bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Associations Comprising Anti-PD-1/PD-L1 in Breast Cancer: Clinical Challenges and Perspectives
Authors: Ledys Fanny , Kalfeist Laura , Galland Loick , Limagne Emeric , Ladoire Sylvain
Published: November 2021

Despite a few cases of long-responder patients, immunotherapy with anti-PD-(L)1 has so far proved rather disappointing in monotherapy in metastatic breast cancer, prompting the use of synergistic therapeutic combinations incorporating immunotherapy by immune-checkpoint inhibitors. In addition, a better understanding of both the mechanisms of sensitivity and resistance to immunotherapy, as well as the immunological effects of the usual treatments for breast cancer, make it possible to rationally consider this type of therapeutic combination. For several years, certain treatments, commonly used to treat patients with breast cancer, have shown that in addition to their direct cytotoxic effects, they may have an impact on the tumor immune microenvironment, by increasing the antigenicity and/or immunogenicity of a “cold” tumor, targeting the immunosuppressive microenvironment or counteracting the immune-exclusion profile. This review focuses on preclinical immunologic synergic mechanisms of various standard therapeutic approaches with anti-PD-(L)1, and discusses the potential clinical use of anti-PD-1/L1 combinations in metastatic or early breast cancer.
Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)
Authors: Koch Katharina , Hartmann Rudolf , Suwala Abigail Kora , Rios Dayana Herrera , Kamp Marcel Alexander , Sabel Michael , Steiger Hans-Jakob , Willbold Dieter , Sharma Amit , Kahlert Ulf Dietrich , Maciaczyk Jarek
Published: November 2021

Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.
Clinical Studies on Cytokine-Induced Killer Cells: Lessons from Lymphoma Trials
Authors: Zhang Ying , Sharma Amit , Weiher Hans , Schmid Matthias , Kristiansen Glen , Schmidt-Wolf Ingo G. H.
Published: November 2021

Cancer is a complex disease where resistance to therapies and relapses often pose a serious clinical challenge. The scenario is even more complicated when the cancer type itself is heterogeneous in nature, e.g., lymphoma, a cancer of the lymphocytes which constitutes more than 70 different subtypes. Indeed, the treatment options continue to expand in lymphomas. Herein, we provide insights into lymphoma-specific clinical trials based on cytokine-induced killer (CIK) cell therapy and other pre-clinical lymphoma models where CIK cells have been used along with other synergetic tumor-targeting immune modules to improve their therapeutic potential. From a broader perspective, we will highlight that CIK cell therapy has potential, and in this rapidly evolving landscape of cancer therapies its optimization (as a personalized therapeutic approach) will be beneficial in lymphomas.
Complications and Discharge after Radical Cystectomy for Older Patients with Muscle-Invasive Bladder Cancer: The ELCAPA-27 Cohort Study
Authors: Geiss Romain , Sebaste Lucrezia , Valter Rémi , Poisson Johanne , Mebarki Soraya , Conti Catherine , Vordos Dimitri , Bringuier Michael , Méjean Arnaud , Mongiat-Artus Pierre , Cudennec Tristan , Canoui-Poitrine Florence , Caillet Philippe , Paillaud Elena
Published: November 2021

Radical cystectomy is the standard of care for localized bladder cancer but is associated with high morbidity and mortality rates—especially among older patients with comorbidities. The association between geriatric assessment parameters on post-operative complications and discharge has not previously been investigated. The present analysis of the Elderly Cancer Patient (ELCAPA) prospective cohort included all patients aged ≥70 having undergone a geriatric assessment and then radical cystectomy for localized muscle-invasive bladder cancer between 2007 and 2018. The primary endpoint was the proportion of patients with one or more complications in the first 30 days after cystectomy. The secondary endpoints were the length of hospital stay (LOS), the 30-day mortality, and discharge rates. Sixty-two patients (median age: 81; range: 79–83.8) were included. The 30-day complication rate was 73%, and 49% of the patients had experienced a major complication, according to the Clavien-Dindo classification. The 30-day mortality rate was 4%. None of the geriatric, oncological, or laboratory parameters were significantly associated with the occurrence or severity of complications. The median (interquartile range) LOS was 18 days (15–23) overall and was longer in patients with complications (19 days vs. 15 days in those without complications; p = 0.013). Thirty days after cystectomy, 25 patients (53%) had been discharged to home and 22 (47%) were still in a rehabilitation unit. In a univariate analysis, a Geriatric-8 score ≤ 14, a loss of one point on the Activities of Daily Living Scale, anemia, at least one grade ≥ 3 comorbidity on the Cumulative Illness Rating Scale-Geriatric, and an inpatient geriatric assessment were associated with a risk of not being discharged to home. In older patients having undergone a geriatric assessment, radical cystectomy is associated with a high complication rate, a longer LOS, and functional decline at 30 days.
Machine Learning Models That Integrate Tumor Texture and Perfusion Characteristics Using Low-Dose Breast Computed Tomography Are Promising for Predicting Histological Biomarkers and Treatment Failure in Breast Cancer Patients
Authors: Park Hyun-Soo , Lee Kwang-sig , Seo Bo-Kyoung , Kim Eun-Sil , Cho Kyu-Ran , Woo Ok-Hee , Song Sung-Eun , Lee Ji-Young , Cha Jaehyung
Published: November 2021

