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Samples from 34 adult patients newly diagnosed with core binding factor leukemia (CBFL) were collected both at the time of diagnosis and at relapse and were centrally analyzed. Eligible patients received either standard induction CT known as "3 + 7" or an equivalent regimen, according to the recruiting center's policy. Patients who achieved CR or CRi received 3 courses of high-dose ARA-C (Cytarabine) 3000 mg/m 2 every 12 h on days 1, 3, and 5, along with midostaurin at the dose of 50 mg b.i.d from Day 8 to Day 21 as part of consolidation therapy. Following the completion of the consolidation phase, patients received midostaurin as a monotherapy at the dose of 50 mg b.i.d. for 1 year as continuation therapy. The CR rate was 97%; we recorded an OS rate of 73.52% and a DFS rate of 48.4% for the entire cohort. The RI was 38.8% in the CBFB::MYH11 and 66.6% in the RUNX1::RUNX1T1 group. MRD (Measurable Residual Disease) was assessed by RQ-PCR at 10 time points throughout the study, as indicated by arrows., (© 2024 Wiley Periodicals LLC.)

Background: Anti-CD19 CAR T-cells have revolutionized outcomes in relapsed/refractory large B-cell lymphomas. Long-term follow-up underscored the role of hematological toxicity in non-relapse mortality, largely driven by infections, leading to the development of the CAR-HEMATOTOX (HT) score for predicting neutropenia. The European scientific community (EHA/EBMT) later reached a consensus, defining a new entity: immune effector cell-associated hematotoxicity (ICAHT)., Aims: To validate the ability of the HT score to predict ICAHT and survival., Methods: The CART-SIE is an ongoing multicenter prospective observational study collecting data on patients affected by B-cell lymphoma treated with commercial anti-CD19 CAR T-cells (ClinicalTrials.gov ID: NCT06339255)., Results: Since 2019 to 2024, 1002 consecutive patients were enrolled. Out of 746 patients infused, the HT score at infusion was evaluable in 389. Median age was 59 years (48-66). Patients with high HT score had greater disease burden and a greater need for bridge therapy. Patients with a HT HIGH score had a 4-fold higher risk of experiencing late ICAHT of grade≥3 (OR=3.99, 95% CI=1.16-13.77, p=0.03). Patients with a HT HIGH score also showed lower overall response rates (ORR) and complete response rates (CRR) at 90 days (CRR at 90 days: 59% HT LOW vs 38% HT HIGH , OR=0.42, 95% CI=0.27-0.66, p=0.0002; ORR at 90 days: 67% HT LOW vs 49% HT HIGH , OR=0.47, 95% CI=0.29-0.74, p=0.001). Adjusted logistic models confirmed that the effect of HT score was independent from baseline characteristics. With a median follow-up of 18 months, patients with a HT HIGH score have lower OS and PFS (1-year OS: 78% HT LOW versus 62% HT HIGH , p=0.0002; 1-year PFS: 49% versus 39%, p=0.003). Adjusted Cox models confirmed that HT was an independent prognostic factor for OS. A high HT-score was found to be associated with higher risk of secondary primary malignancy (HR=2.8, 95% CI=1.03-7.8, p=0.04). A simplified version of HT (simpleHT), based solely on the platelet count and C-reactive protein at infusion, was calculated for 560 patients and proved significant in predicting both OS and PFS (1-year was 72% simpleHT LOW vs 37% simpleHT HIGH , p<0.0001, 1-year PFS was 48% simpleHT LOW vs 22% simpleHT HIGH , p<0.0001)., Conclusion: In our prospective real-world study, we validated the ability of the HT score to predict ICAHT and survival. SimpleHT identified a population at very high risk with an impaired progression free and overall survival., Competing Interests: Declaration of competing interest FS –nothing to disclose., MP –nothing to disclose, AC - Advisory boards: Gilead-Sciences, Ideogen, Roche, SecuraBIO, Takeda; honoraria for lectures/educational events: Abbvie, Eli Lilly, Gilead-Sciences, Incyte, Janssen-Cilag, Novartis, Takeda., BC –Advisory boards and honoraria for lectures/educational events: Kite Gilead, Novartis.., SB - Speaker bureau: BMS; GILEAD, NOVARTIS, ADVISORY BOARD NOVARTIS, TRAVEL ACCOMODATION NOVARTIS, ROCHE, SL –nothing to disclose, PC –nothing to disclose, ADR –consulting fees: Roche, Takeda, Incyte, Kite-Gilead, Novartis, Abbvie; speakers bureaus: Roche, Kite-Gilead, Janssen, Abbvie, Eli-Lilly, Sobi, Incyte, Recordati, Rare Disease; advisory board: Takeda, Kite-Gilead, Roche, Abbvie, Novartis., MCT –personal fees from Novartis, Gilead, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Sanofi, and Incyte., PA –to disclose ., IC –nothing to disclose, MM - advisory board Kite/Gilead; Novartis; BMS. Speakers bureau: Kite/Gilead; Novartis; BMS, AB –nothing to disclose., FB - Advisory boards and honoraria for lectures/educational events: Kite Gilead, Novartis, AS –Advisory Board: Bms (Bristol-Myers-Squibb) / Servier / Gilead / Pfizer / Eisai / Bayer / Msd (Merck Sharp & Dohme). Consultancy: Sanofi/ Incyte. Speaker's Bureau: Takeda / Bms / Roche / Abb-Vie / Amgen / Celgene / Servier / Gilead / Astrazeneca / Pfizer / Lilly / Sandoz / Eisai / Novartis / Bayer / Msd/ Beigene, FSo –nothing to disclose., MN –nothing to disclose., AMB –nothing to disclose., DR –nothing to disclose., MMu –nothing to disclose., GG –nothing to disclose., MK –Advisory boards and honoraria for lectures/educational events: Kite Gilead, Novartis, Janssen-Cilag, Incyte, AbbVie, BeiGene, Menarini StemLine, Roche., JO –personal fees from AbbVie and Incyte., BL –nothing to disclose., FCa –other support from Incyte, Eli Lilly and Company, and AstraZeneca, grants and other support from Roche, and nonfinancial support from BeiGene, Takeda, and GSK outside the submitted work., MMa –nothing to disclose., LA - Honoraria: EUSA Pharma, Novartis. Advisory boards for Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics, Novartis., LF –AbbVie, Biotest, AstraZeneca, Beigene, AbbVie, Janssen., PLZ –Consultant: MSD, Eusapharma, Novartis; Advisory boards: ADC Therapeutics, Astrazeneca, BeiGene, BMS, Celltrion, Eusapharma, Gilead, Incyte, Janssen-Cilag, KyowaKirin, MSD, Novartis, Roche, Sandoz, SecuraBio, Servier, Takeda; speakers bureau: Astrazeneca, Beigene, BMS, Celltrion, Eusapharma, Gilead, Incyte, Janssen-Cilag, Kyowa-Kirin, MSD, Novartis, Roche, Servier, Takeda., RM –nothing to disclose ., PCo - Advisory boards: AbbVie, ADC Therapeutics, Amgen, BeiGene, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda; honoraria for lectures: AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Novartis, Roche, Sanofi, Takeda., (Copyright © 2025. Published by Elsevier Inc.)

