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Supplementary Figure 1 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 2 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 3 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 2 from Synergistic Proapoptotic Activity of Recombinant TRAIL Plus the Akt Inhibitor Perifosine in Acute Myelogenous Leukemia Cells

Supplementary Table 1 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

In the last few years, steps forward in the knowledge of the biology of soft tissue sarcomas (STS) have led to the development of new therapeutic strategies, including immunotherapy.This review outlines the recent findings on immunological features and provides a synopsis of the results of clinical trials with different immunotherapy approaches in STS, discussing criticisms, and how the efficacy of immunotherapy could be improved.The heterogeneity of STS has limited generalized approaches of immunotherapy in the disease. Clinical decisions should encompass a comprehensive characterization of the tumor microenvironment (TME), marked by intra-histotype diversity. Profiling of immune cells, checkpoint molecules, and antigen target/HLA expression is deemed to reshape the classical histotype classification for a selection of the most appropriate immune-based treatment. In a synergistic view, tumor-directed treatments, designed on the genetic and epigenetic histotype make-up, should be monitored for their immunomodulant effect and applied to ensure or amplify immunotherapy response. In light of the dynamic nature of the TME, this immunomonitoring should be conducted at baseline and during treatment, for improved therapeutic decisions and rational sequence of treatment combination, pursuing an immunological marker approach by histotype guidance.

Peripheral T-cell lymphomas not otherwise specified (PTCL/NOS) is the commonest subtype of PTCL. NF–kB related molecules have been found to be variably expressed in PTCL/NOS, suggesting a potential involvement of the NF–kB system in their pathogenesis. However, the actual contribution of NF–kB molecular programs to the PTCL/NOS landscape has not been investigated yet. In this study, we assessed in a large series of PTCL/NOS, the activation status of NF–kB programs and investigated the prognostic impact of such NF–kB expression. Moreover, we explored the possible role of NF–kB inhibitors. We studied the gene expression profiles of 180 PTCL cases and tested two different drugs, the IKK inhibitor BMS-345541 and the proteasome inhibitor Bortezomib, in four PTCL cell lines. We found that most cases (84%) presented with some degree of NF–kB activation, based on the expression of REL and RELA. Functionally, the latter was strictly related with TCR signaling activation, while REL was at least partially TCR independent. We also identified genes related with NF–kB activation in this setting that were mainly involved in cell proliferation and apoptosis inhibition. Further, by reverse engineering we defined the transcriptional network of both REL and RELA in PTCLs that only partially overlapped. On the clinical ground, we found that RELA expression was related to a significantly poorer overall survival, with similar trends for REL. However, most remarkably, when all the three genes were considered together, cases with at least one gene over-expressed, showed a dramatically inferior overall survival (28.67 vs. 56.018 months; p = 0.004). Finally, we showed that NF–kB pharmacological inhibition was associated with cell cycle arrest and cell death in NF–kB positive PTCL cells. In conclusion, we extensively explored NF–kB activation in PTCL/NOS, documenting its negative prognostic role. Further, we showed that NF–kB inhibition might represent a rational therapeutic approach in selected cases.

AimsTo assess survival predictivity of baseline blood cell differential count (BCDC) discretization methods in acutely ill adults visiting the emergency room over one-year.MethodsRetrospective cohort study on one-year survival of adults reporting to the emergency room of the A. Manzoni Hospital (Italy) during 2020. Automated BCDC analysis performed at baseline, assessed hemoglobin, red cell mean volume and distribution width (RDW), platelet distribution width (PDW), platelet-hematocrit, absolute red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets. Discretization cutoffs were defined by: Benchmark laboratory reference values and Tailored (maximally selected rank statistics for linear and sigmoid-shaped distributed variables; optimal-equal hazard ratio (HR) method for U-shaped distributed variables. Explanatory variables (age, gender, inward admission) were analyzed using Cox multivariable regression. Receiver operating characteristic curves used the sum of Cox-significant variables in each method.ResultsOf 11052 patients (median age 67 years, interquartile range (IQR) 51–81, 48% female), 59% (n=6489) were discharged and 41% (n=4563) were admitted. After a 306-day median follow up (IQR 208–417 days), 9455 (86%) patients were alive and 1597 (14%) deceased. Increased HRs were associated with age > 73 years (HR=4.29 CI 3.78–4.87), and hospital admission (HR=2.05, CI 1.83–2.29). Age, sex, hemoglobin, mean corpuscular volume, RDW, PDW, neutrophils, lymphocytes and eosinophils were significant in overall. Benchmark included basophils and platelet count (area under the ROC curve (AUROC) 0.78). Tailored included monocyte counts and PCT (AUROC of 0.82).ConclusionsTailored discretization of BCDC provided meaningful insight regarding acute patient survival.Key messagesWhat is already known on this topicInformation on survival predictivity of BCDC is scarce, particularly in acutely ill patients considering that reference values are based on the general population.What this study addsLaboratory reference interval values predicting survival were hemoglobin, RDW, MCV, neutrophil, lymphocyte, eosinophil, and basophils counts, PLT, and PDW, independently of sex, age, and acute inward admission. Survival predictivity was improved by discretization of hemoglobin, RDW, MCV, neutrophil, lymphocyte, eosinophil, and monocyte counts, and PDW, according to the maximally selected rank statistics and optimal-equal HR method.How this study might affect research, practice, or policyBaseline BCDC discretized by tailored methods may be a useful biomarker for hazard warning in acute illness.

