Cumulative Response Research Articles

Arginase inhibition by rhaponticin increases L-arginine concentration that contributes to Ca2+-dependent eNOS activation

Although arginase primarily participates in the last reaction of the urea cycle, we have previously demonstrated that arginase II is an important cytosolic calcium regulator through spermine production in a p32-dependent manner. Here, we demonstrated that rhaponticin (RPT) is a novel medicinal-plant arginase inhibitor and investigated its mechanism of action on Ca2+-dependent endothelial nitric oxide synthase (eNOS) activation. RPT was uncompetitively inhibited for both arginases I and II prepared from mouse liver and kidney. It also inhibited arginase activity in both aorta and human umbilical vein endothelial cells (HUVECs). Using both microscope and FACS analyses, RPT treatments induced increases in cytosolic Ca2+ levels using Fluo-4 AM as a calcium indicator. Increased cytosolic Ca2+ elicited the phosphorylations of both CaMKII and eNOS Ser1177 in a time-dependent manner. RPT incubations also increased intracellular L-arginine (L-Arg) levels and activated the CaMKII/AMPK/Akt/eNOS signaling cascade in HUVECs. Treatment of L-Arg and ABH, arginase inhibitor, increased intracellular Ca2+ concentrations and activated CaMKII-dependent eNOS activation in ECs of WT mice, but, the effects were not observed in ECs of inositol triphosphate receptor type 1 knockout (IP3R1−/−) mice. In the aortic endothelium of WT mice, RPT also augmented nitric oxide (NO) production and attenuated reactive oxygen species (ROS) generation. In a vascular tension assay using RPT-treated aortic tissue, cumulative vasorelaxant responses to acetylcholine (Ach) were enhanced, and phenylephrine (PE)-dependent vasoconstrictive responses were retarded, although sodium nitroprusside and KCl responses were not different. In this study, we present a novel mechanism for RPT, as an arginase inhibitor, to increase cytosolic Ca2+ concentration in a L-Arg-dependent manner and enhance endothelial function through eNOS activation.

The role of prolonged progestin treatment and factors predicting successful fertility-sparing treatment for early endometrial endometrioid adenocarcinoma

ObjectiveFertility-sparing progestin therapy is highly effective in selected young women with endometrial cancer. In present study, we attempted to evaluate the role of prolonged medication and identify factors predicting successful treatment, and also assess fertility outcomes among young women with early stage endometrial endometrioid carcinoma (EC). Study designWe retrospectively reviewed clinical data from patients aged <45 years with well-differentiated EC at presumed stage IA (without myometrial invasion) who wished to preserve fertility. They were managed with oral progestin at Kaohsiung Chang Gung Memorial Hospital between June 2005 and June 2019. ResultsForty-five patients were included with a median follow-up of 53.5 months (range 12–170 months). Forty-one patients (91.1%) had complete remission, the cumulative complete response (CR) rates at 3, 6, 9, 12, and >12 months were 17.7%, 48.9%, 60.0%, 68.9% and 91.1%, respectively. Among the 41 responders, 23 attempted to conceive and nine (39.1%) achieved pregnancy with 12 live newborn infants. Eleven (27.5%) responders experienced recurrence at a median of 22 months from CR (range 3–54 months). Multivariate Cox regression analysis revealed that non-diabetes (HR: 4.59; 95% CI: 1.62–12.98) and endometrial thickness <2 cm (HR: 0.39; 95% CI: 1.41–17.67) were significantly factors associated with treatment response. ConclusionsWe concluded that prolonged oral progestin treatment was possible with a certain proportion of responders (24.4%) being responded after one year. Diabetes controlled on metformin and endometrial thickness <2 cm could be used as surrogate markers to predict better treatment response.

Cumulative functional responses of larvae and adults of two aphidophagous ladybirds

Cumulative functional responses of larvae and adults of two aphidophagous ladybirds

Magnetic Resonance Imaging-Guided Multi-Stimulus-Responsive Drug Delivery Strategy for Personalized and Precise Cancer Treatment.

