bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of 4 weeks vs 8 weeks of acupuncture for knee osteoarthritis in China: protocol for a randomised controlled trial
Authors: Yu Ying , Liu Cun-Zhi , Wang Xue-Zhou , Xi Ya-Wei , Fu Yi-Ming , Mi Bao-Hong , Tu Jian-Feng
Published: January 2024

Introduction

Knee osteoarthritis represents the prevalent and incapacitating disease. Acupuncture, a widely used clinical treatment for knee osteoarthritis, has been shown to ameliorate pain and enhance joint function in affected individuals. However, there is a lack of evidence comparing different courses of acupuncture for knee osteoarthritis. In this trial, we will assess the effect of 4 weeks vs 8 weeks of acupuncture in patients with knee osteoarthritis.

Methods and analysis

The protocol is a pragmatic, parallel, two-arm randomised controlled trial, with the data analyst and assessor being blinded. 148 eligible patients with knee osteoarthritis will be randomly allocated in a 1:1 ratio to receive 4-week or 8-week acupuncture. Electroacupuncture will be administered three times per week for 4 or 8 weeks, respectively. Patients with knee osteoarthritis in both groups will be followed up to 26 weeks. The primary outcome is the response rate at week 26, and secondary outcomes include knee joint pain, knee joint function, knee joint stiffness, quality of life, patient global assessment, the Osteoarthritis Research Society International response rate and rescue medicine. A cost-effectiveness analysis will be carried out over 26 weeks.

Ethics and dissemination

The protocol has been approved by the Medical Ethical Committee of Beijing University of Chinese Medicine (2023BZYL0506). The study findings will be disseminated through presentation in a medical journal. Additionally, we plan to present them at selected conferences and scientific meetings.

Trial registration number

Chinese Clinical Trials Registry (ChiCTR2300073383;https://www.chictr.org.cn/showproj.html?proj=199310).
What are the observed procedural costs of vascular access surgery? Protocol for a systematic review
Authors: Edgar Ben , Jones Catrin , Aitken Emma , Stevenson Karen , Jackson Andrew , Gaianu Lucian , Thomson Peter , Kasthuri Ram , Stove Callum , Kingsmore David
Published: January 2024

Introduction

A central component in the introduction of a novel surgical procedure or technique is an evaluation of its cost efficiency when compared with a benchmark standard of care. Accurate assessment of costs is thus essential in ensuring appropriate allocation of resources within a healthcare system. The treatment of kidney failure requires a significant volume of resources, and vascular access provision is the main modifiable cost. The costs of providing this service are obscured by generic NHS reference costs, which lack adequate granularity to allow meaningful comparisons between treatments. The aim of this systematic review will be to assess the reporting of procedural costs in all published economic analyses of vascular access surgery and perform a comparison of the reported procedural costs involved in arteriovenous fistula (AVF) and arteriovenous graft (AVG) creation. This will provide an estimate as to the accuracy of the NHS reference costs in this field.

Methods and analysis

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. A systematic search will be performed of the MEDLINE, Embase and Cochrane databases to identify full-text economic analyses of vascular access for haemodialysis in which the procedural cost of AVF or AVG creation is reported. Publications in English from 1 January 2000 to 30 August 2023, will be eligible for inclusion. Studies will be selected by title and abstract review, followed by a full-text review using inclusion and exclusion criteria. Studies not reporting the procedural costs of surgery will be excluded. Data collected will pertain to procedural costs of AVF and AVG creation. Costs will be adjusted to a common currency using a gross domestic product (GDP) deflator index and conversion rates based on purchasing power parities for GDP. Comparison with NHS reference costs will indicate their reliability for use in future economic analyses in this field.

Ethics and dissemination

Ethical approval is not required for this systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations.

PROSPERO registration number

CRD42023458779.
Effect of an algorithm for automatic placing of standardised test order sets on low-value appointments and attendance rates at four Spanish teaching hospitals: an interrupted time series analysis
Authors: Álvaro de la Parra Juan Antonio , del Olmo Rodríguez Marta , Caramés Sánchez Cristina , Blanco Ángel , Pfang Bernadette , Mayoralas-Alises Sagrario , Fernandez-Ferro Jose , Calvo Emilio , Gómez Martín Óscar , Fernández Tabera Jesús , Plaza Nohales Carmen , Nieto Carlota , Short Apellaniz Jorge
Published: January 2024

Objective

Reducing backlogs for elective care is a priority for healthcare systems. We conducted an interrupted time series analysis demonstrating the effect of an algorithm for placing automatic test order sets prior to first specialist appointment on avoidable follow-up appointments and attendance rates.

Design

Interrupted time series analysis.

Setting

4 academic hospitals from Madrid, Spain.

Participants

Patients referred from primary care attending 10 033 470 outpatient appointments from 16 clinical specialties during a 6-year period (1 January 2018 to 30 June 2023).

Intervention

An algorithm using natural language processing was launched in May 2021. Test order sets developed for 257 presenting complaints from 16 clinical specialties were placed automatically before first specialist appointments to increase rates of diagnosis and initiation of treatment with discharge back to primary care.

