bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PC3 Human Prostate Carcinoma Cell Holoclones Contain Self-renewing Tumor-Initiating Cells
Authors: Li Hangwen , Chen Xin , Calhoun-Davis Tammy , Claypool Kent , Tang Dean G.
Published: March 2023

Abstract
Primary keratinocytes exhibit three typical clonal morphologies represented by holoclones, meroclones, and paraclones, with holoclones containing self-renewing stem cells, and meroclones and paraclones containing more mature and differentiated cells. Interestingly, long-term–cultured human epithelial cancer cells in clonal cultures also form holoclones, meroclones, and paraclones, and tumor cell holoclones have been hypothesized to harbor stem-like cells or cancer stem cells. However, the key question of whether tumor cell holoclones genuinely contain tumor-initiating cells has not been directly addressed. Here, using PC3 human prostate carcinoma cells as a model, we provide direct experimental evidence that tumor cell holoclones contain stem-like cells that can initiate serially transplantable tumors. Importantly, holoclones derived from either cultured PC3 cells or holoclone-initiated tumors can be serially passaged and regenerate all three types of clones. In contrast, meroclones and paraclones cannot be continuously propagated and fail to initiate tumor development. Phenotypic characterizations reveal high levels of CD44, α2β1 integrin, and β-catenin expression in holoclones, whereas meroclones and paraclones show markedly reduced expression of these stem cell markers. The present results have important implications in understanding morphologic heterogeneities and tumorigenic hierarchies in human epithelial cancer cells. [Cancer Res 2008;68(6):1820–5]
Data from Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer
Authors: Uddin Shahab , Ahmed Maqbool , Bavi Prashant , El-Sayed Raafat , Al-Sanea Nasser , AbdulJabbar Alaa , Ashari Luai H. , Alhomoud Samar , Al-Dayel Fouad , Hussain Azhar R. , Al-Kuraya Khawla S.
Published: March 2023

Abstract
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC. [Cancer Res 2008;68(9):3379–88]
Data from DNA Damage Signaling in Hematopoietic Cells: A Role for Mre11 Complex Repair of Topoisomerase Lesions
Authors: Morales Monica , Liu Yan , Laiakis Evagelia C. , Morgan William F. , Nimer Stephen D. , Petrini John H.J.
Published: March 2023

Abstract
The Mre11 complex promotes DNA double-strand break repair and regulates DNA damage signaling via activation of the ataxia-telangiectasia mutated (ATM) kinase. The hypermorphic Rad50S allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50S experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation by the Rad50S-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In Rad50S/S mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50S/S is combined with mutations that alter either LSK cell quiescence (myeloid elf-1–like factor/ELF4–deficient mice) or hematopoietic differentiation (p21- and p27-deficient mice), indicating that the LSK population is a primary target of Rad50S pathology. We show that cells from Rad50S/S mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarily during DNA replication. On this basis, we propose that apoptotic attrition of Rad50S/S hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50S/S mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentially oncogenic lesions in Rad50S/S mice. These data provide compelling evidence that the Mre11 complex plays a role in the metabolism of topoisomerase lesions in mammals, and further suggest that such lesions can accumulate in primitive hematopoietic cells and confer significant oncogenic potential. [Cancer Res 2008;68(7):2186–93]
Data from Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category
Authors: Joensuu Emmi I. , Abdel-Rahman Wael M. , Ollikainen Miina , Ruosaari Salla , Knuutila Sakari , Peltomäki Päivi
Published: March 2023

Abstract
Tumor suppressor genes (TSG) may be inactivated by methylation of critical CpG sites in their promoter regions, providing targets for early detection and prevention. Although sporadic cancers, especially colorectal carcinoma (CRC), have been characterized for epigenetic changes extensively, such information in familial/hereditary cancer is limited. We studied 108 CRCs and 63 endometrial carcinomas (EC) occurring as part of hereditary nonpolyposis CRC, as separate familial site-specific entities or sporadically, for promoter methylation of 24 TSGs. Eleven genes in CRC and 6 in EC were methylated in at least 15% of tumors and together accounted for 89% and 82% of promoter methylation events in CRC and EC, respectively. Some genes (e.g., CDH13, APC, GSTP1, and TIMP3) showed frequent methylation in both cancers, whereas promoter methylation of ESR1, CHFR, and RARB was typical of CRC and that of RASSF1(A) characterized EC. Among CRCs, sets of genes with methylation characteristic of familial versus sporadic tumors appeared. A TSG methylator phenotype (methylation of at least 5 of 24 genes) occurred in 37% of CRC and 18% of EC (P = 0.013), and the presence versus absence of MLH1 methylation divided the tumors into high versus low methylation groups. In conclusion, inactivation of TSGs by promoter methylation followed patterns characteristic of tumor type (CRC versus EC) and family category and was strongly influenced by MLH1 promoter methylation status in all categories. Paired normal tissues or blood displayed negligible methylation arguing against a constitutional methylation abnormality in familial cases. [Cancer Res 2008;68(12):4597–605]
Data from Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells
Authors: Cai Jie , Damaraju Vijaya L. , Groulx Normand , Mowles Delores , Peng Yunshan , Robins Morris J. , Cass Carol E. , Gros Philippe
Published: March 2023

