bluuebunny/crossref_metadata_2025 huggingface dataset:
Biogenic Ferrihydrite Nanoparticles: Synthesis, Properties In Vitro and In Vivo Testing and the Concentration Effect
Authors: Stolyar Sergey V. , Kolenchukova Oksana A. , Boldyreva Anna V. , Kudryasheva Nadezda S. , Gerasimova Yulia V. , Krasikov Alexandr A. , Yaroslavtsev Roman N. , Bayukov Oleg A. , Ladygina Valentina P. , Birukova Elena A.
Published: March 2021

Biogenic ferrihydrite nanoparticles were synthesized as a result of the cultivation of Klebsiella oxytoca microorganisms. The distribution of nanoparticles in the body of laboratory animals and the physical properties of the nanoparticles were studied. The synthesized ferrihydrite nanoparticles are superparamagnetic at room temperature, and the characteristic blocking temperature is 23–25 K. The uncompensated moment of ferrihydrite particles was determined to be approximately 200 Bohr magnetons. In vitro testing of different concentrations of ferrihydrite nanoparticles for the functional activity of neutrophilic granulocytes by the chemiluminescence method showed an increase in the release of primary oxygen radicals by blood phagocytes when exposed to a minimum concentration and a decrease in secondary radicals when exposed to a maximum concentration. In vivo testing of ferrihydrite nanoparticles on Wister rats showed that a suspension of ferrihydrite nanoparticles has chronic toxicity, since it causes morphological changes in organs, mainly in the spleen, which are characterized by the accumulation of hemosiderin nanoparticles (stained blue according to Perls). Ferrihydrite can also directly or indirectly stimulate the proliferation and intracellular regeneration of hepatocytes. The partial detection of Perls-positive cells in the liver and kidneys can be explained by the rapid elimination from organs and the high dispersion of the nanomaterial. Thus, it is necessary to carry out studies of these processes at the systemic level, since the introduction of nanoparticles into the body is characterized by adaptive-proliferative processes, accompanied by the development of cell dystrophy and tension of the phagocytic system.
Current FDA-Approved Therapies for High-Grade Malignant Gliomas
Authors: Fisher Jacob P. , Adamson David C.
Published: March 2021

The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.
Prevalence of Neural Autoantibodies in Epilepsy of Unknown Etiology: Systematic Review and Meta-Analysis
Authors: Cabezudo-García Pablo , Mena-Vázquez Natalia , Ciano-Petersen Nicolás L. , García-Martín Guillermina , Estivill-Torrús Guillermo , Serrano-Castro Pedro J.
Published: March 2021

Background: The prevalence of neural autoantibodies in epilepsy of unknown etiology varies among studies. We aimed to conduct a systematic review and meta-analysis to determine the pooled global prevalence and the prevalence for each antibody. Methods: A systematic search was conducted for studies that included prospectively patients ≥16 years old with epilepsy of unknown etiology and systematically determined neural autoantibodies. A meta-analysis was undertaken to estimate pooled prevalence in total patients with a positive result for at least one neural autoantibody in serum and/or cerebrospinal fluid (CSF) and for each autoantibody. Results: Ten of the eleven studies that met the inclusion criteria and a total of 1302 patients with epilepsy of unknown etiology were included in themeta-analysis. The global pooled prevalence (IC95%) was 7.6% (4.6–11.2) in a total of 82 patients with a positive result for any neural autoantibody. None of the controls available in the studies had a positive result. Individual pooled prevalence for each autoantibody was: glycine receptor (GlyR) (3.2%), glutamic acid decarboxylase (GAD) (1.9%), N-methyl-d-aspartate receptor (NMDAR) (1.8%), leucine-rich glioma inactivated-1 protein (LGI1) (1.1%), contactin-2-associated protein (CASPR2) (0.6%) and onconeuronal (0.2%). Conclusions: The pooled prevalence of neural autoantibodies in patients with epilepsy of unknown etiology is small but not irrelevant. None of the controls had a positive result. There was high heterogeneity among studies. In the future, a homogeneous protocol for testing neural autoantibodies is recommended.
Processing of Degraded Speech in Brain Disorders
Authors: Jiang Jessica , Benhamou Elia , Waters Sheena , Johnson Jeremy C. S. , Volkmer Anna , Weil Rimona S. , Marshall Charles R. , Warren Jason D. , Hardy Chris J. D.
Published: March 2021

