bluuebunny/crossref_metadata_2025 huggingface dataset:
Rāgs Around the Clock
Authors: Clarke David
Published: October 2024

Rāgs Around the Clock is a rich and vibrant compendium for the discovery and study of North Indian classical music. The theory and practice of rāg are explored through two interlinked resources: a handbook of essays and analyses offering technical, historical, cultural and aesthetic perspectives; and two online albums – Rāg samay cakra and Twilight Rāgs from North India – featuring khayāl singer Vijay Rajput and accompanists.

Extracts from the albums are also embedded into the text to enhance learning and understanding. Each rāg is accompanied by a description of its chief characteristics and technical features, a notation of the song (bandiś) on which the performance is based, and a transliteration and translation of the song text. Distinctively, Rāg samay cakra also includes spoken renditions of each of the texts, helping non-Hindavi speakers to achieve the correct pronunciation.

Sharing insights from both theory and practice, this collection draws on recent scholarship while also showcasing the vocal idiom – the gāyakī – of Vijay Rajput, a disciple of the late Pandit Bhimsen Joshi. It offers invaluable reading for students and researchers of Indian classical music, world music and ethnomusicology, and a rich repository for teacher and student practitioners of the khayāl vocal style. The combination of an aural and written exploration of rāg will appeal to anyone drawn to this form of music – whether newcomer, student (śiṣyā) or aficionado (rasika).
Introduction
Authors: Clarke David
Published: October 2024

Here, I recount how Rāgs Around the Clock is in part rooted in an introductory course in Indian classical music developed at Newcastle University by myself (David Clarke), Vijay Rajput and Shahbaz Hussain. I further outline the basis of the book’s companion albums—Rāg samay cakra and Twilight Rāgs from North India—in theories of rāg and performing time. Finally, I summarise the book’s structure and key themes, and place it in a wider context of collaboration between Indian and western musicians and musicologists.
The Klaic Effect: Dragan Klaić’s Expert Cooperation with Lublin in the European Capital of Culture Competition and the City’s Peripherality
Authors: Łopuszyńska Hanna
Published: October 2024

The Klaic Effect: Dragan Klaić’s Expert Cooperation with Lublin in the European Capital of Culture Competition and the City’s Peripherality
Culture and theatre critic Dragan Klaić was invited to be an expert collaborator with Lublin during the city’s participation in the 2016 European Capital of Culture competition. In this work, I analyse the researcher’s contribution to the preparation of Lublin’s candidature. I focus on the category of peripherality, which is very important both in Dragan Klaić’s thought and in the context of the city itself. I conclude by stating that Klaić’s projects, through which he proposed ways to both overcome the city’s negative peripherality and to exploit the presence of its positive sides, are still waiting to be realised.
 
Efekt Klaicia. Współpraca ekspercka Dragana Klaicia z Lublinem w konkursie na Europejską Stolicę Kultury a peryferyjność miasta
Krytyk kultury oraz teatru Dragan Klaić został zaproszony do współpracy eksperckiej z Lublinem podczas udziału miasta w konkursie o tytuł Europejskiej Stolicy Kultury 2016. W tej pracy analizuję wkład badacza w przygotowanie kandydatury Lublina. Skupiam się na kategorii peryferyjności, która jest bardzo ważna zarówno w myśli Dragana Klaicia, jak i w kontekście samego miasta. W zakończeniu stwierdzam, że projekty Klaicia, w których proponował on zarówno sposoby przezwyciężenia negatywnej peryferyjności miasta, jak i wykorzystania jej pozytywnych stron, wciąż czekają na swoją realizację.
Atmospheric Variability Drives Anomalies in the Bering Sea Air–Sea Heat Exchange
Authors: Hayden Emily E. , O’Neill Larry W. , Zippel Seth F.
Published: October 2024

High latitudes, including the Bering Sea, are experiencing unprecedented rates of change. Long-term Bering Sea warming trends have been identified, and marine heatwaves (MHWs), event-scale elevated sea surface temperature (SST) extremes, have also increased in frequency and longevity in recent years. Recent work has shown that variability in air–sea coupling plays a dominant role in driving Bering Sea upper-ocean thermal variability and that surface forcing has driven an increase in the occurrence of positive ocean temperature anomalies since 2010. In this work, we characterize the drivers of the anomalous surface air–sea heat fluxes in the Bering Sea over the period 2010–22 using ERA5 fields. We show that the surface turbulent heat flux dominates the net surface heat flux variability from September to April and is primarily a result of near-surface air temperature and specific humidity anomalies. The airmass anomalies that account for the majority of the turbulent heat flux variability are a function of wind direction, with southerly (northerly) wind advecting anomalously warm (cool), moist (dry) air over the Bering Sea, resulting in positive (negative) surface turbulent flux anomalies. During the remaining months of the year, anomalies in the surface radiative fluxes account for the majority of the net surface heat flux variability and are a result of anomalous cloud coverage, anomalous lower-tropospheric virtual temperature, and sea ice coverage variability. Our results indicate that atmospheric variability drives much of the Bering Sea upper-ocean temperature variability through the mediation of the surface heat fluxes during the analysis period.

