Offspring sex modifies the association between early-pregnancy adiposity and 2-year-old physical activity-The Glowing Study.

BACKGROUND: Rodent models suggest that in utero exposure to under and overnutrition programs offspring physical activity (PA) behaviors. Such nexus has not been established in humans. This study evaluated the association of early pregnancy maternal adiposity with offspring PA at age 2 years (2-yo-PA) taking into consideration prenatal and postnatal factors. METHODS: Women (n = 153) were enrolled early in pregnancy (<10 weeks). At enrollment, maternal adiposity [air displacement plethysmography, fat mass index (FMI, kg/m2)] and PA (accelerometers, activity counts) were measured, and age, race, and education self-reported. Gestational weight gain was measured at the research facility. Offspring birthweight and sex were self-reported. At age 2 years, parental feeding practices (child feeding questionnaire) were assessed, whereas anthropometrics (length and weight) and physical activity (accelerometers) were objectively measured. Offspring body mass index z-scores were calculated. Generalized linear regression analysis modeled the association of maternal FMI and 2-yo-PA [average activity counts (AC)4/day]. RESULTS: In bivariate associations, 2-yo-PA did not associate with maternal FMI (ß = -0.22, CI = -0.73 to 0.29, p = 0.398). However, maternal FMI interacted with offspring sex in association with 2-yo-PA. Specifically, 2-yo-PA was lower in girls (ß = -1.14, CI = -2.1 to -0.18, p = 0.02) compared to boys when maternal FMI was ≥7 kg/m2. When stratified by sex, 2-yo-PA of girls negatively associated with maternal FMI (ß = -0.82, CI = -1.43 to 0.29, p = 0.009) while no association was found between maternal FMI and boy's PA (ß = 0.32, CI = -0.38 to 1.01, p = 0.376). CONCLUSIONS: The association of 2-yo-PA and early pregnancy maternal adiposity was modified by offspring sex. Offspring's physical activity decreased with increasing early pregnancy adiposity maternal in girls but not boys in second parity dyads.

Mapping the Spatial Dynamics of the CD4+ T Cell Spectrum in Classical Hodgkin Lymphoma.

As around 25% to 30% of classical Hodgkin lymphoma (cHL) patients with advanced stages do not respond to standard therapies, the tumor microenvironment of cHL is one avenue that may be explored with the aim of improving risk stratification. CD4+ T cells are thought to be one of the main cell types in the tumor microenvironment. However, few immune signatures have been studied, and many of these lack related spatial data. Thus, our aim is to spatially resolve the CD4+ T cell subtypes that influence cHL outcome, depicting new immune signatures or transcriptional patterns that are in crosstalk with the tumor cells. This study was conducted using the NanoString GeoMx digital spatial profiling technology, based on the selection of distinct functional areas of patients' tissues followed by gene-expression profiling. The goals were to assess the differences in CD4+ T cell populations between tumor-rich and immune-predominant areas defined by different CD30 and PD-L1 expression levels and seek correlations with clinical metadata. Our results depict a complex map of CD4+ T cells with different functions and differentiation states that are enriched at distinct locations, the flux of cytokines and chemokines that could be related to these, and the specific relationships with the clinical outcome.

Optically induced ultrafast magnetization switching in ferromagnetic spin valves.

The discovery of spin-transfer torque (STT) enabled the control of the magnetization direction in magnetic devices in nanoseconds using an electrical current. Ultrashort optical pulses have also been used to manipulate the magnetization of ferrimagnets at picosecond timescales by bringing the system out of equilibrium. So far, these methods of magnetization manipulation have mostly been developed independently within the fields of spintronics and ultrafast magnetism. Here we show optically induced ultrafast magnetization reversal taking place within less than a picosecond in rare-earth-free archetypal spin valves of [Pt/Co]/Cu/[Co/Pt] commonly used for current-induced STT switching. We find that the magnetization of the free layer can be switched from a parallel to an antiparallel alignment, as in STT, indicating the presence of an unexpected, intense and ultrafast source of opposite angular momentum in our structures. Our findings provide a route to ultrafast magnetization control by bridging concepts from spintronics and ultrafast magnetism.