This prospective study enrolled 147 women with invasive breast cancer who underwent low-dose breast CT (80 kVp, 25 mAs, 1.01–1.38 mSv) before treatment. From each tumor, we extracted eight perfusion parameters using the maximum slope algorithm and 36 texture parameters using the filtered histogram technique. Relationships between CT parameters and histological factors were analyzed using five machine learning algorithms. Performance was compared using the area under the receiver-operating characteristic curve (AUC) with the DeLong test. The AUCs of the machine learning models increased when using both features instead of the perfusion or texture features alone. The random forest model that integrated texture and perfusion features was the best model for prediction (AUC = 0.76). In the integrated random forest model, the AUCs for predicting human epidermal growth factor receptor 2 positivity, estrogen receptor positivity, progesterone receptor positivity, ki67 positivity, high tumor grade, and molecular subtype were 0.86, 0.76, 0.69, 0.65, 0.75, and 0.79, respectively. Entropy of pre- and postcontrast images and perfusion, time to peak, and peak enhancement intensity of hot spots are the five most important CT parameters for prediction. In conclusion, machine learning using texture and perfusion characteristics of breast cancer with low-dose CT has potential value for predicting prognostic factors and risk stratification in breast cancer patients.
Role of Serum Free Light Chain Assay in Relapsed/Refractory Multiple Myeloma. A Real-Life Unicentric Retrospective Study
Authors: Markovic Uros , Romano Alessandra , Bellofiore Claudia , Condorelli Annalisa , Garibaldi Bruno , Bulla Anna , Duminuco Andrea , Del Fabro Vittorio , Di Raimondo Francesco , Conticello Concetta
Published: November 2021

Background: In the era of novel drugs a growing number of multiple myeloma (MM) patients are treated until disease progression. Serum free light chain (sFLC) assay is recommended for disease monitoring in oligo-secretory and micromolecular MM. Methods: In this real-life survey, a total of 130 relapsed/refractory MM patients treated at our center with at least three lines were investigated as a retrospective cohort. Results: The median age at diagnosis was 64 years and more than half of patients were male. A total of 24 patients (18%) had oligo-secretory/micromolecular disease at diagnosis. More than 20% of 106 normo-secretory patients had oligo-secretory/micromolecular escape. In order to evaluate potential role of sFLC assay before (“pre”) and after (“post”) every treatment line, involved serum free light chain values (iFLC) less than 138 mg/mL and serum free light chain ratios (FLCr) <25 were identified by using ROC curve analysis. The analysis of the entire cohort throughout four treatment lines demonstrated a statistically significant negative impact on progression-free survival (PFS) for both involved pre-sFLC and its ratio (respectively p = 0.0086 and p = 0.0065). Furthermore, both post-iFLC and post-FLCr greater than the pre-established values had a negative impact on PFS of the study cohort; respectively, p = 0.014 and p = 0.0079. Odds ratio analysis evidenced that patients with both involved post-sFLC greater than 138 mg/mL and post-FLCr above 25 at disease relapse had a higher probability of having clinical relapse (respectively p = 0.026 and p = 0.006). Conclusions: Alterations of sFLC values, namely iFLC and FLCr, both prior to treatment initiation and in the course of therapy at every treatment line, could be of aid in relapse evaluation and treatment outcome. We therefore suggest close periodical monitoring of sFLC assay, independently from secretory status.
Adapting Imaging Protocols for PET-CT and PET-MRI for Immunotherapy Monitoring
Authors: Beuthien-Baumann Bettina , Sachpekidis Christos , Gnirs Regula , Sedlaczek Oliver
Published: November 2021