The speech we hear every day is typically “degraded” by competing sounds and the idiosyncratic vocal characteristics of individual speakers. While the comprehension of “degraded” speech is normally automatic, it depends on dynamic and adaptive processing across distributed neural networks. This presents the brain with an immense computational challenge, making degraded speech processing vulnerable to a range of brain disorders. Therefore, it is likely to be a sensitive marker of neural circuit dysfunction and an index of retained neural plasticity. Considering experimental methods for studying degraded speech and factors that affect its processing in healthy individuals, we review the evidence for altered degraded speech processing in major neurodegenerative diseases, traumatic brain injury and stroke. We develop a predictive coding framework for understanding deficits of degraded speech processing in these disorders, focussing on the “language-led dementias”—the primary progressive aphasias. We conclude by considering prospects for using degraded speech as a probe of language network pathophysiology, a diagnostic tool and a target for therapeutic intervention.
Association between Previous Statin Use and Alzheimer’s Disease: A Nested Case-Control Study Using a National Health Screening Cohort
Authors: Kim Ji Hee , Lee Heui Seung , Wee Jee Hye , Kim Yoo Hwan , Min Chan Yang , Yoo Dae Myoung , Choi Hyo Geun
Published: March 2021

A number of studies report the incidence of Alzheimer’s disease (AD) in patients taking statins, but the results are inconsistent. (1) Background: The present study investigated the cross-sectional association between previous statin use and the risk of AD development in Korean residents. (2) Methods: We used the Korean National Health Insurance Service-National Sample Cohort; 17,172 AD patients were matched by age, gender, income, and region of residence with 68,688 control participants at a ratio of 1:4. We used a multiple conditional logistic regression model to analyse the association between the number of days of statin use and AD occurrence. Further analyses were performed to identify whether this association is maintained for different ages, genders, socioeconomic status groups, and covariates. (3) Results: The odds ratio, which was adjusted for potential confounders, for the days of statin use per year in the AD group compared to the control group was 0.95 (95% confidence interval = 0.92–0.98; p = 0.003). The number of days of statin use in the AD group was significantly smaller in the subgroups of non-smokers and individuals with normal weight, alcohol consumption less than once a week, total cholesterol level below 200 mg/dL, systolic blood pressure below 140, diastolic blood pressure below 90, and fasting blood glucose below 100 mg/dL. (4) Conclusions: Our results suggest that statin use prevents the occurrence of AD. The effects of statin use in preventing AD may be greater in individuals at relatively low risk.
Using Functional Connectivity to Examine the Correlation between Mirror Neuron Network and Autistic Traits in a Typically Developing Sample: A fNIRS Study
Authors: Nguyen Thien , Miguel Helga O. , Condy Emma E. , Park Soongho , Gandjbakhche Amir
Published: March 2021

Mirror neuron network (MNN) is associated with one’s ability to recognize and interpret others’ actions and emotions and has a crucial role in cognition, perception, and social interaction. MNN connectivity and its relation to social attributes, such as autistic traits have not been thoroughly examined. This study aimed to investigate functional connectivity in the MNN and assess relationship between MNN connectivity and subclinical autistic traits in neurotypical adults. Hemodynamic responses, including oxy- and deoxy-hemoglobin were measured in the central and parietal cortex of 30 healthy participants using a 24-channel functional Near-Infrared spectroscopy (fNIRS) system during a live action-observation and action-execution task. Functional connectivity was derived from oxy-hemoglobin data. Connections with significantly greater connectivity in both tasks were assigned to MNN connectivity. Correlation between connectivity and autistic traits were performed using Pearson correlation. Connections within the right precentral, right supramarginal, left inferior parietal, left postcentral, and between left supramarginal-left angular regions were identified as MNN connections. In addition, individuals with higher subclinical autistic traits present higher connectivity in both action-execution and action-observation conditions. Positive correlation between MNN connectivity and subclinical autistic traits can be used in future studies to investigate MNN in a developing population with autism spectrum disorder.
Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?
Authors: Lupica Antonino , Di Stefano Vincenzo , Gagliardo Andrea , Iacono Salvatore , Pignolo Antonia , Ferlisi Salvatore , Torrente Angelo , Pagano Sonia , Gangitano Massimo , Brighina Filippo
Published: March 2021

Inherited neuromuscular disorders (INMD) are a heterogeneous group of rare diseases that involve muscles, motor neurons, peripheral nerves or the neuromuscular junction. Several different lab abnormalities have been linked to INMD: sometimes they are typical of the disorder, but they usually appear to be less specific. Sometimes serum biomarkers can point out abnormalities in presymtomatic or otherwise asymptomatic patients (e.g., carriers). More often a biomarker of INMD is evaluated by multiple clinicians other than expert in NMD before the diagnosis, because of the multisystemic involvement in INMD. The authors performed a literature search on biomarkers in inherited neuromuscular disorders to provide a practical approach to the diagnosis and the correct management of INMD. A considerable number of biomarkers have been reported that support the diagnosis of INMD, but the role of an expert clinician is crucial. Hence, the complete knowledge of such abnormalities can accelerate the diagnostic workup supporting the referral to specialists in neuromuscular disorders.
Health and Safety Consideration in the Procurement of Public Construction Projects in Ghana
Authors: Boadu Elijah Frimpong , Sunindijo Riza Yosia , Wang Cynthia Changxin
Published: March 2021

