The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is ...limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.
Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in ...the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.
Diseases that result from infection are, in general, a consequence of specific interactions between a pathogenic organism and the cells. The study of host-pathogen interactions has provided insights ...for the design of drugs with therapeutic properties. One area that has proved to be promising for such studies is the constituted by carbohydrates which participate in biological processes of paramount importance. On the one hand, carbohydrates have shown to be information carriers with similar, if not higher, importance than traditionally considered carriers as amino acids and nucleic acids. On the other hand, the knowledge on molecular recognition of sugars by lectins and other carbohydrate-binding proteins has been employed for the development of new biomedical strategies. Biophysical techniques such as X-Ray crystallography and NMR spectroscopy lead currently the investigation on this field. In this review, a description of traditional and novel NMR methodologies employed in the study of sugar-protein interactions is briefly presented in combination with a palette of NMR-based studies related to biologically and/or pharmaceutically relevant applications.
Purpose. To assess the effects of antioxidant oral supplementation based on docosahexaenoic acid (DHA) in pseudoexfoliative (PEX) glaucoma. Patients and Methods. A prospective 6-month open-label ...randomized controlled trial was conducted in patients with PEX glaucoma and adequate intraocular pressure (IOP) control. Patients in the DHA group received a high-rich DHA (1 g) nutraceutical formulation. Ophthalmological examination, DHA erythrocyte membrane content (% total fatty acids), plasma total antioxidant capacity (TAC), plasma malondialdehyde (MDA), and plasma IL-6 levels were assessed. Results. Forty-seven patients (DHA group 23, controls 24; mean age 70.3 years) were included. In the DHA group, the mean IOP in the right eye decreased from 14.7 3.3 mmHg at baseline to 12.1 1.5 mmHg at 6 months (P=0.01). In the left eye, IOP decreased from 15.1 3.3 mmHg at baseline to 12.2 2.4 mmHg at 6 months (P=0.007). DHA erythrocyte content increased in the DHA group, with significant differences versus controls at 3 months and 6 months (8.1% 0.9 vs. 4.4% 0.7; P<0.0001). At 6 months and in the DHA group only, TAC levels as compared with baseline increased significantly (919.7 117.9 vs. 856.9 180.3 µM copper-reducing equivalents; P=0.01), and both MDA (4.4 0.8 vs. 5.2 1.1 nmol/mL; P = 0.02) and IL-6 (2.8 1.3 vs. 4.7 2.3 pg/mL; P=0.006) levels were lower than in controls. Conclusions. Targeting pathophysiology mechanisms of PEX glaucoma by reducing oxidative stress and inflammation with a high-rich DHA supplement might be an attractive therapeutic approach. Despite the short duration of treatment, decrease in IOP supports the clinical significance of DHA supplementation.
Specific interactions between molecules, including those produced by a given solute, and the surrounding solvent are essential to drive molecular recognition processes. A simple molecule such as ...benzene is capable of recognizing and differentiating among very similar entities, such as methyl 2,3,4,6-tetra-O-methyl-α-d-galactopyranoside (α-Me5Gal), methyl 2,3,4,6-tetra-O-methyl-β-d-galactopyranoside (β-Me5Gal), 1,2,3,4,6-penta-O-acetyl-β-d-galactopyranose (β-Ac5Gal), and methyl 2,3,4,6-tetra-O-methyl-α-d-mannopyranoside (α-Me5Man). In order to determine if these complexes are formed, the interaction energy between benzene and the different carbohydrates was determined, using Calvet microcalorimetry, as the enthalpy of solvation. These enthalpy values were −89.0 ± 2.0, −88.7 ± 5.5, −132.5 ± 6.2, and −78.8 ± 3.9 kJ mol−1 for the four complexes, respectively. Characterization of the different complexes was completed by establishing the molecular region where the interaction takes place using NMR. It was determined that β-Me5Gal is stabilized by the CH/π interaction produced by the nonpolar region of the carbohydrate on the α face. In contrast, α-Me5Man is not specifically solvated by benzene and does not present any stacking interaction. Although α-Me5Gal has a geometry similar to that of its epimer, the obtained NMR data seem to indicate that the axial methoxy group at the anomeric position increases the distance of the benzene molecules from the pyranose ring. Substitution of the methoxy groups by acetate moieties, as in β-Ac5Gal, precludes the approach of benzene to produce the CH/π interaction. In fact, the elevated stabilization energy of β-Ac5Gal is probably due to the interaction between benzene and the methyl groups of the acetyls. Therefore, methoxy and acetyl substituents have different effects on the protons of the pyranose ring.
Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, ...we show that human hematopoietic cells are required to induce sepsis-induced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ ⁻/⁻ mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ ⁻/⁻ mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ ⁻/⁻ mice transplanted with human hematopoietic stem cells humanized bone marrow liver thymic mice (BLT) mice showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide rabies virus glycoprotein (RVG)-9R effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.
