Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill.

Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.

The Bioactivity of a Hydroxytyrosol-Enriched Extract Originated after Direct Hydrolysis of Olive Leaves from Greek Cultivars.

Nowadays, olive leaf polyphenols have been at the center of scientific interest due to their beneficial effects on human health. The most abundant polyphenol in olive leaves is oleuropein. The biological properties of oleuropein are mainly due to the hydroxytyrosol moiety, a drastic catechol group, whose biological activity has been mentioned many times in the literature. Hence, in recent years, many nutritional supplements, food products, and cosmetics enriched in hydroxytyrosol have been developed and marketed, with unexpectedly positive results. However, the concentration levels of hydroxytyrosol in olive leaves are low, as it depends on several agricultural factors. In this study, a rapid and easy methodology for the production of hydroxytyrosol-enriched extracts from olive leaves was described. The proposed method is based on the direct acidic hydrolysis of olive leaves, where the extraction procedure and the hydrolysis of oleuropein are carried out in one step. Furthermore, we tested the in vitro bioactivity of this extract using cell-free and cell-based methods, evaluating its antioxidant and DNA-protective properties. Our results showed that the hydroxytyrosol-enriched extract produced after direct hydrolysis of olive leaves exerted significant in vitro antioxidant and geno-protective activity, and potentially these extracts could have various applications in the pharmaceutical, food, and cosmetic industries.

Hodgkin Lymphoma in Children and Adolescents of Northern Greece: 25-Year Results and Long-term Follow-up.

Aim of this study was to evaluate the long-term therapeutic outcome and treatment-related complications in Hodgkin disease. We reviewed the medical records of 93 patients diagnosed with classic Hodgkin lymphoma, treated, and followed-up during the last 25 years. The cohort study included 49 males and 44 females with median age 11.8 years old (range: 3.95 to 17.42 y). The most common subtype was nodular sclerosis in 47/93 (50.5%). B symptoms were present in 15/93 (16.1%). From January 2009 until December 2020, 55 (59%) patients diagnosed with Hodgkin lymphoma were treated according to European Network for Pediatric Hodgkin Lymphoma (EURONET)-PHL-C1 protocol. Concerning outcome, a total of 89/93 patients are alive. Relapse occurred in 7/93. Second malignancies are reported in a total of 5 patients, 3 solid tumors (thyroid cancer, breast cancer, and osteosarcoma), and 2 acute myeloid leukemias. The overall survival and event-free survival for the whole cohort were 95.7% and 83.9%, respectively. Disease-free survival was 92.5%. Although a considerable high fraction of patients with Hodgkin disease can achieve continuous complete remission, they are at a high risk of developing long-term treatment-related complications. High curative rates as well as prevention of late effects can be achieved by implementation of individualized treatment strategies and innovative treatments.

Antimicrobial Stewardship Programs in PICU Settings: A Systematic Review.

OBJECTIVES: Development of antimicrobial stewardship programs (ASPs) is strategy for prevention and management of emergence of antimicrobial-resistant organisms. In this study, we systematically reviewed the literature on antimicrobial stewardship interventions in PICUs and analyzed approaches, structure, implementation, and outcomes of the ASPs. DATA SOURCES: PubMed and Scopus databases were systematically searched for studies published from January 1, 2007, to December 31, 2020, reporting interventions on judicious use of antimicrobials in PICUs (last search performed February 28, 2021). DATA SELECTION: Studies that evaluated an intervention in a PICU setting or both in PICU and other settings and reported separate results for PICU were eligible for full-text review. Studies that had implemented stewardship in the entire hospital, including the PICU, but without presenting dedicated PICU data were excluded from the analysis. DATA EXTRACTION: The strategy of intervention, structure of ASP team, implementation, and outcomes were assessed with a checklist tool for all studies included in the analysis. Risk of bias was assessed with the Cochrane Risk-of-Bias in Nonrandomized studies of Interventions tool. DATA SYNTHESIS: Thirteen articles were found: 11 that applied ASP in PICUs, and two at hospital level. All PICU-dedicated ASPs applied a multimodal intervention combining strategies simultaneously; audit with feedback (6/11) and facility-specific clinical practice guidelines (7/11) were the most common strategies. A multidisciplinary team was formulated in all ASPs except for three biomarker-based interventions. Six of 11 studies included techniques to enhance behavior change and one implemented a behavior-based intervention. Antibiotic consumption was evaluated in all ASPs, cost in three of 11, antibiotic resistance in one of 11, length of hospitalization in six of 11, and mortality in eight of 11. All hospital-wide ASPs used audit with feedback in addition to facility-specific clinical practice guidelines and assessed antimicrobial consumption, expenditures, length of stay, and mortality. CONCLUSIONS: The prevalence of ASPs in PICUs is limited, and few programs follow all of the currently available recommendations.

