bluuebunny/crossref_metadata_2025 huggingface dataset:
Uncertainty Quantification in Segmenting Tuberculosis-Consistent Findings in Frontal Chest X-rays
Authors: Rajaraman Sivaramakrishnan , Zamzmi Ghada , Yang Feng , Xue Zhiyun , Jaeger Stefan , Antani Sameer K.
Published: June 2022

Deep learning (DL) methods have demonstrated superior performance in medical image segmentation tasks. However, selecting a loss function that conforms to the data characteristics is critical for optimal performance. Further, the direct use of traditional DL models does not provide a measure of uncertainty in predictions. Even high-quality automated predictions for medical diagnostic applications demand uncertainty quantification to gain user trust. In this study, we aim to investigate the benefits of (i) selecting an appropriate loss function and (ii) quantifying uncertainty in predictions using a VGG16-based-U-Net model with the Monto–Carlo (MCD) Dropout method for segmenting Tuberculosis (TB)-consistent findings in frontal chest X-rays (CXRs). We determine an optimal uncertainty threshold based on several uncertainty-related metrics. This threshold is used to select and refer highly uncertain cases to an expert. Experimental results demonstrate that (i) the model trained with a modified Focal Tversky loss function delivered superior segmentation performance (mean average precision (mAP): 0.5710, 95% confidence interval (CI): (0.4021,0.7399)), (ii) the model with 30 MC forward passes during inference further improved and stabilized performance (mAP: 0.5721, 95% CI: (0.4032,0.7410), and (iii) an uncertainty threshold of 0.7 is observed to be optimal to refer highly uncertain cases.
Perineural Capsaicin Treatment Inhibits Collateral Sprouting of Intact Cutaneous Nociceptive Afferents
Authors: Sántha Péter , Lakatos Szandra , Horváth Ágnes , Dux Mária , Jancsó Gábor
Published: June 2022

Perineural treatment of peripheral nerves with capsaicin produces a long-lasting selective regional thermo- and chemo-analgesia and elimination of the neurogenic inflammatory response involving degeneration of nociceptive afferent fibers. In this study, we examined longitudinal changes in mustard oil–induced sensory neurogenic vasodilatation and plasma extravasation following perineural capsaicin treatment of the rat saphenous nerve utilizing scanning laser Doppler imaging and vascular labeling with colloidal silver. Capsaicin treatment resulted in a marked decrease in mustard oil–induced vasodilatation in the skin area served by the saphenous nerve. Repeated imaging of the vasodilatatory response showed no recovery for at least 7 weeks. However, following transection and ligation of the capsaicin-treated saphenous nerve, a substantial recovery of the vasodilatatory response was observed, suggesting a reinnervation of the chemodenervated skin area by collateral sprouting of neighboring intact sciatic nerve afferents. Elimination of the recovered vascular reaction by capsaicin treatment of the sciatic nerve supported this conclusion. Similar results have been obtained by using the vascular labeling technique. These findings indicate an inhibitory effect of persisting cutaneous nerve fibers on the collateral sprouting of intact nerve fibers into the chemodenervated skin area. These observations may bear implications for the development of sensory disturbances following peripheral nerve injuries.
Serum Lactate Dehydrogenase to Phosphate Ratio as an Independent Predictor for Adverse Outcome of Microsurgical Clipping for Ruptured Intracranial Aneurysm: A Propensity-Score Matching Analysis
Authors: Zheng Shufa , Zhang Yibin , Wang Haojie , Xie Xueling , Lin Yuanxiang , Yao Peisen , Lin Zhangya , Kang Dezhi
Published: June 2022

Objective: In this study, we assessed the correlation between the lactate dehydrogenase (LDH) to phosphate ratio and the prognosis of microsurgical clippings for ruptured intracranial aneurysm (rIA) to test the hypothesis that the serum LDH to phosphate ratio could be a predictor of the outcome of microsurgical clipping for rIA. Methods: Records of rIA patients between 2012 and 2018 were retrospectively collected. Age, sex, Hunt-Hess grade, Fisher grade, medical history, aneurysm location, hydrocephalus, laboratory data including serum LDH, phosphate, and LDH to phosphate ratio, related complications, and the outcomes in 3 months were recorded. Results: A total of 1608 rIA patients in our institution were collected, and 856 patients treated by microsurgical clipping were enrolled. On admission, a significantly higher LDH-phosphate ratio was observed in patients with poor outcomes at 3 months (median ± SD, 200.175 ± 107.290 for mRS 0–2 vs. 323.826 ± 219.075 for mRS score 3–6; p = 0.000). An LDH to phosphate ratio of 226.25 in the receiver operating characteristic (ROC) curve was the optimal cutoff value to discriminate between good and poor outcomes at 3 months. The LDH to phosphate ratio ≥ 226.25 on admission was independently correlated with poor outcomes in rIA patients. In addition, Hunt and Hess grade, Fisher grade, pneumonia, and DIND were also independently correlated with poor outcomes. After removing the bias in essential clinical variables between patients with LDH to phosphate, ratio ≥ 226.25 versus <226.25 by PSM, the number of patients with poor outcomes at 3 months increased in patients with an LDH to phosphate ratio of ≥226.25 (p = 0.005). Conclusions: The LDH to phosphate ratio was a potential biomarker and could predict the unfavorable outcome of microsurgical clipping for rIA in 3 months, related to neuronal damage, cerebral hypoxia, and early brain injury after aneurysm ruptures.
Importance of Autonomous Motivation in Construction Labor Productivity Improvement in Vietnam: A Self-Determination Theory Perspective
Authors: Tam Nguyen Van , Watanabe Tsunemi , Hai Nguyen Luong
Published: June 2022

