bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Aging on the Dry Shrinkage Cracking of Lime Soils with Different Proportions
Authors: Yue Jianwei , Chen Ying , Zhao Limin , Wang Siyuan , Su Huicong , Yang Xue , Gao Huijie , Zhang Yiang , Li Wenhao
Published: December 2021

In this study, the reasonable aging time of lime soils with different ratios was determined to investigate the effect of aging on the internal mechanism of the dry shrinkage cracking of lime soil. To this end, the effects of aging time, lime content, and particle size on the volume crack rate, expansion and shrinkage rate, particle size distribution, and pH were analyzed using a dry–wet cycle, screening, and pH tests. In addition, the changes in the particle structure of the samples and the formation of new substances were analyzed. The results revealed that the volume crack and expansion shrinkage rates of the sample initially decreased, and then stabilized with increasing aging time. In addition, the aging time of the sample increased with increasing lime content and particle size. Further, at the initial aging stage, the volume crack and expansion/shrinkage rates of the sample increased with increasing lime content and particle size. With an increase in the aging time, the pH increased and then decreased significantly to 0.57–1.1% at the reasonable aging time. These indicate that the pH exhibited a significant effect on the reasonable aging time, and this will provide useful insights for the restoration of lime soil sites.
Determination of PM1 Sources at a Prague Background Site during the 2012–2013 Period Using PMF Analysis of Combined Aerosol Mass Spectra
Authors: Makeš Otakar , Schwarz Jaroslav , Vodička Petr , Engling Guenter , Ždímal Vladimír
Published: December 2021

Two intensive measurement campaigns using a compact time-of-flight aerosol mass spectrometer were carried out at the suburban site in Prague (Czech Republic) in summer (2012) and winter (2013). The aim was to determine the aerosol sources of the NR-PM1 fraction by PMF analysis of organic (OA) and inorganic aerosol mass spectra. Firstly, an analysis of the OA mass spectra was performed. Hydrocarbon-like OA (HOA), biomass burning OA (BBOA), and two types of oxygenated OA (OOA1) and (OOA2) were identified in summer. In winter, HOA, BBOA, long-range oxygenated OA (LROOA), and local oxygenated OA (LOOA) were determined. The identified HOA and BBOA factors were then used as additional input for the subsequent ME-2 analysis of the combined organic and inorganic spectra. This analysis resulted in six factors in both seasons. All of the previously reported organic factors were reidentified and expanded with the inorganic part of the spectra in both seasons. Two predominantly inorganic factors ammonium sulphate (AMOS) and ammonium nitrate (AMON) were newly identified in both seasons. Despite very similar organic parts of the mass profiles, the daily cycles of HOA and LOOA differed significantly in winter. It appears that the addition of the inorganic part of the mass profile, in some cases, reduces the ability of the model to identify physically meaningful factors.
MORG1—A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes
Authors: Jankowski Eric , Wulf Sophie , Ziller Nadja , Wolf Gunter , Loeffler Ivonne
Published: December 2021

Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model. Renal TGF-ß1 expression and EMT-like changes were reduced in mice with single-allele deficiency of MORG1. Given the well-known role of HIF and ERK signaling in metabolic regulation, here we examined whether protection was also associated with a restoration of lipid metabolism. Despite similar features of TIF in T1DM and T2DM, diabetes-associated changes in renal lipid metabolism differ between both diseases. We found that de novo synthesis of FA/cholesterol and β-oxidation were more strongly disrupted in T1DM, whereas pathological fat uptake into tubular cells mediates lipotoxicity in T2DM. Thus, diminished MORG1 expression exerts renoprotection in the diabetic nephropathy by modulating important factors of TIF and lipid dysregulation to a variable extent in T1DM and T2DM. Prospectively, targeting MORG1 appears to be a promising strategy to reduce lipid metabolic alterations in diabetic nephropathy.
Dysfunctional Learning and Verbal Memory in Patients with Elevated Tau Protein Levels and Serum Recoverin Autoantibodies—Case Series and Review
Authors: Hansen Niels , Bartels Claudia , Rentzsch Kristin , Stöcker Winfried , Fitzner Dirk
Published: December 2021