Development of a Holistic In Vitro Cell-Free Approach to Determine the Redox Bioactivity of Agricultural Products.

In recent years, there has been a strong consumer demand for food products that provide nutritional benefits to human health. Therefore, the assessment of the biological activity is considered as an important parameter for the promotion of high-quality food products. Herein, we introduce a novel methodology comprising a complete set of in vitro cell-free screening techniques for the evaluation of the bioactivity of various food products on the basis of their antioxidant capacity. These assays examine the free radical scavenging activities, the reducing properties, and the protective ability against oxidative damage to biomolecules. The adoption of the proposed battery of antioxidant assays is anticipated to contribute to the holistic characterization of the bioactivity of the food product under examination. Consumer motivations and expectations with respect to nutritious food products with bio-functional properties drive the global food market toward food certification. Therefore, the development and application of scientific methodologies that examine the quality characteristics of food products could increase consumers' trust and promote their beneficial properties for human health.

Enhanced Ca2+ Entry Sustains the Activation of Akt in Glucose Deprived SH-SY5Y Cells.

The two crucial cellular insults that take place during cerebral ischemia are the loss of oxygen and loss of glucose, which can both activate a cascade of events leading to neuronal death. In addition, the toxic overactivation of neuronal excitatory receptors, leading to Ca2+ overload, may contribute to ischemic neuronal injury. Brain ischemia can be simulated in vitro by oxygen/glucose deprivation, which can be reversible by the re-establishment of physiological conditions. Accordingly, we examined the effects of glucose deprivation on the PI3K/Akt survival signaling pathway and its crosstalk with HIF-1α and Ca2+ homeostasis in SH-SY5Y human neuroblastoma cells. It was found that glucose withdrawal decreased HIF-1α protein levels even in the presence of the ischemia-mimicking CoCl2. On the contrary, and despite neuronal death, we identified a strong activation of the master pro-survival kinase Akt, a finding that was also confirmed by the increased phosphorylation of GSK3, a direct target of p-Akt. Remarkably, the elevated Ca2+ influx recorded was found to promptly trigger the activation of Akt, while a re-addition of glucose resulted in rapid restoration of both Ca2+ entry and p-Akt levels, highlighting the plasticity of neurons to respond to ischemic challenges and the important role of glucose homeostasis for multiple neurological disorders.

HIF-1α-derived cell-penetrating peptides inhibit ERK-dependent activation of HIF-1 and trigger apoptosis of cancer cells under hypoxia.