This study explored the extent to which health and safety (H&S) are considered in the procurement of public sector projects in Ghana. This is based on the background that procurement decisions have implications for project H&S management. The enormous size of public procurement projects offers opportunities for public clients to influence the behaviour of the construction market including the promotion of H&S through procurement. To date, no study has fully assessed the extent of H&S considerations in procurement decisions for public sector construction projects in Ghana. To fill this gap, this research has provided an evidence-based assessment of H&S considerations in the various stages of the procurement process for public sector projects in Ghana. Through a questionnaire survey, data were collected from construction industry professionals in Ghana. The data were subjected to statistical analysis to evaluate the extent of H&S considerations. The findings suggest that H&S is given low priority in the procurement of public projects, because clear project objectives relating to H&S are not set, and adequate consideration is not given to H&S at the various procurement stages. Based on the findings, this research has made recommendations to promote H&S in public procurement in Ghana.
Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma
Authors: Akil Hussein , Quintana Mercedes , Raymond Jérémy H. , Billoux Tommy , Benboubker Valentin , Besse Sophie , Auzeloux Philippe , Delmas Véronique , Petit Valérie , Larue Lionel , D’Incan Michel , Degoul Françoise , Rouanet Jacques
Published: March 2021

Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.
Interstitial HDR Brachytherapy in the Treatment of Non-Melanocytic Skin Cancers around the Eye
Authors: Cisek Paweł , Kieszko Dariusz , Bilski Mateusz , Dębicki Radomir , Grywalska Ewelina , Hrynkiewicz Rafał , Bębnowska Dominika , Kordzińska-Cisek Izabela , Rolińska Agnieszka , Niedźwiedzka-Rystwej Paulina , Grzybowska-Szatkowska Ludmiła
Published: March 2021

Background: Eyelid tumors are rare skin cancers, the most common of which is basal cell carcinoma characterized primarily by local growth. In addition to surgery, radiotherapy is among the basic methods of treatment. External beam radiotherapy is associated with the risk of complications within ocular structures, especially the lens. In the case of interstitial brachytherapy, it is possible to administer a high dose to the clinical target volume (CTV), while reducing it in the most sensitive structures. Methods: This paper presents the results of an analysis of 28 patients treated with interstitial high dose rate (HDR) brachytherapy for skin cancers of the upper and lower eyelid; medial and lateral canthus; and the cheek, nose and temples with the infiltration of ocular structures. The patients were treated according to two irradiation schedules: 49 Gy in 14 fractions of 3.5 Gy twice a day for 7 days of treatment, and 45 Gy in 5 Gy fractions twice a day for 5 days. The mean follow-up was 22 months (3–49 months). Results: two patients (6%) had a relapse: a local recurrence within the irradiated area in one of them, and metastases to lymph nodes in the other. The most common early complication was conjunctivitis (74%), and the most common late complication was dry eye syndrome (59%). Conclusions: Interstitial HDR brachytherapy for skin cancers of the upper and lower eyelid; medial and lateral cants; and the cheek, nose and temples with infiltration of ocular structures is a highly effective, short and relatively low burden type of treatment.
Systemic Therapy of Metastatic Melanoma: On the Road to Cure
Authors: Steininger Julian , Gellrich Frank Friedrich , Schulz Alexander , Westphal Dana , Beissert Stefan , Meier Friedegund
Published: March 2021

This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma.
Exploring Volatile Organic Compounds in Breath for High-Accuracy Prediction of Lung Cancer
Authors: Tsou Ping-Hsien , Lin Zong-Lin , Pan Yu-Chiang , Yang Hui-Chen , Chang Chien-Jen , Liang Sheng-Kai , Wen Yueh-Feng , Chang Chia-Hao , Chang Lih-Yu , Yu Kai-Lun , Liu Chia-Jung , Keng Li-Ta , Lee Meng-Rui , Ko Jen-Chung , Huang Guan-Hua , Li Yaw-Kuen
Published: March 2021