The emergence of nano-targeted controlled release liposomal drug carriers has provided a breakthrough in cancer therapy. However, their clinical efficacy is unsatisfactory, which is related to individualized differences in targeted drugs and poor in vivo release efficiency. In this paper, we prepared a class of personalized targeted and precisely controlled-release therapeutic drug carriers (GF liposomes) by co-assembling targeting and traceable o-nitrobenzyl ester lipids to propose a magnetic resonance imaging (MRI)-guided personalized in vivo targeted drug screening strategy and a multi-stimulus superimposed controlled-release strategy. Furthermore, by following the drug release process of drug-loaded liposomes (GF-D), it was found that these liposomes could rely on energy superposition to achieve more sensitive and efficient controlled drug release. In addition, the indispensable adjustment of liposome formulation for personalized MRI-based targeted therapy was verified by differential cellular uptake and in vivo magnetic resonance imaging. In the end, the 10.22-fold tumor suppression effect in the stimulus superposition group (GF-D-UV) indicates that the multi-stimulus cumulative response strategy and MRI-guided in vivo screening strategy can more effectively treat cancer. This contribution provides a concise and clever design idea for the future development of personalized precise and efficient clinical cancer therapies.

Ocimum gratissimum essential oil improved the health, innate immunity and resistance to Aeromonas hydrophila infection in Pseudoplatystoma reticulatum

The essential oil of alfavaca (Ocimum gratissimum) contains important compounds, such as 1.8-cineol and eugenol. This study evaluated the effects of diets containing alfavaca essential oil on the zootechnical performance, plasma glucose, leukocyte respiratory activity, haematology, and intestinal histomorphometry in “cachara” (Pseudoplatystoma reticulatum) challenged with Aeromonas hydrophila. A total of 300 juvenile fish, with an average total length of 14.98 ± 0.28 cm and average weight of 18.84 ± 1.22 g, distributed in 20 tanks of 80 L, were fed twice a day with a diet containing essential oil at 0.5, 1.0, or 1.5% or without its inclusion in five replicates. After 45 days, blood collection and mid-intestinal bowel were sampled, before a challenge with Aeromonas hydrophila was performed. The fish supplemented with 1.0% of essential oil presented better weight gain, mean corpuscular volume, concentration of thrombotic and neutrophils, respiratory activity of leukocytes, and height of villi (p &lt; 0.05) when compared to other groups. The cumulative mortality response was lower for fish fed 1.5% essential oil of alfavaca diets. Thus, the use of alfavaca essential oil is recommended in the diet of cachara catfish (P. reticulatum) at the level of up to 1.0% for 45 days for improvements in the zootechnical, haematological, and intestinal histomorphometric parameters.

Weed competitive ability in wheat: a peek through in its functional significance, present status and future prospects.

Weed competitive ability of a crop is one of the most widely explored aspects in the current scenario of aftermaths of synthetic herbicides such as herbicide resistant weeds emergence, residue accumulation in trophic levels; increased demands of organic produce, global climatic shifts, and other environmental issues. Further weed infestations are known to cause much more economic losses relative to crop attacks by pests. To understand the basic characteristics and underlying processes governing the competitive ability of a crop is therefore prudent, particularly in staples such as wheat. We discuss here an overview of the existing attributes of wheat-weed environment, the significance of crop competitiveness and various associated above-ground and below-ground traits (pertaining to early seed vigor and early seedling germination) discerned through biological, classical genetics and high throughput omics toolbox to provide numerous resources in terms of genome and transcriptome sequences, potential QTLs, genetic variation, molecular markers, association mapping studies, and others. Competitiveness is a cumulative response manifested as morphological, physiological, biochemical or allelochemical response ultimately driven through genetic architecture of a crop and its interaction with environment. Development of wheat competitive cultivar thus requires interdisciplinary approaches and germplasm screening to identify potential donors for competitiveness is an attractive and feasible alternative. For which utilization of landraces and other wild species, already proven to house sufficient genetic heterogeneity, thus poses a competitive advantage. Further, the availability of novel breeding techniques such as rapid generation advance could speed up the development of competitive wheat ideotype.

Cumulative life stressors and stress response to threatened preterm labour as birth date predictors.

