Mutational and transcriptional landscape of pediatric B-cell precursor lymphoblastic lymphoma.

Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in bone marrow/blood (BCP acute lymphoblastic leukemia, BCP-ALL) or less common in extramedullary tissue (BCP lymphoblastic lymphoma, BCP-LBL). Although both presentations are similar in morphology and immunophenotype, molecular studies are virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is due to its rarity and the restriction to small, mostly formalin-fixed paraffin embedded (FFPE) tissues. Here we present the first comprehensive mutational and transcriptional analysis of what we consider the largest BCP-LBL cohort described to date (n=97). Whole exome sequencing indicates a mutational spectrum of BCP-LBL strikingly similar to that found in BCP-ALL. However, epigenetic modifiers were more frequently mutated in BCP-LBL, whereas BCP-ALL was more frequently affected by mutation in genes involved in B-cell development. Integrating copy number alterations, somatic mutations and gene expression by RNA-sequencing revealed that virtually all molecular subtypes originally defined in BCP-ALL are present in BCP-LBL too, with only 7% of lymphomas that were not assigned to a subtype. Similar to BCP-ALL, the most frequent subtypes of BCP-LBL were high hyperdiploidy and ETV6::RUNX1. Tyrosine kinase/cytokine-receptor rearrangements were detected in 7% of BCP-LBL. These results indicate that genetic subtypes can be identified in BCP-LBL using next-generation sequencing, even on FFPE tissue, and may be relevant to guide treatment.

The HGF/Met Receptor Mediates Cytotoxic Effect of Bacterial Cyclodipeptides in Human Cervical Cancer Cells.

BACKGROUND: Human cervix adenocarcinoma (CC) caused by papillomavirus is the third most common cancer among female malignant tumors. Bioactive compounds such as cyclodipeptides (CDPs) possess cytotoxic effects in human cervical cancer HeLa cells mainly by blocking the PI3K/Akt/mTOR pathway and subsequently inducing gene expression by countless transcription regulators. However, the upstream elements of signaling pathways have not been well studied. METHODS: To elucidate the cytotoxic and antiproliferative responses of the HeLa cell line to CDPs by a transcriptomic analysis previously carried out, we identified by immunochemical analyses, differential expression of genes related to the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/MET) receptors. Furthermore, molecular docking was carried out to evaluate the interactions of CDPs with the EGF and MET substrate binding sites. RESULTS: Immunochemical and molecular docking analyses suggest that the HGF/MET receptor participation in CDPs cytotoxic effect was independent of the protein expression levels. However, protein modulation of downstream Met-targets occurred due to the inhibition of phosphorylation of the HGF/MET receptor. Results suggest that the antiproliferative and cytotoxicity of CDPs in HeLa cells involve the HGF/MET receptor upstream of PI3K/Akt/mTOR pathway; assays with the human breast cancer MCF-7 and MDA-MB-231cell lines supported the finding. CONCLUSION: Data provide new insights into the molecular mechanisms involved in CDPs cytotoxicity and antiproliferative effects, suggesting that the signal transduction mechanism may be related to the inhibition of the phosphorylation of the EGF/MET receptor at the level of substrate binding site by an inhibition mechanism similar to that of Gefitinib and foretinib anti-neoplastic drugs.

Open RT Structures: A Solution for TG-263 Accessibility.