Hybrid imaging with positron emission tomography (PET) in combination with computer tomography (CT) is a well-established diagnostic tool in oncological staging and restaging. The combination of PET with magnetic resonance imaging (MRI) as a clinical scanner was introduced approximately 10 years ago. Although MRI provides superb soft tissue contrast and functional information without the radiation exposure of CT, PET-MRI is not as widely introduced in oncologic imaging as PET-CT. One reason for this hesitancy lies in the relatively long acquisition times for a PET-MRI scan, if the full diagnostic potential of MRI is exploited. In this review, we discuss the possible advantages of combined imaging protocols of PET-CT and PET-MRI, within the context of staging and restaging of patients under immunotherapy, in order to achieve “multi-hybrid imaging” in one single patient visit.
Association of High-Intensity Exercise with Renal Medullary Carcinoma in Individuals with Sickle Cell Trait: Clinical Observations and Experimental Animal Studies
Authors: Shapiro Daniel D. , Soeung Melinda , Perelli Luigi , Dondossola Eleonora , Surasi Devaki Shilpa , Tripathi Durga N. , Bertocchio Jean-Philippe , Carbone Federica , Starbuck Michael W. , Van Alstine Michael L. , Rao Priya , Katz Matthew H. G. , Parker Nathan H. , Shah Amishi Y. , Carugo Alessandro , Heffernan Timothy P. , Schadler Keri L. , Logothetis Christopher , Walker Cheryl L. , Wood Christopher G. , Karam Jose A. , Draetta Giulio F. , Tannir Nizar M. , Genovese Giannicola , Msaouel Pavlos
Published: November 2021

Renal medullary carcinoma (RMC) is a lethal malignancy affecting individuals with sickle hemoglobinopathies. Currently, no modifiable risk factors are known. We aimed to determine whether high-intensity exercise is a risk factor for RMC in individuals with sickle cell trait (SCT). We used multiple approaches to triangulate our conclusion. First, a case-control study was conducted at a single tertiary-care facility. Consecutive patients with RMC were compared to matched controls with similarly advanced genitourinary malignancies in a 1:2 ratio and compared on rates of physical activity and anthropometric measures, including skeletal muscle surface area. Next, we compared the rate of military service among our RMC patients to a similarly aged population of black individuals with SCT in the U.S. Further, we used genetically engineered mouse models of SCT to study the impact of exercise on renal medullary hypoxia. Compared with matched controls, patients with RMC reported higher physical activity and had higher skeletal muscle surface area. A higher proportion of patients with RMC reported military service than expected compared to the similarly-aged population of black individuals with SCT. When exposed to high-intensity exercise, mice with SCT demonstrated significantly higher renal medulla hypoxia compared to wild-type controls. These data suggest high-intensity exercise is the first modifiable risk factor for RMC in individuals with SCT.
Floating Carbon-Doped TiO2 Photocatalyst with Metallic Underlayers Investigation for Polluted Water Treatment under Visible-Light Irradiation
Authors: Varnagiris Sarunas , Urbonavičius Marius , Sakalauskaitė Sandra , Demikyte Emilija , Tuckute Simona
Published: November 2021

In the current study, we analysed the influence of metallic underlayers on carbon-doped TiO2 films for RhB decomposition and Salmonella typhimurium inactivation under visible-light irradiation. All the experiments were divided into two parts. First, layered M/C-doped-TiO2 film structures (M = Ni, Nb, Cu) were prepared by magnetron sputtering technique on borosilicate glass substrates in the two-step deposition process. The influence of metal underlayer on the formation of the carbon-doped TiO2 films was characterised by X-ray diffractometer, scanning electron microscope, and atomic force microscope. The comparison between the visible-light assisted photocatalytic activity of M/C-doped TiO2 structures was performed by the photocatalytic bleaching tests of Rhodamine B dye aqueous solution. The best photocatalytic performance was observed for Ni/C-doped-TiO2 film combination. During the second part of the study, the Ni/C-doped-TiO2 film combination was deposited on high-density polyethylene beads which were selected as a floating substrate. The morphology and surface chemical analyses of the floating photocatalyst were performed. The viability and membrane permeability of Salmonella typhimurium were tested in cycling experiments under UV-B and visible-light irradiation. Three consecutive photocatalytic treatments of fresh bacteria suspensions with the same set of floating photocatalyst showed promising results, as after the third 1 h-long treatment bacteria viability was still reduced by 90% and 50% for UV-B and visible-light irradiation, respectively. The membrane permeability and ethidium fluorescence results suggest that Ni underlayer might have direct and indirect effect on the bacteria inactivation process. Additionally, relatively low loss of the photocatalyst efficiency suggests that floating C-doped TiO2 photocatalyst with the Ni underlayer might be seen as the possible solution for the used photocatalyst recovery issue.
Dual-Cycle Mechanism Based Kinetic Model for DME-to-Olefin Synthesis on HZSM-5-Type Catalysts
Authors: Magomedova Maria , Starozhitskaya Anastasiya , Davidov Ilya , Maximov Anton , Kravtsov Maksim
Published: November 2021