Recoverin-antibody-related disease is currently restricted to late-onset ataxia and autoimmune retinopathy, which can be paraneoplastic or not. However, cognitive dysfunction associated with recoverin antibodies has not been reported so far in a homogeneous patient group. Our case series is dedicated to describing the novel phenotype of cognitive impairment associated with recoverin antibodies. We included five patients with cognitive impairment who presented serum recoverin autoantibodies detected by immunoblots in our case series investigation. We also analyzed their psychopathology, clinical data, cerebrospinal fluid (CSF), and neuroimaging data. Five patients with cognitive impairment associated with serum recoverin antibodies exhibited profound dysfunctional learning and verbal memory. In the CSF of 40% of them, we also diagnosed axonal neurodegeneration entailing elevated tau and phosphorylated tau protein levels. Psychopathologies such as affective symptoms (restlessness, depressive mood, anxiety, complaintiveness) and formal thought disorder, such as rumination, were detected in 25–75% of the patients. We hypothesized a role of recoverin autoimmunity in the pineal gland involving consecutive modulation of hippocampus-based memory caused by an altered release of melatonin. We describe a novel phenotype of possible recoverin autoimmunity in patients with cognitive impairment. However, no clear diagnostic clues can be extracted because of the low diagnostic validity of the testing strategies applied. The possibility of recoverin antibody autoimmunity in the pineal gland correlating with a modulation of hippocampus-based memory should be further investigated.
Regional Topological Aberrances of White Matter- and Gray Matter-Based Functional Networks for Attention Processing May Foster Traumatic Brain Injury-Related Attention Deficits in Adults
Authors: Wu Ziyan , Cao Meng , Di Xin , Wu Kai , Gao Yu , Li Xiaobo
Published: December 2021

Traumatic brain injury (TBI) is highly prevalent in adults. TBI-related functional brain alterations have been linked with common post-TBI neurobehavioral sequelae, with unknown neural substrates. This study examined the systems-level functional brain alterations in white matter (WM) and gray matter (GM) for visual sustained-attention processing, and their interactions and contributions to post-TBI attention deficits. Task-based functional MRI data were collected from 42 adults with TBI and 43 group-matched normal controls (NCs), and analyzed using the graph theoretic technique. Global and nodal topological properties were calculated and compared between the two groups. Correlation analyses were conducted between the neuroimaging measures that showed significant between-group differences and the behavioral symptom measures in attention domain in the groups of TBI and NCs, respectively. Significantly altered nodal efficiencies and/or degrees in several WM and GM nodes were reported in the TBI group, including the posterior corona radiata (PCR), posterior thalamic radiation (PTR), postcentral gyrus (PoG), and superior temporal sulcus (STS). Subjects with TBI also demonstrated abnormal systems-level functional synchronization between the PTR and STS in the right hemisphere, hypo-interaction between the PCR and PoG in the left hemisphere, as well as the involvement of systems-level functional aberrances in the PCR in TBI-related behavioral impairments in the attention domain. The findings of the current study suggest that TBI-related systems-level functional alterations associated with these two major-association WM tracts, and their anatomically connected GM regions may play critical role in TBI-related behavioral deficits in attention domains.
Quantification of Moment–Rotation Relationship of Monolithic Precast Beam–Column Connections
Authors: Song Baoxi , Xu Weizhi , Du Dongsheng , Wang Shuguang
Published: December 2021

