Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been--and still are--considered an ...exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC) or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl) tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA) and their genetically matched wild-type vhl (RCC4 VHL) counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066) with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with apoptosis induction in VHL deficient cell line as demonstrated with PARP activation and Annexin V staining. Our study demonstrated the feasibility of selectively targeting the loss of the vhl tumor suppressor gene for potential clinical benefit. Our results may have great impact on the development of new targeted therapies from natural products for the treatment of cancer and other genetic diseases.
BackgroundApproximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted ...inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.MethodsHere, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.ResultsVenetoclax treatment demonstrated specific killing of MYC+/BCL2+ lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.ConclusionsThese results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.
Intravascular lithotripsy (IVL) has demonstrated effectiveness in the treatment of calcified lesions in selected patients with stable coronary disease.
The authors sought to assess the performance of ...coronary IVL in calcified coronary lesions in a real-life, all comers, setting.
The REPLICA-EPIC18 study prospectively enrolled consecutive patients treated with IVL in 26 centers in Spain. An independent core laboratory performed the angiographic analysis and event adjudication. The primary effectiveness endpoint assessed procedural success (successful IVL delivery, final diameter stenosis <20%, and absence of in-hospital major adverse cardiovascular events MACE). The primary safety endpoint measured freedom from MACE at 30 days. A predefined substudy compared outcomes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients.
A total of 426 patients (456 lesions) were included, 63% of the patients presenting with ACS. IVL delivery was successful in 99% of cases. Before IVL, 49% of lesions were considered undilatable. The primary effectiveness endpoint was achieved in 66% of patients, with similar rates among CCS patients (68%) and ACS patients (65%). Likewise, there were no significant differences in angiographic success after IVL between CCS and ACS patients. The rate of MACE at 30 days (primary safety endpoint) was 3% (1% in CCS and 5% in ACS patients P = 0.073).
Coronary IVL proved to be a feasible and safe procedure in a "real-life" setting, effectively facilitating stent implantation in severely calcified lesions. Patients with ACS on admission showed similar angiographic success rates but showed a trend toward higher 30-day MACE compared with patients with CCS. (REPLICA-EPIC18 study Registry of Coronary Lithotripsy in Spain; NCT04298307).
Distributed optical fiber sensors (DOFS) have been postulated as a suitable technique for long-range monitoring of sinkhole-related subsidence, and possibly for the anticipation of catastrophic ...collapse (early-warning systems). The strain data published in previous works refer to artificial experiments considering real and virtual cover collapse sinkholes characterized by rapid subsidence and sharp lateral deformation gradients. The influence of the subsidence mechanism (sagging, collapse, suffosion) on the capability of DOFS to satisfactorily detect active subsidence is discussed. Sagging sinkholes with poorly-defined lateral edges, low lateral deformation gradients and slow subsidence are identified as the most challenging scenario. The performance of BOTDA optical fiber for monitoring such type of sagging sinkholes is evaluated in the active Alcalá sinkhole, which affects a flood-control dike creating a high-risk and -uncertainty scenario. This sinkhole shows active subsidence in sections tens of meters long with maximum subsidence rates ranging between 5 and 35 mm/yr. The comparison of vertical displacement data measured by high-precision leveling and the strain recorded by two types of fiber optic cables shows good spatial and temporal correlation. The subsidence sections are captured in the strain profiles by: (1) troughs of negative strain (contraction) in the area affected by subsidence, with the maximum strain associated with the point of most rapid settlement; and (2) lateral ridges of positive values (extension) in the marginal zones. A subsidence acceleration phase associated with a flood is also captured by substantial increments in the strain values. In this challenging scenario, despite the reasonably good spatial and temporal correlation between the displacement and strain data, the unambiguous identification of the active subsidence area with the fiber optic data alone might be difficult. Better results could be obtained improving the monitoring system (e.g., tighter cable-ground coupling) and testing other types of sinkholes with more localized deformation zones and higher subsidence rates.
•Slow moving sagging sinkhole monitored by BOTDA optical fiber.•Spatial and temporal correlation with subsidence measured by high-precision leveling.•Impact of the subsidence mechanism of the performance of optical fiber sensors.•Potential applicability of optical fiber sensors to early warning.
The aim of this study was to evaluate postoperative complications in patients having major elective surgery using oesophageal Doppler monitor-guided goal-directed haemodynamic therapy (GDHT), in ...which administration of fluids, inotropes, and vasopressors was guided by stroke volume, mean arterial pressure, and cardiac index.
The FEDORA trial was a prospective, multicentre, randomised, parallel-group, controlled patient- and observer-blind trial conducted in adults scheduled for major elective surgery. Randomization and allocation were carried out by a central computer system. In the control group, intraoperative fluids were given based on traditional principles. In the GDHT group, the intraoperative goals were to maintain a maximal stroke volume, with mean arterial pressure >70 mm Hg, and cardiac index ≥2.5 litres min−1 m−2. The primary outcome was percentage of patients with moderate or severe postoperative complications during the first 180 days after surgery.
In total, 450 patients were randomized to the GDHT group (n=224) or control group (n=226). Data from 420 subjects were analysed. There were significantly fewer with complications in the GDHT group (8.6% vs 16.6%, P=0.018). There were also fewer complications (acute kidney disease, pulmonary oedema, respiratory distress syndrome, wound infections, etc.), and length of hospital stay was shorter in the GDHT group. There was no significant difference in mortality between groups.