Preterm birth represents one of the main causes of neonatal morbimortality and a risk factor for neurodevelopmental disorders. Appropriate predictive methods for preterm birth outcome, which consequently would facilitate prevention programs, are needed. We aim to predict birth date in women with a threatened preterm labour (TPL) based on stress response to TPL diagnosis, cumulative life stressors, and relevant obstetric variables. A prospective cohort of 157 pregnant women with TPL diagnosis between 24 and 31weeks gestation formed the study sample. To estimate the stress response to TPL, maternal salivary cortisol, α-amylase levels, along with anxiety and depression symptoms were measured. To determine cumulative life stressors, previous traumas, social support, and family functioning were registered. Then, linear regression models were used to examine the effect of potential predictors of birth date. Lower family adaptation, higher Body Mass Index (BMI), higher cortisol levels and TPL diagnosis week were the main predictors of birth date. Gestational week at TPL diagnosis showed a non-linear interaction with cortisol levels: TPL women with middle- and high-cortisol levels before 29weeks of gestation went into imminent labour. A combination of stress response to TPL diagnosis (salivary cortisol) and cumulative life stressors (family adaptation) together with obstetric factors (TPL gestational week and BMI) was the best birth date predictor. Therefore, a psychosocial therapeutic intervention program aimed to increase family adaptation and decrease cortisol levels at TPL diagnosis as well as losing weight, may prevent preterm birth in symptomatic women.

Nilotinib vs. imatinib in Japanese patients with newly diagnosed chronic myeloid leukemia in chronic phase: 10-year follow‑up of the Japanese subgroup of the randomized ENESTnd trial.

In the 10-year analysis of Japanese patients with newly diagnosed CML-CP in the ENESTnd trial, nilotinib yielded higher cumulative response rates. There were no new occurrences of disease progression or deaths since the 5-year analysis. Cumulative 10-year rates of MMR and MR4.5 were higher in the nilotinib arms [300mg twice daily (BID), 86.2% and 69.0%, respectively; 400mg BID, 78.3% and 69.6%, respectively] than the imatinib arm (400mg once daily, 60.0% and 48.0%, respectively). Nasopharyngitis (85.7%, 77.3%, 79.2%), rash (50.0%, 68.2%, 37.5%), headache (39.3%, 45.5%, 25.0%), and back pain (39.3%, 50.0%, 29.2%) were the most frequently reported all-grade adverse events (AEs) for nilotinib 300 and 400mg BID and imatinib, respectively. Cardiovascular AEs were more common with nilotinib than with imatinib. More patients on nilotinib had pre-diabetic and diabetic levels of HbA1c (300mg BID, 17.9% and 10.7%, respectively; 400mg BID, 22.7% and 18.2%, respectively) compared with imatinib (4.2% each). Overall, 10-year results from the Japanese cohort are consistent with prior results from the full ENESTnd cohort and the Japanese subgroup, and continue to support the long-term use of nilotinib in Japanese patients with newly diagnosed CML-CP, but with proper monitoring and management of comorbidities.

Citrus microcarpa extract as bio-immunostimulator for Edwardsiellosis in red hybrid tilapia culture

This paper described the application of Citrus microcarpa extract as bio-immunostimulator in red hybrid tilapia against Edwardsiellosis infection. Edwardsiellosis due to Edwardsiella tarda is one of the well-known bacterial diseases in aquaculture which leads to significant economic losses. The increasing antibiotic resistant cases among pathogenic bacteria led to many commercial antibiotics no longer effective in controlling bacterial diseases in aquaculture. Hence, in the present study was carried out to evaluate potential of C. microcarpa extract as immunostimulator against Edwardsiellosis infection in red hybrid tilapia. Comparison in terms of cumulative mortalities and antibody response against E. tarda among group of fish received C. microcarpa extract at different concentrations (CM1-1, 1 g kg-1 of fish; CM-2, 2 g kg-1 of fish and CM-4, 4 g kg-1 of fish) and group of fish received no medicated commercial feed (control) was carried out in the present study. Enzyme linked immunosorbent assay (ELISA) was used to monitor antibody response of fish that received medicated feed. The results of the present study showed that the values of antibody response against E. tarda of fish after seven days received C. microcarpa extract (CM-1, 0.113 ± 0.02 OD; CM-2, 0.14 ± 0.02 OD; CM-4, 0.173 ± 0.03 OD) were significantly higher (P &lt; 0.05) compared to fish from group of control (0.0 OD). Whereas cumulative mortality of fish from group of control (53.3 ± 11.5 %) was significantly higher (P &lt; 0.05) compared to fish from all of groups received C. microcarpa extract (CM-1, 13.3 ± 5.8 %; CM-2, 13.3 ± 5.8 % and CM-4, 6.7 ± 5.8 %). The results indicated the potential of C. microcarpa extract as immunostimulator in finfish culture.