Hypoxia is frequently encountered in the microenvironment of solid tumors. Hypoxia-inducible factors (HIFs), the main effectors of cell response to hypoxia, promote cancer cell survival and progression. HIF-1α, the oxygen-regulated subunit of HIF-1, is often correlated with oncogenesis and represents an attractive therapeutic target. We have previously reported that activation HIF-1α by ERK involves modification of two serine residues and masking of a nuclear export signal (NES), all inside a 43-amino acid domain termed ERK Targeted Domain (ETD). Overexpression of ETD variants including wild-type, phospho-mimetic (SE) or NES-less (IA) mutant forms caused HIF-1 inactivation in two hepatocarcinoma cell lines, while a phospho-deficient (SA) form was ineffective and acted as a sequence-specific negative control. To deliver these ETD forms directly into cancer cells, they were fused to the HIV TAT-sequence and produced as cell-permeable peptides. When the TAT-ETD peptides were added to the culture medium of Huh7 cells, they entered the cells and, with the exception of ETD-SA, accumulated inside the nucleus, caused mislocalization of endogenous HIF-1α to the cytoplasm, significant reduction of HIF-1 activity and inhibition of expression of specific HIF-1, but not HIF-2, gene targets under hypoxia. More importantly, transduced nuclear TAT-ETD peptides restricted migration, impaired colony formation and triggered apoptotic cell death of cancer cells grown under hypoxia, while they produced no effects in normoxic cells. These data demonstrate the importance of ERK-mediated activation of HIF-1 for low oxygen adaptation and the applicability of ETD peptide derivatives as sequence-specific HIF-1 and cancer cell growth inhibitors under hypoxia.

Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia.

Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1α by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α that lacks modification by ERK, and the HIF-1α-mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1α to the outer mitochondrial membrane, as well as association with VDAC1 and hexokinase II, which promotes production of a C-terminally truncated active form of VDAC1, denoted VDAC1-ΔC, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1α or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-ΔC and increase resistance to etoposide- or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1α that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.

Neuroblastoma among children in Southern and Eastern European cancer registries: Variations in incidence and temporal trends compared to US.

Neuroblastoma comprises the most common neoplasm during infancy (first year of life). Our study describes incidence of neuroblastoma in Southern-Eastern Europe (SEE), including - for the first time - the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST)/Greece, compared to the US population, while controlling for human development index (HDI). Age-adjusted incidence rates (AIR) were calculated for 1,859 childhood (0-14 years) neuroblastoma cases, retrieved from 13 collaborating SEE registries (1990-2016), and were compared to those of SEER/US (N = 3,166; 1990-2012); temporal trends were assessed using Poisson regression and Joinpoint analyses. The overall AIR was significantly lower in SEE (10.1/million) compared to SEER (11.7 per million); the difference was maximum during infancy (43.7 vs. 53.3 per million, respectively), when approximately one-third of cases were diagnosed. Incidence rates of neuroblastoma at ages <1 and 1-4 years were positively associated with HDI, whereas lower median age at diagnosis was correlated with higher overall AIR. Distribution of primary site and histology was similar in SEE and SEER. Neuroblastoma was slightly more common among males compared to females (male-to-female ratio: 1.1), mainly among SEE infants. Incidence trends decreased in infants in Slovenia, Cyprus and SEER and increased in Ukraine and Belarus. The lower incidence in SEE compared to SEER, especially in infants living in low HDI countries possibly indicates a lower level of overdiagnosis in SEE. Hence, increases in incidence rates in infancy noted in some subpopulations should be carefully monitored to avoid the unnecessary costs health impacts of tumors that could potentially spontaneously regress.

Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: a pooled analysis from the childhood Leukemia International Consortium.

PURPOSE: The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case-control studies participating in the Childhood Leukemia International Consortium. METHOD: Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0-1, > 1-2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed. RESULTS: No association was seen with 'any' maternal coffee consumption during pregnancy, but there was evidence of a positive exposure-response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09-1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations. CONCLUSIONS: Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.

Voriconazole Antifungal Prophylaxis in Children With Malignancies: A Nationwide Study.