PURPOSE: Consistency of nomenclature within radiation oncology is increasingly important as big data efforts and data sharing become more feasible. Automation of radiation oncology workflows depends on standardized contour nomenclature that enables toxicity and outcomes research, while also reducing medical errors and facilitating quality improvement activities. Recommendations for standardized nomenclature have been published in the American Association of Physicists in Medicine (AAPM) report from Task Group 263 (TG-263). Transitioning to TG-263 requires creation and management of structure template libraries and retraining of staff, which can be a considerable burden on clinical resources. Our aim is to develop a program that allows users to create TG-263-compliant structure templates in English, Spanish, or French to facilitate data sharing. METHODS AND MATERIALS: Fifty-three premade structure templates were arranged by treated organ based on an American Society for Radiation Oncology (ASTRO) consensus paper. Templates were further customized with common target structures, relevant organs at risk (OARs) (eg, spleen for anatomically relevant sites such as the gastroesophageal junction or stomach), subsite- specific templates (eg, partial breast, whole breast, intact prostate, postoperative prostate, etc) and brachytherapy templates. An informal consensus on OAR and target coloration was also achieved, although color selections are fully customizable within the program. RESULTS: The resulting program is usable on any Windows system and generates template files in practice-specific Digital Imaging and Communications In Medicine (DICOM) or XML formats, extracting standardized structure nomenclature from an online database maintained by members of the TG-263U1, which ensures continuous access to up-to-date templates. CONCLUSIONS: We have developed a tool to easily create and name DICOM radiation therapy (DICOM-RT) structures sets that are TG-263-compliant for all planning systems using the DICOM standard. The program and source code are publicly available via GitHub to encourage feedback from community users for improvement and guide further development.

Association between bacterial resistance profile and the development of intra-abdominal abscesses in pediatric patients with perforated appendicitis: cohort study.

PURPOSE: The objective of this study was to determine the association between the presence of a microorganism resistant to the antibiotic used in empirical therapy and the development of intra-abdominal abscesses in children with perforated appendicitis. METHODS: A prospective cohort study was conducted in patients under 18 years of age who underwent laparoscopic appendectomy between November 1, 2019, and September 30, 2020, in whom perforated appendicitis was documented intraoperatively. Peritoneal fluid samples were taken for bacteria culture purposes, and clinical and microbiological data were collected from all patients. RESULTS: A total of 232 patients were included in the study. The most isolated microorganisms were Escherichia coli (80.14%) and Pseudomonas aeruginosa (7.45%). In addition, 5.31% of E. coli isolates were classified as ESBL-producing organisms. No association was found between a germ resistant to empiric antimicrobial therapy and the development of a postoperative intra-abdominal abscess. Multivariate analysis showed that being a high-risk patient on admission (OR 2.89 (p = 0.01)) was associated with the development of intra-abdominal abscesses postoperatively. CONCLUSION: E. coli was the most commonly isolated microorganism, with a low rate of ESBL-producing isolates. No association between resistance and risk of postoperative intra-abdominal abscess was found. However, it was identified that being a high-risk patient on admission was associated with this complication. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level I.

Rheology of liquid foods under shear flow conditions: Recently used models.

Proper modeling of flow or viscosity curves as a function of shear rate is a useful tool in any engineering activity. The rheology of foods depends on the composition, processing to which they have been subjected and the state of dispersion in which they are found. Liquid foods are complex biosystems, that show non-Newtonian behavior under flow conditions. This review presents models used in recent decades to describe the experimental rheological behavior of various liquid foods, ranging from Newtonian fluids to the most complex. Some non-Newtonian parameters such as those of the Ostwald-de Waele, Bingham, Herschel-Bulkley, Casson, Cross, and Carreau models are summarized. Examples of thixotropic behavior described by the Weltman and Abu-Jdayil models are also presented. In each model, explanations based on the composition and dispersion state of the food are made. This is useful in innovative processing technologies and for scientists new to the field of food rheology. An attempt is made to exemplify and group the expected behavior for most fluid foods, including some for a dysphagia diet, depending on their composition or the dispersed system formed, which will be useful for professionals who wish to compare reported rheological parameters with those obtained experimentally.

18 F-FDG-PET/CT imaging in diagnostic workup of pediatric precursor B-cell lymphoblastic lymphoma.

18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) imaging is currently not used in standard diagnostics for B-cell precursor lymphoblastic lymphoma (BCP-LBL), and it is unknown whether PET/CT imaging would lead to agreement between detection of lesions with the gold standard imaging methods. Therefore, we performed a retrospective cohort study in which we included 32 pediatric BCP-LBL patients and determined localizations by reviewing local imaging reports. There was a disagreement between protocol-based imaging and PET/CT in 59% of the patients, and the discrepancies mostly comprise of additional lesions detected with PET/CT, typically in lymph node and bone or the absence of bone marrow involvement with PET/CT. If PET/CT was leading in determining definite stage of disease, this would lead to a different stage and therapy branch in 31% and 28% of the patients, respectively.

RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer.

Epithelial/Mesenchymal (E/M) plasticity plays a fundamental role both in embryogenesis and during tumorigenesis. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL1. Besides, we uncover a crosstalk mechanism between the TGF-ß and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Next, since RAGE is a sensor of the tumor microenvironment, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL1 levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in E/M plasticity. These results uncover new molecular insights on the regulation of E/M phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.

Local, systemic and immunologic safety comparison between xenogeneic equine umbilical cord mesenchymal stem cells, allogeneic canine adipose mesenchymal stem cells and placebo: a randomized controlled trial.

Mesenchymal stem cells are multipotent cells with a wide range of therapeutic applications, including, among others, tissue regeneration. This work aims to test the safety (EUC-MSC) of intra-articular administration of equine umbilical cord mesenchymal stem cells in young healthy dogs under field conditions following single and repeated administration. This was compared with the safety profile of allogenic canine adipose derived mesenchymal stem cells (CAD-MSC) and placebo in order to define the safety of xenogeneic use of mesenchymal stem cells when administered intra-articular. Twenty-four police working dogs were randomized in three groups in a proportion 1:1:1. EUC-MSCs and CAD-MSCs were obtained from healthy donors and were manufactured following company SOPs and under GMP and GMP-like conditions, respectively, and compliant all necessary controls to ensure the quality of the treatment. The safety of the treatment was evaluated locally, systemically and immunologically. For this purpose, an orthopedic examination and Glasgow test for the assessment of pain in the infiltrated joint, blood tests, clinical examination and analysis of the humoral and cellular response to treatment were performed. No adverse events were detected following single and repeated MSC administration despite both equine and canine MSC generate antibody titres in the dogs. The intra-articular administration of equine umbilical cord mesenchymal stem cells in dogs has demonstrated to be safe.

Single incision laparoscopic appendectomy with surgical-glove port is cost-effective and reliable in complicated acute appendicitis: A casecontrol multicenter study in Colombia.

Background: The single-port (SPL) and multi-port (MPL) laparoscopic approach are the gold standard of management of acute appendicitis, due to its multiple advantages over open surgery, mainly because of its direct effects on recovery, esthetics and costs of the procedure. However, in third-world countries, the laparoscopic approach is not yet fully reproducible due to the costs of the technique. The surgical-glove port single incision laparoscopic appendectomy (SGP-SILA) has been proposed as a viable option. However, it has never been studied in Colombia. Objective: To evaluate the cost-effectiveness and reliability of SGP-SILA in the management of complicated acute appendicitis, compared to traditional MPL approach. Materials and methods: A retrospective case control study was carried out comparing patients undergoing laparoscopic appendectomy by SGP-SILA vs. MPL, evaluating operating costs associated with intraoperative and postoperative variables in two tertiary centers in Bogota, Colombia. The data were analyzed and expressed according to their nature and distribution. Results: 116 patients were included (SGP-SILA: 62 and MPL: 54). The median surgical time for SGP-SILA was 60 min vs. 39 min for MPL. SGP-SILA was shown to cause lower frequency of surgical site infection (4 vs. 8 patients; p = 0.047). It was found a significant correlation between Grade III surgical site infection and surgery time (p = 0.047) in the MPL group; also, with hospital stay (p < 0.001). Also, a lower risk of surgical site infection was found with the SGP-SILA technique (22% vs. 31%). SGP-SILA generated a reduction in both direct and indirect operating costs of approximately 10% (616 USD vs. 683 USD). Conclusion: SGP-SILA and MPL are feasible and comparable procedures in the resolution of complicated acute appendicitis. SGP-SILA turns out to be more cost-effective compared to MPL, due to the use of more easily accessible instruments. This may be a reproducible technique in low- and middle-income countries.