(1) Background: Lung cancer is silent in its early stages and fatal in its advanced stages. The current examinations for lung cancer are usually based on imaging. Conventional chest X-rays lack accuracy, and chest computed tomography (CT) is associated with radiation exposure and cost, limiting screening effectiveness. Breathomics, a noninvasive strategy, has recently been studied extensively. Volatile organic compounds (VOCs) derived from human breath can reflect metabolic changes caused by diseases and possibly serve as biomarkers of lung cancer. (2) Methods: The selected ion flow tube mass spectrometry (SIFT-MS) technique was used to quantitatively analyze 116 VOCs in breath samples from 148 patients with histologically confirmed lung cancers and 168 healthy volunteers. We used eXtreme Gradient Boosting (XGBoost), a machine learning method, to build a model for predicting lung cancer occurrence based on quantitative VOC measurements. (3) Results: The proposed prediction model achieved better performance than other previous approaches, with an accuracy, sensitivity, specificity, and area under the curve (AUC) of 0.89, 0.82, 0.94, and 0.95, respectively. When we further adjusted the confounding effect of environmental VOCs on the relationship between participants’ exhaled VOCs and lung cancer occurrence, our model was improved to reach 0.92 accuracy, 0.96 sensitivity, 0.88 specificity, and 0.98 AUC. (4) Conclusion: A quantitative VOCs databank integrated with the application of an XGBoost classifier provides a persuasive platform for lung cancer prediction.
Momordicine-I, a Bitter Melon Bioactive Metabolite, Displays Anti-Tumor Activity in Head and Neck Cancer Involving c-Met and Downstream Signaling
Authors: Sur Subhayan , Steele Robert , Isbell T. Scott , Venkata Kalyan Nagulapalli , Rateb Mostafa E. , Ray Ratna B.
Published: March 2021

Head and neck cancer (HNC) is one of the most aggressive cancers, and treatments are quite challenging due to the difficulty in early diagnosis, lack of effective chemotherapeutic drugs, adverse side effects and therapy resistance. We identified momordicine-I (M-I), a bioactive secondary metabolite in bitter melon (Momordica charantia), by performing liquid chromatography-high resolution electrospray ionization mass spectrometry (LC-HRESIMS) analysis. M-I inhibited human HNC cell (JHU022, JHU029, Cal27) viability in a dose-dependent manner without an apparent toxic effect on normal oral keratinocytes. Mechanistic studies showed that M-I inhibited c-Met and its downstream signaling molecules c-Myc, survivin, and cyclin D1 through the inactivation of STAT3 in HNC cells. We further observed that M-I was non-toxic and stable in mouse (male C57Bl/6) blood, and a favorable pharmacokinetics profile was observed after IP administration. M-I treatment reduced HNC xenograft tumor growth in nude mice and inhibited c-Met and downstream signaling. Thus, M-I has potential therapeutic implications against HNC.
A Cystine-Cysteine Intercellular Shuttle Prevents Ferroptosis in xCTKO Pancreatic Ductal Adenocarcinoma Cells
Authors: Meira Willian , Daher Boutaina , Parks Scott Kenneth , Cormerais Yann , Durivault Jerome , Tambutte Eric , Pouyssegur Jacques , Vučetić Milica
Published: March 2021

In our previous study, we showed that a cystine transporter (xCT) plays a pivotal role in ferroptosis of pancreatic ductal adenocarcinoma (PDAC) cells in vitro. However, in vivo xCTKO cells grew normally indicating that a mechanism exists to drastically suppress the ferroptotic phenotype. We hypothesized that plasma and neighboring cells within the tumor mass provide a source of cysteine to confer full ferroptosis resistance to xCTKO PDAC cells. To evaluate this hypothesis, we (co-) cultured xCTKO PDAC cells with different xCT-proficient cells or with their conditioned media. Our data unequivocally showed that the presence of a cysteine/cystine shuttle between neighboring cells is the mechanism that provides redox and nutrient balance, and thus ferroptotic resistance in xCTKO cells. Interestingly, although a glutathione shuttle between cells represents a good alternative hypothesis as a “rescue-mechanism”, our data clearly demonstrated that the xCTKO phenotype is suppressed even with conditioned media from cells lacking the glutathione biosynthesis enzyme. Furthermore, we demonstrated that prevention of lipid hydroperoxide accumulation in vivo is mediated by import of cysteine into xCTKO cells via several genetically and pharmacologically identified transporters (ASCT1, ASCT2, LAT1, SNATs). Collectively, these data highlight the importance of the tumor environment in the ferroptosis sensitivity of cancer cells.
Comparison of Cancer Patients to Non-Cancer Patients among COVID-19 Inpatients at a National Level
Authors: Bernard Alain , Cottenet Jonathan , Bonniaud Philippe , Piroth Lionel , Arveux Patrick , Tubert-Bitter Pascale , Quantin Catherine
Published: March 2021