Labor productivity is an important aspect of the construction industry, and motivation is believed to be an influential factor that affects it. While previous studies have emphasized the role of controlled motivation (i.e., external factors), the role of autonomous motivation (i.e., internal factors) has been ignored. This knowledge gap hampers further efforts to explore new determinants that increase construction labor productivity (CLP). Accordingly, self-determination theory (SDT) is promising in terms of its ability to bridge this gap and explain how autonomous motivation can be generated by integrating reasonable leadership styles and psychological satisfaction. Therefore, this study develops a novel model for assessing the effects of engaging leadership, three basic psychological satisfaction factors (i.e., autonomy, competence, and relatedness), and work motivation on CLP. Based on the data collection in Vietnam, we found that both autonomous motivation and controlled motivation positively and significantly contributed to CLP. In terms of promoting autonomous motivation and improving CLP, competence and relatedness satisfaction played a key role. Ultimately, these results highlighted two crucial features related to CLP improvement in addition to the conventional view: “negative legacy” and “new light of hope”. This study expands and reinforces SDT knowledge by comprehensively illuminating leadership and psychological and motivational indicators in the construction context. It provides substantial practical recommendations for CLP improvement, such as enhancing autonomous motivation, promoting satisfaction with competence and relatedness, and reducing selfish work, which is a novel factor that negatively contributes to CLP. This factor is the first discovered in the construction domain.
KIT Mutations Correlate with Higher Galectin Levels and Brain Metastasis in Breast and Non-Small Cell Lung Cancer
Authors: Funkhouser Avery T. , Strigenz Alexander M. , Blair Bailey B. , Miller Andrew P. , Shealy Jonah C. , Ewing Joseph A. , Martin Julie C. , Funk Christopher R. , Edenfield William J. , Blenda Anna V.
Published: June 2022

To investigate a potential role for galectins as biomarkers that enable diagnosis or prognostication of breast or non-small cell lung cancer, the serum levels of galectins -1, -3, -7, -8, and -9 of cancer patients determined by ELISA assays were compared to the mutation status of 50 known cancer-critical genes, which were determined using multiplex PCR in tumors of the same patients. Mutations in the KIT proto-oncogene, which codes for the c-Kit protein, a receptor tyrosine kinase, correlated with higher levels of galectins -1, -3, -8, and -9 in breast cancer patients and galectin-1 in non-small cell lung cancer patients. Mutations in the KIT gene were more likely found in brain metastases from both of these primary cancers. The most common KIT mutation in our panel was p.M541L, a missense mutation in the transmembrane domain of the c-Kit protein. These results demonstrate an association between KIT oncogenic signaling and elevated serum galectins in patients with metastatic disease. Changes in protein trafficking and the glycocalyx composition of cancer cells may explain the observed alterations in galectin expression. This study can be useful for the targeted selection of receptor tyrosine kinase and galectin inhibitor anti-cancer treatments.
Spline Analysis of Biomarker Data Pooled from Multiple Matched/Nested Case–Control Studies
Authors: Wu Yujie , Gail Mitchell , Smith-Warner Stephanie , Ziegler Regina , Wang Molin
Published: June 2022

Pooling biomarker data across multiple studies enables researchers to obtain precise estimates of the association between biomarker measurements and disease risks due to increased sample sizes. However, biomarker measurements often vary significantly across different assays and laboratories; therefore, calibration of the local laboratory measurements to a reference laboratory is necessary before pooling data. We propose two methods for estimating the dose–response curves that allow for a nonlinear association between the continuous biomarker measurements and log relative risk in pooling projects of matched/nested case–control studies. Our methods are based on full calibration and internalized calibration methods. The full calibration method uses calibrated biomarker measurements for all subjects, even for people with reference laboratory measurements, while the internalized calibration method uses the reference laboratory measurements when available and otherwise uses the calibrated biomarker measurements. We conducted simulation studies to compare these methods, as well as a naive method, where data are pooled without calibration. Our simulation and theoretical results suggest that, in estimating the dose–response curves for biomarker-disease relationships, the internalized and full calibration methods perform substantially better than the naive method, and the full calibration approach is the preferred method for calibrating biomarker measurements. We apply our methods in a pooling project of nested case–control studies to estimate the association of circulating Vitamin D levels with risk of colorectal cancer.
Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand 212Pb-NG001
Authors: Stenberg Vilde Yuli , Tornes Anna Julie Kjøl , Nilsen Hogne Røed , Revheim Mona-Elisabeth , Bruland Øyvind Sverre , Larsen Roy Hartvig , Juzeniene Asta
Published: June 2022