Protoplanetary disks emit radiation across a broad range of wavelengths, requiring a multiwavelength approach to fully understand their physical mechanisms and how they form planets. Observations at sub-millimeter to centimeter wavelengths can provide insights into the thermal emission from dust, free-free emission from ionized gas, and possible gyro-synchrotron emission from the stellar magnetosphere. This Letter focuses on CX Tau, a ${\sim}0.4\,M_\odot$ star with an extended gas emission and a compact and apparently structureless dust disk, with an average millimeter flux when compared to Class II sources in Taurus. We present Karl G. Jansky Very Large Array (VLA) observations in 4 bands (between 9.0 mm and 6.0 cm) and combine them with archival data from the Atacama Large Millimeter/submillimeter Array (ALMA), the Submillimeter Array (SMA) and the Plateau de Bure Interferometer (PdBI). Such a multiwavelength approach allows to separate the dust continuum from other emissions. After isolating the dust thermal emission, we derived an upper limit of the dust disk extent at 1.3 cm which is consistent with theoretical predictions of a radial drift-dominated disk. Centimeter data show a peculiar behavior: deep observations at 6.0 cm did not detect the source, while at 1.3 cm the flux density is anomalously higher than adjacent bands. Intraband spectral indices suggest a dominant contribution from free-free emission, whereas gyro-synchrotron emission is excluded. To explain these observations, we propose strong variability of the free-free emission with timescales shorter than a month. Another possible interpretation is the presence of anomalous microwave emission from spinning dust grains., Comment: Accepted for publication in A&A Letters; 13 pages, 13 figures, 1 table

Aims In patients undergoing cardiac implantable electronic device (CIED) intervention, routine pre-procedure antibiotic prophylaxis is recommended. A more powerful antibiotic protocol has been suggested in patients at high risk of infection. Stratification of individual infective risk could guide the prophylaxis before CIED procedure. Methods and results Patients undergoing CIED surgery were stratified according to the Shariff score in low and high infective risk. Patients in the ‘low-risk’ group were treated with only two antibiotic administrations while patients in the ‘high-risk’ group were treated with a prolonged 9-day protocol, according to renal function and allergies. We followed-up patients for 250 days with clinical outpatient visit and electronic control of the CIED. As primary endpoint, we evaluated CIED-related infections. A total of 937 consecutive patients were enrolled, of whom 735 were stratified in the ‘low-risk’ group and 202 in the ‘high-risk’ group. Despite different risk profiles, CIED-related infection rate at 250 days was similar in the two groups (8/735 in ‘low risk’ vs. 4/202 in ‘high risk’, P = 0.32). At multivariate analysis, active neoplasia, haematoma, and reintervention were independently associated with CIED-related infection (HR 5.54, 10.77, and 12.15, respectively). Conclusion In a large cohort of patients undergoing CIED procedure, an antibiotic prophylaxis based on individual stratification of infective risk resulted in similar rate of infection between groups at high and low risk of CIED-related infection.

The present work is aimed at presenting the data, methods and criteria that are being used for the assessment of ecosystem collapse risk in Italy.

Hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children (< 3 years), is mainly related to Shiga toxins (Stx)-producing Escherichia coli (STEC) infections. STEC are confined to the gut resulting in hemorrhagic colitis, whereas Stx are delivered in blood to target kidney and brain, with unclear mechanisms, triggering HUS in 5 to 15% of infected children. Stx were found on circulating cells, free in sera (soluble Stx) or in blood cell-derived microvesicles (particulate Stx), whereby the relationship between these forms of circulating toxins is unclear. Here, we have examined 2,846 children with bloody diarrhea and found evidence of STEC infection in 5%. Twenty patients were enrolled to study the natural course of STEC infections before the onset of HUS. In patients, Stx were found to be associated to circulating cells and/or free and functionally active in sera. In most children, Stx were bound to neutrophils when high amounts of toxins were found in feces. Time-course analysis showed that Stx increased transiently in patients' sera while the decrease of toxin amount on leukocytes was observed. Notably, patients who recovered (85%) displayed different settings than those who developed HUS (15%). The distinctive feature of the latter group was the presence in blood of particulate Stx2 (Stx2 sedimented at g-forces corresponding to 1 μm microvesicles) the day before diagnosis of HUS, during the release phase of toxins from circulating cells. This observation strongly suggests the involvement of blood cell-derived particulate Stx2 in the transition from hemorrhagic colitis to HUS.

Diet is a major driver of gut microbiota variation and plays a role in metabolic disorders, including metabolic syndrome (MS). Mycorrhized foods from symbiotic agriculture (SA) exhibit improved nutritional properties, but potential benefits have never been investigated in humans. We conducted a pilot interventional study on 60 adults with ≥ 1 risk factors for MS, of whom 33 consumed SA-derived fresh foods and 27 received probiotics over 30 days, with a 15-day follow-up. Stool, urine and blood were collected over time to explore changes in gut microbiota, metabolome, and biochemical, inflammatory and immunologic parameters, previous dietary habits were investigated through a validated food-frequency questionnaire. The baseline microbiota showed alterations typical of metabolic disorders, mainly an increase in Coriobacteriaceae and a decrease in health-associated taxa, which were partly reversed after the SA-based diet. Improvements were observed in metabolome, MS presence (two out of six subjects no longer had MS) or components. Changes were more pronounced with less healthy baseline diets. Probiotics had a marginal, not entirely favorable, effect, although one out of three subjects no longer suffered from MS. These findings suggest that improved dietary patterns can modulate the host microbiota and metabolome, counteracting the risk of developing MS.

Abstract Within the circular economy framework, our study aims to assess the rhamnolipid production from winery and olive oil residues as low-cost carbon sources by nonpathogenic strains. After evaluating various agricultural residues from those two sectors, Burkholderia thailandensis E264 was found to use the raw soluble fraction of nonfermented (white) grape marcs (NF), as the sole carbon and energy source, and simultaneously, reducing the surface tension to around 35 mN/m. Interestingly, this strain showed a rhamnolipid production up to 1070 mg/L (13.37 mg/g of NF), with a higher purity, on those grape marcs, predominately Rha-Rha C14-C14, in MSM medium. On olive oil residues, the rhamnolipid yield of using olive mill pomace (OMP) at 2% (w/v) was around 300 mg/L (15 mg/g of OMP) with a similar CMC of 500 mg/L. To the best of our knowledge, our study indicated for the first time that a nonpathogenic bacterium is able to produce long-chain rhamnolipids in MSM medium supplemented with winery residues, as sole carbon and energy source. Key points • Winery and olive oil residues are used for producing long-chain rhamnolipids (RLs). • Both higher RL yields and purity were obtained on nonfermented grape marcs as substrates. • Long-chain RLs revealed stabilities over a wide range of pH, temperatures, and salinities

Vineyard and olive farming are deeply rooted in the economy, culture, and even the welfare of Mediterranean countries. Although numerous approaches and methods were developed to valorize their agricultural residues, several challenges remain to overcome moving towards the Circular Economy (CE). Conventional treatments of winery and olive mill wastes are becoming increasingly expensive, demanding significant amounts of effort, resources, and energy for safe waste discharge. Therefore, the need to recycle, reuse, and recover energy and valuable biocompounds from the wastes of these two sectors become apparent. In the context of increasing waste production, climate change, coupled with dramatic rises in demand from a much larger global population and customers, CE offers the prospect of a better future. Microbes are able to produce diverse biosurfactants (BS) containing both hydrophilic and hydrophobic moieties that could interact with surfaces, lower surface and interfacial tensions, form micelles, and emulsify immiscible substances. Among several BS classes, rhamnolipids are glycolipids produced by some gram-negative bacteria with various potential applications in numerous fields, including bioremediation of contaminated soils. In contrast to several biosurfactants, this particular class of glycolipids is among the economically competitive biomolecules with its synthetic equivalents. For that, we highlighted the main opportunities, the challenges, and the future aspects towards the production of this particular type of glycolipids using winery and olive oil wastes. Therefore, we proposed the critical points that should be assumed through the path of successful strategies for rhamnolipid production using these two potential agricultural residues. This review might help at boosting the current attempts to find novel CE models. Graphic Abstract: [Figure not available: see fulltext.]