Significance Statement

A long-term ocean warming trend and a recent increase in marine heatwaves in the Bering Sea have been identified. Previous work showed that anomalies in the exchange of heat between the ocean and the atmosphere were the primary driver of Bering Sea temperature variability, but the processes responsible for the heat exchange anomalies were unknown. In this work, we show that the atmosphere is the primary driver of anomalies in the Bering Sea air–sea heat exchange and therefore plays an important role in altering the thermal state of the Bering Sea. Our results highlight the importance of understanding more about how the ocean and the atmosphere interact at high latitudes and how this relationship will be affected by future climate change.
Editors’ Introduction to the Special Issue: New Findings on Family Factors in Juvenile Delinquency Prevention
Authors: Creemers Hanneke E. , Wissink Inge B. , Hoeve Machteld
Published: October 2024

Juvenile delinquency is a serious societal problem with detrimental physical and mental health effects for both victims and offenders. To prevent onset of delinquent behavior or keep it from escalating in frequency and seriousness, effective prevention is imperative. Since the family entails the primary context in which juvenile development takes place, families have a pivotal role in the prevention of juvenile delinquency. This special issue aims to highlight new findings on the role of family factors in the explanation of juvenile delinquency, to increase fundamental knowledge on the impact of family risk and protective factors on juvenile delinquency to inform prevention efforts. It presents findings of six studies with varying methodological designs, including longitudinal and cross-sectional designs using cohort data, network analyses, and genetically informed designs. Together, these studies (1) advance our understanding of the interrelatedness of (family) risk and protective factors in explaining juvenile delinquency; (2) provide more insight in the link between family factors and delinquency in two relatively new areas: the field of online delinquent behavior and the developmental period of emerging adulthood; and (3) increase knowledge on (the effects of) family involvement in preventive programs and interventions. The contributions advance our knowledge about the complex interplay of risk and protective factors contributing to juvenile delinquency, and underscore that families and parents matter in the development and prevention of juvenile delinquency.
An investigation of the relationship between social networking site activities and muscle dysmorphia in young men
Authors: Donnarumma Luigi , Mingoia John
Published: October 2024

While the connection between social networking sites (SNSs) and body image has been reported more broadly in prior literature, the link between SNSs and muscle dysmorphia (MD) is less understood. The aim of this study was to investigate the strength and nature of the relationship between MD and SNSs among men in the general population. With SNSs allowing users to view and interact with online content, this study focussed on three SNS activities: (a) viewing men’s celebrity and fashion content, (b) viewing fitness-related content and (c) the importance of received likes and comments. Young men ( N = 95) completed an online questionnaire recording demographic information, SNS activities and MD symptomatology. A hierarchal regression revealed that the importance of received likes and comments significantly predicted MD symptomatology over and above demographic factors. These findings reflect a need to emphasise the interactive components of SNSs within body image literature.
Leveraging Victim Voices: Unveiling True Needs Through Natural Language Processing in Trauma Narratives
Authors: Muraszkiewicz Julia , Cadman James
Published: October 2024

This article explores the intersection of technology, particularly artificial intelligence and anti-human trafficking and child sexual exploitation (CSE) initiatives. Despite the promises of technology, the overall effectiveness in addressing these crimes is limited. The authors argue that a key factor contributing to this limitation is the insufficient understanding of the crimes, rooted in the absence of meaningful engagement with victims. To address these challenges, the authors propose two strategies. First, they advocate for data-sharing partnerships to access extensive textual data held by organizations. Second, they highlight the use of natural language processing (NLP) to systematically analyse victim narratives without causing further interview fatigue. Embracing NLP is seen as a way to expedite research, enhance scalability and provide a fresh perspective on combating human trafficking and CSE. The article is structured to define key terminology, make a case for a victim-led response, demonstrate the application of NLP and conclude with insights from in-house research. The authors urge stakeholders to consider this new approach in their efforts to combat human trafficking and CSE.
How I Treat: Secondary Acute Myeloid Leukemia
Authors: Green Steven D , Wang Eunice S
Published: October 2024

