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Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: Our primary objective was to describe the baseline characteristics, main reasons for intensive care unit (ICU) admission, and interventions required in the ICU across patients who received CAR-T cell immunotherapy. The secondary objectives were to evaluate different outcomes (ICU mortality) across patients admitted to the ICU after having received CAR-T cell therapy., Materials and Methods: We performed a medical literature review, which included MEDLINE, Embase, and Cochrane Library, of studies published from the inception of the databases until 2022. We conducted a systematic review with meta-analyses of proportions of several studies, including CAR-T cell-treated patients who required ICU admission. Outcomes in the meta-analysis were evaluated using the random-effects model., Results: We included four studies and analyzed several outcomes, including baseline characteristics and ICU-related findings. CAR-T cell recipients admitted to the ICU are predominantly males (62% CI-95% (57-66)). Of the total CAR-T cell recipients, 4% CI-95% (3-5) die in the hospital, and 6% CI-95% (4-9) of those admitted to the ICU subsequently die. One of the main reasons for ICU admission is acute kidney injury (AKI) in 15% CI-95% (10-19) of cases and acute respiratory failure in 10% CI-95% (6-13) of cases. Regarding the interventions initiated in the ICU, 18% CI-95% (13-22) of the CAR-T recipients required invasive mechanical ventilation during their ICU stay, 23% CI-95% (16-30) required infusion of vasoactive drugs, and 1% CI-95% (0.1-3) required renal replacement therapy (RRT). 18% CI-95% (13-22) of the initially discharged patients were readmitted to the ICU within 30 days, and the mean length of hospital stay is 22 days CI-95% (19-25). The results paint a current state of matter in CAR-T cell recipients admitted to the ICU., Conclusions: To better understand immunotherapy-related complications from an ICU standpoint, acknowledge the deteriorating patient on the ward, reduce the ICU admission rate, advance ICU care, and improve the outcomes of these patients, a standard of care and research regarding CAR-T cell-based immunotherapies should be created. Studies that are looking from the perspective of intensive care are highly warranted because the available literature regarding this area is scarce.

Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

We print a tunable photopolymer (photopolymer dispersed liquid crystal -PDLC), using the laser-induced direct transfer technique without absorber layer, which was a challenge for this technique given the low absorption and high viscosity of PDLC, and which had not been achieved so far to our knowledge. This makes the LIFT printing process faster and cleaner and achieves a high-quality printed droplet (aspheric profile and low roughness). A femtosecond laser was needed to reach sufficiently peak energies to induce nonlinear absorption and eject the polymer onto a substrate. Only a narrow energy window allows the material to be ejected without spattering.

Multiple myeloma (MM) is a plasma cell malignancy that affects an increasing number of patients worldwide. Despite all the efforts to understand its pathogenesis and develop new treatment modalities, MM remains an incurable disease. Novel immunotherapies, such as CAR T cell therapy (CAR) and bispecific T cell engagers (BiTE), are intensively targeting different surface antigens, such as BMCA, SLAMF7 (CS1), GPRC5D, FCRH5 or CD38. However, stem cell transplantation is still indispensable in transplant-eligible patients. Studies suggest that the early use of immunotherapy may improve outcomes significantly. In this review, we summarize the currently available clinical literature on CAR and BiTE in MM. Furthermore, we will compare these two T cell-based immunotherapies and discuss potential therapeutic approaches to promote development of new clinical trials, using T cell-based immunotherapies, even as bridging therapies to a transplant., (© 2022. The Author(s).)

There is a dire need to develop an algorithm to improve the recognition of acquired hemophilia A and B (AHA and AHB) in clinical practice. Initial and intensive care unit (ICU) management of the disorder is particular and represents a challenge for the internist/hematologist and the ICU physician. A delay in the proper treatment of bleeding episodes can lead to a life-threatening event. Expert advice should be sought as soon as possible. Succesful resolution involves accurate diagnosis, bleeding control with hemostatic and immunotherapy, and eradication of the autoantibodies to improve overall survival. Current treatment guidelines are based on the literature in the form of cases and observational studies due to a lack of randomized controlled trials. AH can be triggered by many pathologies, presenting as a paraneoplastic syndrome in case of malignancies or as surgical associated acquired hemophilia (SAHA). We have reviewed the literature from 2015 to 2021 regarding the new case reports to further assess if there is an improvement in the clinical approach., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, elusive, and life-threatening condition that is characterized by the pathologic and uncontrolled secondary activation of the cytotoxic T-cells, natural killer cells (NK-cells), and macrophages of the innate immune system. This condition can develop in sporadic or familial contexts associated with hematological malignancies, as a paraneoplastic syndrome, or linked to an infection related to immune system deficiency. This leads to the systemic inflammation responsible for the overall clinical manifestations. Diagnosis should be thorough, and treatment should be initiated as soon as possible. In the current manuscript, we focus on classifying the HLH spectrum, describing the pathophysiology and the tools needed to search for and correctly identify HLH, and the current therapeutic opportunities. We also present the first case of a multiple myeloma patient that developed HLH following therapy with the ixazomib-lenalidomide-dexamethasone protocol.

