bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB225: Toward comprehensive, single-molecule proteomics: Protein identification by short-epitope mapping
Authors: Egertson Jarrett D. , Stawicki Cassandra , Gillies Taryn E. , Joly James H. , Steiner Noah , Cardenas Kevin , Leano Jonathan B. , Chen Kevin , Watts Sophie , Boyce Hunter B. , DiPasquo Dan , Killeen Alana , Lobanov Vadim , Kapp Greg , Patel Sujal , Mallick Parag
Published: June 2022

Protein Identification by Short-epitope Mapping (PrISM) is a novel proteomics method with the goal of comprehensive proteome quantification at single-molecule sensitivity. In this work, we present computational modeling demonstrating the feasibility of this goal and experimental application of the approach leveraging single-molecule protein measurements to identify a small number of model proteins. The implementation of PrISM as presented works by acquiring sequential affinity reagent binding measurements on single protein molecules. Counterintuitively, using affinity reagents with “poor” specificity (i.e. cross-reacting to many proteins) enables identification of tens of thousands of proteins with only hundreds of affinity reagents. To experimentally demonstrate PrISM, we use a small number of affinity reagents to quantify a larger number of proteins. In simulations, PrISM is able to identify more than 98% of proteins in human, mouse, yeast, and E. coli using 300 affinity reagents targeting short trimer epitopes. PrISM is robust to experimental confounders including non-specific binding and noisy, incomplete, or inaccurate estimation of affinity reagent to protein binding characteristics. Simulations of the approach with a chip containing 10 billion protein molecules measured in parallel show a dynamic range of detection of up to 9.5 and 11.5 orders of magnitude for HeLa cells and plasma, respectively. Using such a chip, the PrISM method can identify and quantify over 90% of the human proteome in a single experiment, potentially revolutionizing biomarker discovery and cancer research.

Citation Format: Jarrett D. Egertson, Cassandra Stawicki, Taryn E. Gillies, James H. Joly, Noah Steiner, Kevin Cardenas, Jonathan B. Leano, Kevin Chen, Sophie Watts, Hunter B. Boyce, Dan DiPasquo, Alana Killeen, Vadim Lobanov, Greg Kapp, Sujal Patel, Parag Mallick. Toward comprehensive, single-molecule proteomics: Protein identification by short-epitope mapping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB225.
Abstract LB509: ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking
Authors: Li Liangwei , Liu Wenting , Shen Guodong , Zhang Dayan , Zheng Xiaoli , Cheng Liansheng
Published: June 2022

CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor receptor superfamily that functions as a co-stimulatory molecule of immunocytes. Agonistic antibodies against CD137 have shown promising therapeutic activity in mouse tumor models. However, molecules in the clinical development have shown limitations due to either dose-dependent severe liver toxicity (e.g. Urelumab), or modest antitumor activity (e.g. Utomilumab). We developed ZG033, a fully human IgG4 agonist of CD137 that engages with a exclusive epitope, to achieve a better efficacy and safety profile for immunotherapy. The biophysical properties and anti-tumor activities were determined using in vitro assays and in vivo mice xenograft models, respectively. ZG033 is a safe and potent antibody targeting a ligand competitive epitope, that conserved in human, cynomolgus monkey, and is associated with a differentiated pharmacology and toxicology profile. The complex structure of ZG033/CD137 was determined by X-ray crystallography. The binding affinity to human 4-1BB of ZG033 determined by Surface plasmon resonance (SPR) was moderate (KD=10 nM). ZG033 increased the production of IFN-γ by human CD8+T,CD4+T, NK cells in a Fcγ receptor-dependent manner, displaying an intermediate activation level between that of Urelumab and Utomilumab. In addition, it led to a dose-dependent increase in the CD137-driven NFκB reporter gene activation. In syngeneic mouse tumor models, ZG033 showed robust single agent anti-tumor activity starting from 0.3 mg/kg and induced durable antigen-specific immunological memory that prevents the growth of the same tumor cells in the mice re-challenged as compared to Utomilumab. Furthermore, ZG033 combined with an anti-PD-L1 antibody (Atezolizumab) significantly inhibited the growth of colorectal tumor in a human PBMC-engrafted humanized mouse model. Data from toxicology test in humanized CD137 transgenic mice showed that ZG033 was well-tolerated with normal ALT and AST levels. Even high dose of ZG033 (MTD≥180mg/kg) was achieved in cynomolgus monkeys with no abnormality in hematological indexes, important organs. These data demonstrate that ZG033 is a novel CD137 agonist that displays an favorable safety profile and has a potential in either mono- or combinational immunotherapies.