Class III stars are those in star forming regions without large non-photospheric infrared emission, suggesting recent dispersal of their protoplanetary disks. We observed 30 class III stars in the 1-3 Myr Lupus region with ALMA at ${\sim}856��$m, resulting in 4 detections that we attribute to circumstellar dust. Inferred dust masses are $0.036{-}0.093M_\oplus$, ${\sim}1$ order of magnitude lower than any previous measurements; one disk is resolved with radius ${\sim}80$ au. Two class II sources in the field of view were also detected, and 11 other sources, consistent with sub-mm galaxy number counts. Stacking non-detections yields a marginal detection with mean dust mass ${\sim}0.0048M_\oplus$. We searched for gas emission from the CO J=3-2 line, and present its detection to NO Lup inferring a gas mass ($4.9 {\pm} 1.1$) ${\times}10^{-5} M_\oplus$ and gas-to-dust ratio $1.0{\pm}0.4$. Combining our survey with class II sources shows a gap in the disk mass distribution from $0.09{-}2M_\oplus$ for ${>}0.7M_\odot$ Lupus stars, evidence of rapid dispersal of mm-sized dust from protoplanetary disks. The class III disk mass distribution is consistent with a population model of planetesimal belts that go on to replenish the debris disks seen around main sequence stars. This suggests that planetesimal belt formation does not require long-lived protoplanetary disks, i.e., planetesimals form within ${\sim}$2 Myr. While all 4 class III disks are consistent with collisional replenishment, for two the gas and/or mid-IR emission could indicate primordial circumstellar material in the final stages of protoplanetary disk dispersal. Two class III stars without sub-mm detections exhibit hot emission that could arise from ongoing planet formation processes inside ${\sim}1$ au., 30 pages, 20 figures. This is a pre-copyedited, author-produced PDF of an article accepted for publication in MNRAS following peer review

Context. Observations at millimeter wavelengths of bright protoplanetary disks have shown the ubiquitous presence of structures such as rings and spirals in the continuum emission. The derivation of the underlying properties of the emitting material is nontrivial because of the complex radiative processes involved. Aims. In this paper we analyze new observations from the Atacama Large Millimeter/submillimeter Array (ALMA) and the Karl G. Jansky Very Large Array (VLA) at high angular resolution corresponding to 5 – 8 au to determine the dust spatial distribution and grain properties in the ringed disk of HD 163296. Methods. We fit the spectral energy distribution as a function of the radius at five wavelengths from 0.9 to 9 mm, using a simple power law and a physical model based on an analytic description of radiative transfer that includes isothermal scattering. We considered eight dust populations and compared the models' performance using Bayesian evidence. Results. Our analysis shows that the moderately high optical depth (τ>1) at λ ≤ 1.3 mm in the dust rings artificially lower the millimeter spectral index, which should therefore not be considered as a reliable direct proxy of the dust properties and especially the grain size. We find that the outer disk is composed of small grains on the order of 200 µm with no significant difference between rings at 66 and 100 au and the adjacent gaps, while in the innermost ~30 au, larger grains (≥mm) could be present. We show that the assumptions on the dust composition have a strong impact on the derived surface densities and grain size. In particular, increasing the porosity of the grains to 80% results in a total dust mass about five times higher with respect to grains with 25% porosity. Finally, we find that the derived opacities as a function of frequency deviate from a simple power law and that grains with a lower porosity seem to better reproduce the observations of HD 163296. Conclusions. While we do not find evidence of differential trapping in the rings of HD 163296, our overall results are consistent with the postulated presence of giant planets affecting the dust temperature structure and surface density, and possibly originating a second-generation dust population of small grains., Astronomy & Astrophysics, 664, ISSN:0004-6361, ISSN:1432-0746

The 1.33 mm survey of protoplanetary discs in the Taurus molecular cloud found annular gaps and rings to be common in extended sources (>~55 au), when their 1D visibility distributions were fit parametrically. We first demonstrate the advantages and limitations of nonparametric visibility fits for data at the survey's 0.12" resolution. Then we use the nonparametric model in Frankenstein ('frank') to identify new substructure in three compact and seven extended sources. Among the new features we identify three trends: a higher occurrence rate of substructure in the survey's compact discs than previously seen, underresolved (potentially azimuthally asymmetric) substructure in the innermost disc of extended sources, and a 'shoulder' on the trailing edge of a ring in discs with strong depletion at small radii. Noting the shoulder morphology is present in multiple discs observed at higher resolution, we postulate it is tracing a common physical mechanism. We further demonstrate how a super-resolution frank brightness profile is useful in motivating an accurate parametric model, using the highly structured source DL Tau in which frank finds two new rings. Finally we show that sparse (u, v) plane sampling may be masking the presence of substructure in several additional compact survey sources., Accepted to MNRAS