Soft magnetic materials are at the core of electromagnetic devices. Planar transformers are essential pieces of equipment working at high frequency. Usually, their magnetic core is made of various types of ferrites or iron-based alloys. An upcoming alternative might be the replacement the ferrites with FINEMET-type alloys, of nominal composition of Fe 73.5 Si 13.5 B 9 Cu 3 Nb 1 (at. %). FINEMET is a nanocrystalline material exhibiting excellent magnetic properties at high frequencies, a soft magnetic alloy that has been in the focus of interest in the last years thanks to its high saturation magnetization, high permeability, and low core loss. Here, we present and discuss the measured and modelled properties of this material. Owing to the limits of the experimental set-up, an estimate of the total magnetic losses within this magnetic material is made, for values greater than the measurement limits of the magnetic flux density and frequency, with reasonable results for potential applications of FINMET-type alloys and thin films in high frequency planar transformer cores.

Introduction: The examination of vital signs and their changes during illness can alert physicians to possible impending deterioration and organ dysfunction. The Modified Early Warning Score (MEWS) is used worldwide as a track and trigger system that can help to identify patients at risk of critical illness. Thus, the current study aimed to assess the ability of MEWS to predict the mortality of hematologic patients at the point of transfer from the ward to the intensive care unit (ICU)., Materials and Methods: The present study was retrospective, longitudinal, and observational, conducted at an oncology hospital in the city of Cluj-Napoca, Romania. We included 174 patients with hematological disorders transferred from the ward to the ICU between the 1st of January 2018 and the 1st of May 2020. We assessed the MEWS at the moment of admission in these patients in the ICU. The accuracy of MEWS in predicting mortality was assessed via the area under the receiver operating characteristic curves (AUC), and sensitivity, specificity, and hazard ratio (HR) were calculated for different MEWS cutoffs. MEWS values considering the status at discharge and frequency of death by MEWS were also analyzed., Results: We calculated MEWS values considering the status at discharge ( p < 0.0001), and we assessed the frequency of death by MEWS. We also calculated the hazard ratio (HR) of death depending on the selected MEWS cutoff. The best cutoff point was found to be ≥6, with an accuracy of 0.667, sensitivity of 0.675, specificity of 0.646, and AUC of 0.731. Patients with higher MEWS had a higher probability of mortality., Conclusion: The MEWS and cutoff points were determined on a sample of hematologic patients at the moment of admission to the ICU. The final aim is to encourage physicians to use these scores to improve awareness of organ failure to admit patients to the ICU sooner and limit overall morbidity and mortality. The presence of an ICU physician on ward rounds might help in reducing the timeframe of access to a high-dependency unit (HDU) or ICU. An extension of these scores outside hematologic patients or considering hematologic patients outside ICU must be further studied.

