bluuebunny/crossref_metadata_2025 huggingface dataset:
Zebrafish mafbb Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients
Authors: Han Yujie , Shao Weihao , Zhong Dan , Ma Cui , Wei Xiaona , Ahmed Abrar , Yu Tingting , Jing Wei , Jing Lili
Published: March 2021

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia with osteolysis at the carpal and tarsal bones. Heterozygous missense mutations in the transcription factor MAFB are found in patients with MCTO. MAFB is reported to negatively regulate osteoclastogenesis in vitro. However, the in vivo function of MAFB and its relation to MCTO remains unknown. In this study, we generated zebrafish MAFB homolog mafbb mutant utilizing CRISPR/Cas9 technology. Mafbb deficient zebrafish demonstrated enhanced osteoclast cell differentiation and abnormal cartilage and bone development resembling MCTO patients. It is known that osteoclasts are hematopoietic cells derived from macrophages. Loss of mafbb caused selective expansion of definitive macrophages and myeloid cells, supporting that mafbb restricts myeloid differentiation in vivo. We also demonstrate that MAFB MCTO mutations failed to rescue the defective osteoclastogenesis in mafbb−/− embryos, but did not affect osteoclast cells in wild type embryos. The mechanism of MCTO mutations is likely haploinsufficiency. Zebrafish mafbb mutant provides a useful model to study the function of MAFB in osteoclastogenesis and the related MCTO disease.
Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in Dictyostelium discoideum
Authors: Huber Robert J. , Kim William D. , Mathavarajah Sabateeshan
Published: March 2021

Neddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target proteins, and has been studied extensively in various eukaryotes including fungi, plants, and metazoans. Here, we examine the biological processes influenced by neddylation in the social amoeba, Dictyostelium discoideum, using a well-established inhibitor of neddylation, MLN4924 (pevonedistat). NEDD8, and the target of MLN4924 inhibition, NEDD8-activating enzyme E1 (NAE1), are highly conserved in D. discoideum (Nedd8 and Nae1, respectively). Treatment of D. discoideum cells with MLN4924 increased the amount of free Nedd8, suggesting that MLN4924 inhibited neddylation. During growth, MLN4924 suppressed cell proliferation and folic acid-mediated chemotaxis. During multicellular development, MLN4924 inhibited cyclic adenosine monophosphate (cAMP)-mediated chemotaxis, delayed aggregation, and suppressed fruiting body formation. Together, these findings indicate that neddylation plays an important role in regulating cellular and developmental events during the D. discoideum life cycle and that this organism can be used as a model system to better understand the essential roles of neddylation in eukaryotes, and consequently, its involvement in human disease.
Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases
Authors: Zhang Xuejing , Connelly Jaclyn , Chao Yapeng , Wang Qiming Jane
Published: March 2021

Protein kinase D (PKD) is a family of serine/threonine protein kinases operating in the signaling network of the second messenger diacylglycerol. The three family members, PKD1, PKD2, and PKD3, are activated by a variety of extracellular stimuli and transduce cell signals affecting many aspects of basic cell functions including secretion, migration, proliferation, survival, angiogenesis, and immune response. Dysregulation of PKD in expression and activity has been detected in many human diseases. Further loss- or gain-of-function studies at cellular levels and in animal models provide strong support for crucial roles of PKD in many pathological conditions, including cancer, metabolic disorders, cardiac diseases, central nervous system disorders, inflammatory diseases, and immune dysregulation. Complexity in enzymatic regulation and function is evident as PKD isoforms may act differently in different biological systems and disease models, and understanding the molecular mechanisms underlying these differences and their biological significance in vivo is essential for the development of safer and more effective PKD-targeted therapies. In this review, to provide a global understanding of PKD function, we present an overview of the PKD family in several major human diseases with more focus on cancer-associated biological processes.
Tanshinone IIA Downregulates Lipogenic Gene Expression and Attenuates Lipid Accumulation through the Modulation of LXRα/SREBP1 Pathway in HepG2 Cells
Authors: Gao Wan-Yun , Chen Pei-Yi , Hsu Hao-Jen , Lin Ching-Yen , Wu Ming-Jiuan , Yen Jui-Hung
Published: March 2021

