HbF reactivation in sibling BFU-E colonies: synergistic interaction of kit ligand with low-dose dexamethasone

Mechanisms underlying fetal hemoglobin (HbF) reactivation in stress erythropoiesis have not been fully elucidated. We suggested that a key role is played by kit ligand (KL). Because glucocorticoids (GCs) mediate stress erythropoiesis, we explored their capacity to potentiate the stimulatory effect of KL on HbF reactivation, as evaluated in unilineage erythropoietic culture of purified adult progenitors (erythroid burst-forming units [BFU-Es]). The GC derivative dexamethasone (Dex) was tested in minibulk cultures at graded dosages within the therapeutical range (10−6 to 10−9M). Dex did not exert significant effects alone, but synergistically it potentiated the action of KL in a dose-dependent fashion. Specifically, Dex induced delayed erythroid maturation coupled with a 2-log increased number of generated erythroblasts and enhanced HbF synthesis up to 85% F cells and 55% γ-globin content at terminal maturation (ie, in more than 80%-90% mature erythroblasts). Equivalent results were obtained in unicellular erythroid cultures of sibling BFU-Es treated with KL alone or combined with graded amounts of Dex. These results indicate that the stimulatory effect of KL + Dex is related to the modulation of γ-globin expression rather than to recruitment of BFU-Es with elevated HbF synthetic potential. At the molecular level, Id2 expression is totally suppressed in control erythroid culture but is sustained in KL + Dex culture. Hypothetically, Id2 may mediate the expansion of early erythroid cells, which correlates with HbF reactivation. These studies indicate that GCs play an important role in HbF reactivation. Because Dex acts at dosages used in immunologic disease therapy, KL + Dex administration may be considered to develop preclinical models for β-hemoglobinopathy treatment

Influence of the Occlusion Site

Background: Previous findings suggest that transient myocardial ischemia and reperfusion may elicit changes in the autonomic balance. In this study, a spectral analysis of heart rate variability was used to assess the modifications of sympathovagal balance induced by coronary angioplasty and their relationship with the occlusion site. Methods: We studied 23 patients (17M, 6F, age 58 ± 10 years) with left anterior descending and 19 patients (15M, 4F, age 56 ± 9 years) with right coronary artery stenosis. Spectral analysis of heart rate variability was performed, by autoregressive model, in basal conditions and during each balloon inflation. At least two inflations of 90–120 seconds were performed in each patient. Results: In patients with left anterior descending artery stenosis, the first occlusion induced marked changes in the autonomic balance, which moved toward a sympathetic predominance. The low frequency component of the spectrum and the low-to-high frequency ratio increased from 59 ± 10 normalized units (NU) to 75 ± 10 NU (P < 0.001) and from 2.4 ± 1.4 to 7.3 ± 4.7 (P < 0.001) respectively, while the high frequency component decreased from 30 ± 11 NU to 14 ± 7 NU (P < 0.001). These changes showed a progressive attenuation during repetitive occlusions, and were significantly correlated with the entity of myocardial ischemia assessed by the ST-segment shift measured on the intracoronary electrocardiographic lead. On the contrary, in patients with right coronary artery stenosis the first occlusion was ineffective with regard to the spectral parameters whereas the third occlusion induced a significant increase in the high frequency component (from 31 ± 9 NU to 41 ± 10 NU, P < 0.01) and decrease in the low-to-high frequency ratio (from 2.1 ± 0.9 to 1.3 ± 0.5, P < 0.05) suggesting a vagal activation. The entity of vagal activation was not correlated with the ST-segment shift. Conclusions: Our data indicate that repetitive coronary occlusions induce significant changes in the autonomic balance. The direction and the time course of these changes are related to the occlusion site