A kinetic model for the olefins synthesis from dimethyl ether on zeolite HZSM-5 based catalysts is developed. The model includes the reaction pathways for the synthesis of olefins from oxygenates in the olefinic and aromatic cycles according to modern concepts of the dual-cycle reaction mechanism. The kinetic parameters were determined for the time-stable hydrothermally treated catalysts of various activities Mg-HZSM-5/Al2O3, HZSM-5/Al2O3, and Zr-HZSM-5/Al2O3. The kinetic parameters determination and the solution of the ordinary differential equations system were carried out in the Python software environment. The preliminary estimation of the kinetic parameters was carried out using the Levenberg-Marquardt algorithm, and the parameters were refined using the genetic algorithm. It is shown that reactions activation energies for different catalysts are close, which indicates that the priority of the reaction paths on the studied catalysts is the same. Thus, the topology of the zeolite plays a leading role in the determination of the synthesis routes, rather than the nature of the modifying metal. The developed model fits the experimental data obtained in an isothermal reactor in the range of temperature 320–360 °C, specified contact time 0.1–3.6 h*gcat/gC with a relative error of less than 15%.
Influence of Chemical Activation Temperatures on Nitrogen-Doped Carbon Material Structure, Pore Size Distribution and Oxygen Reduction Reaction Activity
Authors: Volperts Aleksandrs , Plavniece Ance , Kaare Kätlin , Dobele Galina , Zhurinsh Aivars , Kruusenberg Ivar
Published: November 2021

The goal of this research was to synthesize activated nitrogen-doped nanocarbons with high specific surface area and adjustable pore size distribution using wood charcoal as a raw material. The resulting carbon materials were tested for possible application as oxygen reduction reaction catalysts in alkaline media. Activated carbons were obtained using a thermochemical activation method with NaOH. Nitrogen was introduced into activated carbons using dicyandiamide solution. It was demonstrated that the content of introduced nitrogen depends on oxygen content in the structure of the activated carbon. The oxygen reduction reaction activity of the activated and nitrogen-doped carbon material was comparable with a commercial 20% Pt/C catalyst. Electrocatalytic properties of the synthesized N-doped wood-derived carbon catalysts may be associated with the highly developed surface area, specific ratio of micro- and mesopores, as well as the high percentage of pyridinic nitrogen.
Modification of Silica Xerogels with Polydopamine for Lipase B from Candida antarctica Immobilization
Authors: Wang Honghai , Yue Wenda , Zhang Shuling , Zhang Yu , Li Chunli , Su Weiyi
Published: December 2021

Silica xerogels have been proposed as a potential support to immobilize enzymes. Improving xerogels’ interactions with such enzymes and their mechanical strengths is critical to their practical applications. Herein, based on the mussel-inspired chemistry, we demonstrated a simple and highly effective strategy for stabilizing enzymes embedded inside silica xerogels by a polydopamine (PDA) coating through in-situ polymerization. The modified silica xerogels were characterized by scanning and transmission electron microscopy, Fourier tranform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and pore structure analyses. When the PDA-modified silica xerogels were used to immobilize enzymes of Candida antarctica lipase B (CALB), they exhibited a high loading ability of 45.6 mg/gsupport, which was higher than that of immobilized CALB in silica xerogels (28.5 mg/gsupport). The immobilized CALB of the PDA-modified silica xerogels retained 71.4% of their initial activities after 90 days of storage, whereas the free CALB retained only 30.2%. Moreover, compared with the immobilization of enzymes in silica xerogels, the mechanical properties, thermal stability and reusability of enzymes immobilized in PDA-modified silica xerogels were also improved significantly. These advantages indicate that the new hybrid material can be used as a low-cost and effective immobilized-enzyme support.
CO2 Reforming of CH4 Using Coke Oven Gas over Ni/MgO-Al2O3 Catalysts: Effect of the MgO:Al2O3 Ratio
Authors: Park Ho-Ryong , Kim Beom-Jun , Lee Yeol-Lim , Ahn Seon-Yong , Kim Kyoung-Jin , Hong Ga-Ram , Yun Seong-Jin , Jeon Byong-Hun , Bae Jong Wook , Roh Hyun-Seog
Published: December 2021

Research is being actively conducted to improve the carbon deposition and sintering resistance of Ni-based catalysts. Among them, the Al2O3-supported Ni catalyst has been broadly studied for the dry reforming reaction due to its high CH4 activity at the beginning of the reaction. However, there is a problem of deactivation due to carbon deposition of Ni/Al2O3 catalyst and sintering of Ni, which is a catalytically active material. Supplementing MgO in Ni/Al2O3 catalyst can result in an improved MgAl2O4 spinel structure and basicity, which can be helpful for the activation of methane and carbon dioxide molecules. In order to confirm the optimal supports’ ratio in Ni/MgO-Al2O3 catalysts, the catalysts were prepared by supporting Ni after controlling the MgO:Al2O3 ratio stepwise, and the prepared catalysts were used for CO2 reforming of CH4 (CDR) using coke oven gas (COG). The catalytic reaction was conducted at 800 °C and at a high gas hourly space velocity (GHSV = 1,500,000 h−1) to screen the catalytic performance. The Ni/MgO-Al2O3 (MgO:Al2O3 = 3:7) catalyst showed the best catalytic performance between prepared catalysts. From this study, the ratio of MgO:Al2O3 was confirmed to affect not only the basicity of the catalyst but also the dispersion of the catalyst and the reducing property of the catalyst surface.
Carbon-Supported Pt-SnO2 Catalysts for Oxygen Reduction Reaction over a Wide Temperature Range: Rotating Disk Electrode Study
Authors: Mensharapov Ruslan M. , Ivanova Nataliya A. , Spasov Dmitry D. , Kukueva Elena V. , Zasypkina Adelina A. , Seregina Ekaterina A. , Grigoriev Sergey A. , Fateev Vladimir N.
Published: December 2021