Oesophageal Doppler monitor-guided GDHT reduced postoperative complications and hospital length of stay in low–moderate risk patients undergoing intermediate risk surgery, with no difference in mortality at 180 days.
ISRCTN93543537.
The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD).
We performed a multicentre study of 124 patients with BD uveitis refractory ...to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load.
Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening optical coherence tomography (OCT) >250 μm and 35 (49 eyes) had cystoid macular oedema (OCT>300 μm) that improved from 420 μm (s.d. 119.5) at baseline to 271 μm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases.
Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.
The ability to detect human fecal pollution in water is of great importance when assessing the associated health risks. Many microbial source tracking (MST) markers have been proposed to determine ...the origin of fecal pollution, but their application remains challenging. A range of factors, not yet sufficiently analyzed, may affect MST markers in the environment, such as dilution and inactivation processes. In this work, a statistical framework based on Monte Carlo simulations and non-linear regression was used to develop a classification procedure for use in MST studies. The predictive model tested uses only two parameters: somatic coliphages (SOMCPH), as an index of general fecal pollution, and human host-specific bacteriophages that infect Bacteroides thetaiotaomicron strain GA17 (GA17PH). Taking into account bacteriophage dilution and differential inactivation, the threshold concentration of SOMCPH was calculated to be around 500 PFU/100 mL for a limit of detection of 10 PFU/100 mL. However, this threshold can be lowered by increasing the analyzed volume sample, which in turn lowers the limit of detection. The resulting model is sufficiently accurate for application in practical cases involving MST and could be easily used with markers other than those tested here.
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•A model to predict the content of human fecal pollution in water was developed.•Human pollution can be predicted using only two microbiological parameters (SOMCPH and GA17PH).•The effect of natural and artificial inactivation was considered in the predictions.•The model can be used in MST studies with other markers.
Intravascular lithotripsy (IVL) has demonstrated effectiveness in the treatment of calcified lesions in selected patients with stable coronary disease.
The authors sought to assess the performance of ...coronary IVL in calcified coronary lesions in a real-life, all comers, setting.
The REPLICA-EPIC18 study prospectively enrolled consecutive patients treated with IVL in 26 centers in Spain. An independent core laboratory performed the angiographic analysis and event adjudication. The primary effectiveness endpoint assessed procedural success (successful IVL delivery, final diameter stenosis <20%, and absence of in-hospital major adverse cardiovascular events MACE). The primary safety endpoint measured freedom from MACE at 30 days. A predefined substudy compared outcomes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients.
A total of 426 patients (456 lesions) were included, 63% of the patients presenting with ACS. IVL delivery was successful in 99% of cases. Before IVL, 49% of lesions were considered undilatable. The primary effectiveness endpoint was achieved in 66% of patients, with similar rates among CCS patients (68%) and ACS patients (65%). Likewise, there were no significant differences in angiographic success after IVL between CCS and ACS patients. The rate of MACE at 30 days (primary safety endpoint) was 3% (1% in CCS and 5% in ACS patients P = 0.073).
Coronary IVL proved to be a feasible and safe procedure in a “real-life” setting, effectively facilitating stent implantation in severely calcified lesions. Patients with ACS on admission showed similar angiographic success rates but showed a trend toward higher 30-day MACE compared with patients with CCS. (REPLICA-EPIC18 study Registry of Coronary Lithotripsy in Spain; NCT04298307)
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We report, from remote sensing and
in situ observations, a new type of permanent structure in the eastern subtropical Atlantic Ocean, that we call the “Canary Eddy Corridor”. The phenomenon, is a ...zonal long-lived (>3 months) mesoscale eddy corridor, whose source is the flow perturbation of the Canary Current and the Trade Winds at the Canary Islands. The latitudinal range of the corridor spans 22°N–29°N and extends from the Canaries to at least 32ºW, near the mid-Atlantic. This is the main region of long-lived westward-propagating eddies in the subtropical northeast Atlantic. From a age-distribution study we observe that at least 10% of mesoscale eddies in this region are long-lived, with a dominance of anticyclones over cyclones. Another four westward-propagating eddy corridors were also detected: two small corridors north and south of the Azores Front; a small zonal corridor located near 31ºN, south of the island of Madeira; and a small corridor located near the Cape Blanc giant filament. The existence of these corridors may change, at least for the northeastern subtropical Atlantic, the general idea that mesoscale eddies are disorganized, ubiquitous structures in the ocean. The Canary Eddy Corridor constitutes a direct zonal pathway that conveys water mass- and biogeochemical properties offshore from the Canary Island/Northwest Africa upwelling system, and may be seen as a recurrent offshore pump of organic matter and carbon to the oligotrophic ocean interior. Estimates of volume and mass transport indicate that Canary Eddy Corridor westward transport is more than one-fourth of the southward transport of the Canary Current. The westward transport of kinetic energy by the eddies of the Canary Corridor is as important as the southward transport by the Canary Current. The total primary production related to the Corridor may be as high as the total primary production of the northwest Africa upwelling system for the same latitude range.
SMEs in the new economic environment Salas Fumás, Vicente; Maroto Acín, Juan Antonio; Camisón Zornoza, César ...
Papeles de economía española,
01/2001, Letnik:
89-90
Journal Article
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