Secondary acute myeloid leukemia (sAML) has traditionally been used to designate any AML disease arising from an antecedent hematologic disorder or following prior cytotoxic or radiation therapy. We now know sAML comprises multiple disease entities with distinct clinical and biological features: AML-myelodysplastic related (AML-MR), myeloproliferative neoplasm-blast phase (MPN-BP), and AML post-cytotoxic therapy (AML-pCT). These entities largely represent adverse-risk phenotypes with the majority of patients experiencing suboptimal outcomes with standard therapeutic options. Given the aging general population and the increased lifespan of individuals receiving DNA damaging agents for other medical conditions, the incidence of these diseases is steadily rising and now comprise approximately 25-30% of all new AML diagnoses. Despite the plethora of novel agents approved for AML since 2017, many are either not applicable to sAML (i.e. lacking a targetable mutation), have limited efficacy, or have not been studied in these specific entities. Furthermore, these patients are under-represented in clinical trials, and novel therapeutic options are critically needed. Here we present multiple patient cases exemplifying the new nomenclature and classification of the diseases comprising sAML and highlighting their diverse presentations. We provide our therapeutic approach for each clinical scenario and discuss the challenges of treatment with the currently available armamentarium.
Cy-1, a major QTL for tomato leaf curl New Delhi virus resistance, harbors a gene encoding a DFDGD-Class RNA-dependent RNA polymerase in cucumber (Cucumis sativus)
Authors: Koeda Sota , Yamamoto Chihiro , Yamamoto Hiroto , Fujishiro Kohei , Mori Ryoma , Okamoto Momoka , Nagano Atsushi J. , Mashiko Takaaki
Published: October 2024

Background

Tomato leaf curl New Delhi virus (ToLCNDV) (family Geminiviridae, genus Begomovirus) is a significant threat to cucumber (Cucumis sativus) production in many regions. Previous studies have reported the genetic mapping of loci related to ToLCNDV resistance, but no resistance genes have been identified.

Results

We conducted map-based cloning of the ToLCNDV resistance gene in cucumber accession No.44. Agroinfiltration and graft-inoculation analyses confirmed the resistance of No.44 to ToLCNDV isolates from the Mediterranean and Asian countries. Initial mapping involving two rounds of phenotyping with two independent F2 populations generated by crossing the begomovirus-susceptible cultivar SHF and No.44 consistently detected major quantitative trait loci (QTLs) on chromosomes 1 and 2 that confer resistance to ToLCNDV. Fine-mapping of Cy-1, the dominant QTL on chromosome 1, using F3 populations narrowed the candidate region to a 209-kb genomic segment harboring 24 predicted genes. Among these genes, DFDGD-class RNA-dependent RNA polymerase (CsRDR3), an ortholog of Ty-1/Ty-3 of tomato and Pepy-2 of capsicum, was found to be a strong candidate conferring ToLCNDV resistance. The CsRDR3 sequence of No.44 contained multiple amino acid substitutions; the promoter region of CsRDR3 in No.44 had a large deletion; and the CsRDR3 transcript levels were greater in No.44 than in SHF. Virus-induced gene silencing (VIGS) of CsRDR3 using two chromosome segment substitution lines harboring chromosome 1 segments derived from No.44 compromised resistance to ToLCNDV.

Conclusions

Forward and reverse genetic approaches identified CsRDR3, which encodes a DFDGD-class RNA-dependent RNA polymerase, as the gene responsible for ToLCNDV resistance at the major QTL Cy-1 on chromosome 1 in cucumber. Marker-assisted breeding of ToLCNDV resistance in cucumber will be expedited by using No.44 and the DNA markers developed in this study.
COVID-19 pandemic, pregnancy care, perinatal outcomes in Eastern Myanmar and North-Western Thailand: a retrospective marginalised population cohort
Authors: Prins Taco Jan , Watthanaworawit Wanitda , Gilder Mary Ellen , Tun Nay Win , Min Aung Myat , Naing May Phoo , Pateekhum Chanapat , Thitiphatsaranan Woranit , Thinraow Suradet , Nosten Francois , Rijken Marcus J. , van Vugt Michele , Angkurawaranon Chaisiri , McGready Rose
Published: October 2024

Background

The COVID-19 pandemic disrupted routine health care and antenatal and birth services globally. The Shoklo Malaria Research Unit (SMRU) based at the Thailand-Myanmar border provides cross border antenatal care (ANC) and birth services to marginalised pregnant women. The border between the countries entered lockdown in March 2020 preventing cross-border access for women from Myanmar to Thailand. SMRU adapted by opening a new clinic during the COVID-19 pandemic in Myanmar. This study explored the impact of the COVID-19 pandemic and response on access to ANC and pregnancy outcomes for marginalised pregnant women in the border regions between Thailand and Myanmar.