Pt/C and Pt/x-SnO2/C catalysts (where x is mass content of SnO2) were synthesized using a polyol method. Their kinetic properties towards oxygen reduction reaction were studied by a rotating disk electrode (RDE) technique in a temperature range from 1 to 50 °C. The SnO2 content of catalyst samples was 5 and 10 wt.%. A quick evaluation of the catalyst activity, electrochemical behavior and average number of transferred electrons were performed using the RDE technique. It has been shown that the use of x-SnO2 (through modification of the carbon support) in a binary system together with Pt does not reduce the catalyst activity in the temperature range of 1–30 °C. The temperature rising up to 50 °C resulted in composite catalyst activity reduction at about 30%.
Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases
Authors: Strassheim Derek , Sullivan Timothy , Irwin David C. , Gerasimovskaya Evgenia , Lahm Tim , Klemm Dwight J. , Dempsey Edward C. , Stenmark Kurt R. , Karoor Vijaya
Published: November 2021

G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.
Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA
Authors: Key Jana , Torres-Odio Sylvia , Bach Nina C. , Gispert Suzana , Koepf Gabriele , Reichlmeir Marina , West A. Phillip , Prokisch Holger , Freisinger Peter , Newman William G. , Shalev Stavit , Sieber Stephan A. , Wittig Ilka , Auburger Georg
Published: November 2021

Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid
Authors: Merhi Faten , Alvarez-Valadez Karla , Trepiana Jenifer , Lescoat Claire , Groppi Alexis , Dupuy Jean-William , Soubeyran Pierre , Kroemer Guido , Vacher Pierre , Djavaheri-Mergny Mojgan
Published: November 2021

Calcium ions (Ca2+) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca2+ in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic acid (ATRA). We observed that ATRA promotes calcium entry through store-operated calcium (SOC) channels into acute promyelocytic leukemia (APL) cells. This response is associated with changes in the expression profiles of ORAI1 and STIM1, two proteins involved in SOC channels activation, as well as with a significant upregulation of several key proteins associated to calcium signaling. Moreover, ATRA treatment of APL cells led to a significant activation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) and its downstream effector AMP-activated protein kinase (AMPK), linking Ca2+ signaling to autophagy. Pharmacological inhibition of SOC channels and CAMKK2 enhanced ATRA-induced cell differentiation and death. Altogether, our results unravel an ATRA-elicited signaling pathway that involves SOC channels/CAMKK2 activation, induction of autophagy, inhibition of cellular differentiation and suppression of cell death. We suggest that SOC channels and CAMKK2 may constitute novel drug targets for potentiating the anti-cancer effect of ATRA in APL patients.
The Role of T Cell Immunotherapy in Acute Myeloid Leukemia
Authors: Hao Fang , Sholy Christine , Wang Chen , Cao Min , Kang Xunlei
Published: December 2021

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed.
Revisiting the Role of Leukocytes in Cystic Fibrosis
Authors: Averna Monica , Melotti Paola , Sorio Claudio
Published: December 2021

Cystic fibrosis in characterized by pulmonary bacterial colonization and hyperinflammation. Lymphocytes, monocytes/macrophages, neutrophils, and dendritic cells of patients with CF express functional CFTR and are directly affected by altered CFTR expression/function, impairing their ability to resolve infections and inflammation. However, the mechanism behind and the contribution of leukocytes in the pathogenesis of CF are still poorly characterized. The recent clinical introduction of specific CFTR modulators added an important tool not only for the clinical management of the disease but also to the investigation of the pathophysiological mechanisms related to CFTR dysfunction and dysregulated immunity. These drugs treat the basic defect in cystic fibrosis (CF) by increasing CFTR function with improvement of lung function and quality of life, and may improve clinical outcomes also by correcting the dysregulated immune function that characterizes CF. Measure of CFTR function, protein expression profiling and several omics methods were used to identify molecular changes in freshly isolated leukocytes of CF patients, highlighting two roles of leukocytes in CF: one more generally related to the mechanism(s) causing immune dysregulation in CF and unresolved inflammation, and another more applicative role, which identifies in myeloid cells, an important tool predictive of the therapeutic response of CF patients. In this review we will summarize available data on CFTR expression and function in leukocyte populations and will discuss potential clinical applications based on available data.
Lung Ultrasound in the Neonatal Intensive Care Unit: Does It Impact Clinical Care?
Authors: Ruoss J. Lauren , Bazacliu Catalina , Cacho Nicole , De Luca Daniele
Published: November 2021