(1) Background: Several smaller studies have shown that COVID-19 patients with cancer are at a significantly higher risk of death. Our objective was to compare patients hospitalized for COVID-19 with cancer to those without cancer using national data and to study the effect of cancer on the risk of hospital death and intensive care unit (ICU) admission. (2) Methods: All patients hospitalized in France for COVID-19 in March–April 2020 were included from the French national administrative database, which contains discharge summaries for all hospital admissions in France. Cancer patients were identified within this population. The effect of cancer was estimated with logistic regression, adjusting for age, sex and comorbidities. (3) Results: Among the 89,530 COVID-19 patients, we identified 6201 cancer patients (6.9%). These patients were older and were more likely to be men and to have complications (acute respiratory and kidney failure, venous thrombosis, atrial fibrillation) than those without cancer. In patients with hematological cancer, admission to ICU was significantly more frequent (24.8%) than patients without cancer (16.4%) (p < 0.01). Solid cancer patients without metastasis had a significantly higher mortality risk than patients without cancer (aOR = 1.4 [1.3–1.5]), and the difference was even more marked for metastatic solid cancer patients (aOR = 3.6 [3.2–4.0]). Compared to patients with colorectal cancer, patients with lung cancer, digestive cancer (excluding colorectal cancer) and hematological cancer had a higher mortality risk (aOR = 2.0 [1.6–2.6], 1.6 [1.3–2.1] and 1.4 [1.1–1.8], respectively). (4) Conclusions: This study shows that, in France, patients with COVID-19 and cancer have a two-fold risk of death when compared to COVID-19 patients without cancer. We suggest the need to reorganize facilities to prevent the contamination of patients being treated for cancer, similar to what is already being done in some countries.
Fistula-Related Cancer in Crohn’s Disease: A Systematic Review
Authors: Kotsafti Andromachi , Scarpa Melania , Angriman Imerio , Castagliuolo Ignazio , Caruso Antonino
Published: March 2021

Perianal fistulizing Crohn’s disease is a very disabling condition with poor quality of life. Patients with perianal fistulizing Crohn’s disease are also at risk of perianal fistula-related squamous cell carcinoma (SCC). Cancer arising at the site of a chronic perianal fistula is rare in patients with Crohn’s disease and there is a paucity of data regarding its incidence, diagnosis and management. A systematic review of the literature was undertaken using Medline, Embase, Pubmed, Cochrane and Web of Science. Several small series have described sporadic cases with perianal cancer in Crohn’s disease. The incidence rate of SCC related to perianal fistula was very low (<1%). Prognosis was poor. Colorectal disease, chronic perianal disease and HPV infection were possible risk factors. Fistula-related carcinoma in CD (Chron’s disease) can be very difficult to diagnose. Examination may be limited by pain, strictures and induration of the perianal tissues. HPV is an important risk factor with a particular carcinogenesis mechanism. MRI can help clinicians in diagnosis. Examination under anesthesia is highly recommended when findings, a change in symptoms, or simply long-standing disease in the perineum are present. Future studies are needed to understand the role of HPV vaccination in preventing fistula-related cancer.
Predictors of Survival in Subtotally Resected WHO Grade I Skull Base Meningiomas
Authors: Da Broi Michele , Borrelli Paola , Meling Torstein R.
Published: March 2021

Background: Although gross total resection (GTR) is the goal in meningioma surgery, this can sometimes be difficult to achieve in skull base meningiomas. We analyzed clinical outcomes and predictors of survival for subtotally resected benign meningiomas. Methods: A total of 212 consecutive patients who underwent subtotal resection (STR) for benign skull base meningioma between 1990–2010 were investigated. Results: Median age was 57.7 [IQR 18.8] years, median preoperative Karnofsky performance status (KPS) was 80.0 [IQR 20.0], 75 patients (35.4%) had posterior fossa meningioma. After a median follow-up of 6.2 [IQR 7.9] years, retreatment (either radiotherapy or repeated surgery) rate was 16% at 1-year, 27% at 3-years, 34% at 5-years, and 38% at 10-years. Ten patients (4.7%) died perioperatively, 9 (3.5%) had postoperative hematomas, and 2 (0.8%) had postoperative infections. Neurological outcome at final visit was improved/stable in 122 patients (70%). Multivariable analysis identified advanced age and preoperative KPS < 70 as negative predictors for overall survival (OS). Patients who underwent retreatment had no significant reduction of OS. Conclusions: Advanced age and preoperative KPS were independent predictors of OS. Retreatments did not prolong nor shorten the OS. Clinical outcomes in STR skull base meningiomas were generally worse compared to cohorts with high rates of GTR.
NCDB Analysis of Melanoma 2004–2015: Epidemiology and Outcomes by Subtype, Sociodemographic Factors Impacting Clinical Presentation, and Real-World Survival Benefit of Immunotherapy Approval
Authors: Singh Sunny R. K. , Malapati Sindhu J. , Kumar Rohit , Willner Christopher , Wang Ding
Published: March 2021