Abstract
To understand the mechanism of cellular resistance to the nucleoside analogue cytarabine (1-β-d-arabinofuranosylcytosine, AraC), two resistant derivatives of the human leukemic line CCRF-CEM were obtained by stepwise selection in different concentrations of AraC. CEM/4×AraC cells showed low AraC resistance, whereas CEM/20×AraC cells showed high resistance. Both cell lines showed similar patterns of cross-resistance to multiple cytotoxic nucleoside analogues, with the exception that CEM/20×AraC cells remained sensitive to 5-fluorouridine and 2-deoxy-5-fluorouridine. Both cell lines were sensitive to 5-fluorouracil and to a variety of natural product drugs. Although both CEM/4×AraC and CEM/20×AraC cells displayed reduced intracellular accumulation of [3H]AraC, only CEM/4×AraC cells showed reduced uptake of [3H]uridine, which was used to assess nucleoside transport activities. Genes encoding proteins known to be involved in nucleoside transport, efflux, and metabolism were analyzed for the presence of mutations in the two cell lines. In CEM/4×AraC cells, independent mutations were identified at each allele of human equilibrative nucleoside transporter 1 (hENT1; SLC29A1), one corresponding to a single-nucleotide change in exon 4, the other being a complex intronic mutation disrupting splicing of exon 13. In contrast to CEM/20×AraC cells, CEM/4×AraC cells did not bind the hENT1/SLC29A1 ligand nitrobenzylmercaptopurine ribonucleoside and lacked detectable hENT1/SLC29A1 protein. In CEM/20×AraC cells, independent intronic mutations impairing splicing of exons 2 and 3 were found at each allele of the deoxycytidine kinase gene. These studies point to at least two distinct mechanisms of AraC resistance in leukemic cells. [Cancer Res 2008;68(7):2349–57]
Data from RAP80 Responds to DNA Damage Induced by Both Ionizing Radiation and UV Irradiation and Is Phosphorylated at Ser205
Authors: Yan Jun , Yang Xiao-Ping , Kim Yong-Sik , Jetten Anton M.
Published: March 2023

Abstract
Receptor-associated protein (RAP80), a nuclear protein containing two ubiquitin-interacting motifs (UIM), was recently found to be associated with breast cancer-1 (BRCA1) and to translocate to ionizing radiation–induced foci (IRIF). In this study, we show that the BRCT mutant of BRCA1, R1699W, which is associated with increased risk of breast cancer, is unable to interact with RAP80. Previously, we showed that ataxia-telangiectasia mutated protein kinase (ATM) can phosphorylate RAP80 in vitro at Ser205, but whether this site is a target of ATM in whole cells was not established. To address this question, we generated an anti-RAP80Ser205P antibody that specifically recognizes RAP80 phosphorylated at Ser205. Our data show that RAP80 becomes phosphorylated at Ser205 in cells exposed to ionizing irradiation and that RAP80Ser205P translocates to IRIF. We show that this phosphorylation is mediated by ATM and does not require a functional BRCA1. The phosphorylation occurs within 5 minutes after irradiation, long before the translocation of RAP80 to IRIF. In addition, we show that UV irradiation induces translocation of RAP80 to DNA damage foci that colocalize with γ-H2AX. We further show that this translocation is also dependent on the UIMs of RAP80 and that the UV-induced phosphorylation of RAP80 at Ser205 is mediated by ATM- and RAD3-related kinase, not ATM. These findings suggest that RAP80 has a more general role in different types of DNA damage responses. [Cancer Res 2008;68(11):4269–76]
Data from Evidence that Resistance to Nilotinib May Be Due to BCR-ABL, Pgp, or Src Kinase Overexpression
Authors: Mahon François-Xavier , Hayette Sandrine , Lagarde Valérie , Belloc Francis , Turcq Béatrice , Nicolini Franck , Belanger Coralie , Manley Paul W. , Leroy Cédric , Etienne Gabriel , Roche Serge , Pasquet Jean-Max
Published: March 2023