A neonatal point-of-care ultrasound has multiple applications, but its use has been limited in neonatal intensive care units in the Unites States. An increasing body of evidence suggests that lung ultrasound performed by the neonatologist, at the bedside, is reliable and accurate in differentiating neonatal respiratory conditions, predicting morbidity, and guiding invasive interventions. Recent research has shown that a lung ultrasound can assist the clinician in accurately identifying and managing conditions such as respiratory distress syndrome, transient tachypnea of the newborn, and bronchopulmonary dysplasia. In this review, we discuss basic lung ultrasound terminology, evidence for applications of neonatal lung ultrasound, and its use as a diagnostic and predictive tool for common neonatal respiratory pathologies.
Impact of Social and Relational Adversity on Access to Services among US Children with Autism Spectrum Disorder 2016–2019
Authors: Ronis Sarah D. , Lee Eunice , Cuffman Carrie , Burkhart Kimberly
Published: November 2021

To explore the impact of social and relational adversity on access to key health services among US children with autism spectrum disorders (ASD), cross-sectional analyses of the 2016–2019 National Survey of Children’s Health assessed use of key health services by children with ASD, accounting for differences in demographic characteristics, medical needs, and experience of social and relational adversities. sUS children with ASD were more than twice as likely as peers without ASD to report two or more social adversities and more than three times as likely to report two or more relational adversities. In multivariable models, relational adversities were significantly associated with greater odds of medication use for ASD (OR 1.50, 95%CI:1.02, 2.17). Social adversities were neither associated with receipt of behavioral therapies nor prescription of medication to treat ASD. Screening for various forms of adversity among youth with ASD is of great importance; even one adverse experience may be enough to influence care of a child with ASD, with differences in effect according to the nature of the particular adversity. Further research should evaluate the role that childhood adversity plays in physical and mental health outcomes in ASD.
Prevalence of Sleep Disturbances in Pediatric Cancer Patients and Their Diagnosis and Management
Authors: Sheikh Irtiza N. , Roth Michael , Stavinoha Peter L.
Published: November 2021

Sleep disturbances represent an understudied yet common source of distress among pediatric cancer patients and survivors, with deleterious effects on quality of life. Sleep issues stem from multiple risk factors, yet individual contributors are difficult to isolate, consequently impeding the identification of targets for intervention. In many pediatric cancer patients, disrupted sleep and its negative impact on quality of life continue into adulthood and may affect various functional domains. This literature review highlights the types and prevalence of sleep disturbances in pediatric cancer patients during active treatment and through survivorship. Potential etiological and risk factors for disturbed sleep are summarized, including the effects of cancer and its treatment, psychosocial and family factors, as well as individual-patient aspects, such as genetics, mood and coping skills. While existing assessment and management strategies are reviewed, the literature is incomplete, and significant gaps emerge in our understanding of sleep disturbances in pediatric cancer patients and survivors. The review concludes with recommendations of areas where further research is needed. The aims of this review include increasing clinicians’ awareness of sleep disturbances as a significant source of poor quality of life in pediatric cancer patients and survivors and directing researchers to gaps in our understanding of sleep disturbances in pediatric cancer patients and survivors.
The Multi-Scale Dynamics Organizing a Favorable Environment for Convective Density Currents That Redirected the Yarnell Hill Fire
Authors: Kaplan Michael L. , James Curtis N. , Ising Jan , Sinclair Mark R. , Lin Yuh-Lang , Taylor Andrew , Riley Justin , Karim Shak M. S. , Wiles Jackson
Published: November 2021

The deadly shift of the Yarnell Hill, Arizona wildfire was associated with an environment exhibiting gusty wind patterns in response to organized convectively driven circulations. The observed synoptic (>2500 km) through meso-β (approximately 100 km) scale precursor environment that organized a mid-upper tropospheric cross-mountain mesoscale jet streak circulation and upslope thermally direct flow was examined. Numerical simulations and observations indicated that both circulations played a key role in focusing the upper-level divergence, ascent, downdraft potential, vertical wind shear favoring mobile convective gust fronts, and a microburst. This sequence was initiated at the synoptic scale by a cyclonic Rossby Wave Break (RWB) 72 h prior, followed by an anticyclonic RWB. These RWBs combined to produce a mid-continent baroclinic trough with two short waves ushering in cooler air with the amplifying polar jet. Cool air advection with the second trough and surface heating across the Intermountain West (IW) combined to increase the mesoscale pressure gradient, forcing a mid-upper tropospheric subsynoptic jet around the periphery of the upstream ridge over Southern Utah and Northern New Mexico. Convection was triggered by an unbalanced secondary jetlet circulation within the subsynoptic jet in association with a low-level upslope flow accompanying a mountain plains solenoidal circulation above the Mogollon Rim (MR) and downstream mountains.
More on the Supremum Statistic to Test Multivariate Skew-Normality
Authors: Opheim Timothy , Roy Anuradha
Published: November 2021