This study aimed to determine the influence of cellular PSMA expression, radioligand binding and internalization, and repeated administrations on the therapeutic effects of the PSMA-targeting radioligand 212Pb-NG001. Cellular binding and internalization, cytotoxicity, biodistribution, and the therapeutic efficacy of 212Pb-NG001 were investigated in two human prostate cancer cell lines with different PSMA levels: C4-2 (PSMA+) and PC-3 PIP (PSMA+++). Despite 10-fold higher PSMA expression on PC-3 PIP cells, cytotoxicity and therapeutic efficacy of the radioligand was only 1.8-fold better than for the C4-2 model, possibly explained by lower cellular internalization and less blood-rich stroma in PC-3 PIP xenografts. Mice bearing subcutaneous PC-3 PIP xenografts were treated with 0.2, 0.4, and 0.8 MBq of 212Pb-NG001 that resulted in therapeutic indexes of 2.7, 3.0, and 3.5, respectively. A significant increase in treatment response was observed in mice that received repeated injections compared to the corresponding single dose (therapeutic indexes of 3.6 for 2 × 0.2 MBq and 4.4 for 2 × 0.4 MBq). The results indicate that 212Pb-NG001 can induce therapeutic effects at clinically transferrable doses, both in the C4-2 model that resembles solid tumors and micrometastases with natural PSMA expression and in the PC-3 PIP model that mimics poorly vascularized metastases.
Hobnail Papillary Thyroid Carcinoma, A Systematic Review and Meta-Analysis
Authors: Spyroglou Ariadni , Kostopoulos Georgios , Tseleni Sofia , Toulis Konstantinos , Bramis Konstantinos , Mastorakos George , Konstadoulakis Manousos , Vamvakidis Kyriakos , Alexandraki Krystallenia
Published: June 2022

Although papillary thyroid carcinoma (PTC) is considered to have an excellent prognosis, some recently identified more aggressive variants show reduced overall survival rates. Hobnail PTC (HPTC) was newly recognized as one of these aggressive forms, affecting recurrence, metastasis, and overall survival rates. Herein, we performed a systematic review and meta-analysis of studies including cases or case series with patients with HPTC. Furthermore, we included our individual case series consisting of six patients. The pooled mortality rate in the cohort, consisting of 290 patients, was 3.57 (95% CI 1.67–7.65) per 100 person/years. No sex differences could be observed concerning mortality (p = 0.62), but older age and tumor size significantly affected mortality (p = 0.004 and p = 0.02, respectively). The percentage of hobnail cells did not affect mortality (p = 0.97), neither did the presence of BRAF mutations. Classical characteristics such as the presence of extrathyroidal extension (p = 0.001), distant metastases (p < 0.001), and lymph node metastases (p < 0.001) all had a significant impact on mortality. Thus, HPTC appears to correlate with worse overall survival, and all PTC cases should be carefully assessed for this variant.
Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis
Authors: Gallo Stefano , Kong EunBin , Ferro Iolanda , Polacek Norbert
Published: June 2022

The importance of non-coding RNAs for regulating gene expression has been uncovered in model systems spanning all three domains of life. More recently, their involvement in modulating signal transduction, cell proliferation, tumorigenesis and cancer progression has also made them promising tools and targets for oncotherapy. Recent studies revealed a class of highly conserved small ncRNAs, namely vault RNAs, as regulators of several cellular homeostasis mechanisms. The human genome encodes four vault RNA paralogs that share significant sequence and structural similarities, yet they seem to possess distinct roles in mammalian cells. The alteration of vault RNA expression levels has frequently been observed in cancer tissues, thus hinting at a putative role in orchestrating pro-survival characteristics. Over the last decade, significant advances have been achieved in clarifying the relationship between vault RNA and cellular mechanisms involved in cancer development. It became increasingly clear that vault RNAs are involved in controlling apoptosis, lysosome biogenesis and function, as well as autophagy in several malignant cell lines, most likely by modulating signaling pathways (e.g., the pro-survival MAPK cascade). In this review, we discuss the identified and known functions of the human vault RNAs in the context of cell proliferation, tumorigenesis and chemotherapy resistance.
LncRNA ZNF582-AS1 Expression and Methylation in Breast Cancer and Its Biological and Clinical Implications
Authors: Wang Junlong , Katsaros Dionyssios , Biglia Nicoletta , Fu Yuanyuan , Benedetto Chiara , Loo Lenora , Wang Zhanwei , Yu Herbert
Published: June 2022