Abnormal and excessive accumulation of lipid droplets within hepatic cells is the main feature of steatosis and nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). Dysregulation of lipogenesis contributes to hepatic steatosis and plays an essential role in the pathological progress of MAFLD. Tanshinone IIA is a bioactive phytochemical isolated from Salvia miltiorrhiza Bunge and exhibits anti-inflammatory, antiatherosclerotic and antihyperlipidemic effects. In this study, we aimed to investigate the lipid-lowering effects of tanshinone IIA on the regulation of lipogenesis, lipid accumulation, and the underlying mechanisms in hepatic cells. We demonstrated that tanshinone IIA can significantly inhibit the gene expression involved in de novo lipogenesis including FASN, ACC1, and SCD1, in HepG2 and Huh 7 cells. Tanshinone IIA could increase phosphorylation of ACC1 protein in HepG2 cells. We further demonstrated that tanshinone IIA also could suppress the fatty-acid-induced lipogenesis and TG accumulation in HepG2 cells. Furthermore, tanshinone IIA markedly downregulated the mRNA and protein expression of SREBP1, an essential transcription factor regulating lipogenesis in hepatic cells. Moreover, we found that tanshinone IIA attenuated liver X receptor α (LXRα)-mediated lipogenic gene expression and lipid droplet accumulation, but did not change the levels of LXRα mRNA or protein in HepG2 cells. The molecular docking data predicted tanshinone IIA binding to the ligand-binding domain of LXRα, which may result in the attenuation of LXRα-induced transcriptional activation. Our findings support the supposition that tanshinone IIA possesses a lipid-modulating effect that suppresses lipogenesis and attenuates lipid accumulation by modulating the LXRα/SREBP1 pathway in hepatic cells. Tanshinone IIA can be potentially used as a supplement or drug for the prevention or treatment of MAFLD.
A Cationic Surfactant-Decorated Liquid Crystal-Based Aptasensor for Label-Free Detection of Malathion Pesticides in Environmental Samples
Authors: Nguyen Duy Khiem , Jang Chang-Hyun
Published: March 2021

We report a liquid crystal (LC)-based aptasensor for the detection of malathion using a cationic surfactant-decorated LC interface. In this method, LCs displayed dark optical images when in contact with aqueous cetyltrimethylammonium bromide (CTAB) solution due to the formation of a self-assembled CTAB monolayer at the aqueous/LC interface, which induced the homeotropic orientation of LCs. With the addition of malathion aptamer, the homeotropic orientation of LCs changed to a planar one due to the interactions between CTAB and the aptamer, resulting in a bright optical image. In the presence of malathion, the formation of aptamer-malathion complexes caused a conformational change of the aptamers, thereby weakening the interactions between CTAB and the aptamers. Therefore, CTAB is free to induce a homeotropic ordering of the LCs, which corresponds to a dark optical image. The developed sensor exhibited high specificity for malathion determination and a low detection limit of 0.465 nM was achieved. Moreover, the proposed biosensor was successfully applied to detect malathion in tap water, river water, and apple samples. The proposed LC-based aptasensor is a simple, rapid, and convenient platform for label-free monitoring of malathion in environmental samples.
Market Perspectives and Future Fields of Application of Odor Detection Biosensors within the Biological Transformation—A Systematic Analysis
Authors: Full Johannes , Baumgarten Yannick , Delbrück Lukas , Sauer Alexander , Miehe Robert
Published: March 2021

The technological advantages that biosensors have over conventional technical sensors for odor detection and the role they play in the biological transformation have not yet been comprehensively analyzed. However, this is necessary for assessing their suitability for specific fields of application as well as their improvement and development goals. An overview of biological basics of olfactory systems is given and different odor sensor technologies are described and classified in this paper. Specific market potentials of biosensors for odor detection are identified by applying a tailored methodology that enables the derivation and systematic comparison of both the performance profiles of biosensors as well as the requirement profiles for various application fields. Therefore, the fulfillment of defined requirements is evaluated for biosensors by means of 16 selected technical criteria in order to determine a specific performance profile. Further, a selection of application fields, namely healthcare, food industry, agriculture, cosmetics, safety applications, environmental monitoring for odor detection sensors is derived to compare the importance of the criteria for each of the fields, leading to market-specific requirement profiles. The analysis reveals that the requirement criteria considered to be the most important ones across all application fields are high specificity, high selectivity, high repeat accuracy, high resolution, high accuracy, and high sensitivity. All these criteria, except for the repeat accuracy, can potentially be better met by biosensors than by technical sensors, according to the results obtained. Therefore, biosensor technology in general has a high application potential for all the areas of application under consideration. Health and safety applications especially are considered to have high potential for biosensors due to their correspondence between requirement and performance profiles. Special attention is paid to new areas of application that require multi-sensing capability. Application scenarios for multi-sensing biosensors are therefore derived. Moreover, the role of biosensors within the biological transformation is discussed.
Contribution of TMS and TMS-EEG to the Understanding of Mechanisms Underlying Physiological Brain Aging
Authors: Guerra Andrea , Rocchi Lorenzo , Grego Alberto , Berardi Francesca , Luisi Concetta , Ferreri Florinda
Published: March 2021