Primary and secondary outcome measures

Primary outcomes included rate of diagnosis and discharge to primary care and follow-up to first appointment index. The secondary outcome was trend in ‘did not attend’ rates.

Results

Since May 2021, a total of 1 175 814 automatic test orders have been placed. Significant changes in trend of diagnosis and discharge to primary care at first appointment (p=0.005, 95% CI 0.5 to 2.9) and ‘did not attend’ rates (p=0.006, 95% CI −0.1 to −0.8) and an estimated attributable reduction of 11 306 avoidable follow-up appointments per month were observed.

Conclusion

An algorithm for placing automatic standardised test order sets can reduce low-value follow-up appointments by allowing specialists to confirm diagnoses and initiate treatment at first appointment, also leading to early discharge to primary care and a reduction in ‘did not attend’ rates. This initiative points to an improved process for outpatient diagnosis and treatment, delivering healthcare more effectively and efficiently.
The Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) protocol to explore the feasibility of embedding behavioural modifications into the clinical pathway for patients undergoing radical radiotherapy for lung cancer
Authors: Burnett Carole , Bestall Janine , Boland Alison , Burke Shaunna , Callister Matthew , Greenwood-Wilson Samuel , Hewison Jenny , Morgan Emma , Murray Rachael L , Pompili Cecilia , Sloss Andy , Williams Gillian , Franks Kevin
Published: January 2024

Patients with curable non-surgical lung cancer are often current smokers, have co-existing medical comorbidities and are treated with curative radiotherapy. To maximise the benefits of modern radiotherapy, there is an urgent need to optimise the patient’s health to improve survival and quality of life.

Methods and analysis

The Yorkshire Cancer Research-funded Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) (L426) is a single-centre prospective feasibility study to assess embedding behavioural changes into the radical radiotherapy pathway of patients with lung cancer. Feasibility will be assessed by measuring acceptability, demand and implementation. The duration of the study is 24 months. PREHABS has two workstreams: the intervention study and the theory of change (ToC) study.

Intervention study: PREHABS will commence at the R-IDEAL phase 2 trial (exploratory) based on existing evidence and includes support for smoking cessation, increasing activity and dietary well-being. Patients undergoing radical radiotherapy for lung cancer will be recruited from the oncology department at Leeds Teaching Hospitals NHS Trust (LTHT).ToC study: to maximise the acceptability and adherence to the PREHABS, we will use a ToC approach to qualitatively explore the key barriers and enablers of implementing a tailored programme of ‘prehabilitation’. The PREHABS ToC study participants will be recruited from patients with lung cancer undergoing radical radiotherapy and staff from the LTHT oncology department.

Analysis

The primary endpoint analysis will report the number of participants and adherence to the study interventions. Secondary endpoints include continued engagement with study interventions post-treatment. The analysis will focus on descriptive statistics. Thematic analysis of the qualitative data from the ToC study will identify consensus on intervention optimisation and delivery.

Ethics and dissemination

On 12 May 2021, the Cambridge East Ethics Committee granted ethical approval (21/EE/0048). The study is registered in the National Institute for Health and Care Research (NIHR) portfolio. The results will be disseminated through publication in peer-reviewed scientific journals and presented at conferences.

Trial registration number

NIHR portfolio 48420.
All-cause excess mortality among end-stage renal disease (ESRD) patients during the COVID-19 pandemic in Thailand: a cross-sectional study from a national-level claims database
Authors: Jirapanakorn Sutham , Witthayapipopsakul Woranan , Kusreesakul Khanitta , Lakhotia Divya , Tangcharoensathien Viroj , Suphanchaimat Rapeepong
Published: January 2024

Objectives

COVID-19 infection increased nephrology-related risks and mortality rate among end-stage renal disease (ESRD) patients. The pandemic also disrupted essential healthcare services. We aim to explore all-cause excess mortality among ESRD patients who were members of the Universal Coverage Scheme (UCS), the largest public health insurance scheme in Thailand covering citizens who are not employed in the formal sector, including children and older persons.

Design

A cross-sectional study.

Setting

We retrieved the dataset from the UCS claims database—electronic health records used for processing healthcare expense claims from medical facilities of all UCS members. This database links mortality outcome to civil registration. We employed the WHO’s excess mortality methodology using pre-pandemic data to estimate expected deaths during the pandemic period (March 2020 to August 2022).

Participants

This study included ESRD patients from across Thailand, covered by the UCS.

Primary outcome measure

Excess deaths are the difference between predicted and reported deaths.

Results

Over a 30-month period of the pandemic, the total number of all-cause excess deaths among ESRD patients was 4966 (male 1284; female 3682). The excess death per 100 000 ESRD patients was 3601 (male 2012; female 4969). The relative excess death was 5.7% of expected deaths (95% CI 1.7%, 10.0%). The excess deaths were highly concentrated among patients aged 65 and older.