Background: Long non-coding RNAs (lncRNAs) play an important role in cellular activities and functions, but our understanding of their involvement in cancer is limited. Methods: TCGA data on RNA expression and DNA methylation were analyzed for lncRNAs’ association with breast cancer survival, using the Cox proportional hazard regression model. Fresh tumor samples and clinical information from 361 breast cancer patients in our study were used to confirm the TCGA finding on ZNF582-AS1. A RT-qPCR method was developed to measure ZNF582-AS1 expression. Survival associations with ZNF582-AS1 were verified with a meta-analysis. In silico predictions of molecular targets and cellular functions of ZNF582-AS1 were performed based on its molecular signatures and nucleotide sequences. Results:ZNF582-AS1 expression was lower in breast tumors than adjacent normal tissues. Low ZNF582-AS1 was associated with high-grade or ER-negative tumors. Patients with high ZNF582-AS1 had a lower risk of relapse and death. These survival associations were confirmed in a meta-analysis and remained significant after adjustment for tumor grade, disease stage, patient age, and hormone receptor status. Correlation analysis indicated the possible suppression of ZNF582-AS1 expression by promoter methylation. Bioinformatics interrogation of molecular signatures suggested that ZNF582-AS1 could suppress tumor cell proliferation via downregulating the HER2-mediated signaling pathway. Analysis of online data also suggested that HIF-1-related transcription factors could suppress ZNF582-AS1 expression, and the lncRNA might bind to hsa-miR-940, a known oncogenic miRNA in breast cancer. Conclusions: ZNF582-AS1 may play a role in suppressing breast cancer progression. Elucidating the lncRNA’s function and regulation may improve our understanding of the disease.
Proton Therapy in the Management of Pancreatic Cancer
Authors: Kobeissi Jana M. , Simone Charles B. , Lin Haibo , Hilal Lara , Hajj Carla
Published: June 2022

Radiation therapy plays a central role in the treatment of pancreatic cancer. While generally shown to be feasible, proton irradiation, particularly when an ablative dose is planned, remains a challenge, especially due to tumor motion and the proximity to organs at risk, like the stomach, duodenum, and bowel. Clinically, standard doses of proton radiation treatment have not been shown to be statistically different from photon radiation treatment in terms of oncologic outcomes and toxicity rates as per non-randomized comparative studies. Fractionation schedules and concurrent chemotherapy combinations are yet to be optimized for proton therapy and are the subject of ongoing trials.
High Levels of MFG-E8 Confer a Good Prognosis in Prostate and Renal Cancer Patients
Authors: Geoffroy Karen , Laplante Patrick , Clairefond Sylvie , Azzi Feryel , Trudel Dominique , Lattouf Jean-Baptiste , Stagg John , Saad Fred , Mes-Masson Anne-Marie , Bourgeois-Daigneault Marie-Claude , Cailhier Jean-François
Published: June 2022

Milk fat globule-epidermal growth factor-8 (MFG-E8) is a glycoprotein secreted by different cell types, including apoptotic cells and activated macrophages. MFG-E8 is highly expressed in a variety of cancers and is classically associated with tumor growth and poor patient prognosis through reprogramming of macrophages into the pro-tumoral/pro-angiogenic M2 phenotype. To date, correlations between levels of MFG-E8 and patient survival in prostate and renal cancers remain unclear. Here, we quantified MFG-E8 and CD68/CD206 expression by immunofluorescence staining in tissue microarrays constructed from renal (n = 190) and prostate (n = 274) cancer patient specimens. Percentages of MFG-E8-positive surface area were assessed in each patient core and Kaplan–Meier analyses were performed accordingly. We found that MFG-E8 was expressed more abundantly in malignant regions of prostate tissue and papillary renal cell carcinoma but was also increased in the normal adjacent regions in clear cell renal carcinoma. In addition, M2 tumor-associated macrophage staining was increased in the normal adjacent tissues compared to the malignant areas in renal cancer patients. Overall, high tissue expression of MFG-E8 was associated with less disease progression and better survival in prostate and renal cancer patients. Our observations provide new insights into tumoral MFG-E8 content and macrophage reprogramming in cancer.
Liver Resection for Type IV Perihilar Cholangiocarcinoma: Left or Right Trisectionectomy?
Authors: Jeddou Heithem , Tzedakis Stylianos , Orlando Francesco , Robert Antoine , Meneyrol Eric , Bergeat Damien , Robin Fabien , Sulpice Laurent , Boudjema Karim
Published: June 2022