Assessing the immunogenicity of three different inactivated polio vaccine schedules for use after oral polio vaccine cessation, an open label, phase IV, randomized controlled trial

BackgroundAfter global oral poliovirus vaccine (OPV) cessation, the Strategic Advisory Group of Experts on Immunization (SAGE) currently recommends a two-dose schedule of inactivated poliovirus vaccine (IPV) beginning ≥14-weeks of age to achieve at least 90% immune response. We aimed to compare the immunogenicity of three different two-dose IPV schedules started before or at 14-weeks of age. MethodsWe conducted a randomized, controlled, open-label, inequality trial at two sites in Dhaka, Bangladesh. Healthy infants at 6-weeks of age were randomized into one of five arms to receive two-dose IPV schedules at different ages with and without OPV. The three IPV-only arms are presented: Arm C received IPV at 14-weeks and 9-months; Arm D received IPV at 6-weeks and 9-months; and Arm E received IPV at 6 and 14-weeks. The primary outcome was immune response defined as seroconversion from seronegative (<1:8) to seropositive (≥1:8) after vaccination, or a four-fold rise in antibody titers and median reciprocal antibody titers to all three poliovirus types measured at 10-months of age. FindingsOf the 987 children randomized to Arms C, D, and E, 936 were included in the intention-to-treat analysis. At 10-months, participants in Arm C (IPV at 14-weeks and 9-months) had ≥99% cumulative immune response to all three poliovirus types which was significantly higher than the 77–81% observed in Arm E (IPV at 6 and 14-weeks). Participants in Arm D (IPV at 6-weeks and 9-months) had cumulative immune responses of 98–99% which was significantly higher than that of Arm E (p value < 0.0001) but not different from Arm C. InterpretationResults support current SAGE recommendations for IPV following OPV cessation and provide evidence that the schedule of two full IPV doses could begin as early as 6-weeks.

Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease.

Simple SummaryLarge Granular Lymphocytic Leukemia (LGLL) is a clonal disorder of cytotoxic T-cells. Because of the variety of clinical presentations ranging from the mere presence of lymphocytosis to cytopenias and autoimmune conditions, this rare lymphoma may require treatment to control such manifestations. Although first-line treatments are more established, refractory cases are often managed based on the experience of the attending physician. Herein, we review the pathways involved in the pathogenesis of LGLL, including refractory cases, inferring clues as to the potentially actionable targets.Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease.

اثر سطوح مختلف متیونین جیره در دوره رشد بر عملکرد، خصوصیات لاشه، بازده انرژی و پروتئین، ترکیب عضله سینه و برخی فراسنجه ‏های خونی بلدرچین ژاپنی

This research aimed to investigate the effect of different dietary methionine levels on performance, carcass characteristics, energy and protein efficiencies, breast muscle nutrients, and some blood indices in Japanese quails during 11-24 days of age. This experiment was conducted in a completely randomized design during 14 days with 490 quail chicks in seven treatments and five replicates each (14 chicks in each replicate). The experimental diets were the NRC requirement of methionine for quail (0.5 percent), three methionine levels of 7.5, 15, and 22.5 percent lower than that of NRC requirement level (0.4625, 0.425, and 0.3875%, respectively), and three levels higher than that of NRC requirement level (0.5375, 0.575 and 0.6125%, respectively). The results showed that consumption of 0.575% methionine level caused the highest weight gain and lowest feed conversion ratio (linear and quadratic responses). The breast protein content was linearly increased by increasing the methionine level to 0.5%. Consumption of 0.6125% methionine (the highest methionine level) caused the highest relative thigh weight (linear and quadratic responses). The best energy and protein efficiencies were indicated by consumption of 0.575% methionine (linear and quadratic responses). The methionine requirement for optimal weight gain, feed conversion ratio, and energy and protein efficiencies were 0.569, 0.578, 0.54, and 0.35% according to the quadratic broken line. In total, the level of 0.569% was determined for methionine requirement based on the cumulative response of weight gain, feed conversion ratio, and energy and protein efficiencies.