Conclusion

ESRD patients are significantly more vulnerable to pandemic-related mortality than the general population. Health systems’ capacity to contain the pandemic at varying virulence and maintain essential health services for ESRD patients might be related to the size of excess deaths at different periods. The observed excess deaths highlight the importance of established strategies to reduce all-cause mortality such as rapid vaccine rollout for ESRD patients and sustaining dialysis and other essential services for older patients and other high-risk groups.
Study protocol for a 15-week randomised controlled trial assessing the independent effects of high-cholesterol and high-saturated fat diets on LDL cholesterol
Authors: Carter Sharayah , Hill Alison M , Yandell Catherine , Buckley Jonathan D , Coates Alison M
Published: January 2024

Introduction

Previous research has associated high dietary cholesterol intake with raised low-density lipoprotein cholesterol (LDL-C) and thus increased risk for cardiovascular disease (CVD). Emerging research suggests that it is saturated fat, not dietary cholesterol, associated with increased CVD risk. Despite being high in cholesterol, eggs, low in saturated fat, are not adversely associated with blood lipids or CVD risk. This paper describes a randomised controlled counter-balanced, cross-over trial assessing the effects of a high-cholesterol/low-saturated fat (egg) diet and a low-cholesterol/high-saturated fat diet (egg free) on blood lipids and lipoproteins, while accounting for physical activity levels which can also influence these parameters. The primary aim is to demonstrate that high cholesterol intake (from eggs) within a healthy, low-saturated fat diet does not adversely affect blood lipid levels and lipoprotein profiles. Instead, we propose that adverse effects on these parameters are mediated by saturated fat intake. The secondary aim is to explore relationships between changes in blood lutein and zeaxanthin concentrations and alterations in physical activity, examining whether changes in physical activity mediate effects on blood lipids and lipoproteins.

Methods and analysis

Fifty-two adults aged 18–60 years with LDL-C less than 3.5 mmol/L will be randomly allocated to three isocaloric diets for 5 weeks each: a high-cholesterol (600 mg)/low-saturated fat (6%) (egg) diet, a low-cholesterol (300 mg)/high-saturated fat (12%) (egg free) diet and a control diet that is high in both cholesterol (600 mg) and saturated fat (12%). Lipid and lipoprotein levels, lipoprotein size and concentrations, blood pressure, blood glucose, physical activity levels, and plasma lutein and zeaxanthin concentrations will be measured. Treatment effects will be analysed using linear mixed effects models.

Ethics and dissemination

Ethics approval was obtained from the University of South Australia Human Research Ethics Committee no. 204 327. Results will be disseminated through peer-reviewed journals and national and international presentations.

Trial registration number

NCT05267522
Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness—a protocol for a randomised controlled trial (ASTUTE trial)
Authors: Hazell Mae , Reeves Barnaby , Rogers Chris A , Pike Katie , Culliford Lucy , Baos Sarah , Lui Mandy P Y , Beare Nicholas A V , Pavesio Carlos , Denniston Alastair K , Wordsworth Sarah , Keane Pearse A , Wilson Robert , Folkard Annie , Peto Tunde , Sharma Srilakshmi M , Dick Andrew
Published: January 2024

Introduction

Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care.

Methods and analysis

The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted.

Ethics and dissemination

The trial received Research Ethics Committee (REC) approval from South Central – Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available.

Trial registration

ISRCTN31474800. Registered 14 April 2020.
Superpolynomial Lower Bounds Against Low-Depth Algebraic Circuits
Authors: Limaye Nutan , Srinivasan Srikanth , Tavenas Sébastien
Published: January 2024

An Algebraic Circuit for a multivariate polynomial
P
is a computational model for constructing the polynomial
P
using only additions and multiplications. It is a
syntactic
model of computation, as opposed to the Boolean Circuit model, and hence lower bounds for this model are widely expected to be easier to prove than lower bounds for Boolean circuits. Despite this, we do not have superpolynomial lower bounds against general algebraic circuits of depth 3 (except over constant-sized finite fields) and depth 4 (over any field other than F
2
), while constant-depth Boolean circuit lower bounds have been known since the early 1980s.

In this paper, we prove the
first superpolynomial lower bounds against algebraic circuits of all constant depths
over all fields of characteristic 0. We also observe that our super-polynomial lower bound for constant-depth circuits implies the first deterministic sub-exponential time algorithm for solving the Polynomial Identity Testing (PIT) problem for all small-depth circuits using the known connection between algebraic hardness and randomness.
Anthropomorphism and Human-Robot Interaction
Authors: Kim Rae Yule
Published: January 2024

Exploring how human apppreciation for and interactions with robots are influenced by anthropomorphic features.
Mitigating Debugger-based Attacks to Java Applications with Self-debugging
Authors: Pizzolotto Davide , Berlato Stefano , Ceccato Mariano
Published: January 2024

Java bytecode is a quite high-level language and, as such, it is fairly easy to analyze and decompile with malicious intents, e.g., to tamper with code and skip license checks. Code obfuscation was a first attempt to mitigate malicious reverse-engineering based on static analysis. However, obfuscated code can still be dynamically analyzed with standard debuggers to perform step-wise execution and to inspect (or change) memory content at important execution points, e.g., to alter the verdict of license validity checks. Although some approaches have been proposed to mitigate debugger-based attacks, they are only applicable to binary compiled code and none address the challenge of protecting Java bytecode.