Abstract
Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in chronic myeloid leukemia (CML) and in Bcr-Abl–positive acute lymphoblastic leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, second-generation inhibitors of Bcr-Abl tyrosine kinase such as nilotinib or dasatinib have been developed for the treatment of imatinib-resistant or imatinib-intolerant disease. In the current study, we generated nilotinib-resistant cell lines and investigated their mechanism of resistance. Overexpression of BCR-ABL and multidrug resistance gene (MDR-1) were found among the investigated mechanisms. We showed that nilotinib is a substrate of the multidrug resistance gene product, P-glycoprotein, using verapamil or PSC833 to block binding. Up-regulated expression of p53/56 Lyn kinase, both at the mRNA and protein level, was found in one of the resistant cell lines and Lyn silencing by small interfering RNA restored sensitivity to nilotinib. Moreover, failure of nilotinib treatment was accompanied by an increase of Lyn mRNA expression in patients with resistant CML. Two Src kinase inhibitors (PP1 and PP2) partially removed resistance but did not significantly inhibit Bcr-Abl tyrosine kinase activity. In contrast, dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn. Such mechanisms of resistance are close to those observed in imatinib-resistant cell lines and emphasize the critical role of Lyn in nilotinib resistance. [Cancer Res 2008;68(23):9809–16]
Data from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

AbstractPurpose:
To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation.
Patients and Methods:
Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.
Results:
Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events.
Conclusions:
An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.
Cost-Effectiveness of Pit and Fissure Sealing at Schools for Caries Prevention in China: A Markov Modeling Analysis
Authors: Zhou Liangru , Liu Bingjie , Li Yi , Wang Mingsi , Sun Chengyao , Zhang Xin , Liu Guoxiang , Siuzanna Novikova
Published: March 2023

The World Health Organization states that the application of pit and fissure sealants (PFSs) is an effective way to prevent dental caries. Estimates of potential health and economic impacts of PFS upon school-age children provide crucial evidence to support the extension of PFS coverage to all target populations. The China Children’s Oral Disease Comprehensive Intervention Project was launched in 2009 to provide free oral health examinations, PFS application, and oral health education for children aged 7 to 9 years. However, the national-level health and economic impacts of the program are unclear. To provide higher quality evidence at the national level in China, we developed a multi-perspective, multistate Markov model to estimate the cost and effect of PFS application to prevent dental caries. The total cost of the PFS project was 2.087 billion CNY, which can prevent 16.06 million PFMs from caries lesions. Compared with no intervention, PFS application was cost-effective from payer and society perspectives (BCR = 1.22 from the payer’s perspective, BCR = 1.91 from the societal perspective). The incremental cost-effectiveness ratio from both perspectives was negative (−61.46 CNY from the payer’s perspective, and −125.75 CNY from the societal perspective), indicating that PFS was cost-effective and cost-saving. Expanding the coverage of PFS application in school can be a more cost-effective strategy for caries prevention in China.
Potência de ponto relativo a uma circunferência: teoria, construções e problemas
Authors:   Universidade de São Paulo. Faculdade de Zootecnia e Engenharia de Alimentos, Linares Juan López
Published: March 2023

A potência de um ponto relativo a uma circunferência é um invariante derivado da semelhança de triângulos e com muitas aplicações. A discussão nesta obra é organizada em três capítulos: Fundamentos teóricos; Construções, exercícios e desafios; Problemas de olimpíadas internacionais. Este material didático foi utilizado durante algumas das aulas do curso Geometria Olímpica com GeoGebra para professores de Matemática do Ensino Fundamental e Médio de todo o Brasil. O texto conta com 37 figuras que facilitam acompanhar a resolução. Todas têm como complemento links para os gráficos interativos no site do GeoGebra e, vários, a resolução em vídeo do YouTube. O diferencial na utilização do GeoGebra está baseado na disponibilidade gratuita do software, tanto online como aplicativos para computadores e celulares. As construções geométricas podem ser feitas de forma dinâmica, onde exploram-se diversas configurações de um mesmo problema. O GeoGebra serve tanto como calculadora gráfica e numérica, utilizada para a verificação, como ferramenta para a apresentação, passo a passo, de uma demonstração rigorosa.
Some Findings Regarding the Use of Social Media as a Public Relations Tool: Example of TR 42 Region Municipalities
Authors: TUTAR Hasan , PARLAK İsmail Hakkı
Published: March 2023