How the side of an extended liver resection impacts the postoperative prognosis of advanced perihilar cholangiocarcinoma (PHC) is still controversial. We compared the outcomes of right (RTS) and left trisectionectomies (LTS) in Bismuth-Corlette (BC) type IV PHC resection. All patients undergoing RTS or LTS for BC type IV PHC in a single tertiary center between January 2012 and December 2019 were compared retrospectively. The endpoints were perioperative outcomes, long-term overall (OS), and disease-free survival (DFS). Among 67 hepatic resections for BC type IV PHC, 25 (37.3%) were LTS and 42 (63.7%) were RTS. Portal vein and artery resection rates were 40% and 52.4% (p = 0.29), and 24% and 0% (p < 0.001) in the LTS and RTS groups, respectively. The severe complication (Clavien–Dindo > IIIa) rate was comparable (36% vs. 21.5%, p = 0.357) while the postoperative liver failure (POLF) rate was lower in the LTS group (16% vs. 38%, p = 0.048). The R0 resection rate was similar between groups (81% vs. 92%; p = 0.154). The five-year OS rate was higher in the LTS group (66% vs. 30%, p = 0.009) while DFS was comparable (43% vs. 18%, p = 0.11). Based on multivariable analysis, the side of the trisectionectomy was an independent predictor of OS. Compared with RTS, LTS is associated with lower POLF and higher overall survival despite more frequent arterial reconstructions in type IV PHC. Although technically more demanding, LTS may be preferred in the treatment of advanced PHC.
Multivariate Risk Analysis of RAS, BRAF and EGFR Mutations Allelic Frequency and Coexistence as Colorectal Cancer Predictive Biomarkers
Authors: Ionescu Adriana , Bilteanu Liviu , Geicu Ovidiu Ionut , Iordache Florin , Stanca Loredana , Pisoschi Aurelia Magdalena , Miron Adrian , Serban Andreea Iren , Calu Valentin
Published: June 2022

Background: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its predicted evolution. Methods: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF, and EGFR mutations from 60 tumors. We employed a pair-wise association approach to estimate the risk involving AF mutations as outcome variables for clinical data and as predicting variables for tumor-staging. We evaluated correlations between mutations of AFs and also between the mutations and histopathology features (tumor staging, inflammation, differentiation, and invasiveness). Results: KRAS G12/G13 mutations were present in all patients. KRAS Q61 was significantly associated with poor differentiation, high desmoplastic reaction, invasiveness (ypT4), and metastasis (ypM1). NRAS and BRAF were associated with the right-side localization of tumors. Diabetic patients had a higher risk to exhibit NRAS G12/G13 mutations. BRAF and NRAS G12/G13 mutations co-existed in tumors with invasiveness limited to the submucosa. Conclusions: The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment.
Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer
Authors: Maddox Adam L. , Brehove Matthew S. , Eliato Kiarash R. , Saftics Andras , Romano Eugenia , Press Michael F. , Mortimer Joanne , Jones Veronica , Schmolze Daniel , Seewaldt Victoria L. , Jovanovic-Talisman Tijana
Published: June 2022

Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40–60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy in identifying therapy-responsive breast cancers. Here, we deployed quantitative single molecule localization microscopy to assess the molecular features of HER2 in a therapy-responsive setting. Using fluorescently labeled trastuzumab as a probe, we first compared the molecular features of HER2 in trastuzumab-sensitive (BT-474 and SK-BR-3) and trastuzumab-resistant (BT-474R and JIMT-1) cultured cell lines. Trastuzumab-sensitive cells had significantly higher detected HER2 densities and clustering. We then evaluated HER2 in pre-treatment core biopsies from women with breast cancer undergoing neoadjuvant therapy. A complete pathological response was associated with a high detected HER2 density and significant HER2 clustering. These results established the nano-organization of HER2 as a potential signature of therapy-responsive disease.
The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas
Authors: Al-Khreisat Mutaz Jamal , Hussain Faezahtul Arbaeyah , Abdelfattah Ali Mahmoud , Almotiri Alhomidi , Al-Sanabra Ola Mohammed , Johan Muhammad Farid
Published: June 2022

Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment strategies, and outcomes: Hodgkin and non-Hodgkin lymphoma (NHL). Moreover, lymphomas can be further divided into subtypes depending on the cell origin, and immunophenotypic and genetic aberrations. Many factors play vital roles in the progression, pathogenicity, incidence, and mortality rate of lymphomas. Among NHLs, peripheral T cell lymphomas (PTCLs) are rare lymphoid malignancies, that have various cellular morphology and genetic mutations. The clinical presentations are usually observed at the advanced stage of the disease. Many recent studies have reported that the expressions of NOTCH1, GATA3, and c-MYC are associated with poorer prognosis in PTCL and are involved in downstream activities. However, questions have been raised about the pathological relationship between these factors in PTCLs. Therefore, in this review, we investigate the role and relationship of the NOTCH1 pathway, transcriptional factor GATA3 and proto-oncogene c-MYC in normal T cell development and malignant PTCL subtypes.
In-Depth Characterisation of Real-World Advanced Melanoma Patients Receiving Immunotherapies and/or Targeted Therapies: A Case Series
Authors: Sanjida Saira , Betz-Stablein Brigid , Atkinson Victoria , Janda Monika , Barsoum Ramez , Edwards Harrison Aljian , Chiu Frank , Tran My Co , Soyer H Peter , Schaider Helmut
Published: June 2022