Ceftriaxone and methicillin-susceptible staphylococcus aureus: a perspective from pharmacokinetics/pharmacodynamics studies

ABSTRACT Introduction: Usage of ceftriaxone-based therapy to treat Methicillin-Susceptible Staphylococcus aureus (MSSA) infections is a controversial issue, from in vitro to clinical studies. Area covered: We conducted a literature review using PubMed of articles with ceftriaxone pharmacokinetics parameters and built a probability of target attainment (PTA) based on PK values from stable conditions (non-critically-ill patients) with goals of fT>55%, fT>75%, and fT>100%. Ceftriaxone’s minimal inhibitory concentration from 31 MSSA strains (0.25–64 mg/L) was used to build the cumulative fraction response (CFR). The isolates were clinically relevant from blood, bronchoalveolar lavage, and soft tissue biopsy. Expert opinion: The results from controversies about using ceftriaxone for MSSA infections have been commonly addressed in the literature. However, variables such as (i) pharmacokinetic profile, (ii) pharmacodynamic target, (iii) site of infection, and (iv) MIC distributions may influence divergences. From this pharmacokinetics-pharmacodynamics perspective, ceftriaxone may be a reasonable option for MSSA infections when the MIC50 and MIC90 were 4 mg/L and 8 mg/L. CFR analysis demonstrated that ceftriaxone 1 g q24 h could be used if bacteriostasis is the aim (fT>55%), while 1 g q12h should be used for bactericidal effects (fT>75% or fT>100%). These dosing regimens should be considered in other clinical trials.

Pharmacokinetic Behaviour of Enrofloxacin after Single Intramuscular Dosage in American Black Vultures (Coragyps atratus).

The aim of the study was to investigate the intramuscular pharmacokinetics of enrofloxacin in black vultures (Coragyps atratus). The pharmacokinetics of a single intramuscular dose (10 mg/kg) of enrofloxacin was studied in six vultures. Plasma concentrations of enrofloxacin and its active metabolite, ciprofloxacin, were determined by high-performance liquid chromatography (HPLCuv). Pharmacokinetic parameters were estimated using non-compartmental and compartmental analysis. After intramuscular administration, enrofloxacin showed a rapid and complete absorption, reaching a Cmax value of 3.26 ± 0.23 μg/mL at 1.75 ± 0.53 h. A long terminal half-life of 19.58 h has been observed. Using previously published MIC values to perform a PK/PD analysis, cumulative fraction responses obtained after Monte Carlo simulation for AUC/MIC > 30, 50 and 125 were 72.93%, 72.34% and 30.86% for E. coli and 89.29%, 88.89% and 58.57% for Mycoplasma synoviae, respectively. Cumulative fraction responses obtained for Cmax/MIC index were 33.93% and 40.18% for E. coli and M. synoviae, respectively. The intramuscular administration of 10 mg/kg could be appropriate to treat infectious diseases caused by gram-positive bacteria with MIC value lower than 1 µg/mL; however, although enrofloxacin showed a slow elimination in black vultures, plasma concentrations were insufficient to reach the gram-negative stablished breakpoints.

Long-term outcome of tyrosine kinase inhibitor treatment in children and adolescents with newly diagnosed chronic myeloid leukemia in chronic phase.

Long-term outcome of tyrosine kinase inhibitor treatment in children and adolescents with newly diagnosed chronic myeloid leukemia in chronic phase.

Quality response to real exchange rate shocks: A panel SVAR analysis on China's agricultural exports

AbstractThis article applies a panel structural VAR model using complete data of China's monthly agricultural exports to uncover both the dynamics and interproduct and intermarket differences in the responses of product quality to real exchange rate (RER) shocks. It finds that RER appreciation promotes the quality of China's agricultural exports on average compared to discouraging exports, but the effect is fully shown in the short run. The average response peaks in the month immediately after the shock and the average cumulative response converges to a constant level in three months. The quality response to RER shocks substantially differs across both products and markets. More sensitive responses of quality upgrading are found among exports that are less competitive, relatively primary, more reliant on ordinary trade, and exported with nearby and less developed partners. Therefore, greater supports on R&amp;D activities and the adoption of advanced technologies might be needed among other exports.