Methods

A retrospective review of medical records of all pregnancies delivered or followed at antenatal clinics of the SMRU from 2017 to the end of 2022. Logistic regression was done to compare the odds of maternal and neonatal outcomes between women who delivered pre-COVID (2017–2019) and women who delivered in the COVID-19 pandemic (2020–2022), grouped by reported country of residence: Thailand or Myanmar.

Results

Between 2017 and the end of 2022, there were 13,865 (5,576 resident in Thailand and 8,276 in Myanmar) marginalised pregnant women who followed ANC or gave birth at SMRU clinics. Outcomes of pregnancy were known for 9,748 women with an EGA ≥ 28 weeks. Unknown outcome of pregnancy among women living in Thailand did not increase during the pandemic. However, there was a high (60%) but transient increase in unknown outcome of pregnancy for women with Myanmar residence in March 2020 following border closure and decreasing back to the baseline of 20–30% after establishment of a new clinic. Non-literate women were more likely to have an unknown outcome during the pandemic. There was no statistically significant increase in known stillbirths or maternal deaths during the COVID pandemic in this population but homebirth was over represented in maternal and perinatal mortality.

Conclusion

Decreasing barriers to healthcare for marginalised pregnant women on the Thailand-Myanmar border by establishment of a new clinic was possible in response to sudden border closure during the COVID-19 pandemic and most likely preventing an increase in maternal and perinatal mortality.
A randomized controlled trial of a self-guided mobile app targeting repetitive negative thought to prevent depression in university students: study protocol of the Nurture-U Reducing Worry prevention trial
Authors: Watkins. E. R , Phillips D. , Cranston T. , Choueiri H. , Newton M. , Cook H. , Taylor G.
Published: October 2024

Background

Tackling poor mental health in university students has been identified as a priority in higher education. However, there are few evidence-based prevention initiatives designed for students. Repetitive Negative Thought (RNT, e.g. worry, rumination) is elevated in university students and is a well-established vulnerability factor for anxiety and depression. Furthermore, there are now evidence-based cognitive-behavioural interventions to tackle RNT. A mobile self-help cognitive-behavioural app targeting RNT, adapted for students may therefore be an effective, scalable, and acceptable way to improve prevention in students.

Methods

An online single blind, two-arm parallel-group Randomised Controlled Trial (RCT) to examine the incidence of major depression and symptoms of anxiety and depression across 12 months in university students aged over 16 who screen into the study with self-reported high levels of worry and/or rumination and no current diagnosis of major depression. Eligible participants will be randomised to the active intervention arm (usual practice plus using a self-guided mobile app targeting RNT) or to the control arm (usual practice). In total, 648 participants aged over 16, with no current major depression, bipolar disorder or psychosis will be recruited from UK universities. Assessments will take place at baseline (pre-randomisation), 3 months and 12 months post- randomisation. Primary endpoint and outcome is incidence of major depression as determined by self-reported diagnostic criteria at 12-month follow-up. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and academic outcomes are secondary outcomes. Compliance, adverse events, and potentially mediating variables will be carefully monitored.

Discussion

The trial aims to provide a better understanding of the causal role of tackling RNT (worry, rumination) using a self-help mobile app with respect to preventing depression in university students. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective mobile-health public health strategies for preventing common mental health problems.

Trial registration

https://www.isrctn.com/ISRCTN86795807 Date of registration: 27 October 2022
Non-coding RNAs as modulators of radioresponse in triple-negative breast cancer: a systematic review
Authors: Tofolo Maria Vitoria , Berti Fernanda Costa Brandão , Nunes-Souza Emanuelle , Ruthes Mayara Oliveira , Berti Lucas Freitas , Fonseca Aline Simoneti , Rosolen Daiane , Cavalli Luciane Regina
Published: October 2024

Triple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes.