In this article, we propose a novel approach to protect Java bytecode from malicious debugging. Our approach is based on automated program transformation to manipulate Java bytecode and split it into two binary processes that debug each other (i.e., a self-debugging solution). In fact, when the debugging interface is already engaged, an additional malicious debugger cannot attach. To be resilient against typical attacks, our approach adopts a series of technical solutions, e.g., an encoded channel is shared by the two processes to avoid leaking information, an authentication protocol is established to avoid Man-in-the-middle attacks, and the computation is spread between the two processes to prevent the attacker to replace or terminate either of them.

We test our solution on 18 real-world Java applications, showing that our approach can effectively block the most common debugging tasks (either with the Java debugger or the GNU debugger) while preserving the functional correctness of the protected programs. While the final decision on when to activate this protection is still up to the developers, the observed performance overhead was acceptable for common desktop application domains.
Late Cenozoic Faunal and Ecological Change in Africa
Authors: Faith J. Tyler , Rowan John , Du Andrew
Published: January 2024

Africa's fossil record of late Cenozoic mammals documents considerable ecological and evolutionary changes through time. Here, we synthesize those changes in the context of the mechanisms proposed to account for them, including bottom-up (e.g., climate change) and top-down (e.g., hominin impacts) processes. In doing so, we (a) examine how the incompleteness of the fossil record and the varied spatiotemporal scales of the evidence complicate efforts to establish cause-effect relationships; (b) evaluate hypothesized drivers of long-term ecological and evolutionary change, highlighting key unknowns; and (c) synthesize major taxonomic and functional trends through time (e.g., downsizing of faunal communities) considering the proposed drivers. Throughout our review, we point to unresolved questions and highlight research avenues that have potential to inform on the processes that have shaped the history of what are today the most diverse remaining large mammal communities on Earth.▪The study of late Cenozoic African mammal communities is intertwined with questions about the context, causes, and consequences of hominin evolution.▪The fossil record documents major functional (e.g., loss of megaherbivores) and taxonomic (e.g., rise of the Bovidae) changes over the past ∼7 Myr.▪Complexities inherent to the fossil record have made it difficult to identify the processes that drove ecological and evolutionary changes.▪Unanswered questions about the drivers of faunal change and the functioning of past ecosystems represent promising future research directions.
Ecology and Management of African Honey Bees (Apis mellifera L.)
Authors: Frazier Maryann , Muli Elliud , Patch Harland
Published: January 2024

In Africa, humans evolved as honey hunters of honey bee subspecies adapted to diverse geographical regions. Beekeeping today is practiced much as it was when Africans moved from honey hunting to beekeeping nearly 5,000 years ago, with beekeepers relying on seasonally available wild bees. Research suggests that populations are resilient, able to resist diseases and novel parasites. Distinct biomes, as well as environmental pressures, shaped the behavior and biology of these bees and in turn influenced how indigenous beekeeping developed. It appears that passive beekeeping practices that enabled free-living populations contributed to the overall resilience and health of the bee. There is clearly a need for research aimed at a deeper understanding of bee biology and the ecosystems from which they benefit and on which humans depend, as well as a growing realization that the management of these bees requires an indigenous approach that reflects a broader knowledge base and the economics of local communities and markets.
Disposable Point-of-Care Electrochemical Sensor for Uric Acid Determination in Human Urine Utilizing a Pencil Graphite Electrode Modified with Polydopamine/Gold Nanoparticles
Authors: Bayoumy Rehab E. , El-Ragehy Nariman A. , Hassan Nagiba Y. , Mahmoud Amr M.
Published: January 2024

Point-of-care testing (POCT) is an essential approach in clinical analysis due to its rapidity. In the current research and for the first time, we have developed an electrochemical POC sensor for uric acid (UA) determination using pencil graphite electrode (PGE) substrate modified via a facile self-polymerization of dopamine (DA). Alkaline conditions were used to produce polydopamine (PDA) which inspired from mussel adhesive protein. The PDA-modified electrode was further decorated by electrodeposition of gold nanoparticles (Au-NPs). Sensor surface characterization was conducted using surface characterization techniques like X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) imaging. In addition electrochemical characterization methods were performed utilizing electrochemical impedance spectroscopy (EIS) as well as cyclic voltammetry (CV). The sensor yielded a precise voltammetric response upon using differential pulse voltammetry (DPV) (linearity range: 5.0 × 10−5 mol l−1 − 5.0 × 10−4 mol l−1 of UA with 1.57 × 10–5 mol l−1 limit of detection). The developed sensor’s benefits include decreased manufacturing cost and selectivity. Accurate and satisfactory results were obtained upon application to human urine sample analysis.
Genesis of the Early Indosinian Darongshan Granitoid in South China: Response to the Subduction of the Eastern Paleo-Tethys Ocean
Authors: Tian Meng-Yu , Di Yong-Jun , Zhang Chun-Yu , Deng Shu-Guang
Published: January 2024