Citation Format: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Xiaoli Zheng, Liansheng Cheng. ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB509.
Abstract LB522: Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors
Authors: Zana Aureliano , Galbiati Andrea , Gilardoni Ettore , Millul Jacopo , Sturm Theo , Stucchi Riccardo , Bocci Matilde , Elsayed Abdullah , Nadal Lisa , Cirillo Martina , Neri Dario , Cazzamalli Samuele
Published: June 2022

Small Molecule-Drug Conjugates (SMDCs) are modular anti-cancer pro-drugs that include a tumor-targeting small ligand, a cleavable linker and a potent cytotoxic agent. SMDC products that have been developed for clinical applications are targeting internalizing tumor-associated antigens expressed on the surface of tumor cells. We have recently developed a novel non-internalizing small organic ligand (named OncoFAP) of Fibroblast Activation Protein (FAP), a tumor-associated antigen highly expressed in the stroma of most of solid human malignancies. The tumor targeting performance of OncoFAP has been validated by nuclear medicine studies in patients with various solid tumors. In a previous study, we showed that OncoFAP can be used to produce non-internalizing SMDCs that are effective and well tolerated. Here, we describe a new series of OncoFAP-Drug derivatives based on the MMAE tubulin poison and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. We benchmarked the new SMDCs against OncoFAP-MMAE conjugates displaying linker modules which are widely used in approved and clinical stage Antibody-Drug Conjugates, including structures cleaved by Cathepsin B and by reducing agents. We selected OncoFAP-GlyPro-MMAE as the most efficacious and safe SMDC for further clinical development after quantitatively analyzing the biodistribution of MMAE released by OncoFAP-MMAE conjugates. OncoFAP-GlyPro-MMAE selectively delivers high amounts of MMAE at the site of disease, with a tumor-to-kidney ratio of 7-to-1 and of 16-to-1 at 6- and 24-hours post-injection, respectively. Our molecules based on the OncoFAP tumor-targeting ligand and FAP-cleavable linkers promise to be safe and effective against most of human malignancies.

Citation Format: Aureliano Zana, Andrea Galbiati, Ettore Gilardoni, Jacopo Millul, Theo Sturm, Riccardo Stucchi, Matilde Bocci, Abdullah Elsayed, Lisa Nadal, Martina Cirillo, Dario Neri, Samuele Cazzamalli. Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB522.
Abstract LB538: Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC
Authors: Du Qinglin , Zeng Wengang , Yang Xueyan , Liang Liwen , Li Xueqin , Li Yan , Cao Yiqi , Xia Zongjun , Zhang Jing , Ding Qian , Han Shuhua
Published: June 2022

Background: The EGFR tyrosine kinase inhibitors (TKIs) have been effectively used for non-small cell lung cancer (NSCLC) driven by EGFR mutations. However, patients eventually develop drug resistance via various mechanisms such as secondary EGFR mutations and activation of alternative pathways. The cMET amplification is one of the resistant mechanisms. Amivantamab, a bispecific antibody to EGFR/c-Met has shown that concurrent inhibition of EGFR and c-Met can overcome resistance of EGFR-TKIs and improve patient outcomes. Thus, amivantamab has been approved for the treatment of advanced NSCLC patients with EGFR exon20ins mutations in the US. GB263T is a novel EGFR/cMET/cMET tri-specific antibody with enhanced ADCC function. The current study has demonstrated GB263T exhibited robust anti-tumor activity by in vitro and in vivo studies.

Methods: GB263T has been extensively characterized. The binding/blocking activities were analyzed by SPR and ELISA. The protein levels and phosphorylation of EGFR/cMET were detected by Western Blot. Internalization ability was evaluated by confocal microscope. ADCC function was tested by Jurkat-CD16A-NFAT-Luc reporter system. Various CDX and PDX models were used to evaluate the in vivo efficacy in tumor inhibition.

Results: GB263T showed high affinity binding to EGFR and cMET, with robust blocking activity. Moreover, GB263T induced receptor internalization and EGFR/cMET phosphorylation in NSCLC cell lines. GB263T dose-dependently inhibited the proliferation of cells containing EGFR exon 20 insertion mutations and C797S mutations. In addition, potent ADCC function against NSCLC cell lines was observed. Significant in vivo anti-tumor efficacy was demonstrated by multiple tumor models of EGFR exon 20 insertion, EGFR C797S mutation, cMET amplification, and cMET exon 14 skipping mutation.

Conclusions: GB263T is a novel tri-specific antibody that exhibited robust anti-tumor activity. The preclinical data indicate that GB263T has great potential to become an effective therapeutics in the treatment of NSCLC.

Citation Format: Qinglin Du, Wengang Zeng, Xueyan Yang, Liwen Liang, Xueqin Li, Yan Li, Yiqi Cao, Zongjun Xia, Jing Zhang, Qian Ding, Shuhua Han. Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB538.
Abstract LB543: tmHRD: Accurately estimating the homologous recombination deficiency status from clinical panel sequencing data
Authors: Wang Xuwen , Xu Ying , Guan Yanfang , Yi Xin , Wang Jiayin
Published: June 2022