In the human brain, aging is characterized by progressive neuronal loss, leading to disruption of synapses and to a degree of failure in neurotransmission. However, there is increasing evidence to support the notion that the aged brain has a remarkable ability to reorganize itself, with the aim of preserving its physiological activity. It is important to develop objective markers able to characterize the biological processes underlying brain aging in the intact human, and to distinguish them from brain degeneration associated with many neurological diseases. Transcranial magnetic stimulation (TMS), coupled with electromyography or electroencephalography (EEG), is particularly suited to this aim, due to the functional nature of the information provided, and thanks to the ease with which it can be integrated with behavioral manipulation. In this review, we aimed to provide up to date information about the role of TMS and TMS-EEG in the investigation of brain aging. In particular, we focused on data about cortical excitability, connectivity and plasticity, obtained by using readouts such as motor evoked potentials and transcranial evoked potentials. Overall, findings in the literature support an important potential contribution of TMS to the understanding of the mechanisms underlying normal brain aging. Further studies are needed to expand the current body of information and to assess the applicability of TMS findings in the clinical setting.
Cortical Representation and Excitability Increases for a Thenar Muscle Mediate Improvement in Short-Term Cellular Phone Text Messaging Ability
Authors: Meek Anthony W. , Perez Joselyn , Poston Brach , Riley Zachary A.
Published: March 2021

Cortical representations expand during skilled motor learning. We studied a unique model of motor learning with cellular phone texting, where the thumbs are used exclusively to interact with the device and the prominence of use can be seen where 3200 text messages are exchanged a month in the 18–24 age demographic. The purpose of the present study was to examine the motor cortex representation and input–output (IO) recruitment curves of the abductor pollicis brevis (APB) muscle of the thumb and the ADM muscle with transcranial magnetic stimulation (TMS), relative to individuals’ texting abilities and short-term texting practice. Eighteen individuals performed a functional texting task (FTT) where we scored their texting speed and accuracy. TMS was then used to examine the cortical volumes and areas of activity in the two muscles and IO curves were constructed to measure excitability. Subjects also performed a 10-min practice texting task, after which we repeated the cortical measures. There were no associations between the cortical measures and the FTT scores before practice. However, after practice the APB cortical map expanded and excitability increased, whereas the ADM map constricted. The increase in the active cortical areas in APB correlated with the improvement in the FTT score. Based on the homogenous group of subjects that were already good at texting, we conclude that the cortical representations and excitability for the thumb muscle were already enlarged and more receptive to changes with short-term practice, as noted by the increase in FTT performance after 10-min of practice.
EEG-Derived Functional Connectivity Patterns Associated with Mild Cognitive Impairment in Parkinson’s Disease
Authors: Peláez Suárez Alejandro Armando , Berrillo Batista Sheila , Pedroso Ibáñez Ivonne , Casabona Fernández Enrique , Fuentes Campos Marinet , Chacón Lilia Morales
Published: March 2021

Objective: To evaluate EEG-derived functional connectivity (FC) patterns associated with mild cognitive impairment (MCI) in Parkinson’s disease (PD). METHODS: A sample of 15 patients without cognitive impairment (PD-WCI), 15 with MCI (PD-MCI), and 26 healthy subjects were studied. The EEG was performed in the waking functional state with eyes closed, for the functional analysis it was used the synchronization likelihood (SL) and graph theory (GT). RESULTS: PD-MCI patients showed decreased FC in frequencies alpha, in posterior regions, and delta with a generalized distribution. Patients, compared to the healthy people, presented a decrease in segregation (lower clustering coefficient in alpha p = 0.003 in PD-MCI patients) and increased integration (shorter mean path length in delta (p = 0.004) and theta (p = 0.002) in PD-MCI patients). There were no significant differences in the network topology between the parkinsonian groups. In PD-MCI patients, executive dysfunction correlated positively with global connectivity in beta (r = 0.47) and negatively with the mean path length at beta (r = −0.45); alterations in working memory were negatively correlated with the mean path length at beta r = −0.45. CONCLUSIONS: PD patients present alterations in the FC in all frequencies, those with MCI show less connectivity in the alpha and delta frequencies. The neural networks of the patients show a random topology, with a similar organization between patients with and without MCI. In PD-MCI patients, alterations in executive function and working memory are related to beta integration.
Endocrine-Based Treatments in Clinically-Relevant Subgroups of Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer: Systematic Review and Meta-Analysis
Authors: Schettini Francesco , Giuliano Mario , Giudici Fabiola , Conte Benedetta , De Placido Pietro , Venturini Sergio , Rognoni Carla , Di Leo Angelo , Locci Mariavittoria , Jerusalem Guy , Del Mastro Lucia , Puglisi Fabio , Conte PierFranco , De Laurentiis Michelino , Pusztai Lajos , Rimawi Mothaffar F. , Schiff Rachel , Arpino Grazia , De Placido Sabino , Prat Aleix , Generali Daniele
Published: March 2021

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26–41% and 12–27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60–0.65 vs. HR range for single agent ET: 0.59–1.37; OS HR range for combinations: 0.74–0.87 vs. HR range for single agent ET: 0.68–0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.
Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study
Authors: Westerveld Henrike , Schmid Maximilian , Nout Remi , Chargari Cyrus , Pieters Bradley , Creutzberg Carien , Sturdza Alina , Lindegaard Jacob , van Kesteren Zdenko , Mazeron Renaud , Nesvacil Nicole , Fokdal Lars
Published: March 2021

Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if >80 Gy EQD2α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer.
Applications of Melanin and Melanin-Like Nanoparticles in Cancer Therapy: A Review of Recent Advances
Authors: Cuzzubbo Stefania , Carpentier Antoine F.
Published: March 2021

Thanks to the growing knowledge about cancers and their interactions with the immune system, a huge number of therapeutic cancer vaccines have been developed in the past two decades. Despite encouraging results in pre-clinical models, cancer vaccines have not yet achieved significant clinical efficacy. Several factors may contribute to such poor results, including the difficulty of triggering a strong immune response and the immunosuppressive tumor microenvironment. Many strategies are currently being explored. Different types of adjuvants have been incorporated into vaccine formulations to improve their efficacy, as cancer antigens are usually poorly immunogenic. Nanoparticle systems are promising tools as they act as carriers for antigens and can be surface-modified so that they specifically target antigen-presenting cells in lymph nodes. Bioinspired nanomaterials are ideal candidates thanks to their biocompatibility. Recently, melanin-based nanoparticles were reported to efficiently localize into draining lymphoid tissues and trigger immune responses against loaded antigens. In addition, by virtue of their photochemical properties, melanin-based nanoparticles can also play an immunomodulatory role to promote anti-cancer responses in the context of photothermal therapy. In this review, we discuss the above-mentioned properties of melanin, and summarize the promising results of the melanin-based cancer vaccines recently reported in preclinical models.
Thyroid Dysfunction in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (ICIs): Outcomes in a Multiethnic Urban Cohort
Authors: D’Aiello Angelica , Lin Juan , Gucalp Rasim , Tabatabaie Vafa , Cheng Haiying , Bloomgarden Noah A. , Tomer Yaron , Halmos Balazs
Published: March 2021

We sought to characterize thyroid dysfunction and its association with baseline clinical and demographic characteristics, as well as progression-free survival (PFS), in a multiethnic cohort of lung cancer patients treated with ICIs. A retrospective chart review of lung cancer patients receiving an anti-PD1 or PD-L1 agent was performed. Multivariate Cox proportional hazards were fitted to compare time to thyroid dysfunction among race subgroups controlling for age, gender, treatment type, and duration. Thyroid dysfunction was based on laboratory testing; clinical symptoms were not required. PFS at a 24-week landmark analysis point among patients with and without thyroid dysfunction was compared using a log-rank test. We identified 205 subjects that received ICIs, including 76 (37.1%) who developed thyroid dysfunction. Rates of thyroid dysfunction by one year occurred at similar frequencies among all races (p = 0.92). Gender and concurrent chemotherapy showed no significant association with thyroid dysfunction (p = 0.81 and p = 0.67, respectively). Thyrotoxicosis occurred at higher rates in Black (25, 31.6%) subjects than in White (7, 16.7%) and Hispanic (8, 12.7%) subjects when employing the log-rank test (p = 0.016) and multivariate Cox regression (HR 0.48, p = 0.09 for White and HR 0.36, p = 0.01 for Hispanic compared to Black subjects). PFS was similar among subjects with and without thyroid dysfunction when applying the log-rank test (p = 0.353). Gender, concurrent treatment with chemotherapy, and PFS were not associated with thyroid dysfunction in patients receiving ICIs; however, Black race was a risk factor for thyrotoxicosis. The mechanisms underlying the role of race in the development of irAEs warrant further study.
In-Depth Characterization of Stromal Cells within the Tumor Microenvironment Yields Novel Therapeutic Targets
Authors: Walter Sebastian G. , Scheidt Sebastian , Nißler Robert , Gaisendrees Christopher , Zarghooni Kourosh , Schildberg Frank A.
Published: March 2021

Cells within the tumor stroma are essential for tumor progression. In particular, cancer-associated fibroblasts (CAF) and CAF precursor cells (resident fibroblasts and mesenchymal stromal cells) are responsible for the formation of the extracellular matrix in tumor tissue. Consequently, CAFs directly and indirectly mediate inflammation, metastasis, immunomodulation, angiogenesis, and the development of tumor chemoresistance, which is orchestrated by complex intercellular cytokine-mediated crosstalk. CAFs represent a strategic target in antitumor therapy but their heterogeneity hinders effective treatment regimes. In-depth understanding of CAF subpopulations and knowledge of specific functions in tumor progression will ultimately result in more specific and effective cancer treatments. This review provides a detailed description of CAFs and CAF precursor cells and summarizes possible treatment strategies as well as molecular targets of these cells in antitumor therapies.
Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy
Authors: Marcus Damiënne , Lieverse Relinde I. Y. , Klein Carmen , Abdollahi Amir , Lambin Philippe , Dubois Ludwig J. , Yaromina Ala
Published: March 2021

Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by stereotactic body radiation therapy (SBRT), are increasingly investigated in combination with cancer immunotherapy within clinical trials. Despite intensive preclinical studies, the optimal dose per fraction and dose schemes for elaboration of RT induced immunogenic potential remain inconclusive. Compared to the scenario of combined immune checkpoint inhibition (ICI) and RT, multimodal therapies utilizing other immunotherapy principles such as adoptive transfer of immune cells, vaccination strategies, targeted immune-cytokines and agonists are underrepresented in both preclinical and clinical settings. Despite the clinical success of ICI and RT combination, e.g., prolonging overall survival in locally advanced lung cancer, curative outcomes are still not achieved for most cancer entities studied. Charged particle RT (PRT) has gained interest as it may enhance tumor immunogenicity compared to conventional RT due to its unique biological and physical properties. However, whether PRT in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated. In this review, the immunological effects of RT in the tumor microenvironment are summarized to understand their implications for immunotherapy combinations. Attention will be given to the various immunotherapeutic interventions that have been co-administered with RT so far. Furthermore, the theoretical basis and first evidences supporting a favorable immunogenicity profile of PRT will be examined.
Night Work and Breast Cancer Risk in Nurses: Multifactorial Risk Analysis
Authors: Gómez-Salgado Juan , Fagundo-Rivera Javier , Ortega-Moreno Mónica , Allande-Cussó Regina , Ayuso-Murillo Diego , Ruiz-Frutos Carlos
Published: March 2021

Night work has been highlighted by the International Agency for Research on Cancer (IARC) as a likely carcinogenic factor for humans, associated with breast cancer and professions that require continuity of work. Knowing the impact that short and long-term night work has on the nurses’ collective seems a priority, therefore, this study aims to analyse the relationship between night work and the development of breast cancer risk factors in nurses. For this, a cross-sectional study through an online questionnaire on breast cancer risk variables and working life was designed. The study was conducted in Spain and the sample consisted of 966 nurses, of whom 502 were healthy participants and 56 were breast cancer patients. These two groups were compared in the analyses. A descriptive analysis was performed, and the relationship was tested using χ2 independence test and OR calculation. The CHAID (Chi Square Automatic Interaction Detection) data mining method allowed for the creation of a segmentation tree for the main risk variables. The most significant risk variables related to working life have been the number of years worked, nights worked throughout life, and years working more than 3 nights per month. Exceeding 16 years of work has been significant for women and men. When the time worked is less than 16 years, the number of cases increases if there is a family history of cancer and if there have been more than 500 nights of work. High-intensity night work seems more harmful at an early age. The accumulation of years and nights worked increase the risk of breast cancer when factors such as sleep disturbance, physical stress, or family responsibilities come together.
A New Classification System to Predict Functional Outcome after Laryngectomy and Laryngopharyngectomy
Authors: Grasl Stefan , Schmid Elisabeth , Heiduschka Gregor , Brunner Markus , Marijić Blažen , Grasl Matthaeus Ch. , Faisal Muhammad , Erovic Boban M. , Janik Stefan
Published: March 2021

(1) Objective: To evaluate long-term functional outcome in patients who underwent primary or salvage total laryngectomy (TL), TL with partial (TLPP), or total pharyngectomy (TLTP), and to establish a new scoring system to predict complication rate and long-term functional outcome; (2) Material and Methods: Between 1993 and 2019, 258 patients underwent TL (n = 85), TLPP (n = 101), or TLTP (n = 72). Based on the extent of tumor resection, all patients were stratified to (i) localization I: TL; II: TLPP; III: TLTP and (ii) surgical treatment (A: primary resection; B: salvage surgery). Type and rate of complication and functional outcome, including oral nutrition, G-tube dependence, pharyngeal stenosis, and voice rehabilitation were evaluated in 163 patients with a follow-up ≥ 12 months and absence of recurrent disease; (3) Results: We found 61 IA, 24 IB, 63 IIA, 38 IIB, 37 IIIA, and 35 IIIA patients. Complications and subsequently revision surgeries occurred most frequently in IIIB cases but rarely in IA patients (57.1% vs. 18%; p = 0.001 and 51.4% vs. 14.8%; p = 0.002), respectively. Pharyngocutaneous fistula (PCF) was the most common complication (33%), although it did not significantly differ among cohorts (p = 0.345). Pharyngeal stenosis was found in 27% of cases, with the highest incidence in IIIA (45.5%) and IIIB (72.7%) patients (p < 0.001). Most (91.1%) IA patients achieved complete oral nutrition compared to only 41.7% in class IIIB patients (p < 0.001). Absence of PCF (odds ratio (OR) 3.29; p = 0.003), presence of complications (OR 3.47; p = 0.004), and no need for pharyngeal reconstruction (OR 4.44; p = 0.042) represented independent favorable factors for oral nutrition. Verbal communication was achieved in 69.3% of patients and was accomplished by the insertion of voice prosthesis in 37.4%. Acquisition of esophageal speech was reached in 31.9% of cases. Based on these data, we stratified patients regarding the extent of surgery and previous treatment into subgroups reflecting risk profiles and expectable functional outcome; (4) Conclusions: The extent of resection accompanied by the need for reconstruction and salvage surgery both carry a higher risk of complications and subsequently worse functional outcome. Both factors are reflected in our classification system that can be helpful to better predict patients’ functional outcome.
Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation
Authors: Simon Iris , Perales Sonia , Casado-Medina Laura , Rodríguez-Martínez Alba , Garrido-Navas Maria del Carmen , Puche-Sanz Ignacio , Diaz-Mochon Juan J. , Alaminos Clara , Lupiañez Pablo , Lorente Jose A. , Serrano María J. , Real Pedro J.
Published: March 2021

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.
Photocatalytic Nanocomposite Polymer-TiO2 Membranes for Pollutant Removal from Wastewater
Authors: Bouziane Errahmani Khelil , Benhabiles Ouassila , Bellebia Sohbi , Bengharez Zohra , Goosen Mattheus , Mahmoudi Hacene
Published: March 2021

Photocatalytic TiO2-PVDF/PMMA nano-composites flat sheet membranes were fabricated by phase inversion and then employed in a crossflow filtration pilot to remove model pollutants of various sizes and charge from aqueous solution. The dope solution contained a mixture of PVDF and PMMA as polymers, polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) as additives, triethyl phosphate (TEP) as green solvent and TiO2 as immobilized photo catalyst. After undergoing characterization tests such as SEM morphology thickness, porosity, contact angle and water permeability, the membranes were used to eliminate the model pollutants from synthetic aqueous solution. The impact of the operating conditions (i.e., pH, pressure and initial pollutant concentration) and composition of the doping solution on the performance and photocatalytic and antifouling activity of the membranes was investigated. The results showed that Congo Red and Tartrazine despite their small size were rejected at 99% and 81%, respectively, because of their negative charge, while Ciprofloxacin, which is larger than Tartrazine but of neutral charge, crossed the membrane. The permeability did not decrease with a decline in pollutant concentration but diminished when the pressure increased and was reduced by more than half for wastewater.
Modified-TiO2 Photocatalyst Supported on β-SiC Foams for the Elimination of Gaseous Diethyl Sulfide as an Analog for Chemical Warfare Agent: Towards the Development of a Photoreactor Prototype
Authors: Sengele Armelle , Robert Didier , Keller Nicolas , Keller Valérie
Published: March 2021