The accurate prediction of nonlinear structural behaviors under different seismic intensities is an important basis for seismic resilience assessments of building structures. The moment–rotation relationship is often used to characterize the seismic performance of connections, and is widely used in high-efficiency nonlinear structural analysis. In this paper, a method of calculating the curve using a four-linear equivalent model is presented, aiming to quantify the characteristic point parameters of the moment–rotation curves of monolithic precast beam–column (MPBC) connections for engineering design purposes. The method considered the contribution of the elastic flexure of beams and columns, the relative slip of beam longitudinal bars in the core zone, and the formation of plastic hinges at beam ends to the total deflection. Due to the presence of local complex configurations in MPBC connections, the fine fiber section method was used for moment–curvature analysis of critical beam sections. The determination of the sectional analysis processes was controlled by the strain of steel bars or concrete or their coupling effect. In addition, a two-step method was proposed to construct the moment–rotation relationship of cruciform beam–column connections for solving the deformation compatibility of beams on both sides of the column caused by asymmetric reinforcement and the strength difference between new and old concrete. To reflect the current manufacturing level of MPBC connections, 58 representative specimens reported in recent years were analyzed and classified as type 1–5. All types of MPBC connections and their 18 cast-in situ counterparts were calculated using the proposed method for both verification and quantification. The verification showed that the proposed method had good applicability to both cast-in situ and precast beam–column connections. The quantification showed that the characteristic point parameters were slightly different between these two connections. Accordingly, modification coefficients were suggested for MPBC connections to facilitate design.
HDAC Inhibition to Prime Immune Checkpoint Inhibitors
Authors: Borcoman Edith , Kamal Maud , Marret Grégoire , Dupain Celia , Castel-Ajgal Zahra , Le Tourneau Christophe
Published: December 2021

Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with refractory disease. However only a minority of patients experience a durable response with these agents, which has led to the development of combination strategies and novel immunotherapy drugs to further counteract tumor immune escape. Epigenetic regulations can be altered in oncogenesis, favoring tumor progression. The development of epidrugs has allowed targeting successfully these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently shown that epigenetic alterations can also play a key role in tumor immune escape. Epidrugs, like HDAC inhibitors, can prime the anti-tumor immune response, therefore constituting interesting partners to develop combination strategies with immunotherapy agents. In this review, we will discuss epigenetic regulations involved in oncogenesis and immune escape and describe the clinical development of combining HDAC inhibitors with immunotherapies.
Neoadjuvant Treatment Lowers the Risk of Mesopancreatic Fat Infiltration and Local Recurrence in Patients with Pancreatic Cancer
Authors: Safi Sami-Alexander , Haeberle Lena , Rehders Alexander , Fung Stephen , Vaghiri Sascha , Roderburg Christoph , Luedde Tom , Ziayee Farid , Esposito Irene , Fluegen Georg , Knoefel Wolfram Trudo
Published: December 2021

Background: Survival following surgical treatment of ductal adenocarcinoma of the pancreas (PDAC) remains poor. The recent implementation of the circumferential resection margin (CRM) into standard histopathological evaluation lead to a significant reduction in R0 rates. Mesopancreatic fat infiltration is present in ~80% of PDAC patients at the time of primary surgery and recently, mesopancreatic excision (MPE) was correlated to complete resection. To attain an even higher rate of R0(CRM−) resections in the future, neoadjuvant therapy in patients with a progressive disease seems a promising tool. We analyzed radiographic and histopathological treatment response and mesopancreatic tumor infiltration in patients who received neoadjuvant therapy prior to MPE. The aim of our study was to evaluate the need for MPE following neoadjuvant therapy and if multi-detector computed tomographically (MDCT) evaluated treatment response correlates with mesopancreatic (MP) infiltration. Method: Radiographic, clinicopathological and survival parameters of 27 consecutive patients who underwent neoadjuvant therapy prior to MPE were evaluated. The mesopancreatic fat tissue was histopathologically analyzed and the 1 mm-rule (CRM) was applied. Results: In the study collective, both the rate of R0 resection R0(CRM−) and the rate of mesopancreatic fat infiltration was 62.9%. Patients with MP infiltration showed a lower tumor response. Surgical resection status was dependent on MP infiltration and tumor response status. Patients with MDCT-predicted tumor response were less prone to MP infiltration. When compared to patients after upfront surgery, MP infiltration and local recurrence rate was significantly lower after neoadjuvant treatment. Conclusion: MPE remains warranted after neoadjuvant therapy. Mesopancreatic fat invasion was still evident in the majority of our patients following neoadjuvant treatment. MDCT-predicted tumor response did not exclude mesopancreatic fat infiltration.
Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study
Authors: Pusceddu Sara , Vernieri Claudio , Di Maio Massimo , Prinzi Natalie , Torchio Martina , Corti Francesca , Coppa Jorgelina , Buzzoni Roberto , Di Bartolomeo Maria , Milione Massimo , Regnault Benjamin , Truong Thanh Xuan-Mai , Mazzaferro Vincenzo , de Braud Filippo
Published: December 2021