Developments in information and communication technologies accelerate the transition from traditional management to e-governance. In this process, social media expands institutions' communication and interaction opportunities through highly accessible communication tools and platforms. Social media plays a vital role in municipalities' communication, interaction, recognition, and promotion activities, accelerating the transition from a traditional metropolis to an e-municipality. This study it is aimed to determine the social media usage levels of TR 42 region municipalities. The study analyzed the use of social media in the service delivery of the municipalities in the TR 42 region. The research data were obtained from the web pages of the municipalities forming the sample. Research findings show that municipalities actively use social media in the context of e-governance, but they need to make more progress in this area.
Piece of Mind: Presenting the Lived Experience and Scientific Research of Parkinson’s Disease through an Artistic Lens
Authors: Kuhlmann Naila , Robert Jérémie , Thomas Aliki , Blain-Moraes Stefanie
Published: March 2023

Many of the important research advances in understanding and treating Parkinson’s disease never leave the academic sphere, as communication barriers limit accessibility for, and engagement with, broader audiences. To increase meaningful dialogue between academic researchers and community stakeholders, Piece of Mind: Parkinson’s brought together neuroscientists, people with Parkinson’s disease (PD), and artists to co-create a knowledge translation performance based on scientific research and lived experience. The filmed, feature-length performance engages the viewer emotionally and intellectually using circus, dance, music, poetry, and patient testimonials. We provide an overview of our participatory process and a scene-by-scene description of the performance.
The Prospect of Art-Science Interplay in Filmmaking as Research: From Abstract to Implicit Film
Authors: Afdile Mamdooh
Published: March 2023

The neuroscientific and psychological use of fiction films for clinical and academic research is growing. However, artistic research using insights from these fields to advance the filmmaking practice is still in its infancy. Expanding on the author’s previous Leonardo publication proposing the use of scientific hypothesis formation for overcoming filmmaking uncertainty, this artistic research explores the feasibility of integrating scientific findings of abstract and ambiguous image perception to create a novel abstract filmmaking method. This research aims to revive the classical abstract film genre into an implicit cinematic experience.
Crescas and Gersonides on Freedom, Astrology, and Divine Omniscience
Authors: Green Alexander
Published: March 2023

Crescas’s position on human freedom is dialectically rooted in the philosophy of his medieval predecessor, Gersonides. Crescas accepts Gersonides’s view that although the celestial bodies influence human affairs, human beings have the ability to overcome their predetermined fate. However, Crescas rejects Gersonides’s premise that God only knows the universal aspect of the particular. Crescas contends that God’s commandments give their followers the means to obtain freedom from the effects of the heavenly bodies, without denying that practical deliberation is still required in order to actualize God’s promises, even if God knows how the individual will achieve the promised outcome.
Diplomatic Peace
Authors: Kornprobst Markus
Published: March 2023

This article introduces the concept of diplomatic peace. It starts by developing a heuristic frame for identifying understandings of peace embraced by the actors we study. This frame encompasses three faces of peace — restraint, compromise and polylogue — and further differentiates different degrees of each of these faces (induced, co-operative and categorical restraint; profitable, principled and iterated compromise; extended, communal and deliberative polylogue). Then, this heuristic is applied to key United Nations General Assembly declarations and conventions that have passed unanimously since 1946. Studying how diplomats define peace yields remarkable results. Diplomats make far-reaching promises about the kind of peace they purport to pursue, strongly endorsing co-operative restraint, principled compromises and deliberative polylogues. The added value of this article is threefold: it systematically enquires into the nexus of diplomacy and peace, develops a multifaceted concept of peace, and reminds scholars and practitioners of how far-reaching already existing diplomatic promises of peace are.
A new species of Xeroderus Gray, 1835 (Phasmida: Phasmatidae: Xeroderinae) from Papua New Guinea and notes on the genus
Authors: BROCK PAUL D. , HENNEMANN FRANK H.
Published: March 2023

Studies on the genus Xeroderus have revealed a new species from Papua New Guinea: Xeroderus conlei sp. n., which is described and figured from the holotype female only. Keys are provided to compare it with X. kirbyi Gray, 1835 from Australia, the only other species in the genus. Lectotypes are designated for X. kirbyi and the synonym Cooktownia plana Sjöstedt, 1918. Xeroderus brevipennis Redtenbacher, 1908 is found to be a member of Nisyrus Stål, 1877 and is here removed from Xeroderus and transferred to Nisyrus Stål, 1877. N. brevipennis (Redtenbacher, 1908) comb. n. is the first record of Nisyrus from the Solomon Islands. Various additional Australian localities are recorded for X. kirbyi Gray, 1835.
A new species of Asiophlugis (Orthoptera: Tettigoniidae: Phlugidini) from Misamis Oriental (Philippines, Mindanao)
Authors: TAN MING KAI , SALVADOR JEWEL ANNE G. , NUÑEZA OLGA MACAS
Published: March 2023