Estimating the status of homologous recombination deficiency (HRD) is of clinical interest because the homologous recombination-deficient cells are reported sensitive to poly-ADP ribose polymerase (PARP) inhibitors. As HRD status becomes a critical indicator, many approaches have been proposed to measure the HRD status, among which estimating HRD status from cancer sequencing data is the popular strategy, where the representative methods include HRDetect, SigMA, FoundationFocusCDx, MyChoiceHRD, etc. Although sequencing data is the same input of these bioinformatics tools, algorithms prefer different aspects. Some methods focus on germline variants in BRCA1/2 genes and somatic mutational signatures, while some others capture the genomic scars, including loss of heterozygosity (LOH), telomere allele imbalance (TAI) and large-scale state transition (LST). However, there are two major controversial points when applying these tools on clinical sequencing data. First, panel sequencing is the most popular sequencing plan in clinic, but gene panels usually carry only hundreds to a thousand genes. Thus, the panel sequencing can neither capture a large number of mutations to calculate mutational signatures, nor obtain large genomic scars, such as TAI and LST. Second, the associations between the mutations and HRD status is still unclear. Thus, scoring mutations and genomic scars is not reasonable. To solving these issues, we here proposed a machine learning-based method, called tmHRD, which estimates HRD status according to limited mutations and LOHs captured by clinical panel sequencing data. It consists of a semi-supervised learning (TRI) model and a multi-instance learning (MIL) model. The TRI model filters the false positives from mutation calls. Then, the filtered mutation calls from one patient is defined as a package, where each mutation call is an instance in the package. When training the MIL model, in each iteration, a package with known HRD status (label) is given to MIL model. MIL model calculates the correlations among instances and assigns an adjusted weight for each. Thus, the HRD status is only contributed by those mutations associated with. We tested tmHRD on several datasets obtained by the clinical trials we participated. Compared to the existing methods, tmHRD achieved better performance. The average recognition rate of tmHRD was approaching 90%, while the comparison methods show around 80%. The software package, tmHRD, is freely available at https://github.com/Sherwin-xjtu/TriMILhrd/ for academic usages only.

Citation Format: Xuwen Wang, Ying Xu, Yanfang Guan, Xin Yi, Jiayin Wang. tmHRD: Accurately estimating the homologous recombination deficiency status from clinical panel sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB543.
Abstract LB567: Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft
Authors: Passeri Thibault , Dahmani Ahmed , Masliah-Planchon Julien , Naguez Adnan , Michou Marine , El-Botty Rania , Vacher Sophie , Bouarich Rachida , Nicolas André , Polivka Marc , Franck Coralie , Schnitzler Anne , Némati Fariba , Roman-Roman Sergio , Bourdeaut Franck , Adle-Biassette Homa , Mammar Hamid , Froelich Sébastien , Bièche Ivan , Decaudin Didier
Published: June 2022

Background: Chordomas are considered as rare bone neoplasms characterized by a high level of recurrence and a poor long-term prognosis. Considering their chemo-radio-resistance, alternative treatment strategies are therefore strongly requested, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complex including PBMR1 are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this indication.

Methods: Thirty-eight chordoma specimens derived from primary patients’ tumors were grafted into nude mice. Relationship between grafted tumors and clinical, biological and therapeutic features of corresponding patients were investigated. We subjected the established PDX models to histopathological and genetic examination; finally, a therapeutic program focused on the EZH2-inhibition was performed in one PDX model.

Results: Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p=0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed.

Conclusion: Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1variant supports further evaluation of EZH2-inhibitors in this subgroup of chordomas.

Citation Format: Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Adnan Naguez, Marine Michou, Rania El-Botty, Sophie Vacher, Rachida Bouarich, André Nicolas, Marc Polivka, Coralie Franck, Anne Schnitzler, Fariba Némati, Sergio Roman-Roman, Franck Bourdeaut, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, Didier Decaudin. Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB567.
Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study
Authors: Murray Anne M. , Slinin Yelena , Tupper David E. , Pederson Sarah L. , Davey Cynthia , Gilbertson David T. , Drawz Paul , Mello Ryan , Hart Allyson , Johansen Kirsten L. , Reule Scott , Rossom Rebecca , Knopman David S.
Published: June 2022

Introduction: The associations of kidney-metabolic biomarkers with cognitive impairment (CI) beyond the estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) and albuminuria levels are not well understood. In exploratory analysis, our objective was to determine the extent that three kidney-metabolic factors, previously proposed as mechanisms of CI and commonly abnormal in chronic kidney disease (CKD), were associated with prevalent CI in CKD participants, adjusted for kidney function measures. Methods: The study cohort included community-dwelling individuals aged ≥45 years with CKD (eGFR <60), not requiring dialysis, recruited from four health systems. We examined the serum biomarkers bicarbonate (CO2), TNFαR1, and cholesterol as primary exposures. A structured neuropsychological battery conducted by trained staff measured global and domain-specific cognitive performance. Logistic regression analyses estimated the cross-sectional associations between kidney-metabolic measures and global and cognitive domain-specific moderate/severe (Mod/Sev) CI, adjusted for the eGFR, urinary albumin-creatinine ratio (UACR, mg/g), demographics, comorbid conditions, and other kidney-metabolic biomarkers commonly abnormal in CKD. Results: Among 436 CKD participants with mean age 70 years, 16% were Black, the mean eGFR was 34, and the median [IQR] UACR was 49 [0.0, 378] mg/g. In adjusted models, increased TNFαR1 was associated with global Mod/Sev CI (odds ratio [95% confidence interval] = 1.40 [1.02, 1.93]; p = 0.04); low bicarbonate (CO2 <20 mEq/L) with Mod/Sev memory impairment (3.04 [1.09, 8.47]; p = 0.03), and each 10-mg/dL lower cholesterol was associated with Mod/Sev executive function/processing speed impairment (1.12 [1.02, 1.23]; p = 0.02). However, after adjustment for multiple comparisons, these associations were no longer significant nor were any other kidney-metabolic factors significant for any CI classification. Conclusion: In exploratory analyses in a CKD population, three kidney-metabolic factors were associated with CI, but after adjustment for multiple comparisons, were no longer significant. Future studies in larger CKD populations are needed to assess these potential risk factors for CI.
Characterization of the Immune Microenvironment in Inflammatory Breast Cancer Using Multiplex Immunofluorescence
Authors: Badr Nahla M. , McMurray Jack L. , Danial Irini , Hayward Steven , Asaad Nancy Y. , Abd El-Wahed Moshira M. , Abdou Asmaa G. , Serag El-Dien Marwa M. , Sharma Nisha , Horimoto Yoshiya , Sircar Tapan , Vidya Raghavan , Hoar Fiona , Rea Daniel , Jones J. Louise , Stevens Andrea , Spooner David , Merard Reena , Lewis Paul , Hunter Kelly John , Berditchevski Fedor , Shaaban Abeer M.
Published: June 2022

