cytotoxic effects. Glucose consumption did not correlate with the total cell population, or the viable population, indicating that growth is not directly proportional to glucose consumption. Neither of the subpopulations, i.e., viable, necrotic, or apoptotic cells, contributed to this. CONCLUSIONS: Different types of leukemic cells seem to exhibit different patterns of glucose metabolism. Both resistant and sensitive CCRF-CEM cells followed the aerobic pathway of glycolysis. There is probably a rapid change in membrane permeability, causing a general shutdown towards everything that is outside the cell. This could in part also explain the observed resistance. Glucocorticoids do not enter the cell passively anymore and therefore no effects are observed. Based on our observations, ion concentrations are measurable factors both in vitro and in vivo, which makes them possible markers of glucocorticoid cytotoxic action.

Gravitational Influence on Human Living Systems and the Evolution of Species on Earth.

Gravity constituted the only constant environmental parameter, during the evolutionary period of living matter on Earth. However, whether gravity has affected the evolution of species, and its impact is still ongoing. The topic has not been investigated in depth, as this would require frequent and long-term experimentations in space or an environment of altered gravity. In addition, each organism should be studied throughout numerous generations to determine the profound biological changes in evolution. Here, we review the significant abnormalities presented in the cardiovascular, immune, vestibular and musculoskeletal systems, due to altered gravity conditions. We also review the impact that gravity played in the anatomy of snakes and amphibians, during their evolution. Overall, it appears that gravity does not only curve the space-time continuum but the biological continuum, as well.

Inflammation and tissue homeostasis: the NF-κB system in physiology and malignant progression.

Disruption of tissue function activates cellular stress which triggers a number of mechanisms that protect the tissue from further damage. These mechanisms involve a number of homeostatic modules, which are regulated at the level of gene expression by the transactivator NF-κB. This transcription factor shifts between activation and repression of discrete, cell-dependent gene expression clusters. Some of its target genes provide feedback to NF-κB itself, thereby strengthening the inflammatory response of the tissue and later terminating inflammation to facilitate restoration of tissue homeostasis. Disruption of key feedback modules for NF-κB in certain cell types facilitates the survival of clones with genomic aberrations, and protects them from being recognized and eliminated by the immune system, to enable thereby carcinogenesis.

Guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic.

PURPOSE: There is an urgent need to address how to best provide ophthalmic care for patients with retinal disease receiving intravitreal injections with anti-vascular endothelial growth factor agents during the ongoing global COVID-19 pandemic. This article provides guidance for ophthalmologists on how to deliver the best possible care for patients while minimizing the risk of infection. METHODS: The Vision Academy's Steering Committee of international retinal disease experts convened to discuss key considerations for managing patients with retinal disease during the COVID-19 pandemic. After reviewing the existing literature on the issue, members put forward recommendations that were systematically refined and voted on to develop this guidance. RESULTS: The considerations focus on the implementation of steps to minimize the exposure of patients and healthcare staff to COVID-19. These include the use of personal protective equipment, adherence to scrupulous hygiene and disinfection protocols, pre-screening to identify symptomatic patients, and reducing the number of people in waiting rooms. Other important measures include triaging of patients to identify those at the greatest risk of irreversible vision loss and prioritization of treatment visits over monitoring visits where possible. In order to limit patient exposure, ophthalmologists should refrain from using treatment regimens that require frequent monitoring. CONCLUSION: Management of patients with retinal disease receiving intravitreal injections during the COVID-19 pandemic will require adjustment to regular clinical practice to minimize the risk of exposure of patients and healthcare staff, and to prioritize those with the greatest medical need. The safety of patients and healthcare staff should be of paramount importance in all decision-making.

SUSPENDING TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN CASES OF FUTILITY.

PURPOSE: To provide guidance on the management of patients with neovascular age-related macular degeneration and its subtypes who respond poorly to anti-vascular endothelial growth factor (anti-VEGF) therapy, and to identify cases where suspending anti-VEGF treatment may be warranted. METHODS: Through a literature review and the combined knowledge and clinical experience of retinal experts, the Steering Committee of the Bayer-sponsored Vision Academy developed an algorithm for determining when to suspend anti-VEGF treatment of neovascular age-related macular degeneration in cases of futility. RESULTS: Consideration of factors that may cause suboptimal response to anti-VEGF therapy, such as undertreatment or misdiagnosis of the underlying condition, and factors that may preclude continued treatment, such as injection- or drug-induced complications, is necessary for adjusting treatment protocols in patients who respond poorly to anti-VEGF. If poor response to treatment persists after switching to an alternative anti-VEGF agent and no change in response is observed after withholding treatment for a predetermined period of time ("treatment pause"), anti-VEGF treatment may be considered futile and should be suspended. CONCLUSION: This publication introduces an algorithm to guide the management of neovascular age-related macular degeneration in patients showing poor response to anti-VEGF treatment and provides expert guidance for suspending anti-VEGF treatment in cases of futility.

The Non-Coding RNA GAS5 and Its Role in Tumor Therapy-Induced Resistance.

The growth arrest-specific transcript 5 (GAS5) is a >200-nt lncRNA molecule that regulates several cellular functions, including proliferation, apoptosis, invasion and metastasis, across different types of human cancers. Here, we reviewed the current literature on the expression of GAS5 in leukemia, cervical, breast, ovarian, prostate, urinary bladder, lung, gastric, colorectal, liver, osteosarcoma and brain cancers, as well as its interaction with various miRNAs and its effect on therapy-related resistance in these malignancies. The general consensus is that GAS5 acts as a tumor suppressor across different tumor types and that its up-regulation results in tumor sensitization to chemotherapy or radiotherapy. GAS5 seems to play a previously unappreciated, but significant role in tumor therapy-induced resistance.

Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature.

Hypercalcemia of malignancy is the most common life-threatening metabolic disorder in patients with advanced stage cancers and is a sign of poor prognosis. It usually presents with markedly elevated calcium level and is severely symptomatic. It is associated with hematological malignancies, such as multiple myeloma, non-Hodgkin lymphoma, leukemias and solid cancers, particularly renal and breast carcinomas as well as squamous cell carcinomas of any organ. Several mechanisms have been implicated in the development of hypercalcemia of malignancy amongst them the osteolytic related hypercalcemia, parathyroid hormone-related peptide (PTHrP) mediated hypercalcemia, extrarenal 1,25 dixydroxyvitamin D (calcitriol) mediated hypercalcemia and parathyroid hormone (PTH) related hypercalcemia either ectopic in origin or in patients with parathyroid carcinoma. Clinical history and and physical examination could point towards the correct diagnosis confirmed by the above-mentioned biochemical mediators of hypercalcemia. Early diagnosis and treatment lowering calcium levels in the blood can improve symptoms and the quality of life of these patients and avoid delays for further antitumor therapy.