Patients with relapsed/refractory acute myeloid leukaemia (AML), ineligible for intensive chemotherapy and allogeneic stem cell transplantation, have a dismal prognosis. For such cases, hypomethylating agents are a viable alternative, but with limited success. Combination chemotherapy using a hypomethylating agent plus another drug would potentially bring forward new alternatives. In the present manuscript, we present the cell and molecular background for a clinical scenario of a 44-year-old patient, diagnosed with high-grade serous ovarian carcinoma, diagnosed, and treated with a synchronous AML. Once the ovarian carcinoma relapsed, maintenance treatment with olaparib was initiated. Concomitantly, the bone marrow aspirate showed 30% myeloid blasts, consistent with a relapse of the underlying haematological disease. Azacytidine 75 mg/m 2 treatment was started for seven days. The patient was administered two regimens of azacytidine monotherapy, additional to the olaparib-based maintenance therapy. After the second treatment, the patient presented with leucocytosis and 94% myeloid blasts on the bone marrow smear. Later, the patient unfortunately died. Following this clinical scenario, we reproduced in vitro the combination chemotherapy of azacytidine plus olaparib, to accurately assess the basic mechanisms of leukaemia progression, and resistance to treatment. Combination chemotherapy with drugs that theoretically target both malignancies might potentially be of use. Still, further research, both pre-clinical and clinical, is needed to accurately assess such cases., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Hemophilia type A (HA) is the most common type of blood coagulation disorder. While the vast majority of cases are inherited and caused by mutations in the F8 gene, recent data raises new questions regarding the non-heritability of this disease, as well as how other molecular mechanisms might lead to the development of HA or increase the severity of the disease. Some data suggest that miRNAs may affect the severity of HA, but for some patients, miRNA-based interference might cause HA, in the absence of an F8 mutation. A mechanism in HA installation that is also worth investigating and which could be identified in the future is the epigenetic silencing of the F8 gene that might be only temporarily. Acquired HA is increasingly reported and as more cases are identified, the description of the disease might become challenging, as cases without FVIII autoantibodies might be identified., 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., (Copyright © 2021 Zimta, Hotea, Brinza, Blag, Iluta, Constantinescu, Bashimov, Marchis-Hund, Coudsy, Muller-Mohnssen, Dirzu, Gulei, Dima, Serban, Coriu and Tomuleasa.)

Driven by flexibility, precision, repeatability and eco-friendliness, laser-based technologies have attracted great interest to engineer or to analyze materials in various fields including energy, environment, biology and medicine. A major advantage of laser processing relies on the ability to directly structure matter at different scales and to prepare novel materials with unique physical and chemical properties. It is also a contact-free approach that makes it possible to work in inert or reactive liquid or gaseous environment. This leads today to a unique opportunity for designing, fabricating and even analyzing novel complex bio-systems. To illustrate this potential, in this paper, we gather our recent research on four types of laser-based methods relevant for nano-/micro-scale applications. First, we present and discuss pulsed laser ablation in liquid, exploited today for synthetizing ultraclean "bare" nanoparticles attractive for medicine and tissue engineering applications. Second, we discuss robust methods for rapid surface and bulk machining (subtractive manufacturing) at different scales by laser ablation. Among them, the microsphere-assisted laser surface engineering is detailed for its appropriateness to design structured substrates with hierarchically periodic patterns at nano-/micro-scale without chemical treatments. Third, we address the laser-induced forward transfer, a technology based on direct laser printing, to transfer and assemble a multitude of materials (additive structuring), including biological moiety without alteration of functionality. Finally, the fourth method is about chemical analysis: we present the potential of laser-induced breakdown spectroscopy, providing a unique tool for contact-free and space-resolved elemental analysis of organic materials. Overall, we present and discuss the prospect and complementarity of emerging reliable laser technologies, to address challenges in materials' preparation relevant for the development of innovative multi-scale and multi-material platforms for bio-applications.

Chimeric antigen receptor T (CAR-T) cell therapy is a recent therapeutic addition to the field of oncology, the first one approved as represented by tisagenlecleucel followed shortly by approval of axicabtagene ciloleucel. Because this product is derived from T cells, there are several lessons that can be learned from T-cell biology to better understand CAR-T cells. Thus, in this review we discuss the effects that TET2 can have on T cells, macrophages interacting with T cells, and nonimmune cells. In T cells, TET2 mutations have been frequently shown to be associated with FOXP3 expression reduction and instability, which leads to reduction in T regulatory (Treg) cells and increases in T-helper (Th)1 and Th17 cells. This alteration in T-cell polarization balance leads to both an enhanced antitumor activity and an increased probability of autoimmune diseases. In the case of macrophages, TET2 has a similar role, as its reduced activity is associated with an M1 signature but its overexpression is associated with an M2 signature. In nonimmune cells, the role of TET2 is opposite its role in immune cells. Specifically, the reduction in TET2 activity is associated with a decreased immune response both in malignancies and in autoimmune diseases. In the current review, we discuss the role that TET2 plays in T-cell activity and in nonimmune cells in relation to T cells.

Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3140). CT serves as an unpaid editorial board member of Annals of Translational Medicine from Nov 2019 to Oct 2021. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman.

