Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies

PURPOSE: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. METHODS: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of \u3e/=1 g/dL from baseline. RESULTS: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of \u3e/=1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of \u3e/=1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. CONCLUSIONS: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA

Addition of AT1 blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis

Addition of AT1 blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis.BackgroundAngiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy response, particularly for individuals with a poor response to ACE inhibition. We studied whether co-treatment with an angiotensin II subtype 1 (AT1) receptor antagonist (AII-A) improves the individual antiproteinuric response of maximal ACE inhibition in established adriamycin nephrosis.MethodsRats were instituted on lisinopril (75 mg/L) six weeks after disease induction. After two weeks rats were re-stratified for residual proteinuria to continue this regimen, to a higher dose of lisinopril (150 mg/L) or to co-treatment with the AII-A L 158,809 for another four weeks. Groups on monotherapy AII-A and vehicle served as controls (all groups N = 15).ResultsLisinopril lowered proteinuria by 63% from 741 to 246 g/day (range of percentage change -90 to +2%). Neither increasing the dose of the ACE inhibitor nor addition of AII-A to ACE inhibition improved the antiproteinuric efficacy on a group or individual level: non-responders remained non-responders. All drug categories reduced hard end-points of focal glomerulosclerosis to a similar degree.ConclusionsACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level

Pathogenetic connection of lipid profile changes with left ventricle hypertrophic models depending on genes polymorphism' ace (I/D), eNOS (T894G) in patients with essential hypertension

Purpose. To establish the dependence of lipid profile changes in patients with essential arterial hypertension (EAH) on the type of left ventricular hypertrophy (LVH) and gene polymorphism of angiotensin-converting enzyme (ACE, I/D) and endothelial nitric oxide synthase (eNOS, T894G). Design/approach. In a prospective study 120 patients with EAH I-III severity stages: 12,5% (15) persons with EAH I, 60,0% (72) with EAH II, 27,5% (33) with EAH III; 48,3% (58) women and 51,7% (62) men, mean age 52,91±9,24, the disease duration from 2 to 28 years; the control group - 20 healthy individuals were involved. Ventricular mass (LVM) was evaluated by Echo-KG. Plasma lipids were studied by spectrophotometer, analyzed according to the recommendations of the ESC, ESH (2009). Genes' allele polymorphic areas of ACE (I/D), eNOS (T894G) were set by PCR analysis. Findings. High-risk groups of lipid profile changes in patients with EAH is a carriers of DD-genotype of ACE gene by increasing of low density cholesterol level and atherogenic index by 1,3 times (p<0,05). Genetic risk of dyslipidemia in EAH patients with unfavorable eccentric and concentric LVH and ACE and eNOS genes mutations (ID/TT, ID/ TG, DD/TG haplotypes) increases by 2,57-3,86 time (OR=2,57-3,86). Combination of Wild I-allele of ACE gene and G-allele of eNOS gene (II/GG, II/TG haplotypes) is protective against development of hypercholesterolemia in patients with unfavorable patterns of LVH (OR=0,12-0,94) and makes the chances of dyslipidemia risk the lowest in the population of EAH patients (p=0,05). Research limitations/implications. The study is limited by the peculiarities of laboratory and diagnostic tests. Originality/value. The original research without a prototype provides pathogenetic data for early detection and prevention of metabolic disorders in the presence/absence of LVH in patients with EAH