Background: The incidence of invasive melanoma is rising, and approval for the first immune checkpoint inhibitor (ICI) to treat metastatic melanoma occurred in 2011. We aim to describe the epidemiology and outcomes in recent years, sociodemographic factors associated with the presence of metastasis at diagnosis, and the real-world impact of ICI approval on survival based on melanoma subtype and race. Methods: This is a retrospective analysis of the National Cancer Database (NCDB) from the years 2004–2015. The primary outcome was the overall survival of metastatic melanoma by subtype. Secondary outcomes included sociodemographic factors associated with the presence of metastasis at diagnosis and the impact of treatment facility type and ICI approval on the survival of metastatic melanoma. Results: Of the 419,773 invasive melanoma cases, 93.80% were cutaneous, and 4.92% were metastatic at presentation. The odds of presenting with metastatic disease were higher in African Americans (AA) compared to Caucasians (OR 2.37; 95% CI 2.11–2.66, p < 0.001). Treatment of metastatic melanoma at an academic/research facility was associated with lower mortality versus community cancer programs (OR 0.75, 95 % CI 0.69–0.81, p-value < 0.001). Improvement in survival of metastatic melanoma was noted for Caucasians after the introduction of ICI (adjusted HR 0.80, 95% CI 0.78–0.83, p < 0.001); however, this was not statistically significant for AA (adjusted HR 0.80, 95% CI 0.62–1.02, p-value = 0.073) or ocular cases (HR 1.03, 95% CI 0.81–1.31, p-value = 0.797). Conclusion: Real-world data suggest a 20% improvement in survival of metastatic melanoma since the introduction of ICI. The disproportionately high odds of metastatic disease at presentation in AA patients with melanoma suggest the need for a better understanding of the disease and improvement in care delivery.
Photocatalytic Oxygenation of Heterostilbenes—Batch versus Microflow Reactor
Authors: Mlakić Milena , Šalić Anita , Bačić Matea , Zelić Bruno , Šagud Ivana , Horváth Ottó , Škorić Irena
Published: March 2021

On the basis of earlier results with furan and thiophene derivatives of benzobicyclo[3.2.1]octadiene, photocatalytic oxygenation of novel furo- and thieno heterostilbenes with water-soluble manganese(III) porphyrins offered suitable possibilities to study their reactivities and reaction pathways depending on the heteroatom and the catalyst charge. The experiments were carried out in two reactors types (batch and microflow) to investigate the geometric effects. NMR spectroscopy, GC, and UPLC/MS analyses were applied for identification and quantification of the products. As our results indicated, the 2-thienyl and the common p-tolyl groups in the starting compounds remained intact due to their stronger aromaticity. Hence, the thieno derivative underwent oxygenation only at the open-chain part of the molecule, and the rates of its reactions were much lower than those of the furyl analogue. The less stable furan ring was easily oxygenated, its products with highest ratios were 2-furanon derivatives. Epoxide formation occurred at the open-chain parts of both substrates preferably by the anionic catalyst. Nevertheless, the conversion rates of the substrates were higher with the cationic porphyrin, according to electrophilic attacks by photogenerated Mn(V)=O species. Additionally, the reactions were significantly faster in microflow reactors due to the more favorable circumstances of mass transfer, diffusion, and light penetration.
Improvement of Propylene Epoxidation Caused by Silver Plasmon Excitation by UV-LED Irradiation on a Sodium-Modified Silver Catalyst Supported on Strontium Carbonate
Authors: Sugiyama Shigeru , Okitsu Ikumi , Hashimoto Kazuki , Maki Yutaro , Shimoda Naohiro , Furube Akihiro , Kato Yuki , Ninomiya Wataru
Published: March 2021

The effect that UV-LED irradiation exerted on a sodium-modified silver catalyst supported on strontium carbonate (Ag-Na/SrCO3) was examined during an epoxidation of propylene to propylene oxide. Based on our previous study, we used Ag(56)-Na(1)/SrCO3 in this study. The numbers in parentheses refer to the weight percentage of silver and sodium. Although this catalyst system did not contain typical photocatalysts such as titanium oxide or tungsten oxide, UV-LED irradiation of Ag(56)-Na(1)/SrCO3 resulted in an evident improvement in the selectivity and yield of propylene oxide. Such an advantageous effect of UV-LED irradiation could not be discussed based on the bandgap used in photocatalysts and, therefore, we proposed a mechanism based on the plasmon excitation of silver, which could be accomplished using the irradiation wavelength of UV-LED to produce electrons. Since the lifespan of these electrons is expected to be short, it is difficult to place them into direct contact with the gas phase of oxygen. Once the generated electrons move to SrCO3, however, the lifespan is improved, which could allow suitable contact with oxygen in the gas phase to form active oxygen. If the oxygen is active for epoxidation as hydrogen peroxide, this could explain the improvement in activity from UV-LED irradiation.
Cell–Matrix Interactions in the Eye: From Cornea to Choroid
Authors: Pouw Andrew E. , Greiner Mark A. , Coussa Razek G. , Jiao Chunhua , Han Ian C. , Skeie Jessica M. , Fingert John H. , Mullins Robert F. , Sohn Elliott H.
Published: March 2021