Graphical Abstract
Navigating the complexity of a collaborative, system-wide public health programme: learning from a longitudinal qualitative evaluation of the ActEarly City Collaboratory
Authors: Nixon Laura , Sheard Laura , Sheringham Jessica , Creaser Amy , Iqbal Halima , Gansallo Patience , Mansukoski Liina , Bryant Maria , Lockyer Bridget
Published: October 2024

Background

Addressing the upstream social determinants of health (e.g. built environment, education) can reduce the burden of non-communicable diseases. To do so effectively often requires system-wide collaboration. However, collaborating across multiple sectors, organizations and disciplines within a complex system can be challenging. ActEarly was a public health research consortium that aimed to improve child health by building an interdisciplinary, cross-city partnership to develop and/or evaluate upstream interventions, increase research capacity and improve collaboration between researchers, local authorities and communities. This paper explores ActEarly’s experiences of navigating complexity to identify mechanisms that supported its implementation and proposes recommendations for future intersectoral and interdisciplinary population health research collaborations.

Methods

We conducted a longitudinal qualitative study of ActEarly, integrating findings from inductive documentary analysis of internal documents (mainly meetings minutes and reports) (n = 114) and interviews (n = 70) with 45 consortium members at three different timepoints (2018, 2021, 2023). Participants worked across different organizations, cities, roles and levels of seniority in the consortium.

Findings

Clarity, Unity, Flexibility and Feasibility were seen as the key mechanisms required to support ActEarly’s implementation. Clear aims, governance structures and communication were necessary to manage the uncertainty of the complex system. A unified approach, characterized by strong relationships, having a shared vision and communal access to resources supported effective collaboration. Flexibility was required to adjust to different ways of working, respond to wider system events and manage the consortium. Establishing feasible aims that responded to the limitations of the system, the available resources and research infrastructure was required for teams to deliver the work.

Conclusions

Implementing multi-faceted programmes in a complex system can be challenging. We recommend that future whole-systems consortia seeking to improve population health build Clarity, Unity, Flexibility and Feasibility into their programmes, noting the complex interrelationships between these factors. Iterative reflections from all parties should support delivery amidst the uncertainty that comes with running a population health research collaboration, and strong leadership and governance should play a key role in ensuring that these are built into foundations the programme.
Establishment and characterization of 18 Sarcoma Cell Lines: Unraveling the Molecular Mechanisms of Doxorubicin Resistance in Sarcoma Cell Lines
Authors: Cho Young-Eun , Kim Soon-Chan , Kim Ha Jeong , Han Ilkyu , Ku Ja-Lok
Published: October 2024

Sarcomas, malignant tumors from mesenchymal tissues, exhibit poor prognosis despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, with doxorubicin being a cornerstone treatment. Resistance to doxorubicin remains a significant hurdle in therapy optimization. This study aims to dissect the molecular bases of doxorubicin resistance in sarcoma cell lines, which could guide the development of tailored therapeutic strategies. Eighteen sarcoma cell lines from 14 patients were established under ethical approvals and classified into seven subtypes. Molecular, genomic, and transcriptomic analyses included whole-exome sequencing, RNA sequencing, drug sensitivity assays, and pathway enrichment studies to elucidate the resistance mechanisms. Variability in doxorubicin sensitivity was linked to specific genetic alterations, including mutations in TP53 and variations in the copy number of genomic loci like 11q24.2. Transcriptomic profiling divided cell lines into clusters by karyotype complexity, influencing drug responses. Additionally, pathway analyses highlighted the role of signaling pathways like WNT/BETA-CATENIN and HEDGEHOG in doxorubicin-resistant lines. Comprehensive molecular profiling of sarcoma cell lines has revealed complex interplays of genetic and transcriptomic factors dictating doxorubicin resistance, underscoring the need for personalized medicine approaches in sarcoma treatment. Further investigations into these resistance mechanisms could facilitate the development of more effective, customized therapy regimens.
Serum TNFα and IL-17A levels may predict increased depressive symptoms: findings from the Shika Study cohort project in Japan
Authors: Tsuboi Hirohito , Sakakibara Hiroyuki , Minamida-Urata Yuuki , Tsujiguchi Hiromasa , Hara Akinori , Suzuki Keita , Miyagi Sakae , Nakamura Masaharu , Takazawa Chie , Kannon Takayuki , Zhao Jiaye , Shimizu Yukari , Shibata Aki , Ogawa Aya , Suzuki Fumihiko , Kambayashi Yasuhiro , Konoshita Tadashi , Tajima Atsushi , Nakamura Hiroyuki
Published: October 2024

Background

Low-grade systemic inflammation may be a key player in the immune activation that has been reported for mental health deterioration. We hypothesised that elevated serum levels of inflammatory cytokines increase neuroinflammation and exacerbate depressive symptoms.