Mechanical Prevention of Distal Embolization During Primary Angioplasty

Background— Effective myocardial reperfusion after primary percutaneous coronary intervention (PCI) may be limited by distal embolization. We tested the safety, feasibility, and efficacy of the FilterWire-Ex (FW), a distal embolic protection device, as an adjunct to primary PCI. Methods and Results— Fifty-three consecutive patients undergoing primary PCI with FW protection were compared with a matched control group treated by primary PCI alone. Successful FW positioning was obtained in 47 patients (89%) without complications. Histological analysis of the content of the last 13 filters showed multiple embolic debris in all cases. FW use was associated with lower postinterventional corrected TIMI frame count (22±14 versus 31±19; P =0.005) and higher occurrence of grade 3 myocardial blush (66% versus 36%; P =0.006) and early ST-segment elevation resolution (80% versus 54%; P= 0.006). At multivariate analysis, FW use was the only independent predictor of early ST-segment elevation resolution and of grade 3 myocardial blush. FW patients showed lower peak creatine kinase-MB release (236±172 versus 333±219 ng/mL; P =0.013) and greater improvement at 30 days in left ventricular wall motion score index (−0.30±0.19 versus −0.18±0.26; P= 0.008) and ejection fraction (+7±4% versus +4±7%; P =0.012). Conclusions— FW use during primary PCI is feasible and safe. Distal embolization prevention appears to exert a beneficial effect on markers of myocardial reperfusion and on left ventricular function improvement at 30 days

Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Combined fit to the spectrum and composition data measured by the Pierre Auger Observatory including magnetic horizon effects

The measurements by the Pierre Auger Observatory of the energy spectrum and mass composition of cosmic rays can be interpreted assuming the presence of two extragalactic source populations, one dominating the flux at energies above a few EeV and the other below. To fit the data ignoring magnetic field effects, the high-energy population needs to accelerate a mixture of nuclei with very hard spectra, at odds with the approximate E$^{-2}$ shape expected from diffusive shock acceleration. The presence of turbulent extragalactic magnetic fields in the region between the closest sources and the Earth can significantly modify the observed CR spectrum with respect to that emitted by the sources, reducing the flux of low-rigidity particles that reach the Earth. We here take into account this magnetic horizon effect in the combined fit of the spectrum and shower depth distributions, exploring the possibility that a spectrum for the high-energy population sources with a shape closer to E$^{-2}$ be able to explain the observations

Studies of the mass composition of cosmic rays and proton-proton interaction cross-sections at ultra-high energies with the Pierre Auger Observatory

In this work, we present an estimate of the cosmic-ray mass composition from the distributions of the depth of the shower maximum (Xmax) measured by the fluorescence detector of the Pierre Auger Observatory. We discuss the sensitivity of the mass composition measurements to the uncertainties in the properties of the hadronic interactions, particularly in the predictions of the particle interaction cross-sections. For this purpose, we adjust the fractions of cosmic-ray mass groups to fit the data with Xmax distributions from air shower simulations. We modify the proton-proton cross-sections at ultra-high energies, and the corresponding air shower simulations with rescaled nucleus-air cross-sections are obtained via Glauber theory. We compare the energy-dependent composition of ultra-high-energy cosmic rays obtained for the different extrapolations of the proton-proton cross-sections from low-energy accelerator data

Study of downward Terrestrial Gamma-ray Flashes with the surface detector of the Pierre Auger Observatory

The surface detector (SD) of the Pierre Auger Observatory, consisting of 1660 water-Cherenkov detectors (WCDs), covers 3000 km2 in the Argentinian pampa. Thanks to the high efficiency of WCDs in detecting gamma rays, it represents a unique instrument for studying downward Terrestrial Gamma-ray Flashes (TGFs) over a large area. Peculiar events, likely related to downward TGFs, were detected at the Auger Observatory. Their experimental signature and time evolution are very different from those of a shower produced by an ultrahigh-energy cosmic ray. They happen in coincidence with low thunderclouds and lightning, and their large deposited energy at the ground is compatible with that of a standard downward TGF with the source a few kilometers above the ground. A new trigger algorithm to increase the TGF-like event statistics was installed in the whole array. The study of the performance of the new trigger system during the lightning season is ongoing and will provide a handle to develop improved algorithms to implement in the Auger upgraded electronic boards. The available data sample, even if small, can give important clues about the TGF production models, in particular, the shape of WCD signals. Moreover, the SD allows us to observe more than one point in the TGF beam, providing information on the emission angle