Purpose: Tibial valgus osteotomy has shown to be a successful and cost-effective procedure. The advent of image processing and three-dimensional (3D) printing is an interesting tool for achieving more accurate and reproducible results. The aim of our study was to compare the accuracy of the conventional technique and the use of customized guides in the correction of tibial deformities in tibial varus patients, the surgical and clinical benefits, and the impact of treatment in the outpatient setting., Methods: A prospective cohort of 30 patients who underwent tibial valgus osteotomy were selected and randomized into two groups (3D-printed guidewires and conventional techniques). All patients underwent a complete radiological study to plan the surgical procedure. During the surgical procedure, the surgical time and X-ray exposure were analysed. The following results were evaluated: surgical time and X-ray exposure, the correlation between the planned correction and the correction obtained at 3 post-operative months, pre- and post-operative knee injury and osteoarthritis outcome score (KOOS) value at 3 and 12 months, and differences between the two groups in terms of the correction obtained., Results: Radiation exposure in the '3D-guide' group was significantly different (8 [±4.51], p  < 0.05), whereas surgical time was not significantly different between the control and guide 3D groups (60.69 [±8.89] and 53.43 [±11.69], respectively). At the 3-month follow-up, the post-operative hip-knee-ankle and post-operative mechanical-proximal-tibial angle were not significantly different ( p  > 0.05). At 3- and 12-month post-surgery, the Knee Injury and Osteoarthritis Outcome Score (KOOS) did not significantly differ between the conventional technique and the 3D-guide technique ( p  > 0.05). The KOOS at 3 months were 87.86 (±5.64) for the control group and 88.46 (±3.53) for the 3D-guide group, while at 12 months they were 91.5 (±5.72) for the control group and 88.57 (±8.81) for the 3D-guide group., Conclusion: Customized 3D-printed guides do not permit better correction or functional results than the conventional technique; rather, they reduce surgical time and intraoperative radiation exposure., Level of Evidence: II., Competing Interests: The authors declare no conflicts of interest., (© 2025 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Hazelnut skins (HS) are usually managed as waste; however, this by-product is a source of bioactive compounds, with potential applications in feed and food sectors. Phenolic compounds can be extracted using green protocols combining enabling technologies and green solvents. This work investigates subcritical water extraction (SWE) of bioactive compounds from HS. A laboratory-scale study was performed on four different batches, with significant batch-to-batch heterogeneity. The evaluation of polyphenolic profiles and antioxidant activities afforded promising results compared to the benchmark of reflux maceration. To evaluate process effectiveness, the extraction protocol was replicated on a semi-industrial plant that processed 8 kg of matrix. Downstream processes have been optimized for scale-up, demonstrating the effectiveness of SWE in retaining product concentration and bioactivity avoiding excipients in spray-drying phase. Hazelnut extracts exhibited antibacterial properties against animal- and food-borne pathogens, supporting their potential use as sustainable feed ingredients for improved hazelnut production and animal farming practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study aimed to identify communication strategies that virtual humans (VHs) discussing clinical trials can use to foster positive relationships with older women to better deliver research education., Methods: A template thematic analysis and matrix analysis of 10 interviews and 3 focus groups with 37 older women identifying as White non-Hispanic, Black, or Hispanic/Latinx were conducted., Results: VHs can foster positive relationships with older women during clinical trial education by communicating social support. At the same time, VHs should convey credibility. Factors shaping experiences of the VHs' support and credibility include race and ethnicity, comfort with research and technology, and current health status., Conclusion: Deploying communication strategies that foster positive relationships between VHs and older women are crucial for optimizing the use of VHs during clinical trial education for populations historically excluded from research., Practice Implications: This study provides a cohesive framework guiding the development of VH clinical trial educators for older women to meet their communication needs. The framework may extend to other populations historically excluded from research and real human clinical trial educators., Funding: This work was supported by the National Institute on Aging National Institutes of Health, Award R24AG074867 (PIs: Krieger and Anton)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Brexucabtagene autoleucel (brexu-cel) has revolutionized the treatment of patients affected by mantle cell lymphomas. In this prospective, observational multicentre study, we evaluated 106 patients, with longitudinal brexu-cel kinetics in peripheral blood monitored in 61 of them. Clinical outcomes and toxicities are consistent with previous real-world evidence studies. Notably, beyond established poor prognostic factors-such as blastoid variant and elevated lactate dehydrogenase-Bruton tyrosine-kinase inhibitors (BTKi) refractoriness and platelet count emerged as significant predictors of survival. Specifically, the 1-year overall survival was 56% in BTKi-refractory patients compared to 92% in BTKi-relapsed patients (p = 0.0001). Our study also demonstrated that in-vivo monitoring of brexu-cel expansion is feasible and correlates with progression-free survival and toxicities. Progression-free survival at 1 year was 74% in patients categorized as strong expanders, based on brexu-cel peak concentration, versus 54% in poor expanders (p = 0.02). Furthermore, in-vivo expansion helped identify a high-risk group of non-responders, those with progressive or stable disease at the 90-day post-infusion evaluation (OR = 4.7, 95% CI = 1.1-34, p = 0.04) characterized by dismal outcomes. When integrated with other clinical factors, monitoring brexu-cel expansion could assist in recognizing patients at high risk of early relapse., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Since its discovery as a causative gene of the Immunodeficiency with Centromeric instability and Facial anomalies syndrome, ZBTB24 has emerged as a key player in DNA methylation, immunity and development. By extensively analyzing ZBTB24 genomic functions in ICF-relevant mouse and human cellular models, we document here its multiple facets as a transcription factor, with key roles in immune response-related genes expression and also in early embryonic development. Using a constitutive Zbtb24 ICF-like mutant and an auxin-inducible degron system in mouse embryonic stem cells, we showed that ZBTB24 is recruited to centromeric satellite DNA where it is required to establish and maintain the correct DNA methylation patterns through the recruitment of DNMT3B. The ability of ZBTB24 to occupy centromeric satellite DNA is conserved in human cells. Together, our results unveiled an essential and underappreciated role for ZBTB24 at mouse and human centromeric satellite repeat arrays by controlling their DNA methylation and transcription status., (© The Author(s) 2024. Published by Oxford University Press.)

7-methyl-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM2) have been shown to act as human (h) Cav 3.1 voltage-gated calcium channel blockers with promising in vivo anti-absence activity, positioning them as potential antiepileptic drugs. The primary aim of this work was to develop cost-effective and environmentally friendly synthetic procedures for preparing 2-phenylimidazo[1,2-b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD-1 ICR mice after pentylenetetrazol administration and DBA/2 mice with seizures induced by audiogenic stimuli. Their neuroprotective effect against oxidative stress were assessed using C6 rat brain glioma cells. DM1 and DM2 exhibited potent anti-seizure effects in both animal models and demonstrated significant in vitro neuroprotective activity by reducing reactive oxygen species release. To lay the groundwork for the future rational optimization of this promising class of compounds, the molecular bases of DM1 and DM2 activity were investigated by modelling their interaction with hCav 3.1 channels. The calculated binding modes of DM1 and DM2 to hCav 3.1 channels partially mirrored that of the selective Cav 3.1 blocker Z944, paving the way for future lead optimization., (© 2024 Wiley-VCH GmbH.)