Methods

The participants were part of a cohort study for whom data was available for both 2015 and 2019. In 2015, blood samples were collected from 232 participants. Their depressive symptoms were assessed both 2015 and 2019 using the Centre for Epidemiologic Studies Depression Scale (CES-D) (n = 33). The multiplex immunoassay system (Luminex® 200) was used to measure the serum concentrations of IL-6, IL-10, IL-12, IL-17A and TNFα. Data were analysed using linear models with the level of significance considered to be p < 0.05.

Results

After controlling for age, BMI, smoking and alcohol consumption, in 2015 the serum concentrations of IL-17A and TNFα in 2015 were significantly positively associated with the CES-D scores of women (standardised β (B) = .027, p < 0.01 and B = 0.26, p < 0.01, respectively). The serum concentrations of IL-17A and TNFα of men were significantly positively associated with the CES-D scores of 2019 (B = 0.62, p = 0.02 and B = 0.59, p = 0.02, respectively).

Conclusions

In this cross-sectional study, we found a significant positive correlation between the depressive symptoms and serum TNFα and IL-17A levels of women. In addition, our longitudinal findings suggest the possibility that TNFα and IL-17A could elevate the depressive symptoms of men.
IRF2 loss is associated with reduced MHC I pathway transcripts in subsets of most human cancers and causes resistance to checkpoint immunotherapy in human and mouse melanomas
Authors: Sari G. , Dhatchinamoorthy K. , Orellano-Ariza L. , Ferreira L. M. , Brehm M. A. , Rock K.
Published: October 2024

Background

In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms.

Methods

Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo.

Results

Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI.

Conclusions

Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.
In vitro drug testing using patient-derived ovarian cancer organoids
Authors: Chen Lin-Yu , Chou Yu-Ting , Liew Phui-Ly , Chu Ling-Hui , Wen Kuo-Chang , Lin Shiou-Fu , Weng Yu-Chun , Wang Hui-Chen , Su Po-Hsuan , Lai Hung-Cheng
Published: October 2024

Background

Ovarian cancer is the most lethal gynecological cancer. As the primary treatment, chemotherapy has a response rate of only 60–70% in advanced stages, and even lower as a second-line treatment. Despite guideline recommendations, which drugs will be most effective remains unclear. Thus, a strategy to prioritize chemotherapy options is urgently needed. Cancer organoids have recently emerged as a method for in vitro drug testing. However, limited clinical correlations have been assessed with test results from cancer organoids, particularly in gynecological cancers. We therefore aimed to generate patient-derived organoids (PDOs) of ovarian cancer, to assess their drug sensitivities and correlations with patient clinical outcomes.

Methods

PDOs were generated from fresh tumors obtained during surgical resection, which was then cultured under matrix gel and appropriate growth factors. Morphological and molecular characterization of PDOs were assessed by phase contrast microscopy and paraffin-embedded histopathology. Expressions of PAX8, TP53, WT1, CK7, and CK20 were tested by immunohistochemical staining and compared with parental tumor tissues and the human protein atlas database. PDOs were subjected to in vitro drug testing to determine drug sensitivity using Titer-Glo® 3D Cell Viability Assay. PDO viability was measured, and area under the curve calculated, to compare responses to various compounds. Correlations were calculated between selected patients’ clinical outcomes and in vitro drug testing results.

Results

We established 31 PDOs. Among them, 28 PDOs can be expanded, including 15, 11, and 2 from ovarian, endometrial, and cervical cancers, respectively. The PDOs preserved the histopathological profiles of their originating tumors. In vitro drug testing of 10 ovarian cancer PDOs revealed individual differential responses to recommended drugs, and interpersonal heterogeneity in drug sensitivity, even with the same histology type. Among four patients who were platinum sensitive, resistant, or refractory, PDO drug responses correlated well with their clinical courses.

Conclusion

In vitro drug testing using ovarian cancer organoids is feasible and correlates well with patient clinical responses. These results may facilitate development of precision chemotherapy and personalized screening for repurposed or new drugs.
Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer’s disease
Authors: Meng Lingqi , Jin Han , Yulug Burak , Altay Ozlem , Li Xiangyu , Hanoglu Lutfu , Cankaya Seyda , Coskun Ebru , Idil Ezgi , Nogaylar Rahim , Ozsimsek Ahmet , Shoaie Saeed , Turkez Hasan , Nielsen Jens , Zhang Cheng , Borén Jan , Uhlén Mathias , Mardinoglu Adil
Published: October 2024

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.
Deep learning-based multi-frequency denoising for myocardial perfusion SPECT
Authors: Du Yu , Sun Jingzhang , Li Chien-Ying , Yang Bang-Hung , Wu Tung-Hsin , Mok Greta S. P.
Published: October 2024

Background

Deep learning (DL)-based denoising has been proven to improve image quality and quantitation accuracy of low dose (LD) SPECT. However, conventional DL-based methods used SPECT images with mixed frequency components. This work aims to develop an integrated multi-frequency denoising network to further enhance LD myocardial perfusion (MP) SPECT denoising.