Tumor-Intrinsic Perinuclear LOXL2: Prognostic Relevance and Relationship with YAP1 Activation Status in Oral Squamous Cell Carcinoma.

INTRODUCTION: Lysyl oxidase-like 2 (LOXL2) expression and function is frequently altered in different cancers but scarcely explored in oral squamous cell carcinoma (OSCC). This prompted us to investigate the clinical relevance of LOXL2 expression pattern in OSCC and also a possible crosstalk with Hippo/YAP1 pathway signaling. METHODS: Immunohistochemical analysis of LOXL2 protein expression was performed in 158 OSCC patient samples, together with Yes-associated protein 1 (YAP1) activation status. Correlations with clinicopathological parameters and patient survival were assessed. RESULTS: Tumor cell-intrinsic LOXL2 expression showed two distinct expression patterns: diffuse cytoplasmic staining (64.6%) and heterogeneous perinuclear staining (35.4%). Remarkably, perinuclear LOXL2 staining was significantly associated with lymph node metastasis, advanced clinical stage and perineural invasion. Moreover, patients harboring tumors with perinuclear LOXL2 expression exhibited significantly poorer disease-specific survival (DSS) rates, and perinuclear LOXL2 positivity gradually increased in relation to YAP1 activation. Patients harboring tumors with concomitant perinuclear LOXL2 and fully active YAP1 exhibited the worst DSS. Multivariate Cox analysis further revealed combined perinuclear LOXL2 and fully active YAP1 as a significant independent predictor of poor DSS. CONCLUSION: Tumor-intrinsic perinuclear LOXL2 emerges as a clinically and biologically relevant feature associated with advanced disease, tumor aggressiveness, and poor prognosis in OSCC. Moreover, this study unprecedentedly uncovers a functional relationship between perinuclear LOXL2 and YAP1 activation with major prognostic implications. Notably, combined perinuclear LOXL2 and fully active YAP1 was revealed as independent predictor of poor prognosis. These findings encourage targeting oncogenic LOXL2 functions for personalized treatment regimens.

BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed-Sternberg cells.

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.

Novel neuroactive steroids as positive allosteric modulators of NMDA receptors: mechanism, site of action, and rescue pharmacology on GRIN variants associated with neurological conditions.

N-methyl-D-aspartate receptors (NMDARs) play vital roles in normal brain functions (i.e., learning, memory, and neuronal development) and various neuropathological conditions, such as epilepsy, autism, Parkinson's disease, Alzheimer's disease, and traumatic brain injury. Endogenous neuroactive steroids such as 24(S)-hydroxycholesterol (24(S)-HC) have been shown to influence NMDAR activity, and positive allosteric modulators (PAMs) derived from 24(S)-hydroxycholesterol scaffold can also enhance NMDAR function. This study describes the structural determinants and mechanism of action for 24(S)-hydroxycholesterol and two novel synthetic analogs (SGE-550 and SGE-301) on NMDAR function. We also show that these agents can mitigate the altered function caused by a set of loss-of-function missense variants in NMDAR GluN subunit-encoding GRIN genes associated with neurological and neuropsychiatric disorders. We anticipate that the evaluation of novel neuroactive steroid NMDAR PAMs may catalyze the development of new treatment strategies for GRIN-related neuropsychiatric conditions.

Biodiesel production from sewage sludge using supported heteropolyacid as heterogeneous acid catalyst.

Phosphotungstic acid (HPW) and silicotungstic acid (HSiW) were tested as homogeneous and as heterogeneous catalysts (after immobilized on different supports as high surface area graphite -HSAG500-, montmorillonite -MMT- and alumina -Al2O3-) for the in situ transesterification of sewage sludge lipids. Both catalysts exhibited similar performance in homogeneous phase, with slightly higher biodiesel yield for HPW. When the different supports were tested with HPW, the maximum yield obtained follow the trend: MMT > HSAG500 > Al2O3, but a greater leaching of the heteropolyacid (HPA) was observed with MMT. Therefore, HSAG500 showed the best results with a good FAMEs profile. The percentage of active phase was optimized from 1 to 40%, reaching the optimum at 10%. A more heterogeneous surface is obtained with larger quantities, also favouring the HPA leaching. The reaction temperature and the use of sonication as pre-treatment were also optimized. The best results were obtained after sonication with HPW-HSAG500 (10%) as catalyst, catalyst/sludge ratio 1:2, MeOH/sludge ratio 33:1, 120 °C and 21 h of reaction time with a maximum biodiesel yield of 31.1 % (FAMEs/lipids). In view of the results obtained HPW supports on HSAG500 offers a novel alternative as heterogeneous acid catalyst for in situ transesterification using sewage sludge as raw material.