BACKGROUND: Antifungal prophylaxis (AFP) is recommended in at-risk hematology-oncology patients. We evaluated the safety of AFP with voriconazole (VRC) in pediatric hematology/oncology patients. MATERIALS AND METHODS: A retrospective study of VRC AFP in children with malignancies hospitalized in all 7 Greek pediatric hematology/oncology centers during 2008 to 2012 was conducted. Patients' demographics, outcome, and adverse event (AE) data were recorded. RESULTS: Four hundred twenty-nine VRC AFP courses in 249 patients (median age 6 y, 55% boys) were studied. The most common underlying diseases were acute lymphoblastic leukemia (51%), non Hodgkin lymphoma (8.6%), and acute myeloid leukemia (7.7%). The median number of VRC courses per patient was 1.7, whereas the median VRC dose was 7 mg/kg (range, 5 to 7 mg/kg) every 12 hours. During the last 2 weeks before AFP, 51% of the patients had received corticosteroids, 43% suffered from severe neutropenia, and 17.3% from mucositis. The median duration of VRC AFP was 17 days (range, 1 to 31 d). A single breakthrough fungemia due to Candida glabrata was recorded. Only 1 patient died due to the underlying disease. The most common AEs reported in 70/429 (16.3%) courses with ≥1 AE were elevated liver enzymes (50%), hypokalemia (24.3%), and ophthalmological disorders (14.3%). The median time of AE onset was 5 days (range, 1 to 21 d). Among 70 AEs reported, 38.5%, 48.4%, and 12.8% were of grade I, II, and III, respectively. CONCLUSIONS: VRC prophylaxis in pediatric hematology/oncology patients appears to be well tolerated.

Mortality and survival patterns of childhood lymphomas: geographic and age-specific patterns in Southern-Eastern European and SEER/US registration data.

Childhood (0-14 years) lymphomas, nowadays, present a highly curable malignancy compared with other types of cancer. We used readily available cancer registration data to assess mortality and survival disparities among children residing in Southern-Eastern European (SEE) countries and those in the United States. Average age-standardized mortality rates and time trends of Hodgkin (HL) and non-Hodgkin (NHL; including Burkitt [BL]) lymphomas in 14 SEE cancer registries (1990-2014) and the Surveillance, Epidemiology, and End Results Program (SEER, United States; 1990-2012) were calculated. Survival patterns in a total of 8918 cases distinguishing also BL were assessed through Kaplan-Meier curves and multivariate Cox regression models. Variable, rather decreasing, mortality trends were noted among SEE. Rates were overall higher than that in SEER (1.02/106 ), which presented a sizeable (-4.8%, P = .0001) annual change. Additionally, remarkable survival improvements were manifested in SEER (10 years: 96%, 86%, and 90% for HL, NHL, and BL, respectively), whereas diverse, still lower, rates were noted in SEE. Non-HL was associated with a poorer outcome and an amphi-directional age-specific pattern; specifically, prognosis was inferior in children younger than 5 years than in those who are 10 to 14 years old from SEE (hazard ratio 1.58, 95% confidence interval 1.28-1.96) and superior in children who are 5 to 9 years old from SEER/United States (hazard ratio 0.63, 95% confidence interval 0.46-0.88) than in those who are 10 to 14 years old. In conclusion, higher SEE lymphoma mortality rates than those in SEER, but overall decreasing trends, were found. Despite significant survival gains among developed countries, there are still substantial geographic, disease subtype-specific, and age-specific outcome disparities pointing to persisting gaps in the implementation of new treatment modalities and indicating further research needs.

Incidence and time trends of childhood lymphomas: findings from 14 Southern and Eastern European cancer registries and the Surveillance, Epidemiology and End Results, USA.