This review is about verifying and generalizing the supremum test statistic developed by Balakrishnan et al. Exhaustive simulation studies are conducted for various dimensions to determine the effect, in terms of empirical size, of the supremum test statistic developed by Balakrishnan et al. to test multivariate skew-normality. Monte Carlo simulation studies indicate that the Type-I error of the supremum test can be controlled reasonably well for various dimensions for given nominal significance levels 0.05 and 0.01. Cut-off values are provided for the number of samples required to attain the nominal significance levels 0.05 and 0.01. Some new and relevant information of the supremum test statistic are reported here.
Alaskan Bog Blueberry (Vaccinium uliginosum) Extract as an Innovative Topical Approach to Prevent UV-Induced Skin Damage
Authors: Pambianchi Erika , Hagenberg Zachary , Pecorelli Alessandra , Grace Mary , Therrien Jean-Philippe , Lila Mary Ann , Valacchi Giuseppe
Published: December 2021

Our body is continuously exposed to various exogenous aggressors, and, in particular, the skin represents the main target for outdoor stressors, including ultraviolet (UV) radiation. UV exposure is well-known to be associated with the development/worsening of extrinsic photoaging and a multitude of skin conditions. Considering the role of photoprotection in skin health, the research of natural photoprotective molecules becomes of great importance. Therefore, in this work we wanted to evaluate the beneficial protective effects of ripe berries of Vaccinium uliginosum (Alaska bog blueberry (BB)) extract (100 μg/mL) for preventing the cutaneous oxidative, inflammatory, and structural damage induced by exposure to 200 mJ of UVA/UVB radiation. We observed that the topical application of BB extract on human ex vivo skin explants averted the UV-induced cutaneous OxInflammatory phenomenon by quenching the increase in the oxidative and inflammatory marker levels, such as 4-hydroxynonenal (4HNE), heme-oxygenase-1 (HO-1), cyclooxygenase-2 (COX2), and aryl hydrocarbon receptor (AhR); as well as by counteracting the loss of structural proteins (filaggrin and involucrin) induced by UV radiation. Our data propose the use of a topical application of Alaska bog blueberry extract as a natural and valuable approach to ensure photoprotection against UV-induced skin damage and premature aging.
Atmospheric Carbon Dioxide Capture as Carbonate into a Luminescent Trinuclear Cd(II) Complex with Tris(2-aminoethyl)amine Tripodal Ligand
Authors: Mădălan Augustin M.
Published: November 2021

Spontaneous atmospheric CO2 capture as carbonate anion occurred in the synthesis of a trinuclear Cd(II) complex with tris(2-aminoethyl)amine ligand. In reaction two types of compounds were obtained and structurally characterized by X-ray diffraction on a single crystal: initially [{Cd(tren)}3(tren)](ClO4)6·2H2O (1) and subsequently [{Cd(tren)}3(tren)][{Cd(tren)}3(µ3-ηCO3)](ClO4)10 (2). The carbonate anion replaces partially the bridging tren molecule and coordinates in a µ3 fashion. The luminescent properties of the compounds were investigated.
An Experimental and Theoretical Study on the Effect of Silver Nanoparticles Concentration on the Structural, Morphological, Optical, and Electronic Properties of TiO2 Nanocrystals
Authors: Ahmed Faheem , Kanoun Mohammed Benali , Awada Chawki , Jonin Christian , Brevet Pierre-Francois
Published: December 2021

In this work, pure and silver (Ag)-loaded TiO2 nanocrystals (NCs) with various concentrations of Ag were prepared by soft chemical route and the effect of Ag nanoparticles (NPs) on the functional properties of TiO2 was studied. X-ray diffraction (XRD) and Raman studies confirmed that the synthesized product had single-phase nature and high crystalline quality. The crystallite size was decreased from 18.3 nm to 13.9 nm with the increasing in concentration of Ag in TiO2 NCs. FESEM micrographs showed that the pure and AgNPs-loaded TiO2 have spherical morphology and uniform size distribution with the size ranging from 20 to 10 nm. Raman spectroscopy performed on pure and AgNPs-loaded TiO2 confirms the presence of anatase phase and AgNPs. Optical properties show the characteristics peaks of TiO2 and the shifting of the peaks position was observed by changing the concentration of Ag. The tuning of bandgap was found to be observed with the increase in Ag, which could be ascribed to the synergistic effect between silver and TiO2 NCs. Density functional theory calculations are carried out for different Ag series of doped TiO2 lattices to simulate the structural and electronic properties. The analysis of the electronic structures show that Ag loading induces new localized gap states around the Fermi level. Moreover, the introduction of dopant states in the gap region owing to Ag doping can be convenient to shift the absorption edge of pristine TiO2 through visible light.
Diagnostics in Patients Suspect for Breast Cancer in The Netherlands
Authors: Voets Madelon M. , Groothuis-Oudshoorn Catharina G. M. , Veneklaas Liset H. J. , Manohar Srirang , Brinkhuis Mariël , Veltman Jeroen , de Munck Linda , de Geus-Oei Lioe-Fee , Broeders Mireille J. M. , Siesling Sabine
Published: November 2021