Noninvasive detection of microsatellite instability in patients with endometrial cancer.

The analysis of mismatch repair proteins in solid tissue is the standard of care (SoC) for the microsatellite instability (MSI) characterization in endometrial cancer (EC). Uterine aspirates (UAs) or circulating-DNA (cfDNA) samples capture the intratumor heterogeneity and provide a more comprehensive and dynamic molecular diagnosis. Thus, MSI analysis by droplet-digital PCR (ddPCR) in UAs and cfDNA can provide a reliable tool to characterize and follow-up the disease. The UAs, paraffin-embedded tumor tissue (FFPE) and longitudinal plasma samples from a cohort of 90 EC patients were analyzed using ddPCR panel and compared to the SoC. A high concordance (96.67%) was obtained between the analysis of MSI markers in UAs and the SoC. Three discordant cases were validated as unstable by ddPCR on FFPE samples. Besides, a good overall concordance (70.27%) was obtained when comparing the performance of the ddPCR assay on UAs and cfDNA in high-risk tumors. Importantly, our results also evidenced the value of MSI analysis to monitor the disease evolution. MSI evaluation in minimally invasive samples shows great accuracy and sensitivity and provides a valuable tool for the molecular characterization and follow-up of endometrial tumors, opening new opportunities for personalized management of EC.

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report.

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15-20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.

Divergent Changes in Serum Branched-Chain Amino Acid Concentrations and Estimates of Insulin Resistance throughout Gestation in Healthy Women.

BACKGROUND: Branched-chain amino acid (BCAA) concentrations in the blood have been correlated with insulin resistance, but this relation throughout gestation (period in which insulin resistance typically increases) is unclear. OBJECTIVE: The objective of this study was to determine the associations between changes in BCAA concentrations and estimates of insulin resistance throughout gestation. METHODS: Serum BCAA (Leu, Ile, Val) concentrations and insulin resistance/sensitivity [i.e., homeostatic model assessment-2 of insulin resistance (HOMA2-IR), estimated metabolic clearance rate (MCR) of glucose, and estimated first- and second-phase insulin responses] were assessed at early (EP; 8.5 ± 0.2 wk) and/or late (LP; 29.2 ± 0.8 wk) pregnancy in 53 healthy women from the Glowing cohort. Adjusted Spearman correlations were used to evaluate the association between BCAA and insulin resistance/sensitivity measures at EP and LP, adjusted for body fat percentage and gestational weight gain (GWG). A multiple linear regression analysis was used to assess the association between changes in HOMA2-IR and BCAAs throughout gestation. Groups were made post hoc based on the mean percentage change (10% decrease) in Leu throughout gestation, creating a group with a ≥10% decrease in LeuLP-EP (BELOW) and a <10% decrease in LeuLP-EP (ABOVE), and Student's t tests were performed to assess differences between groups. RESULTS: Leu and Ile concentrations positively correlated with HOMA2-IR at both time points, but these relations at EP disappeared/weakened when adjusted for body fat percentage. From EP to LP, the change in Leu (LeuLP-EP) was negatively associated with the change in HOMA2-IR (HOMA2-IRLP-EP) (ß = -0.037, P = 0.006). MCR was lower in the BELOW group compared with the ABOVE group, whereas there was no difference in HOMA2-IR between groups. CONCLUSIONS: In this pregnancy cohort, BCAA concentrations decreased throughout gestation, whereas the mean insulin resistance did not change. These data do not support a connection between changes in blood BCAA concentrations and estimates of insulin resistance in pregnant women. This trial is registered at clinicaltrials.gov as NCT01131117.