Introduction: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poorly characterized immune microenvironment. Methods: We used a five-colour multiplex immunofluorescence panel, including CD68, CD4, CD8, CD20, and FOXP3 for immune microenvironment profiling in 93 treatment-naïve IBC samples. Results: Lower grade tumours were characterized by decreased CD4+ cells but increased accumulation of FOXP3+ cells. Increased CD20+ cells correlated with better response to neoadjuvant chemotherapy and increased CD4+ cells infiltration correlated with better overall survival. Pairwise analysis revealed that both ER+ and triple-negative breast cancer were characterized by co-infiltration of CD20 + cells with CD68+ and CD4+ cells, whereas co-infiltration of CD8+ and CD68+ cells was only observed in HER2+ IBC. Co-infiltration of CD20+, CD8+, CD4+, and FOXP3+ cells, and co-existence of CD68+ with FOXP3+ cells correlated with better therapeutic responses, while resistant tumours were characterized by co-accumulation of CD4+, CD8+, FOXP3+, and CD68+ cells and co-expression of CD68+ and CD20+ cells. In a Cox regression model, response to therapy was the most significant factor associated with improved patient survival. Conclusion: Those results reveal a complex unique pattern of distribution of immune cell subtypes in IBC and provide an important basis for detailed characterization of molecular pathways that govern the formation of IBC immune landscape and potential for immunotherapy.
SLC26A2/DTDST Spectrum: A Cohort of 12 Patients Associated with a Comprehensive Review of the Genotype-Phenotype Correlation
Authors: Silveira Cynthia , da Costa Silveira Karina , Lacarrubba-Flores Maria D. , Sakata Maurício T. , Carbognani Silvia N. , Llerena Jr. Juan , Moreno Carolina A. , Cavalcanti Denise P.
Published: June 2022

Introduction: Pathogenic variants in the SLC26A2/DTDST gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of SLC26A2/DTDST-related disorders. Methods: The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS). We reviewed data from the literature regarding phenotype, zygosity, and genotype in parallel. Results: The local cohort enrolled 12 patients, including one with a Desbuquois-like phenotype. All but one showed biallelic mutations, however, only one allele mutated in a fetus presenting ACG1B was identified. The literature review identified 42 articles and the analyses of genotype and zygosity included the 12 local patients. Discussion: The R279W variant was the most prevalent among the local patients. It was in homozygosity (hmz) in 2 patients with rMED and in compound heterozygosity (chtz) in 9 patients. The genotype and zygosity review of all patients led to the following conclusions: DTD is the most common phenotype in Finland due to a Finnish mutation (c.727–1G>C). Outside of Finland, rMED is the most prevalent phenotype, usually associated with R279W in hmz. In contrast, DTD’s genotype is usually in chtz. Despite a large number of variants (38), just 8 are recurrent (R279W, C653S, c.−26+2T>C, R178*, K575Sfs*10, V340del, G663R, T512K). The last 3 in hmz lead to lethal phenotypes. The Finnish mutation is found only in chtz outside of Finland, being associated with all 4 classical phenotypes. The p.R178* and p.K575Sfs*10 variants should be viewed as lethal mutations since both were mainly described with lethal phenotypes and were never reported in hmz. The existence of 9 patients with only one mutated allele suggests that other mutations in the other allele of these patients still need to be unveiled.
Evaluation of an Efficient and Skin-Adherent Semisolid Sunscreen Nanoformulation
Authors: Frank Luiza Abrahão , Gazzi Rafaela Pletsch , Pohlmann Adriana Raffin , Guterres Silvia Stanisçuaski , Contri Renata Vidor
Published: June 2022