Sex and age variations in the impact of puberty on cortical thickness and associations with internalizing symptoms and suicidal ideation in early adolescence.

PURPOSE: The childhood-to-adolescence transition is a notable period of change including pubertal development, neurodevelopment, and psychopathology onset, that occurs in divergent patterns between sexes. This study examined the effects of sex and puberty on cortical thickness (CT) in children and explored whether CT changes over time related to emergence of psychopathology in early adolescence. METHODS: We used longitudinal data (baseline ages 9-10 and Year 2 [Y2] ages 11-12) from the ABCD Study (n = 9985). Linear and penalized function-on-function regressions modeled the impact of puberty, as it interacts with sex, on CT. Focusing on regions that showed sex differences, linear and logistic regressions modeled associations between change in CT and internalizing problems and suicide ideation. RESULTS: We identified significant sex differences in the inverse relation between puberty and CT in fifteen primarily posterior brain regions. Nonlinear pubertal effects across age were identified in the fusiform, isthmus cingulate, paracentral, and precuneus. All effects were stronger for females relative to males during this developmental window. We did not identify associations between CT change and early adolescent clinical outcomes. CONCLUSION: During this age range, puberty is most strongly associated with regional changes in CT in females, which may have implications for the later emergence of psychopathology.

Brodalumab: Efficacy, safety, and survival in mid-term (52 weeks) on real clinical practice in Andalucia, Spain.

INTRODUCTION: Brodalumab is a recombinant monoclonal antibody (IgG2) that binds with high affinity to the human interleukin-17 (IL-17) receptor A and blocks the biological activity of the proinflammatory cytokines IL-17A, IL-17F, IL-17A/F heterodimer, and IL- 25, resulting in inhibition of inflammation and clinical symptoms associated with psoriasis. Its introduction has managed to increase the levels of efficacy, safety (improving that previously presented by the anti-IL-17 class), and survival. MATERIAL AND METHODS: Retrospective analysis of a multicenter, observational study of real clinical practice including patients with moderate to severe plaque psoriasis in treatment with brodalumab. This cross-sectional analysis includes information of patients between February 2019 and February 2022. A total of five tertiary hospitals in Andalusia (Spain) participated in this study. Analyses were performed "as observed" using GraphPad Prism version 8.3.0 for Windows. RESULTS: Our study included 85 patients, 54 men (63.5%) and 31 women (36.5%), with moderate-severe psoriasis treated with brodalumab. In order to evaluate the efficacy of brodalumab, our patients started with mean Psoriasis Area and Severity Index (PASI) values of 12.8 and body surface area (BSA) of 16.9, as well as a Dermatology Life Quality Index (DLQI) of 15.6, highlighting that they reported that the mean baseline visual analog scale (VAS) pruritus was 6.15. On week 52, mean PASI reached 1.26 and mean BSA 2.3, showing a clear stabilization and even sustained improvement regarding results on week 12. Concerning the brodalumab survival, we obtained 85.8% persistence at week 52. DISCUSSION: Brodalumab showed excellent results in the control of psoriasis in the mid-term with an elevated number of patients maintaining treatment after 52 weeks. There were no statistically significant differences in the efficiency, safety, or survival results of brodalumab between patients coming from previous therapies.

Predicting mortality in penetrating cardiac trauma in developing countries through a new classification: Validation of the Bogotá classification.