A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women.

Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance, and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells [peripheral blood mononuclear cells (PBMCs) and platelets] reflects that of skeletal muscle fibers derived from the same subjects. PBMCs, platelets, and skeletal muscle (vastus lateralis) samples were obtained from 32 young (25-35 yr) women of varying body mass indexes. With the use of extracellular flux analysis and high-resolution respirometry, mitochondrial respiration was measured in intact blood cells as well as in permeabilized cells and permeabilized muscle fibers. Respiratory parameters were not correlated between permeabilized muscle fibers and intact PBMCs or platelets. In a subset of samples (n = 12-13) with permeabilized blood cells available, raw measures of substrate (pyruvate, malate, glutamate, and succinate)-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs (per 106 cells); however, complex I leak and oxidative phosphorylation coupling efficiency correlated between permeabilized platelets and muscle (Spearman's ρ = 0.64, P = 0.030; Spearman's ρ = 0.72, P = 0.010, respectively). Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate muscle mitochondrial function. Select circulating cell bioenergetics phenotypes may possibly inform on overall metabolic health, but this postulate awaits validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.

Electrochemical degradation of naproxen from water by anodic oxidation with multiwall carbon nanotubes glassy carbon electrode.

Naproxen (NPX) degradation was investigated by anodic oxidation both at constant potential and by cyclic voltammetry, using this last technique for optimizing reaction conditions and catalyst properties. Three multiwall carbon nanotubes (MWCNTs)-promoted electrodes were used (MWCNT, MWCNT-COOH and MWCNT-NH2) and a two steps oxidation process was observed in all the cases. At the optimized conditions (volume of MWCNT = 15 µL), the influence of the scan rate indicates the diffusion-adsorption control of the process. Likewise, the kinetic study of NPX degradation at fix potential, considering two different stirring speeds (250 and 500 rpm), indicates that degradation rate increases with the stirring speed. After 20 h, NPX is degraded even an 82.5%, whereas the mineralization reaches almost 70%, as it was obtained from total organic carbon analysis. The pH effect was also analysed, in the range 5-11, observing a positive effect at low pH. Concerning the surface chemistry of the electrode, MWCNT-NH2, with the highest isoelectric point (4.70), is the most promising material due to the improved interactions with the reactant. From these observations, a pathway is proposed, which includes two steps of electrochemical oxidation followed by subsequent oxidation steps, until mineralization of the NPX, attributed mainly to active chlorine species and ·OH.

Carbon nanotube modified glassy carbon electrode for electrochemical oxidation of alkylphenol ethoxylate.

Electrochemical oxidation of an emerging pollutant, 2-(4-methylphenoxy)ethanol (MPET), from water has been studied by cyclic voltammetry (CV). Multiwall carbon nanotubes glassy carbon electrodes (MWCNT-GCE) were used as working electrode due to their extraordinary properties. The oxidation process is irreversible, since no reduction peaks were observed in the reverse scan. The electrocatalytic effect of MWCNT was confirmed as the oxidation peak intensity increases in comparison to bare-GCE. The effect of functional groups on MWCNT was also studied by MWCNT functionalized with NH2 (MWCNT-NH2) and COOH (MWCNT-COOH) groups. The oxidation peak current decreases in the following order: MWCNT > MWCNT-NH2 > MWCNT-COOH. Taking into account the normalized peak current, MWCNT-NH2 exhibits the best results due to its strong interaction with MPET. Under optimal conditions (pH = 5.0 and volume of MWCNT = 10 µL), degradation was studied for MWCNT-GCE and MWCNT-NH2-GCE. A complete MPET removal was observed using MWCNT-GCE after four CV cycles, for a volume/area (V/A) ratio equal to 19. In the case of MWCNT-NH2-GCE, the maximum MPET removal was close to 90% for V/A = 37, higher than that obtained for MWCNT-GCE at the same conditions (≈80%). In both cases, no organic by-products were detected.

Clinical Outcome of Mechanical Thrombectomy for Stroke in the Elderly.