The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch’s membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon’s layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-β, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed.
Analysis of Nucleosides and Nucleotides in Plants: An Update on Sample Preparation and LC–MS Techniques
Authors: Straube Henryk , Witte Claus-Peter , Herde Marco
Published: March 2021

Nucleotides fulfill many essential functions in plants. Compared to non-plant systems, these hydrophilic metabolites have not been adequately investigated in plants, especially the less abundant nucleotide species such as deoxyribonucleotides and modified or damaged nucleotides. Until recently, this was mainly due to a lack of adequate methods for in-depth analysis of nucleotides and nucleosides in plants. In this review, we focus on the current state-of-the-art of nucleotide analysis in plants with liquid chromatography coupled to mass spectrometry and describe recent major advances. Tissue disruption, quenching, liquid–liquid and solid-phase extraction, chromatographic strategies, and peculiarities of nucleotides and nucleosides in mass spectrometry are covered. We describe how the different steps of the analytical workflow influence each other, highlight the specific challenges of nucleotide analysis, and outline promising future developments. The metabolite matrix of plants is particularly complex. Therefore, it is likely that nucleotide analysis methods that work for plants can be applied to other organisms as well. Although this review focuses on plants, we also discuss advances in nucleotide analysis from non-plant systems to provide an overview of the analytical techniques available for this challenging class of metabolites.
CALINCA—A Novel Pipeline for the Identification of lncRNAs in Podocyte Disease
Authors: Talyan Sweta , Filipów Samantha , Ignarski Michael , Smieszek Magdalena , Chen He , Kühne Lucas , Butt Linus , Göbel Heike , Hoyer-Allo K. Johanna R. , Koehler Felix C. , Altmüller Janine , Brinkkötter Paul , Schermer Bernhard , Benzing Thomas , Kann Martin , Müller Roman-Ulrich , Dieterich Christoph
Published: March 2021

Diseases of the renal filtration unit—the glomerulus—are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.
Microglial Cell Morphology and Phagocytic Activity Are Critically Regulated by the Neurosteroid Allopregnanolone: A Possible Role in Neuroprotection
Authors: Jolivel Valérie , Brun Susana , Binamé Fabien , Benyounes Jérémie , Taleb Omar , Bagnard Dominique , De Sèze Jérôme , Patte-Mensah Christine , Mensah-Nyagan Ayikoe-Guy
Published: March 2021

Microglial cells are key players in neural pathogenesis and microglial function regulation appears to be pivotal in controlling neuroinflammatory/neurological diseases. Here, we investigated the effects and mechanism of action of neurosteroid allopregnanolone (ALLO) on murine microglial BV-2 cells and primary microglia in order to determine ALLO-induced immunomodulatory potential and to provide new insights for the development of both natural and safe neuroprotective strategies targeting microglia. Indeed, ALLO-treatment is increasingly suggested as beneficial in various models of neurological disorders but the underlying mechanisms have not been elucidated. Therefore, the microglial cells were cultured with various serum concentrations to mimic the blood-brain-barrier rupture and to induce their activation. Proliferation, viability, RT-qPCR, phagocytosis, and morphology analyzes, as well as migration with time-lapse imaging and quantitative morphodynamic methods, were combined to investigate ALLO actions on microglia. BV-2 cells express subunits of GABA-A receptor that mediates ALLO activity. ALLO (10µM) induced microglial cell process extension and decreased migratory capacity. Interestingly, ALLO modulated the phagocytic activity of BV-2 cells and primary microglia. Our results, which show a direct effect of ALLO on microglial morphology and phagocytic function, suggest that the natural neurosteroid-based approach may contribute to developing effective strategies against neurological disorders that are evoked by microglia-related abnormalities.
Direct Stimulatory Effects of the CB2 Ligand JTE 907 in Human and Mouse Islets
Authors: Ruz-Maldonado Inmaculada , Atanes Patricio , Huang Guo Cai , Liu Bo , Persaud Shanta J
Published: March 2021