A new species of Asiophlugis Gorochov, 1998 (Orthoptera, Tettigoniidae, Phlugidini) is described from southern Philippines, in Mindanao, Misamis Oriental, Gingoog City: Asiophlugis spatulata sp. nov. This new species is characterised by the long, slender and flattened male cercus, with a basal process spatulated at the apex, and with a tooth-like medial process produced along the inner margin; as well as the male tenth abdominal tergite with two long cylindrical latero-apical processes pointing dorsad and externally. This new species represents the second species of Asiophlugis to be recorded from the Philippines.
New species of Ceratoderus and Melanospilus from Southeast Asia (Coleoptera: Carabidae: Paussinae)
Authors: BEDNAŘÍK MICHAL
Published: March 2023

Ceratoderus Westwood, 1841 and Melanospilus Westwood, 1847 are highly modified Paussinae ground beetles placed in close relationships with Paussus Linnaeus, 1775 in the latest studies. Four new species are described from Southeast Asia: Ceratoderus anthicoides sp. nov. (Philippines), C. kalamensis sp. nov. (Sulawesi), Melanospilus pilosus sp. nov. (Malay Peninsula), and M. spectabilis sp. nov. (Thailand). The present findings show how diversity is incompletely known, even in areas where many entomologists conducted field research.
Two new species of Astata Latreille from Iran (Hymenoptera, Astatidae)
Authors: JACOBS HANS-JOACHIM , REZAEI SHOHREH , FALLAHZADEH MAJID
Published: March 2023

Two new digger wasp species of the genus Astata Latreille, 1796 (Hymenoptera, Astatidae), A. ljubomirovi sp. nov. and A. rubriventris sp. nov. are described from Iran. Moreover, A. compta Nurse is newly recorded from the Palaearctic region and Iran, redescribed and illustrated. Diagnostic characters and key features to each species are given. With the present additions, the total number of Astata recorded from Iran increases up to 14.
Two new species of Olesicampe Förster (Hymenoptera, Ichneumonidae) with a key to species known from China and Oriental Region
Authors: HUANG RUI-FEN , KHALAIM ANDREY I. , SHENG MAO-LING , LI TAO
Published: March 2023

Two new species of Olesicampe Förster, 1869, O. minense Sheng & Khalaim, sp. nov. and O. matouense Sheng & Khalaim, sp. nov., collected from Fujian and Jiangxi provinces of the Oriental part of China, are described and illustrated. A key to the species of Olesicampe known in China and Oriental region is provided.
Role of plasma fibrinogen and D-dimer as prognostic biomarkers in patients with non-muscle invasive bladder cancer
Authors: Singla Sahil , Goel Apul , Mishra Sanjay , Lohani Ravi , Sankhwar Satya Narayan , Singh Sashi Raj
Published: March 2023

Background

We aimed to evaluate the role of plasma fibrinogen and D-dimer as prognostic biomarkers in patients with non-muscle invasive bladder cancer (NMIBC).

Methods

The prospective study included 35 patients (30 males) with newly diagnosed NMIBC with no history of thromboembolic event or anti-coagulant intake or active infection and underwent complete trans-urethral resection between September 2020 and December 2021. Patients with deranged hepato-renal functions, refractory hypertension or diagnosed with COVID-19 infection with in one-month before surgery or routine follow-up were excluded. Follow-up was done as per NCCN guidelines. Fibrinogen and D-dimer levels were measured with in seven days of surgery or follow-up and analyzed for recurrence-free survival (RFS) and progression-free survival (PFS). Cox regression analyses were adopted to assess the influence of these two parameters on RFS and PFS.

Results

The mean age was 53.9 years with a median follow-up of 9-months. Nine had recurrence of which six had progression. The cut-off values of fibrinogen and D-dimer were 402.5 mg/dl and 0.55 µg/ml, respectively. Kaplan–Meier analysis demonstrated that high fibrinogen and D-dimer levels were significantly related to poor RFS and PFS (p < 0.001). On multivariate analysis only fibrinogen and D-dimer retained their significance for RFS (p = 0.026 and 0.014, respectively) and PFS (p = 0.027 and 0.042, respectively). High levels of fibrinogen and D-dimer were also present in patients who had recurrence or progression at follow-up visits compared to rest of the patients.