BACKGROUND: Endovascular revascularization with mechanical devices has proven an effective treatment for proximal occlusions of the major intracranial arteries in stroke patients, but there is only limited information as to whether there should be an age limit for its use. We aimed to evaluate the safety and effectiveness of endovascular revascularization in stroke patients aged 80 years and older, and compare the results with younger patients. METHODS: We prospectively collected 81 consecutive patients subjected to mechanical thrombectomy for proximal occlusion of the anterior circulation during a period of 27 months. According to age, patients were divided into those aged less than 80 years (younger group) and those aged 80 years and older (elderly group). We analyzed favorable outcome, successful and futile recanalization, neurological improvement, in-hospital complications, and mortality in both groups. RESULTS: A favorable outcome (modified Rankin Scale score ≤2 at 3 months) was reached by 51.6% in the elderly group and 64% of younger patients, and neurological improvement (improvement of ≥4 points on National Institutes of Health Stroke Scale) was present in 77.4% of the elderly group. Overall, successful recanalization rates were 95.1% and futile recanalization reached 39% without statistically significant differences between both groups. Elderly patients presented more in-hospital complications (61.3% versus 38%) and higher mortality rates (16.1% versus 8%). CONCLUSIONS: Clinical independence was reached in over half of elderly stroke patients treated with mechanical thrombectomy, supporting the use of this treatment without age restriction.

Activated carbon adsorption for mitigating the harmful effects of antibiotics on the biological activated sludge: Effect on heterotrophic kinetics through respirometry.

Conventional wastewater treatment plants (WWTPs) are not designed for the abatement of antibiotics, and their effluents are one of the main entry ways of these emerging contaminants to the aquatic environment, causing major concern due to their toxicity, persistence, and bioaccumulation. When wastewater containing antibiotics enters the bioreactor, they can impact microbial communities of the activated sludge, affecting biodegradation processes of organic matter and nutrients. There is scarce information about the effect of activated carbon on the activated sludge within the bioreactor in presence of antibiotics. In light of this, the effect of representative antibiotics, ciprofloxacin (CIP), nalidixic acid (NAL), and erythromycin (ERY), on the performance of a conventional activated sludge of a WWTP was analyzed by respirometry with and without activated carbon. NAL and ERY negatively affected the net heterotrophic biomass growth rate (r'x,H), with reduction percentages of 26%-90% and 31%-81%, respectively. The addition of activated carbon mitigated this effect, especially for ERY, with increments of even 8% in the r'x,H for the hybrid process when working with 5 ppm of ERY and 80 ppm of activated carbon compared with the value in the absence of antibiotic and activated carbon. This effect was attributed to the enhanced retention of ERY, in comparison to NAL, on the surface of the activated carbon, probably due to its higher molecular size and affinity towards the activated carbon (log Kow = 3.06). This effect was more marked at low sludge retention times (below 8 days). PRACTITIONER POINTS: Ciprofloxacin (CIP), nalidixic acid (NAL), and erythromycin (ERY) were studied. NAL and ERY exerted negative impact on heterotrophic growth rate. Effect of antibiotics on microorganisms in the presence of activated carbon was studied. Activated carbon was mainly relevant for ERY due to its adsorption retention. Enhancement by activated carbon was more significant at low sludge retention times.

The oxygen uptake efficiency slope does not accurately predict V ˙ O2peak of children - the Arkansas Active Kids study.