Introduction: Sunscreens are substances applied on the skin surface to protect the skin from the harmful effects of UV light. Nanoparticles can increase the retention time of the sunscreen on the skin surface and its efficacy, by acting as physical barriers. The present investigation aimed to evaluate the influence of the chitosan coating of benzophenone-3-loaded lipid-core nanocapsules (CH-LCN) on the skin adhesion and photoprotective effect of the sunscreen. Methods: CH-LNC were obtained by the interfacial deposition of preformed polymer. A suitable semisolid formulation was obtained by using hydroxyethyl cellulose as the gel-forming polymer. Skin adhesion experiments were performed in vitro by applying the formulation on porcine skin and keeping it under water at 32 °C for up to 60 min. Photoprotective effect was analyzed in vitro by the capacity of the formulations to protect a photo unstable substance (resveratrol) from degradation under UV light. Results: CH-LNC presented size of around 150 nm, with low polydispersity, positive zeta potential, due to chitosan, and benzophenone-3 encapsulation efficiency of close to 100% (3 mg/mL). The proposed gel presented suitable consistence and pH for skin application and benzophenone-3 concentration of around 3 mg/g. Although coated and uncoated lipid-core nanocapsules increased benzophenone-3 skin adhesion after 10 min of water immersion, only the nanoparticles coated with chitosan were able to do so after 60 min. The chitosan coating of the nanocapsules increased the photoprotection of the sunscreen under UVA and UVB light after 60 min of exposure, probably due to the film-forming properties of chitosan. Conclusion: The chitosan coating of CH-LCN increased the skin adhesion and the photoprotective effect of the sunscreen.
Sex-Disaggregated Analysis of Biology, Treatment Tolerability, and Outcome of Multiple Myeloma in a German Cohort
Authors: Brioli Annamaria , Nägler Theresa Maria , Yomade Olaposi , Rüthrich Maria Madeleine , Scholl Sebastian , Frietsch Jochen J. , Hilgendorf Inken , Ernst Thomas , Sayer Herbert Gottfried , Hochhaus Andreas , Mügge Lars-Olof , von Lilienfeld-Toal Marie
Published: June 2022

Introduction: Multiple myeloma (MM) is a plasma cell disease that affects more men than women. Although there is an obvious imbalance in incidence, knowledge of differences in biology and outcome between the sexes is surprisingly rare. Methods: We performed a unicentric retrospective analysis of patients with MM treated at a tertiary cancer centre between 2003 and 2018. Results: We present a sex-disaggregated analysis of the characteristics and outcome of MM in a cohort of 655 patients (median age at diagnosis 62 years; 363 men with a median age at diagnosis 62 years and 292 women with a median age at diagnosis 63 years, p = 0.086). Most patients (n = 561, 86%) received myeloma-specific treatment. Median overall survival was 76 months (95% CI 63–89) (72 months in men [95% CI 54–90] and 83 months in women [95% CI 66–100], p = ns). Apart from a higher incidence of moderate and severe anaemia in women (p < 0.001), there were no statistically significant differences in the biology of the underlying MM. Similarly, in the group of patients who received high-dose therapy with autologous stem-cell transplantation (ASCT, n = 313), no statistically significant differences apart from more frequent anaemia in women were detected regarding the biology of the disease. However, there was a trend toward a higher plasma cell infiltration of the bone marrow and toward more frequent high-risk features in women. In contrast, relevant comorbidities were significantly more common in men (for example, coronary heart disease in 13% of men vs. 2% of women, p < 0.001). Toxicities after ASCT were not significantly different between the sexes with the exception of severe mucositis, which occurred in 22% of men versus 40% of women (p = 0.001). Conclusion: In conclusion, this first sex-disaggregated analysis of MM patients in Germany supports previous findings that survival is comparable amongst sexes, but women experience more toxicity of high-dose therapy. The higher incidence of clinically relevant anaemia in women warrants further investigation to exclude underlying treatable causes.
Conventional or Drug-Eluting Beads? Randomized Controlled Study of Chemoembolization for Hepatocellular Carcinoma: JIVROSG-1302
Authors: Ikeda Masafumi , Arai Yasuaki , Inaba Yoshitaka , Tanaka Toshihiro , Sugawara Shunsuke , Kodama Yoshihisa , Aramaki Takeshi , Anai Hiroshi , Morita Shinichi , Tsukahara Yoshinori , Seki Hiroshi , Sato Mikio , Kamimura Kenya , Azama Kimei , Tsurusaki Masakatsu , Sugihara Eiji , Miyazaki Masaya , Kobayashi Tatsushi , Sone Miyuki
Published: June 2022