Carbon Fibers Derived from Dry-Spinning of Modified Lignin Precursors

Cost and environmental concerns arise from the manufacture of carbon fibersusing petroleum-based precursors such as polyacrylonitrile (PAN). Toxic by-productssuch as hydrogen cyanide (HCN) are generated during stabilization and carbonization ofPAN-based carbon fibers. These concerns have promoted increasing interest in biomass-based carbon fibers. As the second most abundant biomass material on the earth, lignin isbeing investigated as a potential carbon fiber precursor. Therefore, this research wasfocused on converting lignin materials into carbon fibers with enhanced performanceproperties. Since the 1960s, various types of lignin have been investigated as carbon fiber precursors. Hardwood kraft lignin and organosolv lignin could be converted into carbon fibers without chemical modification, whereas softwood kraft lignin was very difficult to convert without suitable modification or plasticization. Strength of most of the carbon fibers produced from the above lignin precursors were below 800 MPa, which is much lower than that of commercial carbon fibers derived from PAN precursors. Thus, the overall goal of this study was to produce lignin-based carbon fibers with enhanced mechanical properties by a scalable process. The specific objectives were to: (i) identify different types of lignin precursors for their potential of being carbon fiber precursors; (ii) study the modified lignin-acetone solutions to establish a range of suitable combinations of solution concentrations and spinning temperatures; (iii) establish thermal stabilization and carbonization conditions for lignin-based precursor fibers to enhance the performance of resulting carbon fibers; and (iv) to develop a UV/thermal dual stabilization route to increase the speed of stabilization. The lignin precursors investigated in this study included an organosolv lignin, a soda lignin, and a softwood kraft lignin. The organosolv lignin was successfully melt-spun into fibers without any modification of the precursor material. However, it took more than 200 hours for the thermo-oxidative stabilization step. The infusible soda lignin was chemically modified by acetylation into a fusible material, but it could not be cross-linked. The softwood kraft lignin was modified by a similar acetylation reaction and fractionation method, and the resulting material could be melt-spun into fibers, as the melt possessed significant thermal stability. The large extent of acetylation of hydroxyl groups that led to thermal stability also hindered the thermo-oxidative stabilization. Consequently, the melt-spinning approach was abandoned. Instead, to preserve more hydroxyl groups within the precursor material, the acetic anhydride amount used in acetylation of the softwood kraft lignin was reduced from 15 to 0.66 ml per gram lignin. As indicated by FTIR spectroscopy, the hydroxyl peak was significantly increased. In addition, the weight gain of lignin after reaction was reduced from 18% to 5%, indicating a partial acetylation of the hydroxyl groups in softwood kraft lignin. The resulting acetylated softwood kraft (Ace-SKL) lignin could be dry-spun using acetone as solvent, and the fibers could be thermo-oxidatively stabilized. The rheology of Ace-SKL/acetone solutions prepared with different solid contents was investigated for the purpose of dry-spinning into precursor fibers. The solution viscosity was investigated at high shear rates encountered during fiber spinning. The solutions displayed a significant shear-thinning behavior at various temperatures studied with power-law exponents ranging from 0.33 to 0.82, confirming the macromolecular nature of the Ace-SKL lignin/acetone solutions. As expected, elevated temperatures led to lower viscosities and facilitated extrusion at moderate pressures. Dry-spinning was performed over a range of concentrations (1.85 to 2.15 g/ml acetone) and appropriate temperatures (25-50°C). It was observed that all of the resulting dry-spun lignin fibers displayed a crenulated surface pattern, with increased crenulation achieved for fibers spun at higher temperatures. Presence of some doubly-convex and sharp crevices was found on fibers produced from solutions containing lower concentrations (1.85 and 2.00 g lignin/mL solvent). In contrast, no crevices were found on the fibers obtained from the concentrated solution (2.15 g/mL), likely due to the reduced extent of solvent out-diffusion. Dry-spinning at room temperature was also performed to obtained fibers with relatively smooth surface, but the pressure drop was excessive. The results above have established temperature/concentration combinations for dry-spinning of Ace-SKL. About 30% larger surface area could be achieved in the crenulated lignin fibers (as compared with equivalent circular fibers), indicating the potential advantage of such biomass-derived fibers in providing larger fiber/matrix bonding area when used in composites. During thermo-oxidative stabilization, tension of about 2000-2500 g/(g/cm) was applied on fiber tows that led up to 800% extension. In the carbonization step, tension was also applied using a customized graphite rack and tungsten weights, and stabilized Ace-SKL fibers were successfully carbonized at 1000°C. It was found that the load needed to be above 20150 g/(g/cm) to prevent shrinkage of fiber tows. Both tensile strength and modulus were measured as a function of extension during carbonization (EDC). As expected, Ace-SKL carbon fibers with larger EDC had better mechanical properties due to preserved molecular orientation. Carbon fibers derived from lignin precursor fibers obtained from 2.15 g/ml Ace-SKL solution (6 μm diameter) displayed a tensile modulus, strength, and strain-to-failure values of 52 ± 2 GPa, 1050 ± 70 GPa, and 2.0 ± 0.2%, respectively. These values are amongst the best reported for lignin-based carbon fibers. In contrast, the carbon fibers spun from 2.00 g/ml solution with sharp crevices displayed a reduced tensile strength of 790 ± 80 MPa due to occlusion-type defects formed by sharp crevices during spinning. The Ace-SKL carbon fibers displayed low crystallinity as investigated by Wide Angle X-ray Diffraction (WAXD) and Raman spectroscopy. The crenulated surface from dry-spinning was preserved, which can provide a larger specific interfacial area for enhanced fiber/matrix bonding in composite applications. Above results elucidate the importance of precursor composition and processing conditions on microstructure and properties of resulting precursor and carbon fibers. A limitation of the partially acetylated lignin (i.e., with a fraction of hydroxyl moieties converted to acetyl groups) is the slow heating rate during thermal stabilization, which required up to 40 hours due to the slow heating rate needed to prevent the fibers from becoming tacky and sticking to each other. Therefore, a rapid strategy of dual UV-thermoxidative stabilization was developed. The fibers undergo UV-induced reaction close to the surface in a short duration (15 min) such that they can be subsequently stabilized at a rapid heating rate without fibers fusing together. The glass transition temperature of UV irradiated fibers was about 15°C higher than that of fibers without UV treatment. This strategy reduces the total stabilization time significantly from 40 to 4 hour. Stabilized fibers were successfully carbonized at 1000°C and resulting carbon fibers displayed a tensile strength of 900 ± 100 MPa, which is amongst the highest reported for carbon fibers derived from rapidly stabilized lignin precursors. In summary, the results from this study established a route for dry-spinning of partially acetylated softwood kraft lignin into precursor fibers and successful stabilization and carbonization. This precursor could be dissolved in acetone for dry-spinning. The lignin/acetone solutions were investigated to establish suitable concentration/temperature combinations for dry-spinning. The dry-spun precursor fibers were thermally treated under tension to convert into a carbon fiber with tensile strength of more than 1 GPa. Those carbon fibers possessed crenulated surface which could provide larger fiber/matrix interfacial bonding area for composite applications. Furthermore, UV/thermal dual stabilization was developed to reduce the time duration of stabilization

Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [111In-DOTA]MG11

Background: We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [111In-DOTA]MG11 ([(DOTA)DGlu10]gastrin(10–17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug racecadotril (Race). Besides NEP, angiotensin-converting enzyme (ACE) has also been implicated in the catabolism of gastrin analogs. In the present study, we first compared the effects induced by NEP inhibition (using PA, TO, or Race) and/or by ACE inhibition (using lisinopril, Lis) on the biodistribution profile of [111In-DOTA]MG11 in mice. In addition, we compared the efficacy of PA and TO at different administered doses to enhance tumor uptake. Methods: [111In-DOTA]MG11 was coinjected with (a) vehicle, (b) PA (300 μg), (c) TO (150 μg), (d) Lis (100 μg), (e) PA (300 μg) plus Lis (100 μg), or (f) 30–40 min after intraperitoneal (ip) injection of Race (3 mg) in SCID mice bearing AR42J xenografts. In addition, [111In-DOTA]MG11 was coinjected with vehicle, or with progressively increasing amounts of PA (3, 30, or 300 μg) or TO (1.5, 15, and 150 μg) in SCID mice bearing twin A431-CCK2R(+/−) tumors. In all above cases, biodistribution was conducted at 4 h postinjection (pi). Results: During NEP inhibition, the uptake of [111In-DOTA]MG11 in the AR42J tumors impressively increased from 1.8 ± 1.0 % ID/g (controls) to 15.3 ± 4.7 % ID/g (PA) and 12.3 ± 3.6 % ID/g (TO), while with Race tumor values reached 6.8 ± 2.8 % ID/g. Conversely, Lis had no effect on tumor uptake and no additive effect when coinjected with PA. During the dose dependence study in mice, PA turned out to be more efficacious in enhancing tumor uptake of [111In-DOTA]MG11 in the CCK2R-positive tumors compared to equimolar amounts of TO. In all cases, renal accumulation remained low, resulting in notable increases of tumor-to-kidney ratios. Conclusions: This study has confirmed NEP as the predominant degrading enzyme of [111In-DOTA]MG11 and ruled out the involvement of ACE in the in vivo catabolism of the radiotracer. NEP inhibition with the clinically tested NEP