In the last decade there has been tremendous effort in offering better therapeutic management strategies to patients with hematologic malignancies. These efforts have ranged from biological to clinical approaches and resulted in the rapid development of new approaches. The main "problem" that comes with the high influx of newly approved drugs, which not only influences hematologists that frequently work with these drugs but also affects other healthcare professionals that work with hematologists in patient management, including intensive care unit (ICU) physicians, is they have to keep up within their specialty and, in addition, with the side-effects that can occur when encountering hematology-specific therapies. Nonetheless, there are few people that have an in-depth understanding of a specialty outside theirs. Thus, this manuscript offers an overview of the most common side-effects caused by therapies used in hematology nowadays, or that are currently being investigated in clinical trials, with the purpose to serve as an aid to other specialties. Nevertheless, because of the high amount of information on this subject, each chapter will offer an overview of the side-effects of a drug class with each reference of the section being intended as further reading.

Introduction: Childhood acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the acquisition of several genetic lesions in the lymphoid progenitors with subsequent proliferation advantage and lack of maturation. Along the years, it has been repeatedly shown that minimal residual disease (MRD) plays an important role in prognosis and therapy choice. The aim of the current study was to determine the prognostic role of MRD in childhood ALL patients in conjunction with other relevant patient and disease characteristics, thus showing the real-life scenario of childhood ALL. Patients and Methods: The retrospective study includes childhood ALL patients that were treated according to the BFM ALL IC 2009 between January 2016 and December 2018 at the Fundeni Clinical Institute, Bucharest, Romania. Results: None of the variables significantly influenced the induction-related death in our study. None of the variables independently predicted relapse-free survival (RFS) with the highest tendency for statistical significance being represented by poor prednisone response. Non-relapse mortality (NRM) was independently predicted by age, prednisone response, and day 33 flow cytometry-MRD (FCM-MRD). Overall survival (OS) was independently predicted by prednisone response and day 33 FCM-MRD. Event-free survival (EFS) was independently predicted by age, prednisone response, and day 33 FCM-MRD. Conclusion : Prednisone response, day 15 FCM-MRD, day 33 FCM-MRD, and the risk group represent the most important factors that in the current study independently predict childhood ALL prognosis., (Copyright © 2020 Radu, Colita, Pasca, Tomuleasa, Popa, Serban, Gheorghe, Serbanica, Jercan, Marcu, Bica, Teodorescu, Constantinescu, Petrushev, Asan, Jardan, Dragomir, Tanase and Colita.)

Recently, an increasing number of novel drugs were approved in oncology and hematology. Nevertheless, pharmacology progress comes with a variety of side effects, of which cytokine release syndrome (CRS) is a potential complication of some immunotherapies that can lead to multiorgan failure if not diagnosed and treated accordingly. CRS generally occurs with therapies that lead to highly activated T cells, like chimeric antigen receptor T cells or in the case of bispecific T-cell engaging antibodies. This, in turn, leads to a proinflammatory state with subsequent organ damage. To better manage CRS there is a need for specific therapies or to repurpose strategies that are already known to be useful in similar situations. Current management strategies for CRS are represented by anticytokine directed therapies and corticosteroids. Based on its pathophysiology and the resemblance of CRS to sepsis and septic shock, as well as based on the principles of initiation of continuous renal replacement therapy (CRRT) in sepsis, we propose the rationale of using CRRT therapy as an adjunct treatment in CRS where all the other approaches have failed in controlling the clinically significant manifestations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by abnormal proliferation and a lack of differentiation of myeloid blasts. Considering the dismal prognosis this disease presents, several efforts have been made to better classify it and offer a tailored treatment to each subtype. This has been formally done by the World Health Organization (WHO) with the AML classification schemes from 2008 and 2016. Nonetheless, there are still mutations that are not currently included in the WHO AML classification, as in the case of some mutations that influence methylation. In this regard, the present study aimed to determine if some of the mutations that influence DNA methylation can be clustered together regarding methylation, expression, and clinical profile. Data from the TCGA LAML cohort were downloaded via cBioPortal. The analysis was performed using R 3.5.2, and the necessary packages for classical statistics, dimensionality reduction, and machine learning. We included only patients that presented mutations in DNMT3A, TET2, IDH1/2, ASXL1, WT1, and KMT2A . Afterwards, mutations that were present in too few patients were removed from the analysis, thus including a total of 57 AML patients. We observed that regarding expression, methylation, and clinical profile, patients with mutated TET2, IDH1/2, and WT1 presented a high degree of similarity, indicating the equivalence that these mutations present between themselves. Nonetheless, we did not observe this similarity between DNMT3A- and KMT2A -mutated AML. Moreover, when comparing the hypermethylating group with the hypomethylating one, we also observed important differences regarding expression, methylation, and clinical profile. In the current manuscript we offer additional arguments for the similarity of the studied hypermethylating mutations and suggest that those should be clustered together in further classifications. The hypermethylating and hypomethylating groups formed above were shown to be different from each other considering overall survival, methylation profile, expression profile, and clinical characteristics. In this manuscript, we present additional arguments for the similarity of the effect generated by TET2 , IDH1/2, and WT1 mutations in AML patients. Thus, we hypothesize that hypermethylating mutations skew the AML cells to a similar phenotype with a possible sensitivity to hypermethylating agents.

Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells. Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resistant ALL in the real-life setting, by describing Romania's experience with bispecific antibodies for B-cell ALL. Methods: We present the role of novel therapies for relapsed B-cell ALL, including the drugs under investigation in phase I-III clinical trials, as a potential bridge to transplant. Blinatumomab is presented in a critical review, presenting both the advantages of this drug, as well as its limitations. Results: Bispecific antibodies are discussed, describing the clinical trials that resulted in its approval by the FDA and EMA. The real-life setting for relapsed B-cell ALL is described and we present the patients treated with blinatumomab in Romania. Conclusion: In the current manuscript, we present blinatumomab as a therapeutic alternative in the bridge-to-transplant setting for refractory or relapsed ALL, to gain a better understanding of the available therapies and evidence-based data for these patients in 2019., (Copyright © 2019 Deak, Pop, Zimta, Jurj, Ghiaur, Pasca, Teodorescu, Dascalescu, Antohe, Ionescu, Constantinescu, Onaciu, Munteanu, Berindan-Neagoe, Petrushev, Turcas, Iluta, Selicean, Zdrenghea, Tanase, Danaila, Colita, Colita, Dima, Coriu, Einsele and Tomuleasa.)

During recent decades, understanding of the molecular mechanisms of acute lymphoblastic leukemia (ALL) has improved considerably, resulting in better risk stratification of patients and increased survival rates. Age, white blood cell count (WBC), and specific genetic abnormalities are the most important factors that define risk groups for ALL. State-of-the-art diagnosis of ALL requires cytological and cytogenetical analyses, as well as flow cytometry and high-throughput sequencing assays. An important aspect in the diagnostic characterization of patients with ALL is the identification of the Philadelphia (Ph) chromosome, which warrants the addition of tyrosine kinase inhibitors (TKI) to the chemotherapy backbone. Data that support the benefit of hematopoietic stem cell transplantation (HSCT) in high risk patient subsets or in late relapse patients are still questioned and have yet to be determined conclusive. This article presents the newly published data in ALL workup and treatment, putting it into perspective for the attending physician in hematology and oncology., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results

: The initial management of the hematology patient in a critical state is crucial and poses a great challenge both for the hematologist and the intensive care unit (ICU) physician. After years of clinical practice, there is still a delay in the proper recognition and treatment of critical situations, which leads to late admission to the ICU. There is a much-needed systematic ABC (Airway, Breathing, Circulation) approach for the patients being treated on the wards as well as in the high dependency units because the underlying hematological disorder, as well as disease-related complications, have an increasing frequency. Focusing on score-based decision-making on the wards (Modified Early Warning Score (MEWS), together with Quick Sofa score), active sepsis screening with inflammation markers (C-reactive protein, procalcitonin, and presepsin), and assessment of microcirculation, organ perfusion, and oxygen supply by using paraclinical parameters from the ICU setting (lactate, central venous oxygen saturation (ScVO 2 ), and venous-to-arterial carbon dioxide difference), hematologists can manage the immediate critical patient and improve the overall outcome., Competing Interests: The authors declare no conflict of interest.

[This corrects the article DOI: 10.18632/oncotarget.24637.].