Background: Cardiorespiratory fitness (CRF) is a vital indicator of health. However, accurately measuring peak oxygen consumption ( V ˙ O2peak) to determine CRF in children can be challenging. The oxygen uptake efficiency slope (OUES) has been proposed as an alternative metric for predicting V ˙ O2peak in children, but its accuracy and agreement with measured V ˙ O2peak remain unclear. Methods: A post hoc analysis was conducted in 94 children (ages 7-10 years) who completed an incremental cycle ergometer test to measure V ˙ O2peak. Body composition (Dual-energy X-ray absorptiometry) was measured, and fat mass index (FMI, kg/m2) and fat-free mass index (FFMI, kg/m2) were calculated. OUES was determined using all respiratory data (OUES100%) collected during the cycle ergometer test and using data only up to 60% of heart rate reserve (OUES60%HRR). Regression equations to predict V ˙ O2peak (Pred- V ˙ O2peak) were derived from simple and multiple linear regression analysis. Bland-Altman analysis assessed the level of agreement between Pred- V ˙ O2peak and measured V ˙ O2peak. Results: OUES60%HRR (ß = 0.46, p < 0.0001), age (ß = 56.0, p = 0.0004), White race (ß = 173.3, p < 0.0003), FFMI (ß = 0.98.6, p < 0.000), and FMI (ß = -0.40.8, p < 0.000) were retained in the final model. The difference between measured V ˙ O2peak and Pred- V ˙ O2peak was not different from zero (p = 0.999). There was a positive association between the difference of measured V ˙ O2peak and Pred- V ˙ O2peak and the average of the two methods (ß = 0.79, p = 0.0028). Conclusion: There was no mean bias between measured V ˙ O2peak and Pred- V ˙ O2peak. However, magnitude bias was present even after considering other significant predictors of V ˙ O2peak (FMI, FFMI, race, and age) in the regression equation. Caution is advised when using OUES to predict V ˙ O2peak in children.

Targeted Sacral Biopsy With Portable Gamma Camera and Intraoperative Gamma Probe.

ABSTRACT: A 58-year-old man with dysphagia and trismus symptoms presented a lobulated tumor in the right tonsil and ipsilateral laterocervical stony adenopathies in the physical examination. He had prostate carcinoma as clinical precedent. The tonsilar lesion showed focal FDG uptake (SUV max , 10.89) on PET/CT and increased glycemic metabolism in the left sacral wing (SUV max , 10.90) without clear morphological lesion in CT. There was also uptake of the tracer in sacrum in the bone scan. Metastatic involvement was suspected, requiring radioguided biopsy to determine the etiology. Due to radioguided biopsy, histological analysis of the metastasis was performed, with epidermoid carcinoma metastasis diagnosis.

Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG-PET/CT.

The value of circulating tumor DNA (ctDNA) as a biomarker of disease activity in classic Hodgkin lymphoma (cHL) patients has not yet been well established. By profiling primary tumors and ctDNA, we identified common variants between primary tumors and longitudinal plasma samples in most of the cases, confirming high spatial and temporal heterogeneity. Although ctDNA analyses mirrored HRS cell genetics overall, the prevalence of variants shows that none of them can be used as a single biomarker. Conversely, the estimation of hGE/mL, based on measures of total ctDNA, reflects disease activity and is almost perfectly correlated with standard parameters such as PET/CT that are associated with refractoriness.

Energy-efficient picosecond spin-orbit torque magnetization switching in ferro- and ferrimagnetic films.

Electrical current pulses can be used to manipulate magnetization efficiently via spin-orbit torques. Pulse durations as short as a few picoseconds have been used to switch the magnetization of ferromagnetic films, reaching the terahertz regime. However, little is known about the reversal mechanisms and energy requirements in the ultrafast switching regime. In this work we quantify the energy cost for magnetization reversal over seven orders of magnitude in pulse duration, in both ferromagnetic and ferrimagnetic samples, bridging quasi-static spintronics and femtomagnetism. To this end, we develop a method to stretch picosecond pulses generated by a photoconductive switch by an order of magnitude. Thereby we can create current pulses from picoseconds to durations approaching the pulse width available with commercial instruments. We show that the energy cost for spin-orbit torque switching decreases by more than an order of magnitude in all samples when the pulse duration enters the picosecond range. We project an energy cost of 9 fJ for a 100 × 100 nm2 ferrimagnetic device. Micromagnetic and macrospin simulations unveil a transition from a non-coherent to a coherent magnetization reversal with a strong modification of the magnetization dynamical trajectories as pulse duration is reduced. Our results show the potential for high-speed magnetic spin-orbit torque memories and highlight alternative magnetization reversal pathways at fast timescales.

Immune and stromal transcriptional patterns that influence the outcome of classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed-Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-ß) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility.