bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Ashwagandha Withanolides on Muscle Cell Differentiation
Authors: Wang Jia , Zhang Huayue , Kaul Ashish , Li Kejuan , Priyandoko Didik , Kaul Sunil C. , Wadhwa Renu
Published: October 2021

Withania somnifera (Ashwagandha) is used in Indian traditional medicine, Ayurveda, and is believed to have a variety of health-promoting effects. The molecular mechanisms and pathways underlying these effects have not yet been sufficiently explored. In this study, we investigated the effect of Ashwagandha extracts and their major withanolides (withaferin A and withanone) on muscle cell differentiation using C2C12 myoblasts. We found that withaferin A and withanone and Ashwagandha extracts possessing different ratios of these active ingredients have different effects on the differentiation of C2C12. Withanone and withanone-rich extracts caused stronger differentiation of myoblasts to myotubes, deaggregation of heat- and metal-stress-induced aggregated proteins, and activation of hypoxia and autophagy pathways. Of note, the Parkinson’s disease model of Drosophila that possess a neuromuscular disorder showed improvement in their flight and climbing activity, suggesting the potential of Ashwagandha withanolides for the management of muscle repair and activity.
Effects of Nutrients on Platelet Function: A Modifiable Link between Metabolic Syndrome and Neurodegeneration?
Authors: Arnoldussen Ilse A. C. , Witkamp Renger F.
Published: October 2021

Metabolic syndrome increases the risk of vascular dementia and other neurodegenerative disorders. Recent studies underline that platelets play an important role in linking peripheral with central metabolic and inflammatory mechanisms. In this narrative review, we address the activation of platelets in metabolic syndrome, their effects on neuronal processes and the role of the mediators (e.g., serotonin, platelet-derived growth factor). Emerging evidence shows that nutritional compounds and their metabolites modulate these interactions—specifically, long chain fatty acids, endocannabinoids and phenolic compounds. We reviewed the role of activated platelets in neurovascular processes and nutritional compounds in platelet activation.
Natural Products Are a Promising Source for Anthelmintic Drug Discovery
Authors: Jayawardene K. L. T. Dilrukshi , Palombo Enzo A. , Boag Peter R.
Published: October 2021

Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction in livestock performance or control cost. The main method of controlling these devastating conditions is the use of anthelmintic drugs. Unfortunately, there are only a few anthelmintic drug classes available in the market and significant resistance has developed in most of the parasitic species of livestock. Therefore, development of new anthelmintics with different modes of action is critical for sustainable parasitic control in the future. The drug development pipeline is broadly limited to two types of molecules, namely synthetic compounds and natural plant products. Compared to synthetic compounds, natural products are highly diverse, and many have historically proven valuable in folk medicine to treat various gastrointestinal ailments. This review focus on the use of traditional knowledge-based plant extracts in the development of new therapeutic leads, the approaches used as screening techniques, and common bottlenecks and opportunities in plant-based anthelmintic drug discovery.
miRNA-148a Enhances the Treatment Response of Patients with Rectal Cancer to Chemoradiation and Promotes Apoptosis by Directly Targeting c-Met
Authors: Huang Chun-Ming , Huang Ming-Yii , Chen Yen-Cheng , Chen Po-Jung , Su Wei-Chih , Chang Tsung-Kun , Li Ching-Chun , Huang Ching-Wen , Tsai Hsiang-Lin , Wang Jaw-Yuan
Published: October 2021

Patients with locally advanced rectal cancer (LARC) who achieve a pathological complete response (pCR) to neoadjuvant chemoradiotherapy (NACRT) have an excellent prognosis, but only approximately 30% of patients achieve pCR. Therefore, identifying predictors of pCR is imperative. We employed a microRNA (miRNA) microarray to compare the miRNA profiles of patients with LARC who achieved pCR (pCR group, n = 5) with those who did not (non-pCR group, n = 5). The validation set confirmed that miRNA-148a was overexpressed in the pCR group (n = 11) compared with the non-pCR group (n = 40). Cell proliferation and clonogenic assays revealed that miRNA-148a overexpression radio-sensitized cancer cells and inhibited cellular proliferation, before and after irradiation (p < 0.01). Apoptosis assays demonstrated that miRNA-148a enhanced apoptosis before and after irradiation. Reporter assays revealed that c-Met was the direct target gene of miRNA-148a. An in vivo study indicated that miRNA-148a enhanced the irradiation-induced suppression of xenograft tumor growth (p < 0.01). miRNA-148a may be a biomarker of pCR following NACRT and can promote apoptosis and inhibit proliferation in CRC cells by directly targeting c-Met in vitro and enhancing tumor response to irradiation in vivo.
From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients
Authors: Tsantzali Ioanna , Boufidou Fotini , Sideri Eleni , Mavromatos Antonis , Papaioannou Myrto G. , Foska Aikaterini , Tollos Ioannis , Paraskevas Sotirios G. , Bonakis Anastasios , Voumvourakis Konstantinos I. , Tsivgoulis Georgios , Kapaki Elisabeth , Paraskevas George P.
Published: October 2021

Analysis of classical cerebrospinal fluid biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool allowing correct identification of Alzheimer’s disease during life. We describe four patients with more or less atypical or mixed clinical presentation, in which the classical cerebrospinal fluid biomarkers amyloid peptide with 42 and 40 amino acids (Aβ42 and Aβ40, respectively), phospho-tau (τP-181) and total tau (τΤ) were measured. Despite the unusual clinical presentation, the biomarker profile was compatible with Alzheimer’s disease in all four patients. The measurement of classical biomarkers in the cerebrospinal fluid may be a useful tool in identifying the biochemical fingerprints of Alzheimer’s disease, especially currently, due to the recent approval of the first disease-modifying treatment, allowing not only typical but also atypical cases to be enrolled in trials of such treatments.
A Case Report of a Patient on Therapeutic Warfarin Who Died of COVID-19 Infection with a Sudden Rise in D-Dimer
Authors: Agarwal Reita N. , Aggarwal Hersheth , Verma Ashmit , Tripathi Manish K.
Published: October 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has disrupted social and economic life globally. The global pandemic COVID-19 caused by this novel SARS-CoV-2 shows variable clinical manifestations, complicated further by cytokine storm, co-infections, and coagulopathy, leading to severe cases and death. Thrombotic complications arise due to complex and unique interplay between coronaviruses and host cells, inflammatory response, and the coagulation system. Heparin and derivatives are World Health Organization (WHO) recommended anticoagulants for moderate and severe Corona Virus Disease 19 (COVID-19), that can also inhibit viral adhesion to the cell membrane by interfering with heparan sulfate-dependent binding to angiotensin-converting enzyme 2 (ACE2) receptor. Heparin also possesses anti-inflammatory, immunomodulatory, antiviral, and anti-complement activity, which offers a benefit in limiting viral and microbial infectivity and anticoagulation from the immune-thrombosis system. Here we present a case study of the pathophysiology of unexpected COVID-19 coagulopathy of an obese African American patient. While being on therapeutic warfarin since admission, he had a dismal outcome due to cardio-pulmonary arrest after the sudden rise in D-dimer value from 1.1 to >20. This indicates that for such patients on chronic warfarin anticoagulation with “moderate COVID 19 syndromes”, warfarin anticoagulation may not be suitable compared to heparin and its derivatives. Further research should be done to understand the beneficial role of heparin and its derivatives compared to warfarin for COVID-19 inflicted patients.
A DNA Damage Response Gene Panel for Different Histologic Types of Epithelial Ovarian Carcinomas and Their Outcomes
Authors: Chiang Ying-Cheng , Lin Po-Han , Lu Tzu-Pin , Kuo Kuan-Ting , Tai Yi-Jou , Hsu Heng-Cheng , Wu Chia-Ying , Lee Chia-Yi , Shen Hung , Chen Chi-An , Cheng Wen-Fang
Published: October 2021

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.
Long-Term Survival and Clinicopathological Implications of DNA Mismatch Repair Status in Endometrioid Endometrial Cancers in Hong Kong Chinese Women
Authors: Lee Jacqueline Ho Sze , Li Joshua Jing Xi , Chow Chit , Chan Ronald Cheong Kin , Kwan Johnny Sheung Him , Lau Tat San , To Ka Fai , Yim So Fan , Yeung Suet Ying , Kwong Joseph
Published: October 2021

To investigate the role of DNA mismatch repair status (MMR) in survival of endometrioid endometrial cancer in Hong Kong Chinese women and its correlation to clinical prognostic factors, 238 patients with endometrioid endometrial cancer were included. Tumor MMR status was evaluated by immunohistochemistry. Clinical characteristics and survival were determined. Association of MMR with survival and clinicopathological parameters were assessed. MMR deficiency (dMMR) was found in 43 cases (16.5%). dMMR was associated with poor prognostic factors including older age, higher stage, higher grade, larger tumor size and more radiotherapy usage. Long-term survival was worse in dMMR compared to the MMR proficient group. The dMMR group had more deaths, shorter disease-specific survival (DSS), shorter disease-free survival (DFS), less 10-year DSS, less 10-year DFS, and more recurrence. The 5-year DSS and 5-year DFS in the dMMR group only showed a trend of worse survival but did not reach statistical significance. In conclusion, dMMR is present in a significant number of endometrioid endometrial cancers patients and is associated with poorer clinicopathological factors and survival parameters in the long run. dMMR should be considered in the risk stratification of endometrial cancer to guide adjuvant therapy and individualisation for longer follow up plan.
Tumor-Released Products Promote Bone Marrow-Derived Macrophage Survival and Proliferation
Authors: Motta Juliana Maria , Rumjanek Vivian Mary , Mantovani Alberto , Locati Massimo
Published: October 2021

Macrophages play a central role within the tumor microenvironment, with relevant implications for tumor progression. The modulation of their phenotype is one of the mechanisms used by tumors to escape from effective immune responses. This study was designed to analyze the influence of soluble products released by tumors, here represented by the tumor-conditioned media of two tumor cell lines (3LL from Lewis lung carcinoma and MN/MCA from fibrosarcoma), on murine macrophage differentiation and polarization in vitro. Data revealed that tumor-conditioned media stimulated macrophage differentiation but influenced the expression levels of macrophage polarization markers, cytokine production, and microRNAs of relevance for macrophage biology. Interestingly, tumor-derived soluble products supported the survival and proliferation rate of bone marrow precursor cells, an effect observed even with mature macrophages in the presence of M2 but not M1 inducers. Despite presenting low concentrations of macrophage colony-stimulating factor (M-CSF), tumor-conditioned media alone also supported the proliferation of cells to a similar extent as exogenous M-CSF. This effect was only evident in cells positive for the expression of the M-CSF receptor (CD115) and occurred preferentially within the CD16+ subset. Blocking CD115 partially reversed the effect on proliferation. These results suggest that tumors release soluble products that not only promote macrophage development from bone marrow precursors but also stimulate the proliferation of cells with specific phenotypes that could support protumoral functions.
Extracorporeal Shock Wave Therapy Protected the Functional and Architectural Integrity of Rodent Urinary Bladder against Ketamine-Induced Damage
Authors: Chen Yen-Ta , Huang Kuan-Hui , Chiang John Y. , Sung Pei-Hsun , Huang Chi-Ruei , Chu Yi-Ching , Chuang Fei-Chi , Yip Hon-Kan
Published: October 2021

This study tested the hypothesis that extracorporeal-shock-wave (ECSW) protected the functional and anatomical integrity of rat urinary-bladder against ketamine-induced damage. In in vitro study, the rat bladder smooth muscle cells (RBdSMCs) were categorized into G1 (sham-control), G2 (RBdSMCs + menadione), G3 (RBdSMCs + ECSW) and G4 (RBdSMCs + menadione + ECSW). The results showed protein expressions of oxidative-stress/mitochondrial-damaged biomarkers (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D), inflammatory markers (MyD88/TRAF6/p-IKB-α/NF-κB/TNF-α/IL-6/IL-1ß/MMP-9/iNOS), and cell-stress response signalings (ASK1/p-MKK4/p-MKK7/ERK1/2//p-JNK/p-p38/p-53) were significantly increased in G2 than in G1 and G3, and those were significantly reversed in G4 (all p < 0.0001). Adult-male SD rats (n = 24) were equally categorized into group 1 (sham-control), group 2 (ketamine/30 mg/kg/daily i.p. injection for four weeks), group 3 [ketamine/30 mg/kg + ECSW/optimal energy (0.12 mJ/mm2/120 impulses/at 3 h and days 3/7/14/21/28 after ketamine administration)] and group 4 [(ketamine/30 mg/kg + ECSW/higher energy (0.16 mJ/mm2/120 impulses)] and animals were euthanized by day 42. The results showed the urine levels of pro-inflammatory cytokines (TNF-α/IL-6) were lowest in group 1, highest in group 2 and significantly higher in group 3 than in group 4 at days 1/7/14/28 (all p < 0.0001). The duration of urinary bladder contraction was lowest in group 2, highest in group 1 and significantly higher in group 4 than in group 3, whereas the maximal pressure of urinary bladder exhibited an opposite pattern of bladder contraction among the groups (all p < 0.0001). The histopathological findings of fibrosis/inflammation/keratinization and protein expressions of oxidative-stress/mitochondrial-damaged biomarkers (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D), and inflammatory (TLR-2/TLR-4/MyD88/TRAF6/p-IKB-α/NF-κB/TNF-α/IL-1ß/MMP-9/iNOS) and cell-stress response (ASK1/p-MKK4/p-MKK7/ERK1/2//p-JNK/p-p38) signalings and apoptotic/fibrotic biomarkers (cleaved-caspas3/cleaved-PARB/Smad3/TFG-ß) exhibited an identical pattern of urine proinflammatory cytokine among the groups (all p < 0.0001). ECSW effectively attenuated ketamine-induced bladder damage and dysfunction.
Disposable Voltammetric Sensor Modified with Block Copolymer-Dispersed Graphene for Simultaneous Determination of Dopamine and Ascorbic Acid in Ex Vivo Mouse Brain Tissue
Authors: Thirumalai Dinakaran , Lee Seulah , Kwon Minho , Paik Hyun-jong , Lee Jaewon , Chang Seung-Cheol
Published: October 2021

Dopamine (DA) and ascorbic acid (AA) are two important biomarkers with similar oxidation potentials. To facilitate their simultaneous electrochemical detection, a new voltammetric sensor was developed by modifying a screen-printed carbon electrode (SPCE) with a newly synthesized block copolymer (poly(DMAEMA-b-styrene), PDbS) as a dispersant for reduced graphene oxide (rGO). The prepared PDbS–rGO and the modified SPCE were characterized using a range of physical and electrochemical techniques including Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, cyclic voltammetry, electrochemical impedance spectroscopy, and linear sweep voltammetry. Compared to the bare SPCE, the PDbS–rGO-modified SPCE (PDbS–rGO/SPCE) showed better sensitivity and peak-to-peak separation for DA and AA in mixed solutions. Under the optimum conditions, the dynamic linear ranges for DA and AA were 0.1–300 and 10–1100 µM, and the detection limits were 0.134 and 0.88 µM (S/N = 3), respectively. Furthermore, PDbS–rGO/SPCE exhibited considerably enhanced anti-interference capability, high reproducibility, and storage stability for four weeks. The practical potential of the PDbS–rGO/SPCE sensor for measuring DA and AA was demonstrated using ex vivo brain tissues from a Parkinson’s disease mouse model and the control.
Emotional Autobiographical Memory Associated with Insular Resection in Epileptic Patients: A Comparison with Temporal Lobe Resection
Authors: Descamps Mélanie , Boucher Olivier , Nguyen Dang Khoa , Rouleau Isabelle
Published: October 2021

The insula is involved in a wide variety of functions, including social and emotional processing. Despite the numerous connections it shares with brain structures known to play a role in autobiographical memory (AM), little is known on the contribution of the insula to AM processing. The aim of the study was to examine emotional AM retrieval in patients with insular resection for drug-resistant epilepsy. Ten patients who underwent partial or complete insular resection (IR) were matched on age, sex, and education, to fifteen patients who underwent temporal lobectomy (TL), and to fifteen healthy controls. Participants were asked to recall four positive, four negative, and four neutral memories from their past using the autobiographical interview procedure. The results suggest that AM for emotional and neutral events after IR was comparable to that of healthy controls, whereas deficits were observed after TL. However, an independent examiner judged IR patients’ memories as poorer than those of healthy controls on the episodic richness scale, suggesting a lack of some aspects of rich and vivid remembering. Furthermore, analysis on subjective self-rated scales revealed that, contrary to healthy controls, patients with IR judged their neutral memories as more emotional. This study suggests that AM is generally preserved after IR. However, given the small sample size and varied lesion location, one cannot totally exclude a potential role of specific insular sub-regions on some aspects of autobiographical memory. In addition, IR patients showed poor emotional judgment for neutral memories, which is congruent with previous findings of altered emotional processing in this population.
Pain Processing in Cognitive Impairment and Its Association with Executive Function and Memory: Which Neurocognitive Factor Takes the Lead?
Authors: Lautenbacher Stefan , Hoos Annegret , Hajak Göran , Trapp Wolfgang , Kunz Miriam
Published: October 2021

It is well established that individuals with cognitive impairment present with disturbed forms of pain processing of still unknown origin. As a neurocognitive factor, executive functions have become favored candidates for explanation. For further insights, we aimed at comparing executive functions and memory in their association with parameters indicating onset and escalation of pain perception. Subjective ratings of experimentally induced pressure pain applied in ascending series were assessed in older individuals with (N = 32) and without mild cognitive impairments (MCI) (N = 32). We investigated whether executive functioning (Trail Making Test-B (TMT-B), semantic fluency) or memory (word list and figure recall) were more closely linked to the onset and the escalation of pain. For the MCI group, a strong linkage between pain responses and the TMT-B could be found, i.e., poor test performance was associated with weak pain onset but strong pain escalation. The contribution of memory functions was less substantial and systematic. The prominent role of executive function for pain processing in individuals with MCI could be replicated by a test of cognitive flexibility. This lack of adaptability let individuals with MCI be less vigilant to pain at the beginning but allows for escalating pain in the further course. Thus, being first not sufficiently prepared and later overwhelmed as regards pain may be an early problem in MCI individuals with reduced executive functioning.
Experiences of Female Breast Cancer Survivors Concerning Their Return to Work in Spain
Authors: Aguiar-Fernández Francisco , Rodríguez-Castro Yolanda , Botija Mercedes , Martínez-Román Rosana
Published: October 2021

The objective of this study was to analyze the experiences of returning to work of women who had overcome breast cancer, identifying its physical and psychological consequences, the process they underwent, their motivations, and difficulties. A total of 19 female breast cancer survivors, with an age range of 30 to 57 years, participated in two focus groups. A semi-structured script was prepared about their experiences of returning to work. The results indicated that survivors’ self-perception was weakened by the physical and psychological consequences of the treatment of the disease; economic difficulties were one of the main reasons for going back to work; lastly, returning to work was a difficult process, mainly because of their physical/psychological limitations, the scarcity of job adaptation measures, and the limited support of the various public administrations. In addition, most of the women had to cope with seeking a new job without any guidance or job training. Significant difficulties related to the maintenance and return to work of female breast cancer survivors have been revealed. Findings highlighted the need to provide more and better information and guidance to cancer patients concerning their return to work or the search for a new job.
An Approach Concerning Climate Change and Timber Building Resilience: Araucanía Region, South Chile
Authors: Prieto Andrés J. , Verichev Konstantin , Silva Ana
Published: October 2021

This study analysed climate change effects concerning the resilience of timber buildings located in southern Chile, specifically in two cities: Collipulli and Temuco (Araucanía Region). A digital fuzzy logic method was used in a set of timber buildings declared as heritage conservation buildings by Chilean Government standards. The outcomes revealed that climate change impacts did not substantially alter the functional performance of the set of heritage timber buildings examined. This study’s results can assist in developing upcoming strategies or recommendations that can support adaptation policies for administering architectural heritage regarding climate change forecasts. These data will invaluably help stakeholders who support the conservation of timber structures located in the southern environment of Chile and under the changing climatic hazard.
The Relationship between Urban Density and Building Energy Consumption
Authors: Mostafavi Nariman , Heris Mehdi , Gándara Fernanda , Hoque Simi
Published: October 2021

Neighborhood characteristics influence natural urban energy fluxes and the choices made by urban actors. This article focuses on the impact of urban density as a neighborhood physical parameter on building energy consumption profiles for seven different metropolitan areas in the United States. Primarily, 30 × 30 m2 cells were classified into five categories of settlement density using the US Geological Survey’s National Land Cover Dataset (NLCD), the US Census, and Census Block data. In the next step, linear hierarchical spatial and non-spatial models were developed and applied to building energy data in those seven metropolitan areas to explore the links between urban density (and other urban form parameters) and energy performance, using both frequentist and Bayesian statistics. Our results indicate that urban density is correlated with energy-use intensity (EUI), but its impact is not similar across different metropolitan areas. The outcomes of our analysis further show that the distance from buildings within which the influence of urban form parameters on EUI is most significant varies by city and negatively changes with urban density. Although the relationship between urban density parameters and EUI varies across cities, tree-cover area, impervious area, and neighborhood building-covered area have a more consistent impact compared to building and housing density.
Blocking Estrogen Synthesis Leads to Different Hormonal Responses in Canine and Human Triple Negative Inflammatory Breast Cancer
Authors: Caceres Sara , Monsalve Beatriz , Alonso-Diez Angela , Crespo Belén , Illera Maria Jose , de Andres Paloma Jimena , Silvan Gema , Illera Juan Carlos
Published: October 2021

Blocking estrogen synthesis by inhibitors of estrogen synthesis is a widely used therapy against estrogen receptor-positive tumors. However, these therapies are less effective in negative expression tumors. Therefore, this study determined the effectiveness of anti-aromatase and anti-sulfatase therapies in canine and human inflammatory breast cancer. Cell cultures and xenografts from IPC-366 and SUM149 were treated with different doses of letrozole (anti-aromatase) and STX-64 (anti-sulfatase), in order to observe their effectiveness in terms of cell proliferation, tumor progression, and the appearance of metastases and hormonal profiles. The results revealed that both treatments are effective in vitro since they reduce cell proliferation and decrease the secreted estrogen levels. In xenograft mice, while treatment with letrozole reduces tumor progression by 30–40%, STX-64 increases tumor progression by 20%. The hormonal results obtained determined that STX-64 produced an increase in circulating and intratumoral levels of estradiol, which led to an increase in tumor progression. However, letrozole was able to block estrogen synthesis by decreasing the levels of circulating and intratumoral estrogen and thus slowing down tumor progression. In conclusion, letrozole can be an effective treatment for canine and human inflammatory breast cancer. The knowledge of the hormonal profile of breast tumors reflects useful information on the effectiveness of different endocrine treatments.
Ten Year Results of Extensive Nodal Radiotherapy and Moderately Hypofractionated Simultaneous Integrated Boost in Unfavorable Intermediate-, High-, and Very High-Risk Prostate Cancer
Authors: Di Muzio Nadia Gisella , Deantoni Chiara Lucrezia , Brombin Chiara , Fiorino Claudio , Cozzarini Cesare , Zerbetto Flavia , Mangili Paola , Tummineri Roberta , Dell’Oca Italo , Broggi Sara , Pasetti Marcella , Chiara Anna , Rancoita Paola Maria Vittoria , Del Vecchio Antonella , Di Serio Mariaclelia Stefania , Fodor Andrei
Published: October 2021

Aims: To report 10-year outcomes of WPRT and HD moderately hypofractionated SIB to the prostate in UIR, HR, and VHR PCa. Methods: From 11/2005 to 12/2015, 224 UIR, HR, and VHR PCa patients underwent WPRT at 51.8 Gy/28 fractions and SIB at 74.2 Gy (EQD2 88 Gy) to the prostate. Androgen deprivation therapy (ADT) was prescribed in up to 86.2% of patients. Results: Median follow-up was 96.3 months (IQR: 71–124.7). Median age was 75 years (IQR: 71.3–78.1). At last follow up, G3 GI–GU toxicity was 3.1% and 8%, respectively. Ten-year biochemical relapse-free survival (bRFS) was 79.8% (95% CI: 72.3–88.1%), disease-free survival (DFS) 87.8% (95% CI: 81.7–94.3%), overall survival (OS) 65.7% (95% CI: 58.2–74.1%), and prostate cancer-specific survival (PCSS) 94.9% (95% CI: 91.0–99.0%). Only two patients presented local relapse. At univariate analysis, VHR vs. UIR was found to be a significant risk factor for biochemical relapse (HR: 2.8, 95% CI: 1.17–6.67, p = 0.021). After model selection, only Gleason Score ≥ 8 emerged as a significant factor for biochemical relapse (HR = 2.3, 95% CI: 1.12–4.9, p = 0.023). Previous TURP (HR = 3.5, 95% CI: 1.62–7.54, p = 0.001) and acute toxicity ≥ G2 (HR = 3.1, 95% CI = 1.45–6.52, p = 0.003) were significant risk factors for GU toxicity ≥ G3. Hypertension was a significant factor for GI toxicity ≥ G3 (HR = 3.63, 95% CI: 1.06–12.46, p = 0.041). ADT (HR = 0.31, 95% CI: 0.12–0.8, p = 0.015) and iPsa (HR = 0.37, 95% CI: 0.16–0.83, p = 0.0164) played a protective role. Conclusions: WPRT and HD SIB to the prostate combined with long-term ADT, in HR PCa, determine good outcomes with acceptable toxicity.
Effect of Exercise Training on Quality of Life after Colorectal and Lung Cancer Surgery: A Meta-Analysis
Authors: Machado Pedro , Pimenta Sara , Oliveiros Bárbara , Ferreira José Pedro , Martins Raul A. , Cruz Joana
Published: October 2021

Surgical treatment affects health-related quality of life (HRQoL) and increases fatigue symptoms in patients with lung cancer (LC) and colorectal cancer (CRC). We aimed to systematically review the effect of exercise training on HRQoL and fatigue after LC and CRC surgery. Randomized controlled trials published before 21 March 2021, were searched in PubMed, Scopus, Web of Science, SPORTDiscus and PEDro. Eligible trials compared the effect of exercise interventions initiated preoperatively or in the first 3 months after surgery versus usual care on postoperative HRQoL and fatigue. Standardized mean differences (SMD) were pooled using random-effects models. Twelve studies with a total of 777 patients were included. In LC patients (10 studies, n = 651), exercise training in general led to a moderate improvement in the physical domain of HRQoL (0.68: 95% CI: [0.47; 0.89]) and a small reduction in fatigue levels after surgery (SMD = 0.28: 95% CI: [0.02; 0.53]), while no effects were found in other HRQoL domains. In CRC (two studies, n = 126), exercise training showed no effects on HRQoL and fatigue after surgery. Exercise training is an effective intervention to improve physical function and fatigue after LC surgery. Further studies are necessary to clarify the effects of exercise on HRQoL and fatigue after CRC surgery.
How Many Molecules Can Fit in a Zeolite Pore? Implications for the Hydrocarbon Pool Mechanism of the Methanol-to-Hydrocarbons Process
Authors: Parker Stewart , Kombanal Aleena
Published: October 2021

The methanol-to-hydrocarbons (MTH) process is a very advantageous way to upgrade methanol to more valuable commodity chemicals such as light alkenes and gasoline. There is general agreement that, at steady state, the process operates via a dual cycle “hydrocarbon pool” mechanism. This mechanism defines a minimum number of reactants, intermediates, and products that must be present for the reaction to occur. In this paper, we calculate (by three independent methods) the volume required for a range of compounds that must be present in a working catalyst. These are compared to the available volume in a range of zeolites that have been used, or tested, for MTH. We show that this straightforward comparison provides a means to rationalize the product slate and the deactivation pathways in zeotype materials used for the MTH reaction.
A Novel Likely Pathogenic Variant in the BLOC1S5 Gene Associated with Hermansky-Pudlak Syndrome Type 11 and an Overview of Human BLOC-1 Deficiencies
Authors: Boeckelmann Doris , Wolter Mira , Käsmann-Kellner Barbara , Koehler Udo , Schieber-Nakamura Lea , Zieger Barbara
Published: October 2021

Hermansky-Pudlak syndrome (HPS) is a heterogeneous disorder combining oculocutaneous albinism (OCA) and a platelet function disorder of varying severity as its most prominent features. The genes associated with HPS encode for different BLOC- (biogenesis of lysosome-related organelles complex) complexes and for the AP-3 (adaptor protein-3) complex, respectively. These proteins are involved in maturation, trafficking, and the function of lysosome-related organelles (LROs) such as melanosomes and platelet δ-granules. Some patients with different types of HPS can develop additional complications and symptoms like pulmonary fibrosis, granulomatous colitis, and immunodeficiency. A new type of HPS has recently been identified associated with genetic alterations in the BLOC1S5 gene, which encodes the subunit Muted of the BLOC-1 complex. Our aim was to unravel the genetic defect in two siblings with a suspected HPS diagnosis (because of OCA and bleeding symptoms) using next generation sequencing (NGS). Platelet functional analysis revealed reduced platelet aggregation after stimulation with ADP and a severe secretion defect in platelet δ-granules. NGS identified a novel homozygous essential splice site variant in the BLOC1S5 gene present in both affected siblings who are descendants of a consanguine marriage. The patients exhibited no additional symptoms. Our study confirms that pathogenic variants of BLOC1S5 cause the recently described HPS type 11.
New Insights into Molecular Mechanisms Mediating Adaptation to Exercise; A Review Focusing on Mitochondrial Biogenesis, Mitochondrial Function, Mitophagy and Autophagy
Authors: Roberts Fiona Louise , Markby Greg Robert
Published: October 2021

Exercise itself is fundamental for good health, and when practiced regularly confers a myriad of metabolic benefits in a range of tissues. These benefits are mediated by a range of adaptive responses in a coordinated, multi-organ manner. The continued understanding of the molecular mechanisms of action which confer beneficial effects of exercise on the body will identify more specific pathways which can be manipulated by therapeutic intervention in order to prevent or treat various metabolism-associated diseases. This is particularly important as exercise is not an available option to all and so novel methods must be identified to confer the beneficial effects of exercise in a therapeutic manner. This review will focus on key emerging molecular mechanisms of mitochondrial biogenesis, autophagy and mitophagy in selected, highly metabolic tissues, describing their regulation and contribution to beneficial adaptations to exercise.
Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression
Authors: Wang Chun-Chao
Published: October 2021

Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.
The Pro-Survival Oct4/Stat1/Mcl-1 Axis Is Associated with Poor Prognosis in Lung Adenocarcinoma Patients
Authors: Su Yu-Chu , Chen Yi-Cheng , Tseng Yau-Lin , Shieh Gia-Shing , Wu Pensee , Shiau Ai-Li , Wu Chao-Liang
Published: October 2021

The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma.
Dysfunction of Glutamate Delta-1 Receptor-Cerebellin 1 Trans-Synaptic Signaling in the Central Amygdala in Chronic Pain
Authors: Gandhi Pauravi J. , Gawande Dinesh Y. , Shelkar Gajanan P. , Gakare Sukanya G. , Kiritoshi Takaki , Ji Guangchen , Misra Bishal , Pavuluri Ratnamala , Liu Jinxu , Neugebauer Volker , Dravid Shashank M.
Published: October 2021

Chronic pain is a debilitating condition involving neuronal dysfunction, but the synaptic mechanisms underlying the persistence of pain are still poorly understood. We found that the synaptic organizer glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachio-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ+) neurons. Deletion of GluD1 impairs excitatory neurotransmission at the PB-CeLC synapses. In inflammatory and neuropathic pain models, GluD1 and its partner cerebellin 1 (Cbln1) are downregulated while AMPA receptor is upregulated. A single infusion of recombinant Cbln1 into the central amygdala led to sustained mitigation of behavioral pain parameters and normalized hyperexcitability of central amygdala neurons. Cbln2 was ineffective under these conditions and the effect of Cbln1 was antagonized by GluD1 ligand D-serine. The behavioral effect of Cbln1 was GluD1-dependent and showed lateralization to the right central amygdala. Selective ablation of GluD1 from the central amygdala or injection of Cbln1 into the central amygdala in normal animals led to changes in averse and fear-learning behaviors. Thus, GluD1-Cbln1 signaling in the central amygdala is a teaching signal for aversive behavior but its sustained dysregulation underlies persistence of pain. Significance statement: Chronic pain is a debilitating condition which involves synaptic dysfunction, but the underlying mechanisms are not fully understood. Our studies identify a novel mechanism involving structural synaptic changes in the amygdala caused by impaired GluD1-Cbln1 signaling in inflammatory and neuropathic pain behaviors. We also identify a novel means to mitigate pain in these conditions using protein therapeutics.
Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction
Authors: Eljaafari Assia , Pestel Julien , Le Magueresse-Battistoni Brigitte , Chanon Stephanie , Watson Julia , Robert Maud , Disse Emmanuel , Vidal Hubert
Published: October 2021

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.
Molecular Basis of a Dominant SARS-CoV-2 Spike-Derived Epitope Presented by HLA-A*02:01 Recognised by a Public TCR
Authors: Szeto Christopher , Nguyen Andrea T. , Lobos Christian A. , Chatzileontiadou Demetra S. M. , Jayasinghe Dhilshan , Grant Emma J. , Riboldi-Tunnicliffe Alan , Smith Corey , Gras Stephanie
Published: October 2021

The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; however, we lack data on how T cells are able to recognise this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.
Distribution of Cardiometabolic Risk Factors in School-Aged Children with Excess Body Weight in the Al Ain City, United Arab Emirates: A Cross-Sectional Study
Authors: Bhagavathula Akshaya Srikanth , Al-Hamad Sania , Yasin Javed , Aburawi Elhadi H.
Published: October 2021

(1) Background: This study aimed to examine the distribution of cardiometabolic risk factors (CMRF) in school-aged children with excess body weight (overweight and obese) in Al Ain City, United Arab Emirates and identify the factors associated with increased cardiovascular risk factors between boys and girls. (2) Methods: A cross-sectional survey of children aged 6–17 years was conducted in Al Ain from 1 August 2019 to 31 December 2020. Binary logistic regression analysis was performed to investigate the relationship between excess body weight and CMRF between the groups and reported odds ratios (OR) with 95% confidence intervals (CI). (3) Results: A total of 966 school-aged children (490 boys and 476 girls) participated in the study, and the mean age of the children was 11.8 ± 2.9 years. The proportions of overweight and obesity were 13.5% and 10.2% in boys and 11.1% and 10.3% in girls. Higher glucose of ≥100 mg/dL (26.4%), triglycerides of ≥150 mg/dL and low-density lipoprotein cholesterol: ≥130 mg/dL (23.2%) were more prevalent in children with excess body weight. These children were at least two times more likely to have higher triglycerides levels, high total cholesterol (≥200 mg/dL) in girls (OR:2.06, 95% CI: 1.01–4.21) and low high-density lipoprotein (<35 mg/dL) in boys (OR: 2.20; 95% CI: 1.12–4.31). (4) Conclusions: Excess body weight in school-aged children was associated with increased CMRF, particularly triglycerides.
Design of an Active Edible Coating Based on Sodium Caseinate, Chitosan and Oregano Essential Oil Reinforced with Silica Particles and Its Application on Panela Cheese
Authors: Ríos-de-Benito Luis Fernando , Escamilla-García Monserrat , García-Almendárez Blanca , Amaro-Reyes Aldo , Di Pierro Prospero , Regalado-González Carlos
Published: October 2021

Active edible films and coatings incorporating antimicrobial agents such as essential oils are studied to improve the shelf-life of fresh foods. The aim of this work was to study a mixture of sodium caseinate-chitosan (SC:CH), added with mesoporous silica nanoparticles filled with oregano essential oil (MSN-OEO), to produce an active edible coating for Panela cheese and to evaluate its properties during refrigerated storage for 15 days. The OEO was extracted by hydrodistillation and was incorporated into the MSN. Films based on SC:CH of 4:1 and 8:1 ratios with and without MSN-OEO were produced and the mechanical, barrier, physicochemical and microbiological properties of the films were evaluated. The SC:CH 8:1 ratio (w/w) with MSN-OEO showed reduced mean particle size (764.8 ± 23.3 nm), and a stable solution (zeta potential = 29.9 ± 1.1 mV). The thickness and solubility were influenced by the incorporation of MSN-OEO making it thinner and less soluble. Panela cheese samples were coated by the spray method using the SC:CH 8:1 containing MSN-OEO film forming solution. The final pH of the control cheese was 0.5 units lower than that of the coated cheese, whereas final moisture loss of the control cheese was 4.2 times that of the coated cheese. The mesophilic aerobic bacteria and of molds and yeasts populations achieved a reduction of about 2 Log10 UFC/g after 15 days of storage. Due to microbial growth delay, and little moisture loss, this active coating may improve the quality and safety of Panela cheese.
Biogenesis of Silver Nanoparticles and Its Multifunctional Anti-Corrosion and Anticancer Studies
Authors: Hublikar Leena V. , Ganachari Sharanabasava V. , Raghavendra Narasimha , Banapurmath Nagaraj R. , Patil Veerabhadragouda B. , Yunus Khan T. M. , Badruddin Irfan Anjum
Published: October 2021

In the present research, silver nanoparticles were synthesized using ground nutshell and characterized using UV-visible, FTIR and PXRD. The SEM and HR-TEM aided in confirming the nano size, surface morphology and phase purity of the AgNPs. The quantum chemical, electrochemical, and structural studies were carried out to understand electrochemical properties. In addition, biological study such as anti-cancerous activity was carried out, and IC-50 values 80.25 µg/mL for A549 lung cancer cell lines. The effective electrochemical anti-corrosion activities were also studied. The majority constituents of ground nutshell are flavonoids, in a small quantity of alkaloids and phenolic acids, which provide more stability to synthesize silver nanoparticles and avoid agglomeration. These functional moieties enhance the unique properties in the field, as in drug delivery systems, magnetic applications, and metallic, semi-conducting core-shell nanoparticles.