Immunotherapies and targeted therapies have shown significant benefits for melanoma survival in the clinical trial setting. Much less is known about the characteristics and associated outcomes of those receiving such therapies in real-world settings. This study describes the characteristics of patients with advanced melanoma receiving immuno- and/or targeted therapies in a real-world setting. This prospective cohort study enrolled participants aged >18 years, diagnosed with advanced melanoma and currently undergoing immuno- and/or targeted therapies outside a clinical trial for follow-up with three-dimensional (3D) total-body imaging. Participants (n = 41) had a mean age of 62 years (range 29–86), 26 (63%) were male and the majority (n = 26, 63%) had ≥2 comorbidities. After a median of 39 months (range 1–52) follow-up, 59% (n = 24/41) of participants were alive. Despite multiple co-morbidities, the survival of participants with advanced melanoma treated using immuno- and/or targeted therapies was similar or better in our real-world setting compared to those treated in clinical trials using similar therapies. Larger studies powered to evaluate phenotypic and socio-economic characteristics, as well as specific comorbidities associated with survival in a real-world setting, are required to help determine those who will most benefit from immuno- and/or targeted therapies.
Interobserver Reliability and the Sigmoid Takeoff—An Interobserver Study
Authors: Pedersen Malene Roland Vils , Otto Peter Obel , Vagn-Hansen Chris , Sørensen Torben , Rafaelsen Søren Rafael
Published: June 2022

Background: Colorectal cancer is the second most common cancer worldwide. The sigmoid takeoff is the landmark where the colon sigmoid curves toward the sacrum viewed from sagittal magnetic resonance imaging (MRI). The purpose of this study was to assess interobserver variability in the assessment of the anal verge and anorectal junction in patients diagnosed with rectal cancer on magnetic resonance imaging (MRI). Materials and Methods: The rectal MRI examinations were performed using a 1.5- or 3.0-tesla unit using an anterior coil and a standard scan protocol. Two senior radiologists assessed MRI scans from patients under investigation for rectal cancer. The two observers assessed the anal verge and takeoff in cm independently. Difference in agreement between the observers were evaluated using intraclass correlation (ICC) and graphically by Bland–Altman plots. Results: The study population (n = 122) included 68 (55.7%) female and 54 (44.3%) male subjects. The overall median age was 69.5 years (range 39–95 years). There was perfect agreement between the two observers when defining rectal tumor above or below the takeoff landmark. The reliability of measuring the distance from the anal verge to the sigmoid takeoff was 0.712. Conclusion: Overall, the study found a moderate reliability in assessing the location of the sigmoid takeoff, with a low difference in the distance measuring, as well as a good consensus concerning the determination of tumors in relation to the sigmoid takeoff. Routine implementation of this information within the report seems reasonable.
Steam Reforming of Bioethanol Using Metallic Catalysts on Zeolitic Supports: An Overview
Authors: Dalena Francesco , Giglio Emanuele , Marino Alessia , Aloise Alfredo , Giorgianni Gianfranco , Migliori Massimo , Giordano Girolamo
Published: June 2022

Hydrogen is considered one of the energy carriers of the future due to its high mass-based calorific value. Hydrogen combustion generates only water, and it can be used directly as a fuel for electricity/heat generation. Nowadays, about 95% of the hydrogen is produced via conversion of fossil fuels. One of the future challenges is to find processes based on a renewable source to produce hydrogen in a sustainable way. Bioethanol is a promising candidate, since it can be obtained from the fermentation of biomasses, and easily converted into hydrogen via steam catalytic reforming. The correct design of catalysts and catalytic supports plays a crucial role in the optimization of this reaction. The best results have to date been achieved by noble metals, but their high costs make them unsuitable for industrial application. Very satisfactory results have also been achieved by using nickel and cobalt as active metals. Furthermore, it has been found that the support physical and chemical properties strongly affect the catalytic performance. In this review, zeolitic materials used for the ethanol steam reforming reaction are overviewed. We discuss thermodynamics, reaction mechanisms and the role of active metal, as well as the main noble and non-noble active compounds involved in ethanol steam reforming reaction. Finally, an overview of the zeolitic supports reported in the literature that can be profitably used to produce hydrogen through ethanol steam reforming is presented.
‘Come together’—The Regulatory Interaction of Herpesviral Nuclear Egress Proteins Comprises Both Essential and Accessory Functions
Authors: Häge Sigrun , Marschall Manfred
Published: June 2022

Herpesviral nuclear egress is a fine-tuned regulatory process that defines the nucleocytoplasmic release of viral capsids. Nuclear capsids are unable to traverse via nuclear pores due to the fact of their large size; therefore, herpesviruses evolved to develop a vesicular transport pathway mediating the transition across the two leaflets of the nuclear membrane. The entire process involves a number of regulatory proteins, which support the local distortion of the nuclear envelope. In the case of the prototype species of β-Herpesvirinae, the human cytomegalovirus (HCMV), the nuclear egress complex (NEC) is determined by the core proteins pUL50 and pUL53 that oligomerize, form capsid docking lattices and mediate multicomponent assembly with NEC-associated viral and cellular proteins. The NEC-binding principle is based on the hook-into-groove interaction through an N-terminal hook-like pUL53 protrusion that embraces an α-helical pUL50 binding groove. Thus far, the function and characteristics of herpesviral core NECs have been well studied and point to the groove proteins, such as pUL50, as the multi-interacting, major determinants of NEC formation and egress. This review provides closer insight into (i) sequence and structure conservation of herpesviral core NEC proteins, (ii) experimentation on cross-viral core NEC interactions, (iii) the essential functional roles of hook and groove proteins for viral replication, (iv) an establishment of assay systems for NEC-directed antiviral research and (v) the validation of NEC as putative antiviral drug targets. Finally, this article provides new insights into the conservation, function and antiviral targeting of herpesviral core NEC proteins and, into the complex regulatory role of hook and groove proteins during the assembly, egress and maturation of infectious virus.
Biomarkers in Nephropathic Cystinosis: Current and Future Perspectives
Authors: Emma Francesco , Montini Giovanni , Pennesi Marco , Peruzzi Licia , Verrina Enrico , Goffredo Bianca Maria , Canalini Fabrizio , Cassiman David , Rossi Silvia , Levtchenko Elena
Published: June 2022