In the context of a circular economy, this study explores the valorization of blueberry pomace (BP) as a source of bioactive compounds using sustainable extraction methods. Microwave-assisted extraction (MAE) and microwave-assisted subcritical water extraction (MASWE) were employed to obtain two distinct fractions: MAE 1° and MASWE 2°. The first extract, MAE 1°, obtained at 80 °C, had a high total anthocyanin content (21.96 mg Cya-3-glu /g extract ), making it suitable as a natural pigment. Additionally, MAE 1° exhibited significant enzyme inhibition, particularly against α-amylase and β-glucosidase, suggesting potential anti-diabetic and anti-viral applications. The second extract, MASWE 2°, obtained at 150 °C, contained a higher total phenolic content (211.73 mg GAE /g extract ) and demonstrated stronger antioxidant activity. MASWE 2° showed greater inhibition of acetylcholinesterase and tyrosinase, indicating its potential for use in Alzheimer's treatment, skincare, or as a food preservative. MASWE 2° exhibited cytotoxicity against HeLa cells and effectively mitigated H 2 O 2 -induced oxidative stress in HaCat cells, with MAE 1° showing similar but less pronounced effects. A tested formulation combining MAE 1° and MASWE 2° extracts in a 3:2 ratio effectively enhanced anthocyanin stability, demonstrating its potential as a heat-stable pigment. The extract characteristics were compared with a conventional method (MeOH-HCl in reflux condition), and the protocol's sustainability was assessed using several green metric tools, which provided insights into its environmental impact and efficiency.

Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre-mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted "restored" at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis., (© 2024. The Author(s).)

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel's superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: While the detrimental role of donor-specific anti-HLA antibodies (DSAs) is well-described in the setting of hematopoietic stem cell transplantation (HSCT), few studies focus on non donor-specific ones and with controversial results., Methods: We here report our monocenter experience on 64 adult patients receiving allogeneic HSCT from a HLA-mismatched donor between 2014 and 2022 who were tested for the presence of anti-HLA antibodies before transplant, focusing on fifteen patients with non donor-specific anti-HLA antibodies., Results: The survival of patients with non donor-specific anti-HLA antibodies was inferior with respect to patients without anti-HLA antibodies and similar to patients with DSAs. Median survival of patients with non donor-specific anti-HLA antibodies was 21 months (95 % CI: 9-42) vs. 61 months (95 % CI: 17-77) among the anti-HLA antibody-negative patients, with a significantly higher mortality incidence rate ratio (3.3 times-fold greater, p = 0.01). No pattern of death causes was found CONCLUSIONS: In this monocenter series of HLA-mismatched HSCTs, impaired survival was observed in adult patients having non donor-specific anti-HLA antibodies before transplant, similar to those with DSAs. Our findings support those antibodies as a negative predictive factor even if they are not directed against the donor, thus warranting further investigation on larger cohorts., Competing Interests: Conflicts of interests None., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

D-aspartate (D-Asp) is an amino acid found in high concentrations in the testis and pituitary gland. Increasing evidence suggests that D-Asp promotes spermatogenesis by activating testosterone production in the Leydig cells via LH release from the pituitary gland. In vitro studies indicate that D-Asp may also influence steroidogenesis and spermatogenesis through autocrine and paracrine signals. D-Asp enhances StAR and steroidogenic enzyme expressions, facilitating testicular cell proliferation via the GluR/ERK1/2 pathway. Moreover, it supports spermatogenesis by enhancing the mitochondrial function in spermatocytes, aiding in the metabolic shift during meiosis. Enhanced mitochondrial function, along with improved MAM stability and reduced ER stress, has been observed in Leydig and Sertoli cells treated with D-Asp, indicating potential benefits in steroidogenesis and spermatogenesis efficiency. Conversely, D-Asp exerts a notable anti-apoptotic effect in the testis via the AMPAR/AKT pathway, potentially mediated by antioxidant enzyme modulation to mitigate testicular oxidative stress. This review lays the groundwork for future investigations into the molecules promoting spermatogenesis by stimulating endogenous testosterone biosynthesis, with D-amino acids emerging as promising candidates.

Extra virgin olive oil (EVOO) is a cornerstone of the Mediterranean diet. Many studies have highlighted its crucial preventive role against cardiovascular disease, neurodegenerative disorders, metabolic syndrome and cancer, with these effects being due to the synergistic anti-inflammatory and antioxidant activities of minor components, such as polyphenols and tocols. The aim of the present study is to implement new technologies for olive oil mills and develop an efficient large-sized industrial process for the continuous extraction of healthier EVOOs that are enriched with these bioactive compounds. Non-thermal technologies, namely ultrasound (US) and pulsed electric field (PEF), have been tested, separately and in combination, to eliminate the need for traditional malaxation. There is extensive literature to support the efficacy of ultrasound-assisted extraction (UAE) and PEF treatments in EVOO production. A newly designed US device and a PEF industrial chamber have been combined into a single, integrated continuous-flow setup, the performance of which in the extraction of EVOO from green Coratina olives has been evaluated herein. Extraction yields, physico-chemical and organoleptic characteristics, and polyphenol and tocol contents were monitored throughout the trials, and the last three were measured at accelerated aging times (AAT) of 15 and 30 days. The US and combined US-PEF processes not only increased daily oil production (ton/day, by nearly 45%), but also eliminated the need for kneading during malaxation, resulting in significant energy savings (approximately 35%). In addition, these innovations enriched the resulting EVOO with nutritionally relevant minor components (8-12% polyphenols, 3-5% tocols), thereby elevating its quality and market value, as well as overall stability. The introduction of continuous-flow US and PEF technologies is a remarkable innovation for the EVOO industry, as they offer benefits to both producers and consumers. The EVOO resulting from non-thermal continuous-flow production meets the growing demand for healthier, nutrient-enriched products.

Background: To manage industrial waste in accordance with the circular bioeconomy concept it is sometimes necessary to handle grape seeds, an abundant by-product of the wine-making process. This study presents a process based on ultrasound technology for the extraction of grape-seed proteins, due to their nutritional and techno-functional properties. The protein content of extracts obtained under silent and lab-scale conditions was compared with that obtained under semi-industrial ultrasound conditions, and the chemical composition (carbohydrates, total phenols, and lipids) and the elemental profiles of the final, up-scaled downstream extracts were characterized., Results: This work found that the maximum amount of protein in the final product was 378.31 g.kg -1 of the extract. Chemical characterization revealed that each 1 kg of extract had an average content of 326.19 g gallic acid equivalent as total phenols, 162.57 g glucose equivalent as carbohydrates, and 382.76 g of lipophilic compounds. Furthermore, when the extract was checked for hazardous elements, none were found in levels that could be considered a risk for human health., Conclusion: The proposed semi-industrial strategy has the potential to contribute greatly to the valorization of grape seeds through the preparation of a protein-rich extract that can be used as an alternative to synthetic wine stabilizers and for the development of novel food and nutraceutical products. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