Introduction: With the advent of effective systemic therapy, transarterial chemoembolization (TACE) is established as a highly effective locoregional treatment modality for carefully selected patients with hepatocellular carcinoma (HCC). This randomized controlled trial was conducted to clarify whether selective TACE with drug-eluting beads (DEB-TACE) loaded with epirubicin or selective conventional TACE (cTACE) with epirubicin-ethiodized oil might be more effective for obtaining complete response(CR) in patients with HCC. Methods: Between March 2016 and May 2019, Child-Pugh class A or B patients with unresectable HCC who were scheduled to receive selective TACE were randomly assigned at a 1:1 ratio to the DEB-TACE arm or the cTACE arm. The primary endpoint was the CR rate at 3 months, as evaluated according to the modified Response Evaluation Criteria in Solid Tumors by an independent review committee, and the secondary endpoints were the CR rate at 1 month and incidences of adverse events. Results: A total of 200 patients (DEB-TACE, 99 patients; cTACE, 101 patients) were enrolled in the study. The CR rates at 3 months and 1 month were significantly higher in the cTACE arm (75.2%, 84.2%) as compared with the DEB-TACE arm (27.6%, 35.7%). However, the frequencies of adverse events of any grade, including pyrexia (DEB-TACE vs. cTACE, 19.4% vs. 45.5%, p = 0.0001), fatigue (5.1% vs. 15.8%, p = 0.0194), malaise (11.1% vs. 25.7%, p = 0.0103), appetite loss (12.1% vs. 28.7%, p = 0.0048), abdominal pain (12.1% vs. 23.8%, p = 0.0423), increased serum bilirubin (22.2% vs. 48.5%, p = 0.0002), hypoalbuminemia (43.4% vs. 60.3%, p = 0.0154), increased serum aspartate aminotransferase (35.7% vs. 81.2%, p < 0.0001), and increased serum alanine aminotransferase (35.7% vs. 77.2%, p < 0.0001), were also significantly higher in the cTACE arm than in the DEB-TACE arm. Conclusions: Selective cTACE appeared to have higher CR rates for local tumor control as compared to selective DEB-TACE for HCC. However, the frequency of postembolization syndrome was also significantly higher in the cTACE group than in the DEB-TACE group. Thus, to achieve CR, cTACE may be selected over DEB-TACE in patients who can be expected to tolerate postembolization syndrome.
Congenital Cytomegalovirus Awareness and Knowledge among Health Professionals and Pregnant Women: An Action towards Prevention
Authors: Castillo Karen , Hawkins-Villarreal Ameth , Valdés-Bango Marta , Guirado Laura , Scazzocchio Elena , Porta Oriol , Falguera Gemma , López Marta , Palacio Montse , Gratacós Eduard , Figueras Francesc , Goncé Anna
Published: June 2022

Introduction: Cytomegalovirus (CMV) is a major cause of childhood disabilities, and consensus recommendations emphasize the importance of hygienic measures to reduce perinatal infection. Our study aimed to evaluate the level of awareness about CMV among health professionals and pregnant women. Methods: We submitted a 20-item online survey regarding CMV perinatal infection to all obstetricians and midwives in Catalonia (Spain) and a 7-item lay version of the questionnaire to 700 pregnant women. Levels of knowledge were compared among groups. Results: Of the 1,449 health professionals approached, 338 surveys were answered. 72% of professionals considered CMV a relevant problem. 47% of obstetricians and 28% of midwives (p ≤ 0.001) routinely informed pregnant women, and less than half knew the risk of fetal transmission. We observed significant differences in knowledge between obstetricians and midwives concerning the risks of recurrent infections, risk of transmission, and risk of severe infection (60.7% vs. 45.6%, p = 0.006 and 50.6% vs. 22.5%, p ≤ 0.001); and regarding maternal and neonatal symptoms and newborn sequelae (23% vs. 8.8%, p ≤ 0.001). Of the 700 women approached, we obtained a response rate of 72%. Only 23% had previously heard about CMV, 22% identified transmission routes, and 15% preventive measures. Compared to women without risk factors for CMV infection, women at greater risk had heard more about CMV (mothers of children <3 years: 36% vs. 20%, p < 0.001; occupational exposure: 43% vs. 20%, p ≤ 0.001) and had received more information (mothers of children <3 years: 18% vs. 9.5%, p ≤ 0.001; occupational exposure: 23% vs. 9.3%, p = 0.001). Conclusion: Health care professionals have limited knowledge about CMV and may fail to enforce preventive measures. While pregnant women have limited awareness about CMV infection, they recognize the need for information. Health campaigns should be promoted to enhance awareness about this perinatal infection.
Mitochondrial H
2
S Regulates BCAA Catabolism in Heart Failure
Authors: Li Zhen , Xia Huijing , Sharp Thomas E. , LaPenna Kyle B. , Elrod John W. , Casin Kevin M. , Liu Ken , Calvert John W. , Chau Vinh Q. , Salloum Fadi N. , Xu Shi , Xian Ming , Nagahara Noriyuki , Goodchild Traci T. , Lefer David J.
Published: June 2022

Background:

Hydrogen sulfide (H
2
S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H
2
S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload–induced heart failure.

Methods:

Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency.

Results:

Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H
2
S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction.