The goal of this study was to describe the variation in hospital-based diagnostic care activities for patients with symptomatology suspect for breast cancer in The Netherlands. Two cohorts were included: the ‘benign’ cohort (30,334 women suspected of, but without breast cancer) and the ‘malignant’ cohort (2236 breast cancer patients). Hospital-based financial data was combined with tumor data (malignant cohort) from The Netherlands Cancer Registry. Patterns within diagnostic pathways were analyzed. Factors influencing the number of visits and number of diagnostic care activities until diagnosis were identified in the malignant cohort with multivariable Cox and Poisson regression models. Compared to patients with benign diagnosis, patients with malignant disease received their diagnosis less frequently in one day, after an equal average number of hospital visits and higher average number of diagnostic activities. Factors increasing the number of diagnostic care activities were the following: lower age and higher cM-and cN-stages. Factors increasing the number of days until (malignant) diagnosis were as follows: higher BIRADS-score, screen-detected and higher cN-and cT-stages. Hospital of diagnosis influenced both number of activities and days to diagnosis. The diagnostic care pathway of patients with malignant disease required more time and diagnostic activities than benign disease and depends on hospital, tumor and patient characteristics.
Occurrence of Arrhythmias in Women with Thyroid Cancer Receiving Suppressive Doses of Levothyroxine
Authors: Kaziród-Wolski Karol , Kowalska Aldona , Sielski Janusz , Biskup-Frużyńska Magdalena , Piotrowski Grzegorz
Published: November 2021

Aim of the study: To assess the occurrence of cardiac arrhythmias caused by high doses of levothyroxine in patients with thyroid cancer with subclinical hyperthyroidism. Materials and Methods: This prospective study included 98 women divided into three groups according to plasma thyroid stimulating hormone (TSH) concentration: <0.1 µU/mL, 0.1–0.39 µU/mL, or 0.4–4.0 µU/mL (control group). All participants underwent laboratory tests and an electrocardiography (ECG) Holter test to assess their heart rate and the occurrence of arrhythmias. Statistical analysis assessed differences between groups in all clinical parameters and factors influencing the occurrence of arrhythmias. Results: There were no differences between groups in the maximum, average, or minimum heart rate or in the incidence of the studied cardiac arrhythmias. Heart rate in women with a TSH concentration of <0.1 µU/mL depended on age and the presence of arterial hypertension, and heart rate in women with a TSH concentration of 0.4–4.0 µU/mL depended on free triiodothyronine concentration and the presence of arterial hypertension; no relationship was identified for women with a TSH concentration of 0.1–0.39 µU/mL. One-way logistic regression analysis did not identify any factors influencing the occurrence of arrhythmias. Conclusions: While maintaining normal free triiodothyronine levels, the use of suppressive doses of levothyroxine after thyroidectomy for differentiated thyroid cancer does not induce clinically significant arrhythmias or affect average heart rate. None of the studied clinical parameters influenced the risk of arrhythmia.
Morphological and Molecular Characterization of Trichuris sp. (Nematoda: Trichuridae) in Crested Porcupines (Hystrix cristata; Rodentia: Hystricidae) from Italy
Authors: Cavallero Serena , Montalbano Di Filippo Margherita , Mori Emiliano , Viviano Andrea , De Liberato Claudio , Sforzi Andrea , D’Amelio Stefano , Berrilli Federica
Published: November 2021

Adult specimens of Trichuris sp. collected from crested porcupines (Hystrix cristata) from Italy were characterized using an integrative taxonomic approach involving morphological and molecular tools. The morphological features of this Trichuris sp. were compared to data already available for Trichuris spp. from Hystrix sp., revealing diagnostic traits, such as spicule length in males or vulva shape in females, which distinguish this Trichuris sp. from the other species. Evidence from sequences analysis of the partial mitochondrial COX1 region indicated that the taxon under study is a distinct lineage. Biometrical and genetic data suggested this Trichuris sp. to be a valid and separated taxon. However, since molecular data from other Trichuris spp. infecting Hystrix, such as T. infundibulus, T. hystricis, T. javanica, T.landak and T. lenkorani, are missing in public repositories, the number and identity of distinct lineages able to infect porcupines remain only partially defined.