The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM (p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM (p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS (p = 0.079); lanreotide was significantly associated with lower disease progression risk (p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.
Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma
Authors: Pagnuzzi-Boncompagni Marina , Picco Vincent , Vial Valérie , Planas-Bielsa Victor , Vandenberghe Ashaina , Daubon Thomas , Derieppe Marie-Alix , Montemagno Christopher , Durivault Jérôme , Grépin Renaud , Martial Sonia , Doyen Jérôme , Gavard Julie , Pagès Gilles
Published: December 2021

Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB patients. Our purpose was to evaluate the last-generation antiangiogenic drugs for their relevance in the therapeutic arsenal of MB. Methods: We screened three EMA- and FDA-approved antiangiogenic compounds (axitinib, cabozantinib and sunitinib) for their ability to reduce cell viability of five MB cell lines and their low toxicity towards two normal cell lines in vitro. Based on this screening, single-agent and combination therapies were designed for in vivo validation. Results: Axitinib, cabozantinib and sunitinib decreased viability of all the tested tumor cells. Although sunitinib was the most efficient in tumor cells, it also impacted normal cells. Therefore, axitinib showed the highest selectivity index for MB cells as compared to normal cells. The compound did not lead to acute toxicity in juvenile rats and crossed the blood–brain barrier. Moreover, axitinib efficiently reduced the growth rate of experimental brain tumors. Analysis of public databases showed that high expression of axitinib targets correlates with poor prognosis. Conclusion: Our results suggest that axitinib is a compelling candidate for MB treatment.
Combining Transarterial Radioembolization (TARE) and CT-Guided High-Dose-Rate Interstitial Brachytherapy (CT-HDRBT): A Retrospective Analysis of Advanced Primary and Secondary Liver Tumor Treatment
Authors: Fleckenstein Florian Nima , Roesel Maximilian Julius , Krajewska Maja , Auer Timo Alexander , Collettini Federico , Maleitzke Tazio , Böning Georg , Torsello Giovanni Federico , Fehrenbach Uli , Gebauer Bernhard
Published: December 2021

Purpose: Treatment of patients with primary and secondary liver tumors remains challenging. This study analyzes the efficacy and safety of transarterial radioembolization (TARE) combined with CT-guided high-dose-rate interstitial brachytherapy (CT-HDRBT) for the treatment of primary and secondary liver tumors. Patients and Methods: A total of 77 patients (30 female) with various liver malignancies were treated. Primary endpoints were median overall survival (OS) and time to untreatable progression (TTUP). Additionally, subgroup analyses were performed in consideration of diagnosis and procedure sequence. Median OS and TTUP prediction were estimated using Kaplan–Meier analysis and hazard ratios (HR) were calculated using a multivariate Cox proportional hazard model. Results: A total of 115 CT-HDRBT and 96 TARE procedures were performed with no significant complications recorded. Median OS and TTUP were 29.8 (95% CI 18.1–41.4) and 23.8 (95% CI 9.6–37.9) months. Median OS for hepatocellular carcinoma (HCC)-, cholangiocarcinoma carcinoma (CCA) and colorectal cancer (CRC) patients was 29.8, 29.6 and 34.4 months. Patients starting with TARE had a median OS of 26.0 (95% CI 14.5–37.5) compared to 33.7 (95% CI 21.6–45.8) months for patients starting with CT-HDRBT. Hazard ratio of 1.094 per month was shown for patients starting with CT-HDRBT. Conclusion: Combining TARE and CT-HDRBT is effective and safe for the treatment of advanced stage primary and secondary liver tumors. Our data indicate that early TARE during the disease progression may have a positive effect on survival.
Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography
Authors: Ruiz-López Eduardo , Calatayud-Pérez Juan , Castells-Yus Irene , Gimeno-Peribáñez María José , Mendoza-Calvo Noelia , Morcillo Miguel Ángel , Schuhmacher Alberto J.
Published: December 2021