Conclusions:

Our data suggest that 3-MST derived mitochondrial H
2
S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.
Functional Outcomes of Patients ≥85 Years With Acute Ischemic Stroke Following EVT: A HERMES Substudy
Authors: McDonough Rosalie V. , Ospel Johanna M. , Campbell Bruce C.V. , Hill Michael D. , Saver Jeffrey L. , Dippel Diederik W.J. , Demchuk Andrew M. , Majoie Charles B.L.M. , Brown Scott B. , Mitchell Peter J. , Bracard Serge , Guillemin Francis , Jovin Tudor G. , Muir Keith W. , White Philip , Goyal Mayank ,   on behalf of the HERMES Collaborators
Published: June 2022

Background:

Observational studies have shown endovascular treatment (EVT) for acute ischemic stroke to be effective in the elderly, despite resulting in poorer outcomes and higher rates of mortality compared with younger patients. Randomized data on the effect of advanced age on outcomes following EVT are, however, lacking. Our aim was to assess the EVT effect for ischemic stroke in patients aged ≥85 years and the influence of age on outcome in a large, randomized trial dataset.

Methods:

Data were from the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration, a meta-analysis of 7 randomized trials published between January 1, 2010, and May 31, 2017, that tested the efficacy of EVT. A possible multiplicative interaction effect of age on the relationship between treatment and outcome was investigated. Ordinal logistic regression tested the association between EVT and 90-day functional outcome (modified Rankin Scale, primary outcome) in patients ≥85 years. Multivariable binary logistic regression was performed to compare primary and secondary outcomes (modified Rankin Scale score of 0–2/5–6) of patients ≥85 years versus those <85 years.

Results:

We included 1764 patients in the analysis, of whom 77 (4.4%) were ≥85 years old. A significant interaction of age and treatment on poor outcome (modified Rankin Scale score of 5–6,
P
=0.020) and mortality (
P
=0.031) was observed, with older adults having worse functional outcomes at 90 days compared with younger patients (adjusted common odds ratio, 0.20 [95% CI, 0.13–0.33]). However, a benefit of EVT was observed in the ≥85-year-old patient subgroup (common odds ratio, 4.20 [95% CI, 1.56–11.32]). Age ≥85 years was not significantly associated with differing rates of symptomatic intracerebral hemorrhage or reperfusion (adjusted odds ratio, 1.92 [95% CI, 0.71–5.15] and adjusted odds ratio, 0.91 [95% CI, 0.40–2.06], respectively).

Conclusions:

Patients ≥85 years old with independent premorbid function more often achieve good functional outcomes and have lower rates of mortality when treated with EVT compared with conservative management, with an observed treatment effect modification of age on outcome. EVT should therefore not be withheld in this subgroup.
An Evaluation of Flood Fatalities in Nigeria
Authors: Ologunorisa Temi Emmanuel , Eludoyin Adebayo Oluwole , Lateef Bola
Published: June 2022

Flood-induced fatalities are among the more poorly reported effects of flood disasters in many developing countries because of poor data inventory and management. Specific objectives of this study are to assess the spatial and temporal variations in flood fatalities in Nigeria, the most populous country in Africa. The study explored available datasets from the National (Nigerian) Meteorological and Emergency Management Agencies as well as those from the Dartmouth Flood Observatory (DFO) at the University of Colorado Boulder and complemented those with scattered reports from Nigerian newspapers to achieve the stated objectives. Using a mix of statistical and geographical information analysis approaches, the study showed that most of Nigeria is vulnerable to flood, given the nature of the dominant climate that often results in “medium” to “high” rainfall intensity (i.e., rainfall = 38.1–50.1 mm or > 50.1 mm in 24 h, respectively), inadequate settlement planning/land-use and land-cover management, and dam failure. Analysis of the frequency of the flood–fatality relationship indicates an increase in flood fatalities by 4.7% relative to flood cases between 1985 and 2017. The study complemented the results with information from newspapers and some other non-peer-reviewed documents (especially reports from relevant agencies) and revealed the need for a better flood information management system in the country, especially since the national database and DFO records were not the same. The study concluded that flood fatalities are on the increase but are poorly reported. It thus recommends improved information systems for flood and other disasters and their fatalities in the country.

Significance Statement

The purpose of this study is to reveal the state of information on flood disasters in a typical sub-Saharan African country. This is important because information about the distribution and trend of fatalities associated with flood disasters is required for sustainable mitigation planning globally. Our results provide a guide to understanding the distribution and associated factors of flood disasters as well as the contributions of informal (newspaper) sources to the inventory of relevant records.
Measurement properties of performance-based measures to assess physical function in knee osteoarthritis: A systematic review
Authors: Chen Hongbo , Wang Cui , Wu Junhui , Wang Mengying , Wang Siyue , Wang Xiaowen , Wang Jiating , Yu Huan , Hu Yonghua , Shang Shaomei
Published: June 2022

Objective

To systematically review the measurement properties of performance-based measures to assess physical function in people with knee osteoarthritis.

Data sources

PubMed, Web of Science, Embase, Scopus, CINAHL, and PsycINFO were searched in May 2022.

Methods

This study was conducted in accordance with the guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Clinical trials on the psychometric properties of performance-based tools for measuring physical function in people with knee osteoarthritis were included. Two reviewers independently rated measurement properties using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). “Best evidence synthesis” was made using COnsensus-based Standards for the selection of health Measurement INstruments outcomes and the quality of findings.