Methods

Fifty anonymized patients who underwent routine 99mTc-sestamibi stress SPECT/CT scans were retrospectively recruited. Three LD datasets were obtained by reducing the 10 s acquisition time of full dose (FD) SPECT to be 5, 2 and 1 s per projection based on the list mode data for a total of 60 projections. FD and LD projections were Fourier transformed to magnitude and phase images, which were then separated into two or three frequency bands. Each frequency band was then inversed Fourier transformed back to the image domain. We proposed a 3D integrated attention-guided multi-frequency conditional generative adversarial network (AttMFGAN) and compared with AttGAN, and separate AttGAN for multi-frequency bands denoising (AttGAN-MF).The multi-frequency FD and LD projections of 35, 5 and 10 patients were paired for training, validation and testing. The LD projections to be tested were separated to multi-frequency components and input to corresponding networks to get the denoised components, which were summed to get the final denoised projections. Voxel-based error indices were measured on the cardiac region on the reconstructed images. The perfusion defect size (PDS) was also analyzed.

Results

AttGAN-MF and AttMFGAN have superior performance on all physical and clinical indices as compared to conventional AttGAN. The integrated AttMFGAN is better than AttGAN-MF. Multi-frequency denoising with two frequency bands have generally better results than corresponding three-frequency bands methods.

Conclusions

AttGAN-MF and AttMFGAN are promising to further improve LD MP SPECT denoising.
Robustifying and simplifying high-dimensional regression with applications to yearly stock return and telematics data
Authors: Marchese Malvina , Martínez-Miranda María Dolores , Nielsen Jens Perch , Scholz Michael
Published: October 2024

The availability of many variables with predictive power makes their selection in a regression context difficult. This study considers robust and understandable low-dimensional estimators as building blocks to improve overall predictive power by optimally combining these building blocks. Our new algorithm is based on generalized cross-validation and builds a predictive model step-by-step from a simple mean to more complex predictive combinations. Empirical applications to annual financial returns and actuarial telematics data show its usefulness in the financial and insurance industries.
Entomopathogenic potential of indigenous Simplicillium subtropicum (Hypocreales: Cordycipitaceae) isolates from Tamil Nadu, India, against the cotton aphid, Aphis gossypii Glover (Hemiptera: Aphididae)
Authors: Mariappan Krishnaveni , Samuel Jeyarajan Nelson , Sevugapperumal Nakkeeran , Uthandi Sivakumar , Subbarayalu Mohankumar , Krishnamoorthi Premalatha
Published: October 2024

Background

Aphis gossypii Glover (Hemiptera: Aphididae) is an economically important polyphagous pest species infesting many agricultural and horticultural crops causing severe yield losses. In order to develop biopesticides for the management of aphids in an environmentally safe manner, 6 indigenous entomopathogenic fungi Simplicillium subtropicum were isolated from soils of Tamil Nadu and their pathogenicity was tested against A. gossypii under laboratory conditions after characterization.

Results

Phenotypic and molecular characterization was performed for all the isolates for species identification. Results of the pathogenicity test showed that the isolate S6 (PP446637) performed well among other isolates causing 58.33% mortality on 7 days after treatment (DAT) @ 1 × 108 spores/ml. The LC50 and LT50 values were found to be 2.36 × 107 spores/ml at 7 DAT and 160.20 h @ 1 × 108 spores/ml, respectively. SEM images of A. gossypii treated with the isolate S6 (PP446637) revealed that initial phase of infection, i.e., adhesion, formation of germ tube and appressoria starts within 24 h post-infection (hpi), hyphal development and penetration of cuticle occurred within 48 hpi and extrusion of mycelium and conidiogenesis occurred within 72 hpi.