Abstract
Background
Although the use of biomarkers to assess health outcomes has recently gained momentum, literature is still scarce for low- to middle-income countries. This paper explores the ...relationship between primary care coverage and individual health in Brazil using a dataset of blood-based biomarkers collected by the Brazilian National Health Survey. Both survey data and laboratory results were crossed with coverage data from the Family Health Strategy (ESF) program, the most important primary care program in Brazil; the coverage measures aim to capture both direct (household) and indirect (spill-over) effects.
Methods
The empirical strategy used a probit model to estimate the relationship between ESF program coverage and the likelihood of abnormal biomarker levels while controlling for a rich set of individual and household characteristics based on data from the national survey.
Results
Household ESF coverage was associated with a lower likelihood of abnormal results for biomarkers related to anemia (marginal effect between − 2.16 and − 2.18 percentage points), kidney failure (between − 1.01 and − 1.19 p.p.), and arterial hypertension (between − 1.48 and − 1.64 p.p). The likelihood of abnormal levels of white blood cells and thrombocytes was negatively related to primary care coverage (marginal effect between − 1.8 and − 2 p.p.). The spillover effects were relevant for kidney failure and arterial hypertension, depending on the regional level. Although not sensitive to household coverage, diabetes mellitus was negatively associated with the state supply of primary care, and abnormal cholesterol levels did not present any relationship with ESF program coverage.
Conclusions
The presence of spillover effects of ESF program coverage regarding these conditions reveals that the strengthening of primary care by increasing the household registration and the regional density of ESF teams is an efficient strategy to address important comorbidities.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To assess how the COVID-19 outbreak has affected emergency general surgery (EGS) care during the pandemic, indications for surgery, types of procedures, perioperative course, and final ...outcomes.
Methods
This is a retrospective study of EGS patients during the pandemic period. The main outcome was 30-day morbidity and mortality according to severity and COVID-19 infection status. Secondary outcomes were changes in overall management. A logistic regression analysis was done to assess factors predictive of mortality.
Results
One hundred and fifty-three patients were included. Half of the patients with an abdominal ultrasound and/or CT scan had signs of severity at diagnosis, four times higher than the previous year. Non-COVID patients underwent surgery more often than the COVID group. Over 1/3 of 100 operated patients had postoperative morbidity, versus only 15% the previous year. The most common complications were septic shock, pneumonia, and ARDS. ICU care was required in 17% of patients, and was most often required in the SARS-CoV-2-infected group, which also had a higher morbidity and mortality. The 30-day mortality in the surgical series was of 7%, with no differences with the previous year. The strongest independent predictors of overall mortality were age > 70 years, ASA III–IV, ESS > 9, and SARS-CoV-2 infection.
Conclusions
Non-operative management (NOM) was undertaken in a third of patients, and only 14% of operated patients had a perioperative confirmation of -CoV-2 infection. The severity and morbidity of COVID-19-infected patients was much higher. Late presentations for medical care may have added to the high morbidity of the series.
Diabetic retinopathy (DR) is the leading cause of legal blindness in the working population in developed countries. Optical coherence tomography (OCT) angiography (OCTA) has risen as an essential ...tool in the diagnosis and control of diabetic patients, with and without DR, allowing visualisation of the retinal and choroidal microvasculature, their qualitative and quantitative changes, the progression of vascular disease, quantification of ischaemic areas, and the detection of preclinical changes. The aim of this article is to analyse the current applications of OCTA and provide an updated overview of them in the evaluation of DR.
A systematic literature search was performed in PubMed and Embase, including the keywords "OCTA" OR "OCT angiography" OR "optical coherence tomography angiography" AND "diabetes" OR "diabetes mellitus" OR "diabetic retinopathy" OR "diabetic maculopathy" OR "diabetic macular oedema" OR "diabetic macular ischaemia". Of the 1456 studies initially identified, 107 studies were screened after duplication, and those articles that did not meet the selection criteria were removed. Finally, after looking for missing data, we included 135 studies in this review.
We present the common and distinctive findings in the analysed papers after the literature search including the diagnostic use of OCTA in diabetes mellitus (DM) patients. We describe previous findings in retinal vascularization, including microaneurysms, foveal avascular zone (FAZ) changes in both size and morphology, changes in vascular perfusion, the appearance of retinal microvascular abnormalities or new vessels, and diabetic macular oedema (DME) and the use of deep learning technology applied to this disease.
OCTA findings enable the diagnosis and follow-up of DM patients, including those with no detectable lesions with other devices. The evaluation of retinal and choroidal plexuses using OCTA is a fundamental tool for the diagnosis and prognosis of DR.
Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are ...reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