This paper reports a new sustainable protocol for the microwave-assisted catalytic conversion of levulinic acid into N-substituted pyrrolidones over tailor-made mono (Pd, Au) or bimetallic (PdAu) catalysts supported on either highly mesoporous silica (HMS) or titania-doped HMS, exploiting the advantages of dielectric heating. MW-assisted reductive aminations of levulinic acid with several amines were first optimized in batch mode under hydrogen pressure (5 bar) in solvent-free conditions. Good-to-excellent yields were recorded at 150 °C in 90 min over the PdTiHMS and PdAuTiHMS, that proved recyclable and almost completely stable after six reaction cycles. Aiming to scale-up this protocol, a MW-assisted flow reactor was used in combination with different green solvents. Cyclopentyl methyl ether (CPME) provided a 99 % yield of N-(4-methoxyphenyl) pyrrolidin-2-one at 150 °C over PdTiHMS. The described MW-assisted flow synthesis proves to be a safe procedure suitable for further industrial applications, while averting the use of toxic organic solvents., (© 2023 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

D-Aspartic Acid (D-Asp) affects spermatogenesis by enhancing the biosynthesis of the sex steroid hormones acting either through the hypothalamus-pituitary-testis axis or directly on Leydig cells. Recently, in vitro studies have also demonstrated the direct effects of D-Asp on the proliferation and/or activity of germ cells. However, although D-Asp is present in Sertoli cells (SC), the specific role of the amino acid in these cells remains unknown. This study investigated the effects of D-Asp on the proliferation and activity of TM4 SC, focusing on the mitochondrial compartment and its association with the endoplasmic reticulum (ER). We found that D-Asp enhanced the proliferation and activity of TM4 cells as evidenced by the activation of ERK/Akt/PCNA pathway and the increase in the protein levels of the androgen receptor. Furthermore, D-Asp reduced both the oxidative stress and apoptotic process. An increase in mitochondrial functionality and dynamics, as well as a reduction in ER stress, were also found in D-Asp-treated TM4 cells. It is known that mitochondria are closely associated with ER to form the Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAM), the site of calcium ions and lipid transfer from ER to the mitochondria, and vice versa . The data demonstrated that D-Asp induced stabilization of MAM in TM4 cells. In conclusion, this study is the first to demonstrate a direct effect of D-Asp on SC activity and to clarify the cellular/molecular mechanism underlying these effects, suggesting that D-Asp could stimulate spermatogenesis by improving the efficiency of SC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Falvo, Grillo, Latino, Chieffi Baccari, Di Fiore, Venditti, Petito and Santillo.)

In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification., (© 2024 Wiley Periodicals LLC.)

Background: Induction with daratumumab-based regimens followed by autologous stem cell transplantation is the current standard for newly diagnosed multiple myeloma (NDMM) patients eligible for intensive chemotherapy. However, concerns emerged regarding potential negative effects following daratumumab-based treatment on CD34+ mobilization. We here compared CD34+ mobilization and clonogenic potential between daratumumab and non-daratumumab based therapy without upfront plerixafor administration among patients affected by NDMM., Materials and Methods: Clinical, mobilization and clonogenic data from 41 consecutively enrolled NDMM patients were analyzed. Patients underwent collection of autologous CD34+ by apheresis at the ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, from January 2021 to March 2023. Clonogenicity analysis was performed on BFU-E and CFU-GM., Results: Seventy-five percent of daratumumab-treated patients underwent >1 apheresis, compared to 24% of non-daratumumab patients (p=0.0017). Daratumumab-treated patients had significantly lower CD34+ count (mean 38 vs 79/μL, respectively; p=0.0011), with a median CD34+ harvest of 3.98×10 6 /kg (range 1.68-9.18) vs 6.87×10 6 /kg (range 1.63-16.85) in non-daratumumab-treated (p=0.0006). In multivariate analysis the likelihood of undergoing >1 apheresis was significantly higher in older patients (OR 1.2, 95% CI 1-1.4, Z=2.10, p=0.03) and daratumumab-treated patients (OR 15, 95% CI 2.8-129, p=0.004). Moreover, daratumumab-based induction therapy demonstrated an independent negative association with BFU-E colony formation (p=0.0148), even when accounting for patient age and CD34+ levels., Discussion: Our findings underscore the impact of daratumumab-based treatment on CD34+ mobilization in a real-life, upfront plerixafor-free population of NDMM patients. Higher probability of requiring multiple apheresis occurred among daratumumab-treated patients. Interestingly, the observation that daratumumab might negatively impact BFU-E colony formation, independent of CD34+ cell count, offers novel biological perspectives. Appropriate strategies should be adopted by the Apheresis teams to mitigate these potential negative effects.

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs., (© 2024. The Author(s).)