Neuroimaging has transformed neuro-oncology and the way that glioblastoma is diagnosed and treated. Magnetic Resonance Imaging (MRI) is the most widely used non-invasive technique in the primary diagnosis of glioblastoma. Although MRI provides very powerful anatomical information, it has proven to be of limited value for diagnosing glioblastomas in some situations. The final diagnosis requires a brain biopsy that may not depict the high intratumoral heterogeneity present in this tumor type. The revolution in “cancer-omics” is transforming the molecular classification of gliomas. However, many of the clinically relevant alterations revealed by these studies have not yet been integrated into the clinical management of patients, in part due to the lack of non-invasive biomarker-based imaging tools. An innovative option for biomarker identification in vivo is termed “immunotargeted imaging”. By merging the high target specificity of antibodies with the high spatial resolution, sensitivity, and quantitative capabilities of positron emission tomography (PET), “Immuno-PET” allows us to conduct the non-invasive diagnosis and monitoring of patients over time using antibody-based probes as an in vivo, integrated, quantifiable, 3D, full-body “immunohistochemistry” in patients. This review provides the state of the art of immuno-PET applications and future perspectives on this imaging approach for glioblastoma.
Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential
Authors: Greco Giulia , Schnekenburger Michael , Catanzaro Elena , Turrini Eleonora , Ferrini Fabio , Sestili Piero , Diederich Marc , Fimognari Carmela
Published: December 2021

In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities.
Whole-Exome Sequencing of HPV Positive Tonsillar and Base of Tongue Squamous Cell Carcinomas Reveals a Global Mutational Pattern along with Relapse-Specific Somatic Variants
Authors: Ährlund-Richter Andreas , Holzhauser Stefan , Dalianis Tina , Näsman Anders , Mints Michael
Published: December 2021

To identify predictive/targetable markers in human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000–2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metastases) from these 17 patients. One variant—a high-impact deletion in the CDC27 gene—was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.
Single-Cells Isolation and Molecular Analysis: Focus on HER2-Low CTCs in Metastatic Breast Cancer
Authors: D’Amico Paolo , Reduzzi Carolina , Qiang Wenan , Zhang Youbin , Gerratana Lorenzo , Zhang Qiang , Davis Andrew A. , Shah Ami N. , Manai Maroua , Curigliano Giuseppe , Cristofanilli Massimo
Published: December 2021

Although the detection of CTCs expressing HER2 at low intensity (HER2-low CTCs) has been shown to have a negative prognostic value in metastatic breast cancer (MBC) patients, the biological intrinsic nature of HER2-low CTCs remains unexplored. Considering the technical challenges behind the selective collection of immunophenotype-specific CTCs, we developed a pipeline to individually capture HER2-low CTCs. Four different breast cancer cell lines (MDA-MB-231, T47D, MDA-MB-453, and SKBR3), that are known to express HER2 at different immunohistochemistry levels (respectively classified as 0, 1+, 2+, and 3+), were spiked in healthy donor blood tubes (7.5 mL) and processed with the CellSearch® (Menarini Silicon Biosystems, Bologna, Italy) for enrichment and the DEPArray NxT™ for single cell selection. The HER2 signal-intensities of each cell line was compared using the nonparametric Mann–Whitney U test. The optimal cut-offs to distinguish HER2 1+ from 0 and 2+ cells were calculated performing the Receiver operating characteristic (ROC) curve. Median HER2 signal-intensities detected with the DEPArray NxT™ were: 2.59 (0), 3.58 (1+), 5.23 (2+) and 38.37 (3+). DEPArray NxT efficiently differentiated each single cell line (p < 0.001). The area under the ROC curve was 0.69 and 0.70 (respectively 0 vs. 1+ and 1+ vs. 2+) and the optimal calculated cut-offs were 2.85 (lower) and 4.64 (upper). HER2-low CTCs can be detected and separately collected using predetermined intensity cut-offs. This study will allow standardized single-cell or pooled collection of HER2-low CTCs for downstream molecular analyses.
Novel Biomarkers and Druggable Targets in Advanced Melanoma
Authors: Ferrucci Pier Francesco , Cocorocchio Emilia
Published: December 2021

Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities.
Exercise and Childhood Cancer—A Historical Review
Authors: Morales Javier S. , Valenzuela Pedro L. , Velázquez-Díaz Daniel , Castillo-García Adrián , Jiménez-Pavón David , Lucia Alejandro , Fiuza-Luces Carmen
Published: December 2021