PURPOSE: To describe epidemiologic patterns of childhood (0-14 years) lymphomas in the Southern and Eastern European (SEE) region in comparison with the Surveillance, Epidemiology and End Results (SEER), USA, and explore tentative discrepancies. METHODS: Childhood lymphomas were retrieved from 14 SEE registries (n = 4,702) and SEER (n = 4,416), diagnosed during 1990-2014; incidence rates were estimated and time trends were evaluated. RESULTS: Overall age-adjusted incidence rate was higher in SEE (16.9/106) compared to SEER (13.6/106), because of a higher incidence of Hodgkin (HL, 7.5/106 vs. 5.1/106) and Burkitt lymphoma (BL, 3.1 vs. 2.3/106), whereas the incidence of non-Hodgkin lymphoma (NHL) was overall identical (5.9/106 vs. 5.8/106), albeit variable among SEE. Incidence increased with age, except for BL which peaked at 4 years; HL in SEE also showed an early male-specific peak at 4 years. The male preponderance was more pronounced for BL and attenuated with increasing age for HL. Increasing trends were noted in SEER for total lymphomas and NHL, and was marginal for HL, as contrasted to the decreasing HL and NHL trends generally observed in SEE registries, with the exception of increasing HL incidence in Portugal; of note, BL incidence trend followed a male-specific increasing trend in SEE. CONCLUSIONS: Registry-based data reveal variable patterns and time trends of childhood lymphomas in SEE and SEER during the last decades, possibly reflecting diverse levels of socioeconomic development of the populations in the respective areas; optimization of registration process may allow further exploration of molecular characteristics of disease subtypes.

Glucose Levels Before the Onset of Asparaginase Predicts Transient Hyperglycemia in Children With Acute Lymphoblastic Leukemia.

BACKGROUND: Transient hyperglycemia (TH) represents an acknowledged adverse event that occurs during treatment in children with acute lymphoblastic leukemia (ALL) and has recently been associated with an increased risk for developing metabolic disturbances in future life. Our aim was to estimate the incidence of TH and to identify risk factors, thus serving as markers for identifying candidates for prevention interventions. PROCEDURE: All patients treated with induction treatment for ALL in our department from January 2004 to April 2015 had their data retrieved from medical files and retrospectively analyzed. RESULTS: One hundred and two children with ALL treated at our department were identified (49 females and 53 males) with a mean age of 6.03 ± 3.78 years at the time of diagnosis. Sixteen patients developed TH (15.68%). Age at diagnosis >10 years is associated with an 11-fold increase in the risk of developing TH. Additionally, fasting glucose on the eighth day of treatment is an important prognostic factor as fasting glucose >100 mg/dl at that time point is associated with a threefold increase in developing TH during residual treatment period. CONCLUSIONS: Fasting glucose levels >110 mg/dl on the eighth day of treatment could serve as a trigger for intervention strategies that will prevent the development of TH in pediatric patients treated for ALL. Additional studies are needed to confirm and further extend this preliminary observation.

Successful Treatment of Disseminated Fusariosis in a 15-Month-Old Boy With Refractory Acute Lymphoblastic Leukemia Using High-Dose Voriconazole.

BACKGROUND: Infections due to rare molds, such as Fusarium spp., cause severe and difficult-to-control diseases with increasing frequency. Data on fusariosis in children and on the use of voriconazole (VCZ), considered a drug of choice, are scarce in infants and children <2 years of age. CASE PRESENTATION: We present the first, to our knowledge, pediatric case of disseminated mycosis due to Fusarium musae in a 15-month-old boy with relapsed/refractory acute lymphoblastic leukemia, diagnostics and outcome. Herein, at this severely immunocompromised patient, after prompt diagnosis, disseminated fusariosis was successfully treated with high-dose VCZ at a final dose of 15 mg/kg of body weight twice a day. This occurred by achieving adequate drug exposures as determined by drug susceptibility testing and followed by therapeutic drug monitoring without observed toxicity. CONCLUSIONS: Appropriate diagnostic approach and timely administration of optimal antifungal therapy with VCZ were important for the successful treatment of disseminated fusariosis. Therapeutic drug monitoring, especially in <2-year-old children, is necessary to achieve sufficient drug exposure for optimal therapeutic response without toxicity.

Off-label Use of Ceftazidime/Avibactam in Neonatal Intensive Care Unit: A Real-life Experience and Literature Review.