Introduction: The total knee arthroplasty (TKA) has been shown to be a successful and cost-benefit procedure in terms of pain improvement in patient with symptomatic knee osteoarthritis. However, almost a 20% of the patients are not satisfied with the result of the surgery., Material and Method: We have carried out a transversal unicentric cases controls study with clinical cases of the own hospital, obtained by a clinical records revision. A total of 160 patients with a TKA with at least 1 year of follow-up were selected. Demographic variables, functional scales (WOMAC and VAS) and rotation of the femoral component through the analysis of the images obtained by CT scan were collected., Results: The total was 133 patients that was divided in two groups. A control group and pain group. The Control group was made up of 70 patients with a mean age of 69.59 years (23 men and 47 women) and the pain group was made up of 63 patients with a mean age of 69.48 years (13 men and 50 women). We didn't find difference regarding the analysis of the rotation of the femoral component. In addition, we were not found significant differences when applying a stratification by sex. And, the analysis of the malrotation of the femoral component, previously defining limits of value rotation considered as extreme, in any of the case did not show significant differences., Conclusion: The results of the study confirm that malrotation of the femoral component had no influence on the presence of pain at a minimum of one year of follow-up after TKA implantation., (Copyright © 2023 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: The total knee arthroplasty (TKA) has been shown to be a successful and cost-benefit procedure in terms of pain improvement in patient with symptomatic knee osteoarthritis. However, almost a 20% of the patients are not satisfied with the result of the surgery., Material and Method: We have carried out a transversal unicentric cases controls study with clinical cases of the own hospital, obtained by a clinical records revision. A total of 160 patients with a TKA with at least 1year of follow-up were selected. Demographic variables, functional scales (WOMAC and VAS) and rotation of the femoral component through the analysis of the images obtained by CT scan were collected., Results: The total was 133 patients that was divided in two groups. A control group and pain group. The control group was made up of 70 patients with a mean age of 69.59years (23 men and 47 women) and the pain group was made up of 63 patients with a mean age of 69.48years (13 men and 50 women). We did not found difference regarding the analysis of the rotation of the femoral component. In addition, we were not found significant differences when applying a stratification by sex. The analysis of the malrotation of the femoral component, previously defining limits of value rotation considered as extreme, in any of the case did not show significant differences., Conclusion: The results of the study confirm that malrotation of the femoral component had no influence on the presence of pain at a minimum of one year of follow-up after TKA implantation., (Copyright © 2023 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Many laboratory studies demonstrated that the exposure to microplastics causes testosterone deficiency and spermatogenic impairment in mammals; however, the mechanism underlying this process remains still unclear. In this study, we investigated the effects of polystyrene microplastics (PS-MP) on the proliferation and functionality of cultured Leydig (TM3) and Sertoli (TM4) cells, focusing on the mitochondrial compartment and its association with the endoplasmic reticulum (ER). The in vitro exposure to PS-MP caused a substantial reduction in cellular viability in TM3 and TM4 cells. In TM3 cells PS-MP inhibited the protein levels of StAR and of steroidogenic enzymes 3β-HSD and 17β-HSD, and in TM4 cells PS-MP inhibited the protein levels of the androgen receptors other than the activity of lactate dehydrogenase (LDH). PS-MP inhibited the functions of TM3 and TM4, as evidenced by the decrease of the phosphorylation of ERK1/2 and Akt in both cell lines. The oxidative stress caused by PS-MP decreased antioxidant defense in TM3 and TM4 cells, promoting autophagic and apoptotic processes. Furthermore, we found mitochondrial dysfunction and activation of ER stress. It is known that mitochondria are closely associated with ER to form the Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAM), the site of calcium ions transfer as well as of lipid biosynthesis-involved enzymes and cholesterol transport from ER to the mitochondria. For the first time, we studied this aspect in PS-MP-treated TM3 and TM4 cells and MAMs dysregulation was observed. This study is the first to elucidate the intracellular mechanism underlying the effects of PS-MPs in somatic testicular cells, corroborating that PS-MP might be one of the causes of an increase in male infertility through the impairment of steroidogenesis in Leydig cells and of the nurse function of Sertoli cells. Thus, our findings contributed with new information to the mechanism underlying the effects of PS-MP on the male reproductive system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In a first-of-its-kind study, we assessed the capabilities of large language models (LLMs) in making complex decisions in haematopoietic stem cell transplantation. The evaluation was conducted not only for Generative Pre-trained Transformer 4 (GPT-4) but also conducted on other artificial intelligence models: PaLm 2 and Llama-2. Using detailed haematological histories that include both clinical, molecular and donor data, we conducted a triple-blind survey to compare LLMs to haematology residents. We found that residents significantly outperformed LLMs (p = 0.02), particularly in transplant eligibility assessment (p = 0.01). Our triple-blind methodology aimed to mitigate potential biases in evaluating LLMs and revealed both their promise and limitations in deciphering complex haematological clinical scenarios., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) mediate the communication between the Endoplasmic Reticulum (ER) and the mitochondria, playing a fundamental role in steroidogenesis. This study aimed to understand how D-aspartate (D-Asp), a well-known stimulator of testosterone biosynthesis and spermatogenesis, affects the mechanism of steroidogenesis in rat testes. Our results suggested that D-Asp exerts this function through MAMs, affecting lipid trafficking, calcium signaling, ER stress, and mitochondrial dynamics. After 15 days of oral administration of D-Asp to rats, there was an increase in both antioxidant enzymes (SOD and Catalase) and in the protein expression levels of ATAD3A, FACL4, and SOAT1, which are markers of lipid transfer, as well as VDAC and GRP75, which are markers of calcium signaling. Additionally, there was a decrease in protein expression levels of GRP78, a marker of aging that counteracts ER stress. The effects of D-Asp on mitochondrial dynamics strongly suggested its active role as well. It induced the expression levels of proteins involved in fusion (MFN1, MFN2, and OPA1) and in biogenesis (NRF1 and TFAM), as well as in mitochondrial mass (TOMM20), and decreased the expression level of DRP1, a crucial mitochondrial fission marker. These findings suggested D-Asp involvement in the functional improvement of mitochondria during steroidogenesis. Immunofluorescent signals of ATAD3A, MFN1/2, TFAM, and TOMM20 confirmed their localization in Leydig cells showing an intensity upgrade in D-Asp-treated rat testes. Taken together, our results demonstrate the involvement of D-Asp in the steroidogenesis of rat testes, acting at multiple stages of both MAMs and mitochondrial dynamics, opening new opportunities for future investigation in other steroidogenic tissues.

Background: Fabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities, neuropathic pain, gastrointestinal symptoms and fatigue. Challenges are faced by health care professionals in evaluating symptom burden in the current clinical setting, and the demand for alternative methods for monitoring disease-specific symptoms has seen an acceleration in recent years. Smartphone technologies offer the potential for continuity of care and surveillance. As a part of a quality improvement project, a disease specific app was developed in collaboration with a software company (Health Touch Ltd) and made available for patient use in May 2018. The Fabry mobile app records five categories: pain, gastrointestinal symptoms, sweating, activity levels, medications. Fabry disease patients with gastrointestinal and pain symptoms attending the Lysosomal Storage Disorders Unit of the Royal Free London NHS Foundation Trust were reviewed to assess eligibility and invited to download the app for recording their symptoms (activity, sweating, pain and gastrointestinal) and medications. Patient-generated data were transmitted to a secure website for clinicians to review., Results: One-hundred and thirty-nine symptomatic Fabry disease patients who had a smartphone (iPhone or android) were invited to download the app. Sixty-seven patients (26 males and 41 females; median age, 49 years [range, 20-81]) downloaded and tracked the Fabry App at least once. The median frequency of use per patient was 6 (range, 1-629). Pain in the hands and abdominal pain were significantly higher (p = 0.009 and p = 0.007, respectively) in patients with classic phenotype compared with patients with non-classic phenotypes., Conclusions: We demonstrated the feasibility and acceptability of a smartphone app to facilitate the remote assessment and monitoring of Fabry disease symptom burden on a daily/weekly basis, as an alternative to the current standard of care that requires patients to recall their symptoms during 6 to 12 monthly annual clinic visits. Patients who were more likely to use the app had greater disease burden. This innovation has the potential to assess disease progression, early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among Fabry patients, and to record long-term effects of Fabry-specific therapies., (© 2024. The Author(s).)

We recently identified TMEM230 as a master regulator of the endomembrane system of cells. TMEM230 expression is necessary for promoting motor protein dependent intracellular trafficking of metalloproteins for cellular energy production in mitochondria. TMEM230 is also required for transport and secretion of metalloproteinases for autophagy and phagosome dependent clearance of misfolded proteins, defective RNAs and damaged cells, activities that decline with aging. This suggests that aberrant levels of TMEM230 may contribute to aging and regain of proper levels may have therapeutic applications. The components of the endomembrane system include the Golgi complex, other membrane bound organelles, and secreted vesicles and factors. Secreted cellular components modulate immune response and tissue regeneration in aging. Upregulation of intracellular packaging, trafficking and secretion of endosome components while necessary for tissue homeostasis and normal wound healing, also promote secretion of pro-inflammatory and pro-senescence factors. We recently determined that TMEM230 is co-regulated with trafficked cargo of the endomembrane system, including lysosome factors such as RNASET2. Normal tissue regeneration (in aging), repair (following injury) and aberrant destructive tissue remodeling (in cancer or autoimmunity) likely are regulated by TMEM230 activities of the endomembrane system, mitochondria and autophagosomes. The role of TMEM230 in aging is supported by its ability to regulate the pro-inflammatory secretome and senescence-associated secretory phenotype in tissue cells of patients with advanced age and chronic disease. Identifying secreted factors regulated by TMEM230 in young patients and patients of advanced age will facilitate identification of aging associated targets that aberrantly promote, inhibit or reverse aging. Ex situ culture of patient derived cells for identifying secreted factors in tissue regeneration and aging provides opportunities in developing therapeutic and personalized medicine strategies. Identification and validation of human secreted factors in tissue regeneration requires long-term stabile scaffold culture conditions that are different from those previously reported for cell lines used as cell models for aging. We describe a 3 dimensional (3D) platform utilizing non-biogenic and non-labile poly ε-caprolactone scaffolds that supports maintenance of long-term continuous cultures of human stem cells, in vitro generated 3D organoids and patient derived tissue. Combined with animal component free culture media, non-biogenic scaffolds are suitable for proteomic and glycobiological analyses to identify human factors in aging. Applications of electrospun nanofiber technologies in 3D cell culture allow for ex situ screening and the development of patient personalized therapeutic strategies and predicting their effectiveness in mitigating or promoting aging., (Copyright © 2024. Published by Elsevier Inc.)

Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, in whom reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI-based or a chemotherapy-based approach is better is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The current study aimed to compare transplantation outcomes after RIC with TBI-based or thiotepa-based regimens in patients with ALL. The study cohort comprised patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000 and 2020 who received an RIC regimen containing either TBI (4 to 6 Gy) or thiotepa. We identified a total of 265 patients, including 117 who received a TBI-based RIC regimen and 148 who received a thiotepa-based RIC regimen. Univariate analysis revealed no significant differences in the following transplantation outcomes for TBI versus thiotepa: relapse, 23% versus 28% (P = .24); nonrelapse mortality, 20% versus 26% (P = .61); leukemia-free survival, 57% versus 46% (P = .12); overall survival, 67% versus 56% (P = .18); graft-versus-host disease (GVHD]/relapse-free survival, 45% versus 38% (P = .21); grade II-IV acute GVHD, 30% in both groups (P = .84); grade III-IV acute GVHD, 9% versus 10% (P = .89). The sole exception was the incidence of chronic GVHD, which was higher in the recipients of TBI-based regimens (43% versus 29%; P = .03). However, multivariate analysis revealed no differences in transplantation outcomes between the 2 groups. In patients aged ≥40 years receiving RIC, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens, as no differences were observed in the main transplantation outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state-specific "regulatory transposable elements." Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a subset of regulatory transposable elements shared with pluripotent/stem cells, including Tigger3a. Using chromatin editing technology, we show how such elements promote prostate cancer growth by regulating AR transcriptional activity. Collectively, our results suggest that oncogenesis arises from lineage-specific transcription factors hijacking pluripotent/stem cell regulatory transposable elements., Significance: We show that oncogenesis relies on co-opting transposable elements from pluripotent stem cells as regulatory elements altering the recruitment of lineage-specific transcription factors. We further discover how co-option is dependent on active chromatin states with important implications for developing treatment options against drivers of oncogenesis across the repetitive DNA. This article is featured in Selected Articles from This Issue, p. 2293., (©2023 The Authors; Published by the American Association for Cancer Research.)

Pomegranate ( Punica granatum L.) is well known for its high content of bioactives, including polyphenols, flavonoids, and tannins, which have been shown to exhibit a wide range of biological activities, such as antioxidant, antimicrobial, and anticancer effects. It is worth noting that the majority of these molecules are found in the peels, which are usually disposed of after processing, causing a significant amount of waste, amounting to more than 3.6 million t/y. This work investigates microwave-assisted extraction (MAE) in water for the recovery of antioxidants from pomegranate peels (PP), including the optimisation of temperature and extraction times. The total phenolic, anthocyanin, flavonoid, and tannin contents of the recovered extracts were determined, as well as their antioxidant activities, which were found to be 356.35 mgGAE/gExtr, 303.97 µgCy3G/gExtr, 37.28 mgQE/gExtr, 56.48 mgGAE/gExtr, and 5.72 mmolTE/gExtr, respectively (according to the adopted reference). All results were compared with those obtained using a conventional protocol. In addition, the potential for water recycling by means of downstream nanofiltration in optimised MAE was investigated, leading to overall water reuse of approx. 75%. Power consumption (20.92 W/mgGAE) and common green metrics, Reaction Mass Efficiency (RME), E-Factor, and the Process Mass Intensiti/efficiency (PMI, PME), were considered in evaluating the proposed PP valorisation strategy. Finally, the biological activities of the main products were assessed. The antimicrobial properties of the PP extracts against three Gram-positive and three Gram-negative bacteria and their antiproliferative activity towards human cancer cells were tested. S. aureus bacteria was the most susceptible to the PP extracts. All tested products displayed antiproliferative activity against HeLa cells when higher concentrations were tested, with D-PP/NF (obtained from dried PP and sequential nanofiltration) being the most effective. This result was also confirmed via clonogenic analysis, which generally indicated the possible anti-cancer activity of pomegranate peel extracts obtained using this green approach.

Flow cytometry (FCM) can investigate dozens of parameters from millions of cells and hundreds of specimens in a short time and at a reasonable cost, but the amount of data that is generated is considerable. Computational approaches are useful to identify novel subpopulations and molecular biomarkers, but generally require deep expertize in bioinformatics and the use of different platforms. To overcome these limitations, we introduce CRUSTY, an interactive, user-friendly webtool incorporating the most popular algorithms for FCM data analysis, and capable of visualizing graphical and tabular results and automatically generating publication-quality figures within minutes. CRUSTY also hosts an interactive interface for the exploration of results in real time. Thus, CRUSTY enables a large number of users to mine complex datasets and reduce the time required for data exploration and interpretation. CRUSTY is accessible at https://crusty.humanitas.it/ ., (© 2023. Springer Nature Limited.)

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2-3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2-3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2-3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2-4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2-3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

An 80-year-old male patient affected by Charcot-Marie-Tooth (CMT) disease came to our attention in July 2020, for the occurrence of low back pain and lower limb weakness, and also saddle anesthesia, urinary and faecal retention were referred. His diagnosis of CMT is dated back to 1955 and through the years, the clinical picture slowly worsened but never got particularly severe. The quick symptoms outbreak and the presence of urinary disturbances were red flags, which lead us to direct the diagnostic orientation elsewhere. A Magnetic Resonance Imaging of the thoraco-lumbar spinal cord was then performed and it was suggestive for synovial cyst at T10-T11. The patient underwent a decompression with laminectomy and then stabilized through arthrodesis. In the very next days after the surgery, the patient showed a sudden and significant improvement of his condition. At the last visit, he showed a remarkable relief of the symptoms, walking by himself.

The recovery of valuable bioactive compounds from the main underutilised by-products of the food industry is one of the greatest challenges to be addressed in circular economy. Potato peels are the largest waste generated during potato processing. However, they could be a potential source of valuable bioactive compounds, such as polyphenols, that can be reused as natural antioxidants. Currently, environmentally benign enabling technologies and new types of non-toxic organic solvents for the extraction of bioactive compounds may dramatically improve the sustainability of these processes. This paper focuses on the potential inherent in the valorisation of violet potato peels (VPPs) by recovering antioxidants using natural deep eutectic solvents (NaDES) under ultrasound (US)- and microwave (MW)-assisted extraction. Both the enabling technologies provided performances that were superior to those of conventional extractions in terms of antioxidant activity determined by the DPPH· (2,2-diphenyl-1-picrylhydrazyl) assay. In particular, the most promising approach using NaDES is proven to be the acoustic cavitation with a Trolox eq. of 1874.0 mmol TE /g Extr (40 °C, 500 W, 30 min), vs. the 510.1 mmol TE /g Extr of hydroalcoholic extraction (80 °C, 4 h). The shelf-life of both hydroalcoholic and NaDES-VPPs extracts have been assessed over a period of 24 months, and found that NaDES granted a 5.6-fold shelf-life extension. Finally, the antiproliferative activity of both hydroalcoholic and NaDES-VPPs extracts was evaluated in vitro using the MTS assay on human tumour Caco-2 cells and normal human keratinocyte cells (HaCaT). In particular, NaDES-VPPs extracts exhibited a significantly more pronounced antiproliferative activity compared to the ethanolic extracts without a noteworthy difference between effects on the two cell lines.

Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular senescence by transcriptionally and post-transcriptionally modulating the expression of many important genes involved in senescence-associated pathways and processes. Among the different lncRNAs associated to senescence, Senescence Associated Long Non-coding RNA (SALNR) was found to be down-regulated in different cellular models of senescence. Since its release in 2015, SALNR has not been annotated in any database or public repository, and no other experimental data have been published. The SALNR sequence is located on the long arm of chromosome 10, at band 10q23.33, and it overlaps the 3' end of the HELLS gene. This investigation helped to unravel the mystery of the existence of SALNR by analyzing publicly available short- and long-read RNA sequencing data sets and RT-PCR analysis in human tissues and cell lines. Additionally, the expression of HELLS has been studied in cellular models of replicative senescence, both in silico and in vitro. Our findings, while not supporting the actual existence of SALNR as an independent transcript in the analyzed experimental models, demonstrate the expression of a predicted HELLS isoform entirely covering the SALNR genomic region. Furthermore, we observed a strong down-regulation of HELLS in senescent cells versus proliferating cells, supporting its role in the senescence and aging process., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Consiglio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The inflorescences of Humulus lupulus L. are the most valuable ingredient in the brewing industry. Only female cones are used as their bitterness and aroma, much associated with beer, are granted by the production of resins and essential oils, respectively. The traditional brewing process for the extraction of the organic volatiles in hops is called dry hopping. It consists of extended maceration at low temperature after the fermentation phase. New extraction technologies can improve extraction rates and product quality while saving time and money. This article proves that multiple-effect fractional condensation under a vacuum is suitable for flavouring applications and especially for performing dry hopping without contamination risks and reductions in hop amounts. This technique leads to the recovery of aqueous aromatic fractions that are very rich in hop sesquiterpenes and monoterpenes. These suspensions are extremely stable when stored at 5-8 °C and avoid degradation even after several months. This feature is crucial for the marketing of non-alcoholic beverages, where the dilution of essential oils is otherwise problematic.

Total body irradiation (TBI) at a dose of 12 Gy combined with cyclophosphamide (CyTBI12Gy) is one of the standard myeloablative regimens for patients with acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cyclophosphamide may be substituted with fludarabine (FluTBI12Gy) to reduce toxicity. We retrospectively compared outcomes of CyTBI12Gy with FluTBI12Gy for patients with AML treated in complete remission (CR) with allo-HCT from either a matched sibling or unrelated donor. Of 1684 adults who met inclusion criteria, 109 patients in each group were included in a matched-pair analysis. The cumulative incidence of relapse at 2 years was 25% in the FluTBI12Gy compared to 28% in the CyTBI12Gy group (p = .44) while non-relapse mortality (NRM) was 17% versus 19%, (p = .89) respectively. The rates of leukemia-free survival and overall survival were 65% versus 54% (p = .28) and 70% versus 60.5% (p = .17). Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly lower for FluTBI12Gy than CyTBI12Gy (16% vs. 34%, p = .005), while the incidences of grade 3-4 acute GVHD and chronic GVHD did not differ significantly. The probability of GVHD and relapse-free survival was 49% in the FluTBI12Gy and 41% in the CyTBI12Gy group (p = .17). We conclude that for patients with AML treated with allo-HCT in CR, cyclophosphamide may be substituted with fludarabine in a regimen based on TBI at a dose of 12 Gy without negative impact on the efficacy. FluTBI12Gy is associated with reduced risk of grade 2-4 acute GVHD and encouraging survival rates., (© 2023 Wiley Periodicals LLC.)

Frustrated Lewis pairs (FLPs), discovered in the last few decades for homogeneous catalysts and in the last few years also for heterogeneous catalysts, are stimulating the scientific community's interest for their potential in small-molecule activation. Nevertheless, how an FLP activates stable molecules such as CO 2 is still undefined. Through a careful spectroscopic study, we here report the formation of FLPs over a highly defective CeO 2 sample prepared by microwave-assisted synthesis. Carbon dioxide activation over FLP is shown to occur through a bidentate carbonate bridging the FLP and implying a Ce 3+ -to-CO 2 charge transfer, thus enhancing its activation. Carbon dioxide reaction with methanol to form monomethylcarbonate is here employed to demonstrate active roles of FLP and, eventually, to propose a reaction mechanism clarifying the role of Ce 3+ and oxygen vacancies.

The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing., Methods: With the aim to analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan [BU]-based; n = 618; 79%; treosulfan [TREO]-based; n=162; 21%)., Results: No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients ( P  < 0.001); more active diseases at the time of SCT ( P  < 0.001); a higher prevalence of patients with either hematopoietic cell transplantation-comorbidity index ≥3 ( P  < 0.001) or a good Karnofsky performance status ( P  = 0.025); increased use of peripheral blood stem cells as graft sources ( P  < 0.001); and greater use of reduced intensity conditioning regimens ( P  = 0.013) and of haploidentical donors ( P  < 0.001). Moreover, the 2-y cumulative incidence of relapse with myeloablative doses of BU was significantly lower than that registered with reduced intensity conditioning (21% versus 31%; P  = 0.0003). This was not observed in the TREO-based group., Conclusions: Despite a higher number of risk factors in the TREO group, no significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival according to the type of alkylator, suggesting that TREO has no advantage over BU in terms of efficacy and toxicity in acute myeloid leukemia and myelodysplastic syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Introduction: Baastrup's disease (BD) is a common cause of low back pain which is often underdiagnosed. It is characterized by adjacent interspinous processes contact and it can be associated with cystic lesions. The aim of this review was to evaluate the epidemiology, diagnosis, and treatment options of patients with BD., Evidence Acquisition: The present study is performed according to PRISMA statement. Medline via PubMed and Embase, Scopus, Cochrane Library database were searched using the keywords: "Baastrup," "kissing spines," "syndrome," "disease." A total of 35 papers met our inclusion criteria. Full texts were reviewed for demographic, clinical data and treatment., Evidence Synthesis: 1308 patients were included in the studies. The mean age of the enrolled patients was 59.6 years. The M:F ratio was 1.3:1. Population-based studies demonstrated a decade on decade increase in the incidence. Standard and dynamic flexion-extension radiographs of the lumbar spine were performed in 213 (16.2%) of cases. MRI was performed in 735 patients (56.2%) whereas FDG PET/CT was used to demonstrate BD in 77 included cases (5.9%). CT scan was performed in 574 cases (43.9%). Twenty-six studies reported the treatment choice for a total of 277 patients. Anti-inflammatory drugs and physical therapy were chosen in 99 cases (35.7%). Percutaneous infiltrations and surgical decompression in 80 (28.9%) and 196 (70.7%) patients respectively., Conclusions: Baastrup's disease is a common cause of low back pain. Proper diagnosis needs for imaging investigations and dynamic flexion-extension radiographs. Conservative and surgical therapies are available but there is a need for randomized clinical trials.