Childhood cancer survivors are at risk of developing important adverse effects, many of which persist for years after the end of treatment. The implementation of interventions aiming at attenuating tumor/treatment-associated adverse effects is therefore a major issue in pediatric oncology, and there is growing evidence that physical exercise could help in this regard. The present review aims to summarize the main milestones achieved in pediatric exercise oncology. For this purpose, we conducted a systematic review of relevant studies written in English in the electronic database PubMed (from inception to 14 August 2021). This review traces the field of pediatric exercise oncology throughout recent history based on three fundamental pillars: (i) exercise during childhood cancer treatment; (ii) exercise during/after hematopoietic stem cell transplantation; and (iii) exercise after childhood cancer treatment. Accumulating evidence––although still preliminary in many cases––supports the safety and potential benefits of regular exercise (with no major contraindications in general) in the childhood cancer continuum, even during the most aggressive phases of treatment. Exercise can indeed represent an effective coadjuvant therapy for attenuating cancer-related adverse effects.
FDA-Approved Drugs for Hematological Malignancies—The Last Decade Review
Authors: Sochacka-Ćwikła Aleksandra , Mączyński Marcin , Regiec Andrzej
Published: December 2021

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.
Aging Aggravates Cachexia in Tumor-Bearing Mice
Authors: Geppert Julia , Walth Alina , Terrón Expósito Raúl , Kaltenecker Doris , Morigny Pauline , Machado Juliano , Becker Maike , Simoes Estefania , Lima Joanna , Daniel Carolin , Berriel Diaz Mauricio , Herzig Stephan , Seelaender Marilia , Rohm Maria
Published: December 2021

Background: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models. Methods: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer. Results: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients. Conclusions: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.
Highly Enhanced Catalytic Stability of Copper by the Synergistic Effect of Porous Hierarchy and Alloying for Selective Hydrogenation Reaction
Authors: Yuan Hao , Wang Zhao , Jin Shunjing , Xiao Shanshan , Liu Siming , Hu Zhiyi , Chen Lihua , Su Baolian
Published: December 2021

Supported copper has a great potential for replacing the commercial palladium-based catalysts in the field of selective alkynes/alkadienes hydrogenation due to its excellent alkene selectivity and relatively high activity. However, fatally, it has a low catalytic stability owing to the rapid oligomerization of alkenes on the copper surface. In this study, 2.5 wt% Cu catalysts with various Cu:Zn ratios and supported on hierarchically porous alumina (HA) were designed and synthesized by deposition–precipitation with urea. Macropores (with diameters of 1 μm) and mesopores (with diameters of 3.5 nm) were introduced by the hydrolysis of metal alkoxides. After in situ activation at 350 °C, the catalytic stability of Cu was highly enhanced, with a limited effect on the catalytic activity and alkene selectivity. The time needed for losing 10% butadiene conversion for Cu1Zn3/HA was ~40 h, which is 20 times higher than that found for Cu/HA (~2 h), and 160 times higher than that found for Cu/bulky alumina (0.25 h). It was found that this type of enhancement in catalytic stability was mainly due to the rapid mass transportation in hierarchically porous structure (i.e., four times higher than that in bulky commercial alumina) and the well-dispersed copper active site modified by Zn, with identification by STEM–HAADF coupled with EDX. This study offers a universal way to optimize the catalytic stability of selective hydrogenation reactions.
TNFα Mediates Inflammation-Induced Effects on PPARG Splicing in Adipose Tissue and Mesenchymal Precursor Cells
Authors: Cataldi Simona , Aprile Marianna , Melillo Daniela , Mucel Inès , Giorgetti-Peraldi Sophie , Cormont Mireille , Italiani Paola , Blüher Matthias , Tanti Jean-François , Ciccodicola Alfredo , Costa Valerio
Published: December 2021