Early diagnosis and effective therapy are essential for improving the overall prognosis and quality of life of patients with nephropathic cystinosis. The severity of kidney dysfunction and the multi-organ involvement as a consequence of the increased intracellular concentration of cystine highlight the necessity of accurate monitoring of intracellular cystine to guarantee effective treatment of the disease. Cystine depletion is the only available treatment, which should begin immediately after diagnosis, and not discontinued, to significantly slow progression of renal and extra-renal organ damage. This review aims to discuss the importance of the close monitoring of intracellular cystine concentration to optimize cystine depletion therapy. In addition, the role of new biomarkers in the management of the disease, from timely diagnosis to implementing treatment during follow-up, is overviewed.
Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes
Authors: Ngono Ayissi Kenza , Gorwood Jennifer , Le Pelletier Laura , Bourgeois Christine , Beaupère Carine , Auclair Martine , Foresti Roberta , Motterlini Roberto , Atlan Michael , Barrail-Tran Aurélie , Le Grand Roger , Desjardins Delphine , Fève Bruno , Lambotte Olivier , Capeau Jacqueline , Béréziat Véronique , Lagathu Claire
Published: June 2022

For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.
Peroxisome Metabolism Contributes to PIEZO2-Mediated Mechanical Allodynia
Authors: Gong Yi , Laheji Fiza , Berenson Anna , Qian April , Park Sang-O , Kok Rene , Selig Martin , Hahn Ryan , Sadjadi Reza , Kemp Stephan , Eichler Florian
Published: June 2022

Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, Abcd1−/y mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
cAMP Signalling Pathway in Biocontrol Fungi
Authors: Sun Zhan-Bin , Yu Shu-Fan , Wang Chu-Lun , Wang Ling
Published: June 2022

Biocontrol is a complex process, in which a variety of physiological and biochemical characteristics are altered. The cAMP signalling pathway is an important signal transduction pathway in biocontrol fungi and consists of several key components. The G-protein system contains G-protein coupled receptors (GPCRs), heterotrimeric G-proteins, adenylate cyclase (AC), cAMP-dependent protein kinase (PKA), and downstream transcription factors (TFs). The cAMP signalling pathway can regulate fungal growth, development, differentiation, sporulation, morphology, secondary metabolite production, environmental stress tolerance, and the biocontrol of pathogens. However, few reviews of the cAMP signalling pathway in comprehensive biocontrol processes have been reported. This work reviews and discusses the functions and applications of genes encoding each component in the cAMP signalling pathway from biocontrol fungi, including the G-protein system components, AC, PKA, and TFs, in biocontrol behaviour. Finally, future suggestions are provided for constructing a complete cAMP signalling pathway in biocontrol fungi containing all the components and downstream effectors involved in biocontrol behavior. This review provides useful information for the understanding the biocontrol mechanism of biocontrol fungi by utilising the cAMP signalling pathway.
Evidence of Delta Phase of Fe in MBE-Grown Thin Epitaxial Films on GaAs
Authors: Goswami Ramasis , Qadri Syed B.
Published: June 2022

Fe/GaAs is an important system for the study of spin injection behavior that can vary with the nature and interfaces of Fe films. Here, we investigate the effect of interfacial strain on the microstructure, interfaces and phase-formation behavior in epitaxially grown Fe films. To vary the strain, we have characterized Fe films of various thicknesses ranging from 10 to 1000 nm which were grown using molecular beam epitaxy on GaAs (011) and AlGaAs (001) substrates. High resolution X-ray diffraction studies revealed that films with higher thicknesses exhibited an equilibrium α-Fe phase, while the films with less than 10 nm thicknesses indicated the presence of δ-Fe. Transmission electron microscopy revealed the interface for 10-nm-thick films had strain lobes with no interfacial phase formation for films deposited at room temperature. At a higher deposition temperature of 175 °C, similar strain lobes were observed for a 10-nm-thick film. Extended annealing at 200 °C transformed the metastable δ-Fe phase to an equilibrium α-Fe. However, at higher temperature, the interface contained an intermixing layer of (FeAl)GaAs. We demonstrate that the interfacial strain plays a major role in stabilizing the metastable δ-Fe on GaAs.
Failure Analysis of Chromium Plating Layer on the Surface of the Piston Rod of the Hydraulic Jack
Authors: Zhang Qiankun , Wang Jiangang , Shen Wenjing , Huang Fengshan , Zhao Yongjie
Published: June 2022