(Abridged) Exoplanetary research has provided us with exciting discoveries of planets around very low-mass (VLM) stars (e.g., TRAPPIST-1 and Proxima Centauri). However, current theoretical models strive to explain planet formation in these conditions and do not predict the development of giant planets. Recent high-resolution observations from ALMA of the disk around CIDA 1, a VLM star in Taurus, show substructures hinting at the presence of a massive planet. We aim to reproduce the dust ring of CIDA 1, observed in the dust continuum emission in ALMA Band 7 (0.9 mm) and Band 4 (2.1 mm), along with its $^{12}$CO (J=3-2) and $^{13}$CO (J=3-2) channel maps, assuming the structures are shaped by the interaction of the disk with a massive planet. We seek to retrieve the mass and position of the putative planet. We model the protoplanetary disk with a set of hydrodynamical simulations, varying the mass and locations of the embedded planet. We compute the dust and gas emission using radiative transfer simulations, and, finally, we obtain the synthetic observations treating the images as the actual ALMA observations. Our models indicate that a planet with a minimum mass of $\sim1.4\,\text{M}_\text{Jup}$ orbiting at a distance of $\sim 9-10$ au can explain the morphology and location of the observed dust ring at Band 7 and Band 4. We can reproduce the low spectral index ($\sim 2$) observed where the dust ring is detected. Our synthetic images reproduce the morphology of the $^{12}$CO and $^{13}$CO observed channel maps where the cloud absorption allowed a detection. Applying an empirical relation between planet mass and gap width in the dust, we predict a maximum planet mass of $\sim4 - 8\,\text{M}_\text{Jup}$. Our results suggest the presence of a massive planet orbiting CIDA 1, thus challenging our understanding of planet formation around VLM stars., Accepted for publication in A&A, 22 pages, 21 figures, 3 tables

Recent observations have revealed that most proto-planetary discs show a pattern of bright rings and dark gaps. However, most of the high-resolution observations have focused only on the continuum emission. In this Paper we present high-resolution ALMA band 7 (0.89mm) observations of the disc around the star CI Tau in the $^{12}$CO & $^{13}$CO $J=3$-2 and CS $J=7$-6 emission lines. Our recent work demonstrated that the disc around CI Tau contains three gaps and rings in continuum emission, and we look for their counterparts in the gas emission. While we find no counterpart of the third gap and ring in $^{13}$CO, the disc has a gap in emission at the location of the second continuum ring (rather than gap). We demonstrate that this is mostly an artefact of the continuum subtraction, although a residual gap still remains after accounting for this effect. Through radiative transfer modelling we propose this is due to the inner disc shadowing the outer parts of the disc and making them colder. This raises a note of caution in mapping high-resolution gas emission lines observations to the gas surface density - while possible, this needs to be done carefully. In contrast to $^{13}$CO, CS emission shows instead a ring morphology, most likely due to chemical effects. Finally, we note that $^{12}$CO is heavily absorbed by the foreground preventing any morphological study using this line.

Dippers are a common class of young variable star exhibiting day-long dimmings with depths of up to several tens of percent. A standard explanation is that dippers host nearly edge-on (70 deg) protoplanetary discs that allow close-in (< 1 au) dust lifted slightly out of the midplane to partially occult the star. The identification of a face-on dipper disc and growing evidence of inner disc misalignments brings this scenario into question. Thus we uniformly (re)derive the inclinations of 24 dipper discs resolved with (sub-)mm interferometry from ALMA. We find that dipper disc inclinations are consistent with an isotropic distribution over 0-75 deg, above which the occurrence rate declines (likely an observational selection effect due to optically thick disc midplanes blocking their host stars). These findings indicate that the dipper phenomenon is unrelated to the outer (>10 au) disc resolved by ALMA and that inner disc misalignments may be common during the protoplanetary phase. More than one mechanism may contribute to the dipper phenomenon, including accretion-driven warps and "broken" discs caused by inclined (sub-)stellar or planetary companions., Accepted to MNRAS (19 pages, 7 figures, 2 tables)