Low-grade chronic inflammation and reduced differentiation capacity are hallmarks of hypertrophic adipose tissue (AT) and key contributors of insulin resistance. We identified PPARGΔ5 as a dominant-negative splicing isoform overexpressed in the AT of obese/diabetic patients able to impair adipocyte differentiation and PPARγ activity in hypertrophic adipocytes. Herein, we investigate the impact of macrophage-secreted pro-inflammatory factors on PPARG splicing, focusing on PPARGΔ5. We report that the epididymal AT of LPS-treated mice displays increased PpargΔ5/cPparg ratio and reduced expression of Pparg-regulated genes. Interestingly, pro-inflammatory factors secreted from murine and human pro-inflammatory macrophages enhance the PPARGΔ5/cPPARG ratio in exposed adipogenic precursors. TNFα is identified herein as factor able to alter PPARG splicing—increasing PPARGΔ5/cPPARG ratio—through PI3K/Akt signaling and SRp40 splicing factor. In line with in vitro data, TNFA expression is higher in the SAT of obese (vs. lean) patients and positively correlates with PPARGΔ5 levels. In conclusion, our results indicate that inflammatory factors secreted by metabolically-activated macrophages are potent stimuli that modulate the expression and splicing of PPARG. The resulting imbalance between canonical and dominant negative isoforms may crucially contribute to impair PPARγ activity in hypertrophic AT, exacerbating the defective adipogenic capacity of precursor cells.
Extracellular Vesicles in Musculoskeletal Regeneration: Modulating the Therapy of the Future
Authors: Abreu Hugo , Canciani Elena , Raineri Davide , Cappellano Giuseppe , Rimondini Lia , Chiocchetti Annalisa
Published: December 2021

Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases.
Bmp Signal Gradient Modulates Convergent Cell Movement via Xarhgef3.2 during Gastrulation of Xenopus Embryos
Authors: Yoon Jaeho , Kumar Vijay , Goutam Ravi Shankar , Kim Sung-Chan , Park Soochul , Lee Unjoo , Kim Jaebong
Published: December 2021

Gastrulation is a critical step in the establishment of a basic body plan during development. Convergence and extension (CE) cell movements organize germ layers during gastrulation. Noncanonical Wnt signaling has been known as major signaling that regulates CE cell movement by activating Rho and Rac. In addition, Bmp molecules are expressed in the ventral side of a developing embryo, and the ventral mesoderm region undergoes minimal CE cell movement while the dorsal mesoderm undergoes dynamic cell movements. This suggests that Bmp signal gradient may affect CE cell movement. To investigate whether Bmp signaling negatively regulates CE cell movements, we performed microarray-based screening and found that the transcription of Xenopus Arhgef3.2 (Rho guanine nucleotide exchange factor) was negatively regulated by Bmp signaling. We also showed that overexpression or knockdown of Xarhgef3.2 caused gastrulation defects. Interestingly, Xarhgef3.2 controlled gastrulation cell movements through interacting with Disheveled (Dsh2) and Dsh2-associated activator of morphogenesis 1 (Daam1). Our results suggest that Bmp gradient affects gastrulation cell movement (CE) via negative regulation of Xarhgef3.2 expression.
Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease
Authors: Dietl Paul , Frick Manfred
Published: December 2021

The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.
A Novel Hyperactive Nud1 Mitotic Exit Network Scaffold Causes Spindle Position Checkpoint Bypass in Budding Yeast
Authors: Vannini Michael , Mingione Victoria R. , Meyer Ashleigh , Sniffen Courtney , Whalen Jenna , Seshan Anupama
Published: December 2021

Mitotic exit is a critical cell cycle transition that requires the careful coordination of nuclear positioning and cyclin B destruction in budding yeast for the maintenance of genome integrity. The mitotic exit network (MEN) is a Ras-like signal transduction pathway that promotes this process during anaphase. A crucial step in MEN activation occurs when the Dbf2-Mob1 protein kinase complex associates with the Nud1 scaffold protein at the yeast spindle pole bodies (SPBs; centrosome equivalents) and thereby becomes activated. This requires prior priming phosphorylation of Nud1 by Cdc15 at SPBs. Cdc15 activation, in turn, requires both the Tem1 GTPase and the Polo kinase Cdc5, but how Cdc15 associates with SPBs is not well understood. We have identified a hyperactive allele of NUD1, nud1-A308T, that recruits Cdc15 to SPBs in all stages of the cell cycle in a CDC5-independent manner. This allele leads to early recruitment of Dbf2-Mob1 during metaphase and requires known Cdc15 phospho-sites on Nud1. The presence of nud1-A308T leads to loss of coupling between nuclear position and mitotic exit in cells with mispositioned spindles. Our findings highlight the importance of scaffold regulation in signaling pathways to prevent improper activation.
Scope of Practice and Principles of Care of Naturopathic Medicine in North America: A Commentary
Authors: Solomonian Leslie
Published: December 2021