The Bangxi–Chenxing suture zone is an essential area from which information about the closure history of the eastern Paleo-Tethys Ocean can be obtained. The Darongshan granitoid, which is adjacent to this suture, lies among the widely distributed granitic rocks and few basic rocks in the southern Guangxi Province. Herein, we report the petrogeochemistry, zircon U–Pb ages, and zircon Hf isotopic data of the Darongshan pluton in this region. The LA-ICP-MS U–Pb zircon analysis indicates that the Darongshan pluton had formed at 249.9±2.6 Ma. The Darongshan granites are silica-rich (SiO2=65.68–72.91 wt%, mean=69.89 wt%) with high Na2O contents (Na2O=0.46–6.58 wt%, mean=3.49), relatively high Mg (Mg#=35.12–73.31, mean=57.73), and an average Fe2O3T+TiO2+MnO+MgO of 4.96. These features are similar to those of the Mg-andesitic/dioritic rock- (MA-) like tonalite–trondhjemite–granodiorites (TTGs). Chemical analyses show that all rocks are enriched in large-ion lithophile elements (Rb, Th, and U) and light rare earth elements, with weak negative Eu anomalies (Eu/Eu∗=0.27–0.67), and Ta, Nb, and Ti depletion, with typical arc-like affinity. The zircon Hf isotopic results show zircon ƐHft values ranging from -18.2 to -7.4 and the TDM2 model ages 1.74–2.41 Ga. The petrogeochemistry and zircon Hf isotopic signatures indicate the magma generation of the Darongshan granitoid with fluid/melt released from the subducted slab and the fluid/melt assimilated and mixed with the mantle peridotite during ascent. Combining previous extant information on Permo–Triassic subduction/collision-related magmatism in the Bangxi–Chenxing with that of the Jinshajiang–Ailaoshan–Song Ma suture zones, the Darongshan granitoid is interpreted as a magmatic formation that was generated in an active continental margin arc environment during the subduction of the Early Indosinian eastern Paleo-Tethys Ocean and the South China Block, further supporting the idea that closure occurred during the Middle–Late Triassic.
Mediterranean-Oriented Dietary Intervention Is Effective to Reduce Liver Steatosis in Patients with Nonalcoholic Fatty Liver Disease: Results from an Italian Clinical Trial
Authors: Zanini Barbara , Benini Federica , Marullo Monica , Simonetto Anna , Rossi Angelo , Cavagnoli Paola , Bonalumi Alessia , Marconi Silvia , Pigozzi Marie Graciella , Gilioli Gianni , Valerio Alessandra , Donato Francesco , Castellano Maurizio , Ricci Chiara
Published: January 2024

Background of the Study. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries. Lifestyle interventions are recommended as the primary therapy for NAFLD. Methodology. In this clinical trial, NAFLD patients were enrolled in a 12-month dietary intervention aimed to improve their eating habits according to the Mediterranean pattern, with scheduled appointments every three months. After the exclusion of steatosis, healthy subjects were recruited and received general advice based on current Italian food-based dietary guidelines. Results. One hundred and fifty five subjects aged 20–59 years underwent (i) liver ultrasound (US), (ii) clinical and anthropometric evaluations, (iii) blood tests, and (iv) assessment of dietary habits. According to US evaluation, 73 of them had severe, moderate, or mild liver steatosis (NAFLD patients) and 82 had no liver steatosis (healthy controls). Fifty-eight NAFLD patients and 73 controls completed the study. Among NAFLD patients, 26 (45%) downgraded steatosis severity, 12 of which achieved complete steatosis regression (21%). Three of the healthy controls developed NAFLD. The NAFLD patients improved their dietary habits and reduced BMI and waist circumference, during the study period, more than healthy controls. Liver steatosis remission/regression was independent of changes in BMI or liver enzymes and was more frequent among patients with mild steatosis at baseline. Conclusions. Mediterranean dietary advices, without a personalised meal planning, were efficient in reducing/remitting NAFLD, especially among patients with mild disease, which argues in favour of early identification and lifestyle intervention. This trial is registered with NCT03300661.
Data from Extrinsic Apoptosis Is Impeded by Direct Binding of the APL Fusion Protein NPM-RAR to TRADD
Authors: Chattopadhyay Anuja , Hood Brian L. , Conrads Thomas P. , Redner Robert L.
Published: January 2024

Abstract
A subset of acute promyelocytic leukemia (APL) cases has been characterized by the t(5;17)(q35;q21) translocation variant, which fuses nucleophosmin (NPM) to retinoic acid receptor α (RARA). The resultant NPM-RAR fusion protein blocks myeloid differentiation and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) PML-RAR fusion. The contribution of the N-terminal 117 amino acids of NPM contained within NPM-RAR has not been well studied. As a molecular chaperone, NPM interacts with a variety of proteins implicated in leukemogenesis. Therefore, a proteomic analysis was conducted to identify novel NPM-RAR–associated proteins. TNF receptor type I–associated DEATH domain protein (TRADD) was identified as a relevant binding partner for NPM-RAR. This interaction was validated by coprecipitation and colocalization analysis. Biologic assessment found that NPM-RAR expression impaired TNF-induced signaling through TRADD, blunting TNF-mediated activation of caspase-3 (CASP3) and caspase-8 (CASP8), to ultimately block apoptosis.