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

Abstract: Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised. This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process. The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text. The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites.“To maximise the benefit to society, you need to not just do research but do it well” Douglas G Altma

Angiotensin-Converting Enzyme Inhibitor Therapy Affects Left Ventricular Mass in Patients With Ejection Fraction >40% After Acute Myocardial Infarction

AbstractObjectives. We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy decreases left ventricular (LV) mass in patients with a left ventricular ejection fraction (LVEF) >40% and no evidence of heart failure after their first acute Q wave myocardial infarction (MI).Background. Recently, ACE inhibitor therapy has been shown to have an early mortality benefit in unselected patients with acute MI, including patients without heart failure and a LVEF >35%. However, the effects on LV mass and volume in this patient population have not been studied.Methods. Thirty-five patients with a LVEF >40% after their first acute Q wave MI were randomized to titrated oral ramipril (n = 20) or conventional therapy (control, n = 15). Magnetic resonance imaging (MRI) performed an average of 7 days and 3 months after MI provided LV volumes and mass from summated serial short-axis slices.Results. Left ventricular end-diastolic volume index did not change in ramipril-treated patients (62 ± 16 [SD] to 66 ± 17 ml/m2) or in control patients (62 ± 16 to 68 ± 17 ml/m2), and stroke volume index increased significantly in both groups. However, LV mass index decreased in ramipril-treated patients (82 ± 18 to 73 ± 19 g/m2, p = 0.0002) but not in the control patients (77 ± 15 to 79 ± 23 g/m2). Systolic arterial pressure did not change in either group at 3-month follow-up.Conclusions. In patients with a LVEF >40% after acute MI, ramipril decreased LV mass, and blood pressure and LV function were unchanged after 3 months of therapy. Whether the decrease in mass represents a sustained effect that is associated with a decrease in morbid events requires further investigation.(J Am Coll Cardiol 1997;29:49–54)

ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS IN THE SETTING OF CHRONIC KIDNEY DISEASE

Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are the mainstays of therapy for hypertension, heart failure with reduced ejection fraction, and coronary artery disease. Additionally, multiple clinical guidelines recommend an ACE-I or ARB to be used in chronic kidney disease (CKD) patients with elevated albuminuria. However, how albuminuria measures relate to the prescription of ACE-I/ARB is unclear. Despite the benefits of ACE-Is and ARBs, they may predispose to hyperkalemia and acute kidney injury, risks that are particularly high among patients with low estimated glomerular filtration rate (eGFR). Clinical evidence is lacking regarding the risk-benefit balance of discontinuing ACE-I/ARB in patients with advanced CKD. Using electronic heath records data from the Geisinger Health System, we assessed the utilization pattern of ACE-Is and ARBs in real-world clinical practice, and applied causal inference tools to investigate the associations of ACE-I/ARB discontinuation with health outcomes. In a cohort of individuals without recorded contraindications or allergy to ACE-I/ARB, only 43.1% of individuals with albumin-to-creatinine ratio (ACR) > 300 mg/g and 40.9% of those with diabetes and ACR >30 mg/g initiated ACE-I/ARB within 6 months of the ACR measurement. We also found that individuals with higher levels of albuminuria were more likely to initiate ACE-I/ARB, providing evidence that results from albuminuria testing change patient care. Among users of ACE-I/ARB, we estimated that the majority had a therapy discontinuation by 5 years after therapy initiation. There were strong associations of advanced CKD stages with therapy discontinuation, with patients with G4 CKD (eGFR: 15-29 ml/min/1.73 m2) more than twice as likely to discontinue therapy compared to people with eGFR ≥90 mL/min/1.73m2. Among users with an eGFR decline to below 30 ml/min/1.73 m2, ACE-I/ARB discontinuation after the eGFR decline was associated with higher risks of mortality and major adverse cardiovascular events, and no significant difference in the risk of end-stage kidney disease. In conclusion, continuing ACE-I/ARB in patients with declining renal function may provide cardiovascular and survival benefits. However, ACE-I/ARB discontinuation is common especially among users with advanced CKD stages. Our findings suggest that adherence to albuminuria testing provides an opportunity to enhance utilization of ACE-I/ARB