Cumulative vulnerabilities as a potential moderator of response to reduced nicotine content cigarettes

Risk for smoking increases in a summative manner corresponding to the number of co-occurring vulnerabilities present (cumulative vulnerability). We examined whether cumulative vulnerabilities moderate response to reduced nicotine content cigarettes in a secondary analysis of results from 775 participants in three 12-week randomized clinical trials examining research cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco). Participants were categorized as having 0–1, 2–3, or ≥ 4 cumulative vulnerabilities. Vulnerabilities included: rural residence, current substance use disorder, current affective disorder, low educational attainment, poverty, unemployment, physical disability. The primary outcome was total cigarettes per day (CPD) during Week 12; secondary outcomes included CPD across weeks, toxin exposure, dependence severity, craving/withdrawal (17 dependent measures). Results were analyzed using repeated measures analysis of covariance and growth-curve modeling. Total CPD during Week 12 increased as cumulative-vulnerability increased (P = 0.004), and decreased as nicotine content decreased (P < 0.001), with no significant interaction of cumulative vulnerability and dose (P = 0.67). Effects on other outcomes generally followed that same pattern. The only exception across the other outcomes was on Questionnaire-on-Smoking-Urges Factor-2 ratings for usual-brand cigarettes where cumulative vulnerability, dose, and time interacted (P = 0.007), with craving at the 0.4 and 2.4 mg/g doses decreasing over time, but inconsistently across vulnerability categories. Overall, we saw little evidence that cumulative vulnerabilities moderate response to reduced nicotine content cigarettes suggesting that a policy reducing nicotine content in cigarettes to minimally addictive levels could benefit even highly vulnerable smokers including those residing in rural or other regions with overrepresentation of co-occurring vulnerabilities.Clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

Cerebral blood flow response rate to task-activation using a novel method can discriminate cognitive impairment from healthy aging

Objective. A new method to classify individuals as ‘responders’ to task-activated cerebral blood flow velocity (CBFv) has recently been developed. This study investigated whether CBFv response rate to task-activation is affected by Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Approach. The 95th thresholds for cross correlation function peak and variance ratio were derived from 270 unstimulated, healthy hemispheres, and were used to classify the presence of a response to task-activation. Thresholds were applied to five cognitive tasks (attention, verbal fluency, language, visuospatial, memory) in CBFv data from 30 healthy older adults (HC), 35 AD and 22 MCI participants. Cumulative response rate (CRR) was calculated from the sum of responses across five tasks, for both hemispheres. Area under the curve (AUC) was derived from receiver operating characteristic (ROC) curve analysis. Main results. The number of responders differed significantly between tasks (p < 0.005) and diagnostic groups (p = 0.011). On post hoc tests there were more responders in the visuospatial (79%–90%) compared to fluency (45%–80%), language (50%–77%), and memory (44%–70%) tasks bilaterally, and responders were greater in the HC (70%) compared to AD (41%) and MCI (23%) groups to at least eight out of ten tasks. At an optimal threshold of 7.5 out of 10 responses, the AUC-ROC distinguished HC from AD and MCI with a; sensitivity 66% and specificity 70% (AUC = 0.72). Significance. Using a novel method to classify responders to cognitive task-activation, HC demonstrated a higher CRR than those with MCI or AD, and a threshold of <8 responses distinguished healthy ageing from dementia.

Focal electroretinogram and microperimetry testing of photoreceptor-retinal pigment epithelium function in intermediate age-related macular degeneration.

PurposeTo compare the performance of focal electroretinogram (FERG) and fast mesopic microperimetry in evaluating macular function of intermediate age‐related macular degeneration (iAMD) subjects with preserved visual acuity.MethodsCross‐sectional, observational study. Participants with drusen >125 µm and VA ≥80 ETDRS letters and age‐ and sex‐comparable healthy subjects were consecutively enrolled in the study. Three photopic FERG recordings of the central 9° of the macula with luminance modulated stimuli flickering at 42.5 Hz and a fast mesopic microperimetry with a custom pattern of 3 central (CS) and 3 paracentral (pCS) stimuli at 1.2° and 6° from fixation were acquired.ResultsOverall, 112 eyes of 77 participants (age 73.0 ± 7.1 years, 47 iAMD eyes) were analysed. Mean FERG amplitude, CS and pCS (all p < 0.05) were lower in the iAMD group. A significant association was observed between FERG amplitude and iAMD (OR 9.58, p < 0.001) in multiple logistic regression analysis. Z‐scores of FERG were lower than microperimetry in iAMD (p = 0.002) but not for healthy participants. AUC of the ROC curve was greater for FERG than microperimetry (0.895 versus 0.644 and 0.675, both p < 0.05).ConclusionFocal ERG objectively measures a cumulative response originating from the photoreceptor‐RPE complex of the central 9° of the macula and demonstrated high accuracy in identifying decreased central macular function in iAMD patients with preserved visual acuity, performing better than fast mesopic microperimetry. Focal ERG should be considered a reliable technique for measuring retinal sensitivity of iAMD patients.