Aims: The endocannabinoid system is a complex cell-signaling network through which endogenous cannabinoid ligands regulate cell function by interaction with CB1 and CB2 cannabinoid receptors, and with the novel cannabinoid receptor GPR55. CB1, CB2, and GPR55 are expressed by islet β-cells where they modulate insulin secretion. We have previously shown that administration of the putative CB2 antagonist/inverse agonist JTE 907 to human islets did not affect the insulinotropic actions of CB2 agonists and it unexpectedly stimulated insulin secretion on its own. In this study, we evaluated whether the lack of antagonism could be related to the ability of JTE 907 to act as a GPR55 agonist. Materials and Methods: We used islets isolated from human donors and from Gpr55+/+ and Gpr55−/− mice and quantified the effects of incubation with 10 μM JTE 907 on dynamic insulin secretion, apoptosis, and β-cell proliferation by radioimmunoassay, luminescence caspase 3/7 activity, and immunofluorescence, respectively. We also measured islet IP1 and cAMP accumulation using fluorescence assays, and monitored [Ca2+]i elevations by Fura-2 single cell microfluorometry. Results: JTE 907 significantly stimulated insulin secretion from islets isolated from human donors and islets from Gpr55+/+ and Gpr55−/− mice. These stimulatory effects were accompanied by significant elevations of IP1 and [Ca2+]i, but there were no changes in cAMP generation. JTE 907 also significantly reduced cytokine-induced apoptosis in human and mouse islets and promoted human β-cell proliferation. Conclusion: Our observations show for the first time that JTE 907 acts as a Gq-coupled agonist in islets to stimulate insulin secretion and maintain β-cell mass in a GPR55-independent fashion.
The Role of Sleep in the Transition from Acute to Chronic Musculoskeletal Pain in Youth—A Narrative Review
Authors: Andreucci Alessandro , Groenewald Cornelius B. , Rathleff Michael Skovdal , Palermo Tonya M.
Published: March 2021

Musculoskeletal pain is common in the general pediatric population and is a challenge to youth, their parents, and society. The majority of children experiencing musculoskeletal pain will recover; however, a small subgroup of youth develops chronic pain. There is limited understanding of the factors that affect the transition from acute to chronic pain in youth. This review introduces sleep deficiency in the acute to chronic pain transition, exploring the potential mediational or mechanistic role and pathways of sleep in this process, including the interaction with sensory, psychological, and social components of pain and highlighting new avenues for treatment. Biological mechanisms include the increased production of inflammatory mediators and the effect on the hypothalamus-pituitary-adrenal (HPA) axis and on the dopaminergic signaling. Psychological and social components include the effect of sleep on the emotional-affective and behavioral components of pain, the negative impact on daily and social activities and coping strategies and on the reward system, increased pain catastrophizing, fear of pain, pain-related anxiety, hypervigilance, and social isolation. Future longitudinal studies are needed to elucidate these mechanistic pathways of the effect of sleep on the transition from acute to chronic pain, which may lead to the development of new treatment targets to prevent this transition.
Association of Acculturation and Latino Parents’ Oral Health Beliefs and Knowledge
Authors: Tiwari Tamanna , Poravanthattil Anila , Rai Nayanjot , Wilson Anne
Published: March 2021

The purpose of our study was to explore the association of acculturation and Latino parent behavioral and psychosocial characteristics. A cross-sectional survey was conducted with 197 parent-children triads. Participating parents completed survey questions encompassing oral health knowledge, behaviors and beliefs from a validated oral health instrument. The mean score for acculturation in this sample was 3.8, where acculturation was dichotomized to a categorical variable. The bivariate associations between the independent variables (caregiver psychosocial factors and socio-economic factors (SES) factors) and acculturation (more/less acculturated) were conducted using logistic regression analysis, and for the final model a multivariate logistic regression model was used. In the bivariate analyses, less acculturated parents reported lower oral health knowledge (p = 0.02), higher social support (p = 0.028) and chronic stress (p = 0.015) and lower perceived susceptibility to dental caries in their children (p = 0.039). The bivariate analysis demonstrated that less acculturated parents had less education and employment (p < 0.0001) than more acculturated parents. The multivariate logistic model demonstrated that social support (p = 0.028), chronic stress (p = 0.015) and health beliefs as barriers to access dental care (p = 0.039) were higher in less acculturated parents compared to more acculturated parents. Less acculturated parents demonstrated lower oral health knowledge, higher stress and more barriers to accessing oral health care for their children. Oral health interventions for Latino families should incorporate strategies that include consideration of parental oral health beliefs.
Te-Embedded Nanocrystalline PbTe Thick Films: Structure and Thermoelectric Properties Relationship
Authors: Wu Tingjun , Lim Jae-Hong , Lee Kyu-Hwan , Kim Jiwon , Myung Nosang V.
Published: March 2021

The Te-embedded PbTe nanocrystallline thick films (i.e., 50 µm) were electrodeposited, where the fraction and average grain size of PbTe and Te phases were tuned by adjusting the applied potential followed by post thermal treatment. The crystal grain boundary and Te nano-inclusion in the films played critical roles in their thermoelectric properties. The Te-embedded PbTe thick film with the average grain size of around 100 nm showed lower energy barrier height (EB = 0.023 eV) than thick films with the average grain size of a few tens of nm (EB = 0.11). Although decrease in the energy barrier reduced the Seebeck coefficient, however, it enhanced the electrical conductivity, which resulted in an increase in power factor (PF). The highest power factor was 183 μw K−2 cm−1, achieved at the energy barrier of 0.023 eV.