Naturopathic medicine is a growing profession in North America that provides expertise in complementary and alternative, or integrative care to pediatric patients. It is imperative that healthcare providers have an understanding of the training and scope of other health professionals in order to effectively make decisions regarding research, collaborative clinical care, and policy. Given the prevalence of use of complementary and alternative medicine by children and families in North America, and the growing interest in “integrative” medicine, we aim to offer an overview of naturopathic care for children. This document describes the principles, training, and scope of naturopathic medicine, including health promotion, disease prevention, and illness management. It describes the process by which naturopathic doctors create an integrative healthcare plan for children, evaluate and apply evidence, and integrate ethical issues in practice management, and speaks to the role naturopathic doctors have regarding advocacy for community and planetary health as it relates to pediatrics.
Water Repellency/Proof/Vapor Permeability Characteristics of Coated and Laminated Breathable Fabrics for Outdoor Clothing
Authors: Kim Hyun-Ah
Published: December 2021

This study examined the water repellency (WR), waterproof, and water vapor permeability (WVP) characteristics of twelve types of laminated and coated woven fabrics for outdoor clothing. These characteristics were compared with the fabric structural parameters, such as cover factor, thickness, and weight, and surface modification (finishing) factors, such as coating, laminating, and Teflon treatments. In addition, an eco-friendly process for surface modification was proposed followed by a summary. Superior waterproof-breathable characteristics with 100% water-repellency were achieved in specimen 3 in group A by treatment with a hydrophilic laminated finish using nylon woven fabric with a cover factor between 0.7 and 0.9 in a 2.5-layered fabric, which was the best specimen with waterproof-breathable characteristics. A high WVP in the coated and laminated fabrics was observed in the fabrics with a low weave density coefficient (WDC) and low thickness per unit weight of the fabric, whereas superior water repellency and waterproof characteristics were observed in the high-cover-factor (WDC) fabric with appropriate fabric thickness. The determination coefficient (R2) from regression analysis between the WVP and fabric structural parameters indicated a higher contribution of the fabric structural parameters than surface modification factors, such as coating and laminating to the WVP in the coated and laminated fabrics. Furthermore, the cover factor was the most important factor influencing the WVP of the waterproof-breathable fabrics. Of twelve coated and laminated fabrics, the laminated nylon and nylon/cotton composite fabrics showed superior WVP with high WR and waterproof characteristics. Accordingly, based on the WR, waterproof, and WVP characteristics of the coated and laminated breathable fabrics, the laminating method, as an eco-friendly process, is recommended to obtain better waterproof-breathable fabrics.
Study of Crack Sensitivity of Peritectic Steels
Authors: Liu Kai , Cheng Shusen , Li Yaqiang
Published: December 2021

By comprehensively considering both the high temperature mechanical properties and peritectic transformation during peritectic steel solidification, the strain εCth is proposed to evaluate the crack sensitivity of peritectic steels produced in the brittle temperature range in the present work. The zero ductility temperature (ZDT) and the zero strength temperature (ZST) of Fe–C–0.32Si–1.6Mn–0.01P–0.015S steel under nonequilibrium conditions by taking the effect of the peritectic transformation on the solute segregation into account were calculated by the CK microsegregation model (Clyne–Kurz model) and were compared with the measured data. The comparison results show that this model can well simulate the nonequilibrium solidification process of peritectic steel. Then, based on the calculation of the CK microsegregation model, the strain during the peritectic phase transformation in the brittle temperature range (ZDT < TB < LIT) was calculated under nonequilibrium conditions. The results show that the calculated strain is in good agreement with the actual statistical longitudinal crack data indicating that the strain can therefore be used to predict the crack sensitivity of peritectic steels effectively.