In the context of the increase in chemical threat due to warfare agents, the development of efficient methods for destruction of Chemical Warfare Agents (CWAs) are of first importance both for civilian and military purposes. Amongst possible methods for destruction of CWAs, photocatalytic oxidation is an alternative one. The present paper reports on the preparation of Ta and Sn doped TiO2 photocatalysts immobilized on β-SiC foams for the elimination of diethyl sulfide (DES) used as a model molecule mimicking Yperite (Mustard Gas) in gaseous phase. Photo-oxidation efficiency of doped TiO2 catalyst has been compared with TiO2-P25. Here, we demonstrate that the Sn doped-TiO2 with a Polyethylene glycol (PEG)/TiO2 ratio of 7 exhibits the best initial activity (up to 90%) but is deactivates more quickly than Ta doped-TiO2 (40% after 800 min). The activity of the catalysts is strongly influenced by the adsorption properties of the support, as β-SiC foams adsorb DES and other sulfur compounds. This adsorption makes it possible to limit the poisoning of the catalysts and to maintain an acceptable conversion rate even after ten hours under continuous DES flow. Washing with NaOH completely regenerates the catalyst after a firs treatment and even seems to “wash” it by removing impurities initially present on the foams.
The Role of Chloroplast Membrane Lipid Metabolism in Plant Environmental Responses
Authors: Cook Ron , Lupette Josselin , Benning Christoph
Published: March 2021

Plants are nonmotile life forms that are constantly exposed to changing environmental conditions during the course of their life cycle. Fluctuations in environmental conditions can be drastic during both day–night and seasonal cycles, as well as in the long term as the climate changes. Plants are naturally adapted to face these environmental challenges, and it has become increasingly apparent that membranes and their lipid composition are an important component of this adaptive response. Plants can remodel their membranes to change the abundance of different lipid classes, and they can release fatty acids that give rise to signaling compounds in response to environmental cues. Chloroplasts harbor the photosynthetic apparatus of plants embedded into one of the most extensive membrane systems found in nature. In part one of this review, we focus on changes in chloroplast membrane lipid class composition in response to environmental changes, and in part two, we will detail chloroplast lipid-derived signals.
Immunologically Inert Nanostructures as Selective Therapeutic Tools in Inflammatory Diseases
Authors: Talamini Laura , Matsuura Eiji , De Cola Luisa , Muller Sylviane
Published: March 2021

The current therapies based on immunosuppressant or new biologic drugs often show some limitations in term of efficacy and applicability, mainly because of their inadequate targeting and of unwanted adverse reactions they generate. To overcome these inherent problems, in the last decades, innovative nanocarriers have been developed to encapsulate active molecules and offer novel promising strategies to efficiently modulate the immune system. This review provides an overview of how it is possible, exploiting the favorable features of nanocarriers, especially with regard to their immunogenicity, to improve the bioavailability of novel drugs that selectively target immune cells in the context of autoimmune disorders and inflammatory diseases. A focus is made on nanoparticles that selectively target neutrophils in inflammatory pathologies.
Review: Tissue Engineering of Small-Diameter Vascular Grafts and Their In Vivo Evaluation in Large Animals and Humans
Authors: Fang Shu , Ellman Ditte Gry , Andersen Ditte Caroline
Published: March 2021

To date, a wide range of materials, from synthetic to natural or a mixture of these, has been explored, modified, and examined as small-diameter tissue-engineered vascular grafts (SD-TEVGs) for tissue regeneration either in vitro or in vivo. However, very limited success has been achieved due to mechanical failure, thrombogenicity or intimal hyperplasia, and improvements of the SD-TEVG design are thus required. Here, in vivo studies investigating novel and relative long (10 times of the inner diameter) SD-TEVGs in large animal models and humans are identified and discussed, with emphasis on graft outcome based on model- and graft-related conditions. Only a few types of synthetic polymer-based SD-TEVGs have been evaluated in large-animal models and reflect limited success. However, some polymers, such as polycaprolactone (PCL), show favorable biocompatibility and potential to be further modified and improved in the form of hybrid grafts. Natural polymer- and cell-secreted extracellular matrix (ECM)-based SD-TEVGs tested in large animals still fail due to a weak strength or thrombogenicity. Similarly, native ECM-based SD-TEVGs and in-vitro-developed hybrid SD-TEVGs that contain xenogeneic molecules or matrix seem related to a harmful graft outcome. In contrast, allogeneic native ECM-based SD-TEVGs, in-vitro-developed hybrid SD-TEVGs with allogeneic banked human cells or isolated autologous stem cells, and in-body tissue architecture (IBTA)-based SD-TEVGs seem to be promising for the future, since they are suitable in dimension, mechanical strength, biocompatibility, and availability.
HPV and Other Microbiota; Who’s Good and Who’s Bad: Effects of the Microbial Environment on the Development of Cervical Cancer—A Non-Systematic Review
Authors: Läsche Matthias , Urban Horst , Gallwas Julia , Gründker Carsten
Published: March 2021

Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.
Neonatal Respiratory Distress Secondary to Meconium Aspiration Syndrome
Authors: Olicker Arielle L. , Raffay Thomas M. , Ryan Rita M.
Published: March 2021

Infants born through meconium-stained amniotic fluid (MSAF) are 100 times more likely than infants born through clear amniotic fluid to develop respiratory distress in the neonatal period. Meconium aspiration syndrome (MAS) is a common cause of respiratory distress in term and post-mature neonates. MAS is defined as respiratory distress accompanied by a supplemental oxygen requirement in an infant born with MSAF, in the absence of any other identified etiology to explain the symptoms. Therapy for MAS is supportive, and should be tailored to each infant’s specific pathophysiology. In cases of MAS with severe persistent pulmonary hypertension of the newborn (PPHN), patients may remain hypoxic despite aggressive ventilation, and in these cases surfactant, inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) can be life-saving. Long-term prognosis for MAS is more related to severity of initial hypoxemia and possible neurological insult than to the pulmonary pathology.
Microcracks Reduction in Laser Hardened Layers of Ductile Iron
Authors: Hurtado-Delgado Eduardo , Huerta-Larumbe Lizbeth , Miranda-Pérez Argelia , Aguirre-Sánchez Álvaro
Published: March 2021

A study of surface hardening of Ductile Iron (DI) with and without austempering heat treatment was developed. The chemical composition of the material contains alloying elements such as Cu and Ni, that allow to obtain a Ductile Iron Grade 120-90-02, based on ASTM A536, which was heat treated to be transformed to Austempered Ductile Iron (ADI). Specimens of 10 × 10 × 5 mm3 were obtained for application of surface hardening by Nd:YAG UR laser of 150 W maximum power. The parameters used were advance speed of 0.2 and 0.3 mm/s and power at 105, 120, 135 and 144 W; the departure microstructures were fully pearlitic in the samples without heat treatment, and ausferrite for austempered samples. Microstructural characterization of hardened samples was performed were analyzed and martensite and undissolved carbides were identified in the pearlitic samples, while in ausferrite samples it was found finer martensite without carbides. The depth of hardened surface to different conditions and their respective microhardness were measured. The results indicate that the surface hardening via laser is a suitable method for improving wear resistance by means of hardness increment in critical areas without compromising the core ductility of DI components, but the surface ductility is enhanced when the DI is austempered before the laser hardening, by the reduction of surface microcracks.
Improving the Laser Texture Strategy to Get Superhydrophobic Aluminum Alloy Surfaces
Authors: Volpe Annalisa , Covella Sara , Gaudiuso Caterina , Ancona Antonio
Published: March 2021

Changing the wetting properties of surfaces is attracting great interest in many fields, in particular to achieve a surface with a superhydrophobic behavior. Laser machining is an emerging technique to functionalize materials with high precision and flexibility without any chemical treatment. However, when it is necessary to treat large area surfaces laser-based methods are still too slow to be exploited in industrial productions. In this work, we show that by improving the laser texture strategy it is possible to reduce the laser processing time to produce superhydrophobic aluminum alloy surfaces. Three different surface texture geometries were micromachined; namely, square, circular and triangular lattice grooves. We found that if the spacing between the grooves is narrow, i.e., when the percentage of the textured surface is high, the volume of air trapped inside the micromachined structures plays an important role in the wetting behavior. Meanwhile, when the groove spacing approaches the droplet dimensions, the texture geometry has a preponderant influence. Based on these findings an appropriate choice of the laser texture strategy allowed the fabrication of superhydrophobic aluminum alloy surfaces with a 10% reduction of processing time.