Chimeric antigen receptor-modified T cells (CAR-T cells) and donor lymphocyte infusion (DLI) are important protocols in lymphocyte engineering. CAR-T cells have emerged as a new modality for cancer immunotherapy due to their potential efficacy against hematological malignancies. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in lymphocyte T cell activation subsequent to antigen binding. In present-day medicine, four generations of CAR-T cells are described depending on the intracellular signaling domain number of T cell receptors. DLI represents a form of adoptive therapy used after hematopoietic stem cell transplant for its anti-tumor and anti-infectious properties. This article covers the current status of CAR-T cells and DLI research in the intensive care unit (ICU) patient, including the efficacy, toxicity, side effects and treatment., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

Background: Ultrasonography-assessed hyomental distance (HMD) ratio has been found to discriminate between obese patients with Cormack-Lehane grades 1 or 2 vs. those with grades 3 or 4. The aim of our study is to evaluate the performance of the HMD evaluated ultrasonographically in neutral, ramped, and maximum hyperextended positions, as well as for the ratios obtained by dividing the HMD in the ramped position to that in the neutral position (HMDR1) and by dividing the HMD in maximum hyperextension to that in the neutral position (HMDR2), in order to predict the occurrence of Cormack-Lehane grades 3 or 4 during direct laryngoscopy., Methods: Ultrasound measurements were performed preoperatively in 25 patients with morbid obesity, measuring the HMD in the neutral, ramped, and maximum hyperextended positions. Pre-epyglotic soft tissue thickness, Mallampati and upper lip bite test scores were recorded. Cormack-Lehane grading was considered as an outcome variable in the Receiver Operating Characteristics curve analysis., Results: HMD in the neutral, ramped and maximum hyperextended positions presented similar sensitivities, 100% [39.8-100.0]. For HMD, specificity was 42.86% [21.8-66.0] in the neutral position, 61.9% [38.4-81.9] in the ramped postion, and 71.4% [47.8-88.7] in the maximum hyperextended position. For HMDR1, the cut-off value was 1.12. This threshold provides 75% [19.4-99.4] sensitivity and 76.2% [52.8-91.8] specificity. For HMDR2, a cut-off value of 1.23 provides 100% [39.8-100.0] sensitivity and 90.5% [69.6-98.8] specificity., Conclusion: HMDR2 seems to have superior diagnostic accuracy in predicting difficult laryngoscopy in the obese population compared to HMDR1, as well as compared to the HMD in the neutral, ramped, and maximum hyperextended positions.

The ability of matrix-assisted pulsed laser evaporation (MAPLE) technique to transfer and deposit high-quality thin organic, bioorganic, and composite films with minimum chemical modification of the target material has been utilized in numerous applications. One of the outstanding problems in MAPLE film deposition, however, is the presence of residual solvent (matrix) codeposited with the polymer material and adversely affecting the quality of the deposited films. In this work, we investigate the possibility of alleviating this problem by reducing the amount of matrix in the target. A series of coarse-grained molecular dynamics simulations are performed for a model lysozyme-water system, where the water serves the role of volatile "matrix" that drives the ejection of the biomolecules. The simulations reveal a remarkable ability of a small (5-10 wt %) amount of matrix to cause the ejection of intact bioorganic molecules. The results obtained for different laser fluences and water concentrations are used to establish a "processing map" of the regimes of molecular ejection in matrix-assisted pulsed laser deposition. The computational predictions are supported by the experimental observation of the ejection of intact lysozyme molecules from pressed lysozyme targets containing small amounts of residual water. The results of this study suggest a new approach for deposition of thin films of bioorganic molecules with minimum chemical modification of the molecular structure and minimum involvement of solvent into the deposition process.

It is accepted so far that the formation of photonic nanojets requires the use of large dielectric spheres (several wavelengths in diameter). Here we show both numerically and experimentally that similar effects can be obtained with properly engineered sub-wavelength core-shell colloids. The design of the spheres is strongly inspired by a far-field approach for the generation of Bessel beams.

In this work, antitumor compounds, lactoferrin [recombinant iron-free (Apo-rLf)], cisplatin (Cis) or their combination were embedded within a biodegradable polycaprolactone (PCL) polymer thin film, by a modified approach of a laser-based technique, matrix-assisted pulsed laser evaporation (MAPLE). The structural and morphological properties of the deposited hybrid films were analyzed by Fourier-transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). The in vitro effect on the cells' morphology and proliferation of murine melanoma B16-F10 cells was investigated and correlated with the films' surface chemistry and topography. Biological assays revealed decreased viability and proliferation, lower adherence, and morphological modifications in the case of melanoma cells cultured on both Apo-rLf and Cis thin films. The antitumor effect was enhanced by deposition of Apo-rLf with Cis within the same film. The unique capability of the new approach, based on MAPLE, to embed antitumor active factors within a biodegradable matrix for obtaining novel biodegradable hybrid platform with increased antitumor efficiency has been demonstrated.