Implications: This study identifies a novel mechanism through which NPM-RAR affects leukemogenesis. Mol Cancer Res; 12(9); 1283–91. ©2014 AACR.
Data from The Nuclear Pool of Tetraspanin CD9 Contributes to Mitotic Processes in Human Breast Carcinoma
Authors: Rappa Germana , Green Toni M. , Lorico Aurelio
Published: January 2024

Abstract
Tetraspanin-29 (CD9) is an integral membrane protein involved in several fundamental cell processes and in cancer metastasis. Here, characterization of a panel of breast cancer cells revealed a nuclear pool of CD9, not present in normal human mammary epithelial cells. Antibody binding to surface CD9 of breast cancer cells resulted in increased nuclear CD9 fluorescence. CD9 was also found, along with a plasma membrane–associated pool, in the nuclei of all primary ductal breast carcinoma patient specimens analyzed. In all patients, about 40% of the total CD9 cellular fluorescence was nuclear. CD9 colocalized at the nuclear level with CEP97, a protein implicated in centrosome function, and with the IGSF8, an established CD9 partner in the plasma membrane. Co-immunoprecipitation of CEP97 and IGSF8 with CD9 was shown in nuclear extracts from breast cancer cells expressing a CD9–GFP fusion protein. However, by fluorescence resonance energy transfer (FRET) analysis, no direct binding of CD9 with either protein was observed, suggesting that CD9 is part of a larger nuclear protein complex. CD9 depletion or exposure of parental breast cancer cells to anti-CD9 mAb resulted in polynucleation and multipolar mitoses. These data indicate that the nuclear CD9 pool has an important role in the mitotic process.

Implications: The discovery of a nuclear pool of CD9 has prognostic and/or therapeutic potential for patients with ductal carcinoma of the breast. Mol Cancer Res; 12(12); 1840–50. ©2014 AACR.
Data from Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer
Authors: Labanca Estefanía , De Luca Paola , Gueron Geraldine , Paez Alejandra , Moiola Cristian P. , Massillo Cintia , Porretti Juliana , Giudice Jimena , Zalazar Florencia , Navone Nora , Vazquez Elba , De Siervi Adriana
Published: January 2024

Abstract
Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1–negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1–NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer.

Implications: Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2. Mol Cancer Res; 13(11); 1455–64. ©2015 AACR.
Data from Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells
Authors: Carrillo Alexia M. , Hicks Mellissa , Khabele Dineo , Eischen Christine M.
Published: January 2024

Abstract
The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2–p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11–Rad50–Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53.

Implications: Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53. Mol Cancer Res; 13(8); 1197–205. ©2015 AACR.
Data from The lncRNA DRAIC/PCAT29 Locus Constitutes a Tumor-Suppressive Nexus
Authors: Sakurai Kouhei , Reon Brian J. , Anaya Jordan , Dutta Anindya
Published: January 2024

Abstract
Long noncoding RNAs (lncRNA) are emerging as major regulators of cellular phenotypes and implicated as oncogenes or tumor suppressors. Here, we report a novel tumor-suppressive locus on human chromosome 15q23 that contains two multiexonic lncRNA genes of 100 kb each: DRAIC (LOC145837) and the recently reported PCAT29. The DRAIC lncRNA was identified from RNA-seq data and is downregulated as prostate cancer cells progress from an androgen-dependent (AD) to a castration-resistant (CR) state. Prostate cancers persisting in patients after androgen deprivation therapy (ADT) select for decreased DRAIC expression, and higher levels of DRAIC in prostate cancer are associated with longer disease-free survival (DFS). Androgen induced androgen receptor (AR) binding to the DRAIC locus and repressed DRAIC expression. In contrast, FOXA1 and NKX3-1 are recruited to the DRAIC locus to induce DRAIC, and FOXA1 specifically counters the repression of DRAIC by AR. The decrease of FOXA1 and NKX3-1, and aberrant activation of AR, thus accounts for the decrease of DRAIC during prostate cancer progression to the CR state. Consistent with DRAIC being a good prognostic marker, DRAIC prevents the transformation of cuboidal epithelial cells to fibroblast-like morphology and prevents cellular migration and invasion. A second tumor-suppressive lncRNA PCAT29, located 20 kb downstream of DRAIC, is regulated identically by AR and FOXA1 and also suppresses cellular migration and metastasis. Finally, based on TCGA analysis, DRAIC expression predicts good prognosis in a wide range of malignancies, including bladder cancer, low-grade gliomas, lung adenocarcinoma, stomach adenocarcinoma, renal clear cell carcinoma, hepatocellular carcinoma, skin melanoma, and stomach adenocarcinoma.