Introduction: Penetrating chest trauma (PCT) represents 10% of worldwide mortality, with developing countries counting as some of the most affected by high mortality rates due to cardiac trauma. Colombia is considered one of the most violent countries due to the high mortality rate associated with war and crime, hence the validation of an own classification for penetrating cardiac injuries (PCI) is mandatory. Methods: Retrospective cross-sectional study which included adult patients with PCIs at a level 4 trauma center in Colombia, between January 2018 and April 2020. We used our own system (Bogotá Classification) and compared it with traditional systems (e.g., Ivatury's, OIS-AAST), by analyzing the mechanism of injury (MOI), the hemodynamic status of the patient at admission, the inpatient management, the individual outcomes, and some demographic variables. Bivariate statistical analysis, spearman correlation, and logistic regression were performed. Results: Four hundred and ninety-nine patients were included. Bivariate analysis demonstrated a significant relationship between mortality and hemodynamic state, MOI, its location and degree of lesion, cardiac/vessel injury, cardiac tamponade, time between injury and medical care, fluid reanimation, as well as the Ivatury's classification and the new classification (p < 0.005). The adequate correlation between Ivatury's and Bogotá classification supports the latter's clinical utility for patients presenting with PCI. Likewise, logistic regression showed a statistically significant association among mortality rates (p < 0.005). Conclusions: The Bogotá classification showed similar performance to the Ivatury's classification, correlating most strongly with mortality. This scale could be replicated in countries with similar social and economic contexts.

Training for the future: Introducing foundational skills necessary to promote patient-centered care practice in medical physics graduate programs.

Current medical physics graduate training in the United States seldom explicitly includes education on foundational skills necessary to produce Patient-Centered Care (PCC)-focused healthcare providers. Such abilities include effective communication, critical reflection, and ethical decision-making. In this article, we present examples of curricula used to purposefully introduce these skills into graduate training to fill this gap. Presented didactic activities include an introduction to patient communication, ethics in medical physics, and a primer in health disparities for medical physicists. Although development of new curricula is resource-intensive when left to individual programs, we here propose resource-sharing and interprofessional collaboration to overcome these barriers.

Novel application of ultrasound and microwave-assisted methods for aqueous extraction of coconut oil and proteins.

Alternative methods for wet extraction of coconut oil and protein assisted by ultrasound or microwave were developed and compared. Coconut milk was prepared by milling the pulp (5:1 water to coconut pulp ratio), further destabilised at pH 4 and centrifuged to obtain the cream and cream protein fractions (control process). Microwave-assisted treatment applied in milk (1 min, 3 pulses of 20 s; 2.5 GHz; 4.31 kW/kg by pulse) generated a significant increase in cream obtained, and in the coconut oil extraction yield (~ 20%) compared to its control. The ultrasound-assisted treatment (2.5 min; 24 kHz; 0.573 kW/kg, 6.85 W/cm2) also improved oil extraction (10-16%). Moreover, a higher protein yield was achieved in ultrasound treated samples when compared to their control (49.6-86.1%). Large particles of 11 m µ , probably aggregates of particles, and smaller particles of 3.6 m µ , were detected in coconut milk, which were reduced by ultrasound effect. Alternative treatments caused a greater liberation of total phenols in coconut cream. Coconut proteins in water (0.1%) showed high negative electrokinetic potential. The surface pressure of coconut proteins at the air/water interface was not modified by assisted treatments.

Pediatric Precursor B-Cell Lymphoblastic Malignancies: From Extramedullary to Medullary Involvement.

B-cell lymphoblastic lymphoma (BCP-LBL) and B-cell acute lymphoblastic leukemia (BCP-ALL) are the malignant counterparts of immature B-cells. BCP-ALL is the most common hematological malignancy in childhood, while BCP-LBL accounts for only 1% of all hematological malignancies in children. Therefore, BCP-ALL has been well studied and treatment protocols have changed over the last decades, whereas treatment for BCP-LBL has stayed roughly the same. Clinical characteristics of 364 pediatric patients with precursor B-cell malignancies were studied, consisting of BCP-LBL (n = 210) and BCP-ALL (n = 154) patients. Our results indicate that based on the clinical presentation of disease, B-cell malignancies probably represent a spectrum ranging from complete isolated medullary disease to apparent complete extramedullary disease. Hepatosplenomegaly and peripheral blood involvement are the most important discriminators, as both seen in 80% and 95% of the BCP-ALL patients and in 2% of the BCP-LBL patients, respectively. In addition, we show that the overall survival rates in this cohort differ significantly between BCP-LBL and BCP-ALL patients aged 1−18 years (p = 0.0080), and that the outcome for infants (0−1 years) with BCP-LBL is significantly decreased compared to BCP-LBL patients of all other pediatric ages (p < 0.0001).