Effect of intensive treatment on diabetic nephropathy in patients with type I diabetes

Effect of intensive treatment on diabetic nephropathy in patients with type I diabetes. We evaluated the long-term effect of an intensive treatment of diabetic nephropathy (anti-hypertensive drugs, low protein diet, multiple insulin injections to achieve a good metabolic control) on glomerular filtration rate (GFR) and albumin excretion rate (AER). Fourteen type I diabetic patients (mean age 45 ± 9.5 years, mean duration of diabetes 23.5 ± 7.3 years, 8 males/6 females) with glomerular filtration rate <70 ml/min-1/1.73 m2 and albumin excretion rate >30 µg/min were treated intensively for 36 months. This intensive treatment consisted of multiple insulin injections, antihypertensive therapy with ACE inhibitors and a low-protein diet (0.8 g/kg body wt/day.) Renal function was evaluated as GFR and AER. HbA1C mean value decreased significantly from 8.7 ± 0.8% to 6.5 ± 0.5% (P < 0.0002). GFR rose from 58 ± 12 ml/min-1/l.73 m2 to 84 µ 11 ml/min-1/l.73 m2 (P < 0.0008). AER decreased from 208 µg/min (range: 73 to 500) to 63.8 µg/min (range 15 to 180; P < 0.05). Systolic and diastolic blood pressure decreased respectively from 144 ± 26 mm Hg to 120 ± 15 mm Hg and from 89 ± 9 mm Hg to 75 ± 8 mm Hg (P < 0.01). We obtained a rise of GFR and a reduction of proteinuria after three years of this treatment. We suggest that this intensive treatment in all patients with early stage diabetic nephropathy may be effective in slowing the progression to renal failure

Day-to-day physical activity producing low gravitational impacts is associated with faster visual processing speed at age 69:cross-sectional study

Background Little is known about how different physical activity (PA) parameters relate to cognitive function in older adults. Using accelerometers calibrated to detect vertical impacts from ground reaction forces we examined the associations of low, medium and higher impact PA with processing speed, verbal memory and cognitive state in older adults. Methods Participants were 69-year old British men and women from the Medical Research Council National Survey of Health and Development included in a vertical impacts and bone sub-study (n = 558; 48.2% female). Counts of low (0.5 < g < 1.0 g), medium (1 < g < 1.5 g), or higher (≥1.5 g) magnitude impacts were derived from vertical acceleration peaks recorded over 7 days by hip-worn accelerometers. Processing speed was assessed by a timed visual letter search task, verbal memory by a 15-word list learning test and cognitive state by the Addenbrooke’s Cognitive Examination (ACE-III). Potential confounders were childhood cognitive ability, adult socioeconomic position, body mass index and depression. Results In initial sex-adjusted models, low magnitude impacts were associated with better performance in all three cognitive function tests; standard deviation differences in test scores per doubling in number of low impacts: letter search speed = 0.10 (95% confidence intervals (CI): 0.03 to 0.16), word learning test = 0.05 (95% CI: 0.00 to 0.11), ACE-III scale = 0.09 (95% CI: 0.03 to 0.14). After adjustment for confounders, differences persisted for letter search speed (0.09; 95% CI: 0.02 to 0.16) but were closer to the null for the word learning test (0.02; 95% CI: − 0.04 to 0.07) and ACE-III scores (0.04; 95% CI: − 0.01 to 0.09). Low impacts remained associated with letter search speed after sensitivity analyses excluding those with functional and musculoskeletal problems, and after adjustment for impacts in higher bands. Modest positive associations between higher magnitude impacts and cognitive test scores were most likely due to chance. Conclusion Accelerometer-derived low impact physical activity was associated with better visual processing speed in 69-year old men and women independently of childhood cognitive ability and other measured confounders. Day-to-day low impact physical activity may therefore have the potential to benefit cognitive health in older adults