Implications: This study reveals a novel tumor-suppressive locus encoding two hormone-regulated lncRNAs, DRAIC and PCAT29, that are prognostic for a wide variety of cancer types. Mol Cancer Res; 13(5); 828–38. ©2015 AACR.
Data from Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway
Authors: Kardos Gregory R. , Wastyk Hannah C. , Robertson Gavin P.
Published: January 2024

Abstract
Many processes are deregulated in melanoma cells and one of those is protein production. Although much is known about protein synthesis in cancer cells, effective ways of therapeutically targeting this process remain an understudied area of research. A process that is upregulated in melanoma compared with normal melanocytes is proline biosynthesis, which has been linked to both oncogene and tumor suppressor pathways, suggesting an important convergent point for therapeutic intervention. Therefore, an RNAi screen of a kinase library was undertaken, identifying aldehyde dehydrogenase 18 family, member A1 (ALDH18A1) as a critically important gene in regulating melanoma cell growth through proline biosynthesis. Inhibition of ALDH18A1, the gene encoding pyrroline-5-carboxylate synthase (P5CS), significantly decreased cultured melanoma cell viability and tumor growth. Knockdown of P5CS using siRNA had no effect on apoptosis, autophagy, or the cell cycle but cell-doubling time increased dramatically suggesting that there was a general slowdown in cellular metabolism. Mechanistically, targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis, which could be reversed with proline supplementation. Thus, targeting ALDH18A1 in melanoma can be used to disrupt proline biosynthesis to limit cell metabolism thereby increasing the cellular doubling time mediated through the GCN2 pathway.

Implications: This study demonstrates that melanoma cells are sensitive to disruption of proline synthesis and provides a proof-of-concept that the proline synthesis pathway can be therapeutically targeted in melanoma tumors for tumor inhibitory efficacy. Mol Cancer Res; 13(10); 1408–20. ©2015 AACR.
Data from RhoC Is an Unexpected Target of RhoGDI2 in Prevention of Lung Colonization of Bladder Cancer
Authors: Griner Erin M. , Dancik Garrett M. , Costello James C. , Owens Charles , Guin Sunny , Edwards Michael G. , Brautigan David L. , Theodorescu Dan
Published: January 2024

Abstract
RhoGDI2 (ARHGDIB) suppresses metastasis in a variety of cancers but the mechanism is unclear, thus hampering development of human therapeutics. RhoGDI2 is a guanine nucleotide dissociation inhibitor (GDI) for the Rho family of GTPases thought to primarily bind to Rac1; however, Rac1 activation was not decreased by RhoGDI2 expression in bladder cancer cells. To better understand the GTPase-binding partners for RhoGDI2, a mass spectrometry–based proteomic approach was used in bladder cancer cells. As expected, endogenous RhoGDI2 coimmunoprecipitates with Rac1 and unexpectedly also with RhoC. Further analysis demonstrated that RhoGDI2 negatively regulates RhoC, as knockdown of RhoGDI2 increased RhoC activation in response to serum stimulation. Conversely, overexpression of RhoGDI2 decreased RhoC activation. RhoC promoted bladder cancer cell growth and invasion, as knockdown increased cell doubling time, decreased invasion through Matrigel, and decreased colony formation in soft agar. Importantly, RhoC knockdown reduced in vivo lung colonization by bladder cancer cells following tail vein injection in immunocompromised mice. Finally, unbiased transcriptome analysis revealed a set of genes regulated by RhoGDI2 overexpression and RhoC knockdown in bladder cancer cells.

Implications: RhoGDI2 suppresses bladder cancer metastatic colonization via negative regulation of RhoC activity, providing a rationale for the development of therapeutics that target RhoC signaling. Mol Cancer Res; 13(3); 483–92. ©2014 AACR.
Data from Lymphocyte Invasion in IC10/Basal-Like Breast Tumors Is Associated with Wild-Type TP53
Authors: Quigley David , Silwal-Pandit Laxmi , Dannenfelser Ruth , Langerød Anita , Vollan Hans Kristian Moen , Vaske Charles , Siegel Josie Ursini , Troyanskaya Olga , Chin Suet-Feung , Caldas Carlos , Balmain Allan , Børresen-Dale Anne-Lise , Kristensen Vessela
Published: January 2024

Abstract
Lymphocytic infiltration is associated with better prognosis in several epithelial malignancies including breast cancer. The tumor suppressor TP53 is mutated in approximately 30% of breast adenocarcinomas, with varying frequency across molecular subtypes. In this study of 1,420 breast tumors, we tested for interaction between TP53 mutation status and tumor subtype determined by PAM50 and integrative cluster analysis. In integrative cluster 10 (IC10)/basal-like breast cancer, we identify an association between lymphocytic infiltration, determined by an expression score, and retention of wild-type TP53. The expression-derived score agreed with the degree of lymphocytic infiltration assessed by pathologic review, and application of the Nanodissect algorithm was suggestive of this infiltration being primarily of cytotoxic T lymphocytes (CTL). Elevated expression of this CTL signature was associated with longer survival in IC10/Basal-like tumors. These findings identify a new link between the TP53 pathway and the adaptive immune response in estrogen receptor (ER)–negative breast tumors, suggesting a connection between TP53 inactivation and failure of tumor immunosurveillance.