Laparoendoscopic surgery for the treatment of gastrointestinal stromal tumors: A case series.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The standard management for localized GIST is the complete surgical resection. For this procedure, laparoendoscopic cooperative surgery (LECS) has been proposed as a safe and effective alternative. We want to show our experience with LECS technique for the management of GIST and a literature review. MATERIALS AND METHODS: A retrospective, cross-sectional study was carried out, which included patients with a diagnosis of localized GIST treated with LECS technique between January 2011 and December 2018. RESULTS: During the period of the study, 21 patients were managed by LECS technique, with a male-female rate 3:1. Average surgical time was 98.5 min, 100% negative borders in all patients. Intraoperative bleeding was 30.7 cc and all patients had orally tolerance in the first 24 h. None of them required ICU management, no mortality was reported. CONCLUSIONS: The LECS technique has demonstrated to be a viable, safe, and effective technique for the management of gastric GIST's, showing superiority in organ function preservation and in the range of oncological margins. Prospective studies are necessary to obtain knowledge about the outcome of patients managed through LECS technique.

INTRODUCCIÓN: Los tumores del estroma gastrointestinal (GIST) son las neoplasias mesenquimales más comunes del tracto gastrointestinal. El tratamiento estándar para los GIST localizados es la resección quirúrgica completa. Para este procedimiento, el abordaje cooperativo laparo-endocopico (ACLE) se ha propuesto como una alternativa segura y eficaz. Queremos mostrar nuestra experiencia con la técnica ACLE para el manejo de GIST y unzaa revisión de la literatura. MATERIAL Y MÉTODOS: Se realizó un estudio retrospectivo, transversal, que incluyó pacientes con diagnóstico de GIST localizado tratados con la técnica ACLE entre enero de 2011 y diciembre de 2018. RESULTADOS: Durante el periodo de estudio se manejaron 21 pacientes con técnica de ACLE, con una tasa hombre-mujer de 3:1. El tiempo quirúrgico promedio fue de 98.5 min, con 100% de bordes negativos en todos los pacientes. El sangrado intraoperatorio fue de 30.7 cc y todos los pacientes tuvieron tolerancia oral en las primeras 24H. Ninguno de ellos requirió manejo en UCI, no se reportó mortalidad. CONCLUSIONES: La técnica ACLE ha demostrado ser una técnica viable, segura y eficaz para el manejo de los GIST gástricos. Mostrando superioridad en la preservación de la función orgánica y en los magines oncológicos. Son necesarios estudios prospectivos para conocer el resultado de los pacientes manejados mediante la técnica ACLE.

Effect of agave fructans on xanthan rheology: Impact on sodium caseinate emulsion properties.

The influence of agave fructans (AF) (1-10%) and xanthan (from 0.03% to 0.25%) in combination with sodium caseinate (SC) at 1% on the rheological and physicochemical properties of aqueous phases and emulsions was evaluated. Steady-state flow behavior, particle size distribution, and stability studies were used to characterize the systems. The aqueous systems displayed the shear-thinning behavior characteristic of xanthan solutions; however, this behavior was modified by the presence of SC and AF due to interactions between AF-SC and AF-xanthan based on predominant hydrogen bonding because of the hydroxyl groups on AF. In emulsions, an increase in viscosity due to the effect of the AF concentration reflects a probable association of fructan aggregates on the surface of SC particles that reinforce the interfacial layer of SC, while xanthan contributes to an increase in the viscosity of the continuous phase, which effectively prevents coalescence and floc formation even at higher concentrations, despite the possible existence of a depletion flocculation effect attenuated by the interaction between AF-SC and AF-xanthan. PRACTICAL APPLICATION: These results can be of use, in an important way, in the design of stable functional emulsions in which there is an application for agave fructans recognized as dietary fiber, also considering their peculiar way of interacting with xanthan favoring its stabilizing functionality.