BACKGROUND: Multi/extensively drug-resistant bacterial infections have recently increased and new antimicrobial options are needed for difficult-to-treat infections. Ceftazidime/avibactam (CZA) has been approved for patients 3 months to 18 years of age, but real-life data on its off-label use in neonates and young infants are still scarce. MATERIALS: We report demographic, clinical and microbiologic data as well as outcome and safety of all cases of infants treated with CZA between January 1, 2021 and September 30, 2022 in a tertiary neonatal intensive care unit. We also review all neonatal cases previously reported. RESULTS: Twenty-one patients [17 males, with median gestational age 29 +2 (IQR 6 +6 ) weeks] received 31 CZA courses at a dose of 20-50 mg/kg/dose of ceftazidime q8h for suspected or proved multi/extensively drug-resistant infections. Median postnatal age at the onset of treatment was 44 days (IQR: 94 days). Twelve bacteremias, 2 urinary tract infections and 1 ventilator-acquired pneumonia were recorded. Twelve (39%) treatments were targeted, while 19 (61%) were empirically started due to known colonization with Klebsiella pneumoniae carbapenemase-producing Gram-negative bacteria. All patients had received multiple antibiotics prior and concomitantly with CZA. The most common pathogen identified at targeted administrations was carbapenem-resistant Klebsiella pneumoniae (83%). No serious adverse events attributed to the drug were detected. Twenty-one courses of CZA administration to 20 neonates with a median gestational age of 28.5 (IQR 3.5) weeks were previously reported without significant related adverse events. CONCLUSIONS: Favorable clinical and microbiologic responses in neonatal intensive care unit patients treated with CZA off-label were observed without significant and unexpected adverse events in critically ill neonates.

Evolving Aspects of Prognostic Factors for Pediatric Cancer.

Advances in risk-directed therapy based on prognostic factors that include clinical, biologic, and genetic features of cancer in children have yielded improved and prolonged responses [...].

Proteomics in Childhood Acute Lymphoblastic Leukemia: Challenges and Opportunities.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and one of the success stories in cancer therapeutics. Risk-directed therapy based on clinical, biologic and genetic features has played a significant role in this accomplishment. Despite the observed improvement in survival rates, leukemia remains one of the leading causes of cancer-related deaths. Implementation of next-generation genomic and transcriptomic sequencing tools has illustrated the genomic landscape of ALL. However, the underlying dynamic changes at protein level still remain a challenge. Proteomics is a cutting-edge technology aimed at deciphering the mechanisms, pathways, and the degree to which the proteome impacts leukemia subtypes. Advances in mass spectrometry enable high-throughput collection of global proteomic profiles, representing an opportunity to unveil new biological markers and druggable targets. The purpose of this narrative review article is to provide a comprehensive overview of studies that have utilized applications of proteomics in an attempt to gain insight into the pathogenesis and identification of biomarkers in childhood ALL.

Use of Newer and Repurposed Antibiotics against Gram-Negative Bacteria in Neonates.

Antimicrobial resistance has become a significant public health problem globally with multidrug resistant Gram negative (MDR-GN) bacteria being the main representatives. The emergence of these pathogens in neonatal settings threatens the well-being of the vulnerable neonatal population given the dearth of safe and effective therapeutic options. Evidence from studies mainly in adults is now available for several novel antimicrobial compounds, such as new ß-lactam/ß-lactamase inhibitors (e.g., ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam), although old antibiotics such as colistin, tigecycline, and fosfomycin are also encompassed in the fight against MDR-GN infections that remain challenging. Data in the neonatal population are scarce, with few clinical trials enrolling neonates for the evaluation of the efficacy, safety, and dosing of new antibiotics, while the majority of old antibiotics are used off-label. In this article we review data about some novel and old antibiotics that are active against MDR-GN bacteria causing sepsis and are of interest to be used in the neonatal population.