The aim of the present study is to develop a new industrial process for the continuous-flow extraction of virgin olive oil (VOO) using the non-thermal ultrasound (US) and pulsed electric field (PEF) treatments. These technologies have been tested both separately and in combination, with the aim of making the malaxation step unnecessary. The ultrasound-assisted extraction (UAE) and PEF treatments are both effective technologies for VOO production and have been well documented in the literature. The present study combines a new continuous-flow set-up, with four US units and PEF treatment. The industrial-plant prototype is able to improve VOO yields, thanks to powerful non-thermal physical effects (acoustic cavitation and electroporation), from 16.3% up to 18.1%. Moreover, these technologies increased the content of nutritionally relevant minor components, which, in turn, improves VOO quality and its commercial value (overall tocopherols and tocotrienols improved from 271 mg/kg under the conventional process to 314 mg/kg under the US process). The combined UAE and US-PEF process also increased the extraction yield, while overcoming the need for kneading in the malaxation step and saving process water (up to 1512 L per working day). Continuous-flow US and PEF technologies may be a significant innovation for the VOO industry, with benefits both for oil millers and consumers. The VOO obtained via non-thermal continuous-flow production can satisfy the current trend towards healthier nutrient-enriched products.

(1) Background: The aim of our study is to investigate the main oral lesion patterns in patients with oral graft-versus-host disease and to describe and validate the use of endoscopy enhanced with narrow-band imaging (NBI) as a personalized, reliable and user-friendly tool for the early detection of oral potentially diseases. (2) Methods: We retrospectively evaluated the medical records of 20 patients with chronic GVHD and with oral manifestations, who were referred to our "Interdisciplinary Center for Oropharyngeal Pathology (CIPO)" from January 2017 to July 2022. (3) Results: Data on GVHD, oral localization and NBI endoscopic evaluation are collected. A total of six mucositis, one mucosal erythematous change, ten lichenoid-like changes, eight erosive lesions, one leukoplakia, two erythroplakia and two case of blisters were observed. Two vascular abnormalities were seen with NBI, leading to one excisional biopsy. The patient was diagnosed with squamous cell carcinoma. (4) Conclusion: Our study is the first to highlight the relevance of the routine use of endoscopy with NBI in patients with oral chronic GVHD. We highlighted its role as a reliable, reproducible, easy-to-use and tailor-made tool in the follow-up of those patients and to allow an earlier identification of aberrant neoangiogenesis related to oral potentially malignant disorders and oral cancer.

Objective: To verify the safety and potential effect on ALS progression of a low-intensity immunosuppressive regimen followed by autologous hematopoietic stem cell transplantation (aHSCT) in amyotrophic lateral sclerosis (ALS) patients., Methods: ALS eligible patients underwent a set of clinical and laboratory evaluations at T-4 (screening), T-1 (pre-treatment visit), and for the 12 consecutive months after treatment (T3, T6, T9, T12). We evaluated the tolerability of the procedure, its efficacy on clinical course and quality of life (QoL)., Results: Eight of the 11 ALS patients enrolled received the established immunoablative protocol. The procedure was well tolerated and side effects were those expected. One patient died 4 months after the conditioning regimen and another patient underwent tracheotomy just before T3 for a sudden respiratory failure, but he is still alive 4 years after the procedure without being ventilated any more. A third patient died 10 months after conditioning. In the other cases, there was no statistical difference in all functional measures and QoL pre- and post-treatment; however, a transitory slopes' reduction of ALSFRS-R and seated SVC% after the conditioning procedures was reported. Moreover, although not statistically significant, trends of reduction of CD4 + and increment of CD8 + were found., Conclusions: aHSCT was overall well tolerated, but it was not followed by any significant modification in disease progression. Considering the negative results of this small trial, further studies aimed to evaluate the possible efficacy of the aHSCT using a higher-intensity regimen should be carefully and with caution evaluated., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with peripheral blood stem cells (PBSCs) to treat acute myelogenous leukemia (AML) is increasing. We explored whether the addition of antithymocyte globulin (ATG) to post-transplantation cyclophosphamide (PTCy) allows better outcomes compared with PTCy alone in haplo-HCT with PBSCs (haplo-PBSCT). We included 441 adult patients undergoing a first haplo-PBSCT for AML in first or second complete remission; graft-versus-host disease (GVHD) prophylaxis contained either PTCy alone (n = 374) or ATG plus PTCy (n = 67), in addition to cyclosporine A (CsA) and mycophenolate mofetil (MMF) as other immunosuppressive agents. All transplantations were performed between 2011 and 2019. No major imbalances were observed between the 2 groups. For both groups, the median patient age was 56 years, and the median year of haplo-PBSCT was 2017. Most patients received a reduced-intensity conditioning regimen (57% in the PTCy group and 61% in the ATG+PTCy group; P = .54). The median follow-up was 19 months in the PTCy group versus 15 months in the ATG+PTCy group (P = .59), and the rate of neutrophil engraftment in the 2 groups was 97% and 98%, respectively. In univariate analysis, there were no statistical differences in transplantation outcomes between the 2 groups. In multivariate analysis, ATG+PTCy was associated with a lower risk of chronic GVHD compared with PTCy alone (hazard ratio, .46; 95% confidence interval, .23 to .93; P = .03). No between-group differences in the other transplantation outcomes were seen. In haplo-PBSCT, the addition of ATG to PTCy (with CsA and MMF) is feasible and better at preventing chronic GVHD and is associated with survival and transplantation outcomes comparable to those with PTCy alone, without increasing transplantation toxicity, mortality, or relapse incidence., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The vast array of cell states found across human tissue arises from chromatin variants, which correspond to segments of the genome, known as DNA elements, adopting a different chromatin state over cell state transitions. Oncogenesis stems from alterations to the chromatin states over DNA elements that result in cancer-associated chromatin variants. Here, we review how cancer-associated chromatin variants call attention to repetitive DNA elements, and guide the functional characterization of transposable elements to decode their role in oncogenesis. We further discuss prevailing opportunities in the study of repetitive DNA elements to move towards the 'complete cancer genome' goal for precision medicine in oncology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population., (© 2022. The Author(s).)

Chestnut peels are a poorly characterized, underexploited by-product of the agri-food industry. This raw material is rich in bioactive compounds, primarily polyphenols and tannins, that can be extracted using different green technologies. Scaling up the process for industrial production is a fundamental step for the valorization of the extract. In this study, subcritical water extraction was investigated to maximize the extraction yield and polyphenol content. Lab-scale procedures have been scaled up to the semi-industrial level as well as the downstream processes, namely, concentration and spray drying. The extract antioxidant capacity was tested using in vitro and cellular assays as well as a preliminary evaluation of its antiadipogenic activity. The temperature, extraction time, and water/solid ratio were optimized, and the extract obtained under these conditions displayed a strong antioxidant capacity both in in vitro and cellular tests. Encouraging data on the adipocyte model showed the influence of chestnut extracts on adipocyte maturation and the consequent potential antiadipogenic activity. Chestnut peel extracts characterized by strong antioxidant power and potential antiadipogenic activity were efficiently obtained by removing organic solvents. These results prompted further studies on fraction enrichment by ultra- and nanofiltration. The semi-industrial eco-friendly extraction process and downstream benefits reported here may open the door to production and commercialization.