Conclusion

This study reveals the entomopathogenic potential of indigenous S. subtropicum isolates against A. gossypii and suggests their use for the eco-friendly management of aphids.
Multicolor single-molecule localization microscopy: review and prospect
Authors: Chen Xi , Wang Xiangyu , Huang Fang , Ma Donghan
Published: October 2024

Single-molecule localization microscopy (SMLM) surpasses the diffraction limit by randomly switching fluorophores between fluorescent and dark states, precisely pinpointing the resulted isolated emission patterns, thereby reconstructing the super-resolution images based on the accumulated locations of thousands to millions of single molecules. This technique achieves a ten-fold improvement in resolution, unveiling the intricate details of molecular activities and structures in cells and tissues. Multicolor SMLM extends this capability by imaging distinct protein species labeled with various fluorescent probes, providing insights into structural intricacies and spatial relationships among different targets. This review explores recent advancements in multicolor SMLM, evaluates the strengths and limitations of each variant, and discusses the future prospects.
Mortality associated with clozapine: what is the evidence?
Authors: Fernandez-Egea Emilio , Flanagan Robert J. , Taylor David , Gaughran Fiona , Lawrie Stephen M. , Jenkins Christopher , Smith Shubulade , Howes Oliver D. , MacCabe James H.
Published: October 2024

While clozapine has risks, relative risk of fatality is overestimated. The UK pharmacovigilance programme is efficient, but comparisons with other drugs can mislead because of reporting variations. Clozapine actually lowers mortality, partly by reducing schizophrenia-related suicides, but preventable deaths still occur. Clozapine should be used earlier and more widely, but there should be better monitoring and better management of toxicity.
Perioperative lenvatinib combined with tislelizumab plus transcatheter arterial chemoembolization in resectable hepatocellular carcinoma with high-risk of recurrence: A prospective, single-arm, phase 2 trial.
Authors: Wu Jia-Yi , Fu Yang-Kai , Wen Tianfu , Wang Shuang-Jia , Chen Jiafei , Zhang Zhibo , Liu Chongyuan , Wang Wei , Fang Lu , Tang Zhong , Chen Yufeng , Yan Maolin
Published: October 2024

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Background:
Early recurrence is common after surgery for hepatocellular carcinoma (HCC) and associated with poor prognosis. There is no standard of care neoadjuvant therapy. The combinations of lenvatinib, anti-PD-1 antibodies and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. This study aims to explore the efficacy and safety of triple therapy in the neoadjuvant therapy of resectable HCC patients with high-risk of recurrence.
Methods:
This prospective, single-arm, phase 2 trial (ChiCTR2100048249) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily was initiated within 7-10 days after TACE treatment. Surgery was performed 8 weeks after treatment. After 4-8 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months. Primary endpoint was relapse-free survival (RFS). Secondary endpoints were objective response rate (ORR) by mRECIST, major pathological reactions, R0 resection rates, overall survival, and adverse events (AE).
Results:
From April 2022 to June 2023, 29 patients (median age, 54 years) from ten Chinese hospitals were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (79.3%) and HBV infection (93.1%). According to mRECIST, the ORR was 89.7% (26/29, CR 4, PR 22), and the DCR was 96.7% (28/29). No grade 3 or above AE were observed. The most common AE were rash (4/29, 13.8%), thrombocytopenia (3/29, 10.3%), fatigue (3/29, 10.3%), elevated aspartate aminotransferase (2/29, 6.9%), elevated alanine aminotransferase (2/29, 6.9%), and hypertension (2/29, 6.9%). In 29 patients, 26 patients had received surgical treatment (R0 resection rates were 100%), 20 patients (20/26, 76.9%) achieved major pathological reaction (necrosis > 90%), and 4 patients (4/26, 15.4%) achieved complete pathological response. 2 patient (6.9%) refused surgery. 1 patient (3.4%) developed disease progression and lost the chance of surgery. After a median follow-up of 8.0 months (interquartile range 4.6-12.3 months), one patient died of severe pneumonia caused by COVID-19 infection 9.9 months after operation. Tumor recurrence was detected in 3 patients. The 6- and 12-month RFS rates were 90% and 82.5%, respectively. Median RFS and overall survival were not reached.
Conclusions:
Lenvatinib, tislelizumab, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2100048249.
Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study
Authors: Westerveld Aimée S.R. , Tytgat Godelieve A.M. , van Santen Hanneke M. , van Noesel Max M. , Loonen Jacqueline , de Vries Andrica C.H. , Louwerens Marloes , Koopman Maria M.W. , van der Heiden-van der Loo Margriet , Janssens Geert O. , de Krijger Ronald R. , Ronckers Cecile M. , van der Pal Helena J.H. , Kremer Leontien C.M. , Teepen Jop C.
Published: October 2024

PURPOSE

Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors.

METHODS

We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors.

RESULTS

In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine (
131I
MIBG) treatment. Survivors treated with
131I
MIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without
131I
MIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6).

CONCLUSION

Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs.
131I
MIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care.