The piston rod of the hydraulic jack was a kind of artillery alloy structural steel of 40Cr and its surface was the chromium plating layer. The piston rod worked for a while; the defects of corrosion pit and peeling appeared on the chromium layer. A stereo-microscope, metallographic microscope, and scanning electron microscope (SEM) were used to observe the macromorphology, micromorphology, and microstructure of the failed parts. The composition analysis was performed by the energy dispersive spectroscopy (EDS), and a Vickers hardness tester was used to measure the hardness. The results showed that pores and penetrating cracks existed in the chromium layer, leading to the corrosion medium invading the interface and forming a corrosion source. Then, the corrosion intensified, resulting in the bubbling, cracking, and peeling of the chromium layer. More O and minor S elements were detected in the corrosion pit. Finally, the fracture of the chromium layer was a 45° angle destruction mode. The peeling of the chromium layer was caused by the pores and microcracks, working medium, and poor working environment. Some suggestions were put forward to prevent the peeling of the chromium layer.
Vibration Reduction Characteristics and Vibration Control of Aviation Hydraulic Pipeline by Hard Coating
Authors: Cui Zhining , Yu Xiaoguang , Ran Ziqing , Liu Jiaming , Li Chunqiu , Gao Lei
Published: June 2022

Aviation hydraulic pipelines are an important channel for power transmission in aviation hydraulic systems. Due to long-term exposure to complex vibration environments, hydraulic pipeline systems are susceptible to accumulated fatigue damage failure, which poses a great threat to aircraft safety and reliability. At present, there are only passive ways to reduce hydraulic pipeline vibration, such as adding vibration isolators and damping bearings. These methods have a poor vibration damping effect and are not safe. In this study, a hard coating was used as a new vibration reduction method for aviation hydraulic pipelines to reduce the damage caused by vibrations. For this purpose, three different hard-coating materials were optimally selected, and model creation, finite element analysis, and experimental research were carried out to study the vibration responses of hard-coated aviation hydraulic pipelines under the actual working conditions of an aircraft. The optimal solution was obtained through orthogonal experiments. The vibration reduction rate of the aviation hydraulic pipelines could reach 20.33% under the constant-frequency excitation of the low-pressure rotor of the engine, and the vibration reduction rate under the constant-frequency excitation of the high-pressure rotor could reach 26.60%. The rationality of the model was verified, and it was proven that the hard coating could meet the demands of vibration control in practical engineering and provide a reference for the vibration analysis and vibration control design of aviation hydraulic piping systems.
Reduced On-Resistance and Improved 4H-SiC Junction Barrier Schottky Diodes Performance by Laser Annealing on C-Face Ohmic Regions in Thin Structures
Authors: Kim Kihyun , Kang Yehwan , Yun Seungbok , Yang Changheon , Jung Eunsik , Hong Jeongsoo , Kim Kyunghwan
Published: June 2022

In this study, we investigated the characteristics of the n-type Ni/SiC ohmic contact using the laser annealing process on thin wafers. The electrical behavior of the ohmic contacts was tested in 4H-SiC JBS diode devices. As a result, a wafer thickness of 100 μm in the 4H-SiC JBS diode achieved a forward voltage of 1.33 V at 20 A with a laser annealing process using Ni silicide. Using a laser annealing process on a wafer thickness of 100 μm, an on-resistance decrease of almost 22% was demonstrated. Based on our experimental results, we suggest an alternative laser annealing fabrication scheme to obtain low on-resistance SiC power devices with thin structures after SiC grinding.
Tracheomegaly as a Potential Predictor of Severe Tracheal Damage in COVID-19 Patients on Long-Term Mechanical Ventilation
Authors: Tarle Marko , Raguž Marina , Đerke Filip , Orešković Darko , Peršec Jasminka , Lukšić Ivica
Published: June 2022

Tracheomegaly (TM) is a rare appearance that is radiologically defined as an excessive enlargement of the tracheal diameter. We present a comprehensive analysis of tracheal diameter measurements and TM incidence in patients admitted and treated due to COVID-19 pneumonitis and its association with possible respiratory complications. In this retrospective study, we included 1015 patients divided into three groups: 383 patients treated using mechanical ventilation (MV), 132 patients treated using high-flow ventilation (HFV), and 500 randomly selected patients using nasal catheter (NC) oxygenation. The tracheal lumen diameter was measured continuously using a chest X-ray, and the cuff/trachea (C/T) diameter ratio was calculated. We detected TM in 71 patients (18.54%). Regression analysis showed statistical significance in MV patients for the trachea diameter at the level of the cuff, maximal trachea diameter and C/T diameter ratio, and days on MV. Respiratory complications showed a significant association with the C/T diameter ratio. The C/T diameter ratio was shown to be a reliable potential predictor of the occurrence of respiratory complications. The results of the study highlight the importance of the early detection and prevention of TM in COVID-19 patients on MV using a chest X-ray and measurement of the C/T diameter ratio.