Conclusions

High levels of fibrinogen and D-dimer may indicate worse prognosis in patients with NMIBC, suggesting that these two can be used as prognostic biomarkers.
Effects of OsomeFood Clean Label plant-based meals on the gut microbiome
Authors: Jacky Dwiyanto , Bibi Chia , Meng Look Melvin Chee , Jason Fong , Gwendoline Tan , Jeremy Lim , Wie Chong Chun
Published: March 2023

Background

Plant-based diets offer more beneficial microbes and can modulate gut microbiomes to improve human health. We evaluated the effects of the plant-based OsomeFood Clean Label meal range (‘AWE’ diet), on the human gut microbiome.

Methods

Over 21 days, ten healthy participants consumed OsomeFood meals for five consecutive weekday lunches and dinners and resumed their regular diets for other days/meals. On follow-up days, participants completed questionnaires to record satiety, energy and health, and provided stool samples. To document microbiome variations and identify associations, species and functional pathway annotations were analyzed by shotgun sequencing. Shannon diversity and regular diet calorie intake subsets were also assessed.

Results

Overweight participants gained more species and functional pathway diversity than normal BMI participants. Nineteen disease-associated species were suppressed in moderate-responders without gaining diversity, and in strong-responders with diversity gains along with health-associated species. All participants reported improved short-chain fatty acids production, insulin and γ-aminobutyric acid signaling. Moreover, fullness correlated positively with Bacteroides eggerthii; energetic status with B. uniformis, B. longum, Phascolarctobacterium succinatutens, and Eubacterium eligens; healthy status with Faecalibacterium prausnitzii, Prevotella CAG 5226, Roseburia hominis, and Roseburia sp. CAG 182; and overall response with E. eligens and Corprococcus eutactus. Fiber consumption was negatively associated with pathogenic species.

Conclusion

Although the AWE diet was consumed for only five days a week, all participants, especially overweight ones, experienced improved fullness, health status, energy and overall responses. The AWE diet benefits all individuals, especially those of higher BMI or low-fiber consumption.
Hypotension prediction index guided versus conventional goal directed therapy to reduce intraoperative hypotension during thoracic surgery: a randomized trial
Authors: Šribar Andrej , Jurinjak Irena Sokolović , Almahariq Hani , Bandić Ivan , Matošević Jelena , Pejić Josip , Peršec Jasminka
Published: March 2023

Purpose

Intraoperative hypotension is linked to increased incidence of perioperative adverse events such as myocardial and cerebrovascular infarction and acute kidney injury. Hypotension prediction index (HPI) is a novel machine learning guided algorithm which can predict hypotensive events using high fidelity analysis of pulse-wave contour. Goal of this trial is to determine whether use of HPI can reduce the number and duration of hypotensive events in patients undergoing major thoracic procedures.

Methods

Thirty four patients undergoing esophageal or lung resection were randomized into 2 groups -“machine learning algorithm” (AcumenIQ) and “conventional pulse contour analysis” (Flotrac). Analyzed variables were occurrence, severity and duration of hypotensive events (defined as a period of at least one minute of MAP below 65 mmHg), hemodynamic parameters at 9 different timepoints interesting from a hemodynamics viewpoint and laboratory (serum lactate levels, arterial blood gas) and clinical outcomes (duration of mechanical ventilation, ICU and hospital stay, occurrence of adverse events and in-hospital and 28-day mortality).

Results

Patients in the AcumenIQ group had significantly lower area below the hypotensive threshold (AUT, 2 vs 16.7 mmHg x minutes) and time-weighted AUT (TWA, 0.01 vs 0.08 mmHg). Also, there were less patients with hypotensive events and cumulative duration of hypotension in the AcumenIQ group. No significant difference between groups was found in terms of laboratory and clinical outcomes.

Conclusions

Hemodynamic optimization guided by machine learning algorithm leads to a significant decrease in number and duration of hypotensive events compared to traditional goal directed therapy using pulse-contour analysis hemodynamic monitoring in patients undergoing major thoracic procedures. Further, larger studies are needed to determine true clinical utility of HPI guided hemodynamic monitoring.

Trial registration

Date of first registration: 14/11/2022

Registration number: 04729481-3a96-4763-a9d5-23fc45fb722d
RRM2 and CDC6 are novel effectors of XBP1-mediated endocrine resistance and predictive markers of tamoxifen sensitivity
Authors: Barua David , Sultana Afrin , Islam Md Nahidul , Cox Fergus , Gupta Ananya , Gupta Sanjeev
Published: March 2023

Background

Endocrine-resistant breast cancers have elevated expression of XBP1, where it drives endocrine resistance by controlling the expression of its target genes. Despite the in-depth understanding of the biological functions of XBP1 in ER-positive breast cancer, effectors of endocrine resistance downstream of XBP1 are poorly understood. The aim of this study was to identify the XBP1-regulated genes contributing to endocrine resistance in breast cancer.

Methods

XBP1 deficient sub-clones in MCF7 cells were generated using the CRISPR-Cas9 gene knockout strategy and were validated using western blot and RT-PCR. Cell viability and cell proliferation were evaluated using the MTS assay and colony formation assay, respectively. Cell death and cell cycle analysis were determined using flow cytometry. Transcriptomic data was analysed to identify XBP1-regulated targets and differential expression of target genes was evaluated using western blot and qRT-PCR. Lentivirus and retrovirus transfection were used to generate RRM2 and CDC6 overexpressing clones, respectively. The prognostic value of the XBP1-gene signature was analysed using Kaplan–Meier survival analysis.

Results

Deletion of XBP1 compromised the upregulation of UPR-target genes during conditions of endoplasmic reticulum (EnR) stress and sensitized cells to EnR stress-induced cell death. Loss of XBP1 in MCF7 cells decreased cell growth, attenuated the induction of estrogen-responsive genes and sensitized them to anti-estrogen agents. The expression of cell cycle associated genes RRM2, CDC6, and TOP2A was significantly reduced upon XBP1 deletion/inhibition in several ER-positive breast cancer cells. Expression of RRM2, CDC6, and TOP2A was increased upon estrogen stimulation and in cells harbouring point-mutants (Y537S, D538G) of ESR1 in steroid free conditions. Ectopic expression of RRM2 and CDC6 increased cell growth and reversed the hypersensitivity of XBP1 KO cells towards tamoxifen conferring endocrine resistance. Importantly, increased expression of XBP1-gene signature was associated with poor outcome and reduced efficacy of tamoxifen treatment in ER-positive breast cancer.

Conclusions

Our results suggest that RRM2 and CDC6 downstream of XBP1 contribute to endocrine resistance in ER-positive breast cancer. XBP1-gene signature is associated with poor outcome and response to tamoxifen in ER-positive breast cancer.
Caregiver, secondary victim: outcome of caring for patients with COVID -19: a qualitative content analysis study
Authors: Faghani Safieh , Ahmadi Fazlollah , Mohammadi Eesa
Published: March 2023

Background

Considering the importance of caring for patients with COVID -19 at home and the majority of care being the responsibility of family caregivers, it is necessary to identify and assess the problems during the implementation of patient care in family caregivers. Therefore, the present study was conducted to discover the different consequences of caring for patients with COVID-19 in family caregivers.

Method

Using Purposive sampling, 15 female family caregivers were included in the study. This study was conducted between 2021 and 2022 in Iran. Unstructured face-to-face and virtual interviews were used to collect data until data saturation was reached. Data were analyzed through Granheim and Lundman conventional content analysis approach.

Results

The analysis of data related to the outcome of caring for patients with COVID -19 in family caregivers, led to the extraction of six subcategories: " caregivers experiencing physical symptoms ", "perception of extra pressure and psychological symptoms in the caregiver", "disruption in marital relations", "feeling of homelessness and rejection" and " role pressure due to lack of family support". The subcategories led to the development of the main category "caregiver, the secondary victim", which is experienced by family caregivers during the provision of care for patients with COVID -19.

Conclusion

Family caregivers experience high levels of negative consequences from providing care to patients with COVID-19. Therefore, more attention should be paid to all dimensions of caregiver health such as physical, mental, and marital to provide quality care to patients finally.
The effect of ambient ozone exposure on three types of diabetes: a meta-analysis
Authors: Yu Sirui , Zhang Mingzhi , Zhu Jiamin , Yang Xu , Bigambo Francis Manyori , Snijders Antoine M. , Wang Xu , Hu Weiyue , Lv Wei , Xia Yankai
Published: March 2023

Background

Ozone as an air pollutant is gradually becoming a threat to people's health. However, the effect of ozone exposure on risk of developing diabetes, a fast-growing global metabolic disease, remains controversial.

Objective

To evaluate the impact of ambient ozone exposure on the incidence rate of type 1, type 2 and gestational diabetes mellitus.

Method

We systematically searched PubMed, Web of Science, and Cochrane Library databases before July 9, 2022, to determine relevant literature. Data were extracted after quality evaluation according to the Newcastle Ottawa Scale (NOS) and the agency for healthcare research and quality (AHRQ) standards, and a meta-analysis was used to evaluate the correlation between ozone exposure and type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2D), and gestational diabetes mellitus (GDM). The heterogeneity test, sensitivity analysis, and publication bias were performed using Stata 16.0.