Results

Thirty-six out of 3425 publications were eligible for inclusion. Thirty-two performance-based measures were evaluated including 26 single-activity measures and 6 multi-activity measures. Measurement properties evaluated included internal consistency (2 measures), reliability (23 measures), measurement error (20 measures), hypotheses testing for construct validity (22 measures), and responsiveness (23 measures). On balance of the limited evidence, the walk 40 m fast-paced test and 6-minute walking test were the best rated walking tests. The 30-second chair stand test and timed up and go test were the best rated sit-to-stand tests. The Performance Tests Measures and Physical Activity Restrictions may be the suitable multi-activity measures for knee osteoarthritis.

Conclusions

Further good quality research investigating the measurement properties, and in particular, the measurement error of performance-based measures in patients with knee osteoarthritis is needed.
Depth-profile of impairments in endothelin-1 – induced focal cortical ischemia
Authors: Vinokurova Daria , Zakharov Andrey , Chernova Kseniya , Burkhanova-Zakirova Gulshat , Horst Viktor , Lemale Coline L , Dreier Jens P , Khazipov Roustem
Published: June 2022

The development of ischemic lesions has primarily been studied in horizontal cortical space. However, how ischemic lesions develop through the cortical depth remains largely unknown. We explored this question using direct current coupled recordings at different cortical depths using linear arrays of iridium electrodes in the focal epipial endothelin-1 (ET1) ischemia model in the rat barrel cortex. ET1-induced impairments were characterized by a vertical gradient with (i) rapid suppression of the spontaneous activity in the superficial cortical layers at the onset of ischemia, (ii) compartmentalization of spreading depolarizations (SDs) to the deep layers during progression of ischemia, and (iii) deeper suppression of activity and larger histological lesion size in superficial cortical layers. The level of impairments correlated strongly with the rate of spontaneous activity suppression, the rate of SD onset after ET1 application, and the amplitude of giant negative ultraslow potentials (∼−70 mV), which developed during ET1 application and were similar to the tent-shaped ultraslow potentials observed during focal ischemia in the human cortex. Thus, in the epipial ET1 ischemia model, ischemic lesions develop progressively from the surface to the cortical depth, and early changes in electrical activity at the onset of ET1-induced ischemia reliably predict the severity of ischemic damage.
Ureaplasma urealyticum induces polymorphonuclear elastase to change semen properties and reduce sperm motility: a prospective observational study
Authors: Liu Huang , Song Xiaoyan , Huang Mulan , Zhan Huashen , Wang Shiyang , Zhu Shenghui , Pang Tao , Zhang Xinzong , Zeng Qingqi
Published: June 2022

Objective

To elucidate the mechanism underlying how Ureaplasma urealyticum (UU) affects sperm quality and identify a therapeutic target.

Methods

In this prospective observational study, the differences in and relationships among semen volume, pH, viscosity, liquefaction time, sperm concentration, sperm motility [progressive motility (PR)], and seminal polymorphonuclear (PMN) elastase were analyzed in 198 normal semen samples (control group) and 198 UU-infected semen samples (observation group). The UU-infected samples were treated and the above parameters were compared between the two groups.

Results

The semen volume, viscosity, liquefaction time, and seminal PMN elastase were significantly higher in the observation than control group, but the pH and PR were significantly lower. In the observation group, the pH and PR were significantly higher after than before treatment, whereas the semen volume, PMN elastase, viscosity, and liquefaction time were lower. UU was closely related to semen volume, pH, viscosity, liquefaction time, sperm motility (PR), and PMN elastase. PMN elastase had significant negative effects on semen pH and sperm motility (PR) but positive effects on viscosity and liquefaction time.

Conclusion

UU might induce PMN elastase to increase the liquefaction time and viscosity of semen, eventually decreasing PR. PMN elastase might be a therapeutic target of UU.
Analysis of Travelers’ Risk Perceptions About Public Transit Systems During COVID-19 Pandemic
Authors: Raghuram Kadali B , Gadiraju Surya SSR , Gaddam Hari Krishna
Published: June 2022

The epidemic novel coronavirus disease 2019, abbreviated as COVID-19, has changed people’s mobility choices significantly, which has had a great impact on public transportation because of the public’s risk perception. The pandemic forced many people to shift toward private transport modes, which resulted in a decrease in public transport ridership and significantly altered travel behavior in urban areas. In this context, the present study investigated the public’s COVID-19 risk perception when public transportation is used (i.e., risk-taking behavior) and factors that significantly affect the use of public transportation. To fulfill this objective, a Google form-based questionnaire was prepared and circulated online. A total of 1,720 responses were collected using the survey form. These responses were processed for outliers and incomplete responses, and a total of 1,486 data samples were used for the analysis. A factor-based regression model was developed to study the risk-taking behavior of travelers while using public transportation during the COVID-19 pandemic. From the analysis, it is inferred that the travelers’ attitude negatively correlated with risk-taking behavior, whereas technology, motivation, concerns, and education positively affected COVID-19 risk perception when using public transit. Further, the study concluded that the behavior of travelers has a significant impact on their risk-taking behavior through their attitude and social norms. The findings of this study will be useful to urban transport planners in making suitable policies to increase public transportation ridership during pandemics.