A Real Life Evaluation of Efficacy and Safety of Ponatinib Therapy in CML Patients

Ponatinib, an oral tyrosine kinase inhibitor with potent activity against native and mutant BCR-ABL1, is approved for patients with refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated, or for patients with the T315I mutation.Aim The aim of study was to assess real life efficacy and safety of ponatinib in a retrospective analysis of 49 patients with resistant/refractory CML from 9 Italian Hematological Institution.Results: At baseline, median age was 55 years and median time since diagnosis was 4,4 years; BCR-ABL1 kinase domain mutations were reported in 30,6 % of patients, with T315I only in 4 (26,6%) patients. The majority of Patients were heavily pretreated, with 26,5% having received 2 prior TKIs and 46,9% having received ≥3 prior TKIs; 28,2 % of patients were in 2nd line treatment due to resistance. At Ponatinb start, 42 patients were in chronic phase, 4 in accelerate phase and 3 in blastic phase. 18 pts showed comorbidities, no cardiovascular and/or cerebrovascular eventswere present at diagnosis and before starting Ponatinib. Baseline cardiovascular risk factors for all patients were Diabetes 3/18, hypertension 12/18, hypercholesterolemia 1/18; general history of cardiovascular disease,(not ischemic) was reported in 3/18 patients at baseline. Concomitant medications were: Antihypertensives in 12/18, aspirin in 1/18, antidiabetes agents in 3/18, lipid-modifying agents in 1/18. The 91,8% patients performed cardiovascular evaluation before starting treatment resulting in normal cardiovascular function in the majority of them. Abnormalities were present in only 4 pts: one lower ejection fraction, one pericardic effusion and two hypertensive cardiomyopathies.The initial dose was 45 mg/day in 24 (48,9%), 30 mg/day in 16 pts (32,6%) and 15 mg/day in 9 pts (18,3%).31 out of 49 patients obtained a response to Ponatinib. The cumulative response rates was: major cytogenetic response (MCyR), 4%; complete cytogenetic response (CCyR), 59.1%; molecular response 32,6% (major molecular response (MMR) 12,2%; Deep MR (MR4, MR 4.5, MR5) 20,4%. Characteristics of response to Ponatinib therapy are reported in table 1. Interestingly, almost all molecular responder patients maintained Ponatinib response.At the time of analysis, 36 patients are still on therapy. Ponatinib was discontinued in5 of the 31 responders patients due to side effects (n= 2), death (n=2), lost to follow-up (n=1). The side effects reported were vascular CNS stoke and back pain with bad compliance. The two deaths occurred after bone marrow transplantation in one patient and for causes not disease related for the other.Dose reduction was performed in 11 out of 31 responder patients because side effects (n=8: 5 dermatological, 1 atrial fibrillation, 1 hematological, 1hypertension ) or optimal response (n=3 ).The adverse events were reported in 21 of 49 patients. Non hematological side effects were: 9 dermatological, and 2 arthralgia , 1 patients developed diabetes, 2 patients ipercolesterolemia; 5 patients had hematological side effects (1 piastrinopenia, 3 pancitopenia, 1 MDS with trysomy 8). About cardiovascular events, only 5 patients showed these effects (1 atrial fibrillation, 3 hypertension, 1carotid thrombosis, 1 ischemic cardiopathy ), no one severe.CONCLUSION As in 5-yr long term results of PACE trial, also in our real life retrospective analysis, Ponatinib continues to show deep, lasting response in heavily-pretreated pts with CP-CML. In our analysis, almost all patients who obtained the molecular response, maintained it during the treatment, despite dose reduction, which should be associated to improved survival, also in a heavily-pretreated pts. [Display omitted] DisclosuresSpecchia:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Pane:Novartis: Honoraria, Speakers Bureau.