Results

Our search identified 667 studies from three databases, 19 of which were included in our analysis after removing duplicate and ineligible studies. Among the remaining studies, three were on T1D, five were on T2D, and eleven were on GDM. The result showed that ozone exposure was positively correlated with T2D [effect size (ES) = 1.06, 95% CI: 1.02, 1.11] and GDM [pooled odds ratio (OR) = 1.01, 95% CI: 1.00, 1.03]. Subgroup analysis demonstrated that ozone exposure in the first trimester of pregnancy might raise the risk of GDM. However, no significant association was observed between ozone exposure and T1D.

Conclusion

Long-term exposure to ozone may increase the risk of T2D, and daily ozone exposure during pregnancy was a hazard factor for developing GDM. Decreasing ambient ozone pollution may reduce the burden of both diseases.
CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma
Authors: Thieme Elana , Bruss Nur , Sun Duanchen , Dominguez Edward C. , Coleman Daniel , Liu Tingting , Roleder Carly , Martinez Melissa , Garcia-Mansfield Krystine , Ball Brian , Pirrotte Patrick , Wang Lili , Xia Zheng , Danilov Alexey V.
Published: March 2023

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.
HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer
Authors: Raju Ganji Seeta Rama , Pavitra Eluri , Bandaru Sai Samyuktha , Varaprasad Ganji Lakshmi , Nagaraju Ganji Purnachandra , Malla Rama Rao , Huh Yun Suk , Han Young-Kyu
Published: March 2023

HOX transcript antisense intergenic RNA (HOTAIR) is an oncogenic non-coding RNA whose expression is strongly correlated with the tumor grade and prognosis of a variety of carcinomas including breast cancer (BC). HOTAIR regulates various target genes via sponging and epigenetic mechanisms and controls various oncogenic cellular and signaling mechanisms including metastasis and drug resistance. In BC cells, HOTAIR expression is regulated by a variety of transcriptional and epigenetic mechanisms. In this review, we describe the regulatory mechanisms that govern HOTAIR expression during cancer development and explore how HOTAIR drives BC development, metastasis, and drug resistance. In the final section of this review, we focus on the role of HOTAIR in BC management, therapeutic treatment, and prognosis, highlighting its potential therapeutic applications.
A method of diamorphine (heroin) administration for harm reduction
Authors: Kavanagh Oisín N. , Machado Tatiane C.
Published: March 2023

As societal attitudes toward narcotics have changed, harm reduction strategies have emerged which make it safer to inject intravenous drugs. Diamorphine (heroin) is commonly sold as its free base—better known as brown—which has extremely poor aqueous solubility. As such, it needs to be chemically modified (cooked) to enable administration. Needle exchange programmes commonly supply citric or ascorbic acids which facilitate intravenous administration by increasing heroin solubility. If heroin users mistakenly add too much acid, the low solution pH can cause damage to their veins and, after repeated injury, could result in the loss of that injection site. Currently, advice cards supplied with these exchange kits suggest that the acid should be measured in pinches, which could result in considerable error. This work employs Henderson–Hasselbalch models to analyse the risk of venous damage by placing solution pH within the context of the buffer capacity of the blood. These models also highlight the significant risk of heroin supersaturation and precipitation within the vein, an event that has the potential to cause further harm to the user. This perspective closes with a modified administration method which could be included as part of a wider harm reduction package.
DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer
Authors: Koka Hela , Bodelon Clara , Horvath Steve , Lee Priscilla Ming Yi , Wang Difei , Song Lei , Zhang Tongwu , Hurson Amber N. , Guida Jennifer Lyn , Zhu Bin , Bailey-Whyte Maeve , Wang Feng , Wu Cherry , Tsang Koon Ho , Tsoi Yee-Kei , Chan W. C. , Law Sze Hong , Hung Ray Ka Wai , Tse Gary M. , Yuen Karen Ka-wan , Karlins Eric , Jones Kristine , Vogt Aurelie , Zhu Bin , Hutchinson Amy , Hicks Belynda , Garcia-Closas Montserrat , Chanock Stephen , Barnholtz-Sloan Jill , Tse Lap Ah , Yang Xiaohong R.
Published: March 2023

Background

Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong.

Methods

We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath’s pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson’s correlation (r), Kruskal–Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors.

Results

DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e−16) than in tumor tissue (Pearson r = 0.31, P = 7.8e−06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e−06) and PGR (Pearson r = 0.36, P = 2.4e−05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA.

Conclusions

Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.