Implications: The association of lymphocytic invasion of ER-negative breast tumors with the retention of wild-type TP53 implies a novel protective connection between TP53 function and tumor immunosurveillance. Mol Cancer Res; 13(3); 493–501. ©2014 AACR.
Data from MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC
Authors: Alam Maroof , Ahmad Rehan , Rajabi Hasan , Kufe Donald
Published: January 2024

Abstract
The LIN28B→let-7 pathway contributes to regulation of the epithelial–mesenchymal transition (EMT) and stem cell self-renewal. The oncogenic MUC1-C transmembrane protein is aberrantly overexpressed in lung and other carcinomas; however, there is no known association between MUC1-C and the LIN28B→let-7 pathway. Here in non–small cell lung cancer (NSCLC), silencing MUC1-C downregulates the RNA-binding protein LIN28B and coordinately increases the miRNA let-7. Targeting MUC1-C function with a dominant-negative mutant or a peptide inhibitor provided confirming evidence that MUC1-C induces LIN28B→let-7 signaling. Mechanistically, MUC1-C promotes NF-κB p65 chromatin occupancy of the LIN28B first intron and activates LIN28B transcription, which is associated with suppression of let-7. Consistent with let-7–mediated inhibition of HMGA2 transcripts, targeting of MUC1-C also decreases HMGA2 expression. HMGA2 has been linked to stemness, and functions as a competing endogenous RNA (ceRNA) of let-7–mediated regulation of the TGFβ coreceptor TGFBR3. Accordingly, targeting MUC1-C suppresses HMGA2 mRNA and protein, which is associated with decreases in TGFBR3, reversal of the EMT phenotype, and inhibition of self-renewal capacity. These findings support a model in which MUC1-C activates the ⇑LIN28B→⇓let-7→⇑HMGA2 axis in NSCLC and thereby promotes EMT traits and stemness.

Implications: A novel pathway is defined in which MUC1-C drives LIN28B→let-7→HMGA2 signaling, EMT, and self-renewal in NSCLC. Mol Cancer Res; 13(3); 449–60. ©2014 AACR.
Supplementary Figures S1-S16 from Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7)
Authors: Filosto Simone , Vardhanabhuti Saran , Canales Miguel A. , Poiré Xavier , Lekakis Lazaros J. , de Vos Sven , Portell Craig A. , Wang Zixing , To Christina , Schupp Marco , Poddar Soumya , Trinh Tan , Warren Carmen M. , Aguilar Ethan G. , Budka Justin , Cheng Paul , Chou Justin , Bot Adrian , Shen Rhine R. , Westin Jason R.
Published: January 2024

Supplementary Fig. 1. Duration of response did not associate with CAR T-cell peak expansion.

Supplementary Fig. 2. CAR T-cell peak did not associate with ongoing response in secondline LBCL.

Supplementary Fig. 3. Early CAR T-cell expansion correlated with ongoing response.

Supplementary Fig. 4. Naive T cells associated with improved outcome.

Supplementary Fig. 5. Association between toxicity and central memory T-cell product phenotype.

Supplementary Fig. 6. Association of product T-cell phenotypes/subpopulations with CAR Tcell expansion.

Supplementary Fig. 7. Naive enriched CAR T-cell product was more efficacious in vitro against tumor cells.

Supplementary Fig. 8. Select serum inflammatory and immune-modulatory analytes correlated with reduced efficacy and elevated toxicity at baseline and on day 0.

Supplementary Fig. 9. Association of T-cell subsets with posttreatment inflammatory serum analytes.

Supplementary Fig. 10. Elevated inflammatory profile at baseline differentially correlated with product phenotype.

Supplementary Fig. 11. Naive T-cell phenotype associated with higher peak level of VEGF.

Supplementary Fig. 12. Coculture IFN-γ associated with toxicity and T-cell phenotype.

Supplementary Fig. 13. Coculture IFN-γ association with toxicity and overall best response (CR versus others) by patient.

Supplementary Fig. 14. Association of apheresis CD27+CD28+CD8+ naive T cells with response.

Supplementary Fig. 15. T naive phenotype in second-line versus third-line LBCL.

Supplementary Fig. 16. Gating strategy for CD27 and CD28 costimulatory markers.
Table S2 from Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel
Authors: Paiva Bruno , Manrique Irene , Rytlewski Julie , Campbell Timothy , Kazanecki Christian C. , Martin Nathan , Anderson Larry D. , Berdeja Jesús G. , Lonial Sagar , Raje Noopur S. , Lin Yi , Moreau Philippe , San-Miguel Jesús F. , Munshi Nikhil C. , Kaiser Shari M.
Published: January 2024

HR for PFS according to MRD status