bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a deprescribing tool on the use of sedative hypnotics among older patients: study protocol for a cluster randomised controlled trial in Swiss primary care (the HYPE trial)
Authors: Weiss Katja , Pichierri Giuseppe , Grischott Thomas , Groth Susan , Neuner-Jehle Stefan
Published: February 2024

Introduction

Benzodiazepines and other sedative hypnotics (BSH) are potentially inappropriate and harmful medications in older people due to their higher susceptibility for adverse drug events. BSH prescription rates are constantly high among elderly patients and even increase with higher age and comorbidity. Deprescribing BSH can be challenging both for healthcare providers and for patients for various reasons. Thus, physicians and patients may benefit from a supportive tool to facilitate BSH deprescribing in primary care consultations. This study intends to explore effectiveness, safety, acceptance and feasibility of such a tool.

Methods and analysis

In this prospective, cluster randomised, controlled, two-arm, double-blinded trial in the ambulatory primary care setting, we will include general practitioners (GPs) from German-speaking Switzerland and their BSH consuming patients aged 65 years or older, living at home or in nursing homes. GPs will be randomly assigned to either intervention or control group. In the intervention group, GPs will participate in a 1-hour online training on how to use a patient support tool (decision-making guidance plus tapering schedule and non-pharmaceutical alternative treatment suggestions for insomnia). The control group GPs will participate in a 1-hour online instruction about BSH epidemiology and sleep hygiene counselling. This minimal intervention aims to prevent unblinding of control group GPs without jeopardising their ‘usual care’.

The primary outcome will be the percentage of patients who change their BSH use (ie, stop, reduce or switch to a non-BSH insomnia treatment) within 6 months from the initial consultation.

Expected benefit

Based on the results of the study, we will learn how GPs and their patients benefit from a supportive tool that facilitates BSH deprescribing in primary care consultations. The study will emphasise on exploring barriers and facilitators to BSH deprescribing among patients and providers. Positive results given, the study will improve medication safety and the quality of care for patients with sleeping disorders.

Ethics and dissemination

The study has been approved by the Ethics Committee of the Canton of Zurich (KEK-ZH Ref no. 2023-00054, 4 April 2023). Informed consent will be sought from all participating GPs and patients. The results of the study will be publicly disseminated.

Trial registration number

ISRCTN34363838
Rationale and protocol of the LAQUA-HF trial: a factorial randomised controlled trial evaluating the effects of neurohormonal and diuretic agents on health-status reported outcomes in heart failure patients
Authors: Shiraishi Yasuyuki , Ikemura Nobuhiro , Urashima Mitsuyoshi , Kohno Takashi , Nakano Shintaro , Tanaka Toshikazu , Nagatomo Yuji , Ikoma Takenori , Ono Tomohiko , Numasawa Yohei , Sakamoto Munehisa , Nishikawa Kei , Takei Makoto , Hakuno Daihiko , Nakamaru Ryo , Ueda Ikuko , Kohsaka Shun
Published: February 2024

Introduction

The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects.

Methods and analysis

In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients’ QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients’ health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint.

Ethics and dissemination

The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses.

Trial registration number

UMIN000045229
Remote ischaemic conditioning combined with bimanual task training to enhance bimanual skill learning and corticospinal excitability in children with unilateral cerebral palsy: a study protocol of a single centre, phase II randomised controlled trial
Authors: Surkar Swati M , Willson John D , Cassidy Jessica M , Kantak Shailesh , Patterson Charity G
Published: February 2024

Introduction

Children with unilateral cerebral palsy (UCP) have difficulty in bimanual coordination that restricts the child’s independence in daily activities. Although several efficacious interventions to improve bimanual coordination exist, these interventions often require higher training doses and have modest effect sizes. Thus, there is a critical need to find an effective priming agent that, when paired with task-specific training, will facilitate neurobiological processes to enhance the magnitude of training effects and subsequently improve functional capabilities of children with UCP. The aim of this study is to determine the effects of a novel priming agent, remote ischaemic conditioning (RIC), combined with bimanual training on bimanual skill learning and corticospinal excitability in children with UCP.

Methods and analyses

46 children, aged 8–16 years, will be randomly assigned to receive RIC or sham conditioning combined with 5 days of bimanual skill (cup stacking) training (15 trials per session). RIC or sham conditioning will be performed with a standard conditioning protocol of five cycles of alternative inflation and deflation of a pressure cuff on the affected arm with the pressure of at least 20 mm Hg above systolic blood pressure for RIC and 25 mm Hg for sham conditioning. Primary outcomes will be movement time and corticospinal excitability measures determined with a single-pulse transcranial magnetic stimulation (TMS). Secondary outcomes include Assisting Hand Assessment, spatio-temporal kinematic variables and paired pulse TMS measures. All measures will be conducted before and immediately after the intervention. A mixed model analysis of variance will test the group×time interaction for all outcomes with group (RIC and sham) as between-subject and time (preintervention, postintervention) as within-subject factors.

Ethics and dissemination

The study has been approved by the University Medical Centre Institutional Review Board (UMCIRB #21-001913). We will disseminate the study findings via peer-reviewed publications and presentations at professional conferences.

Trial registration number

NCT05777070
Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL - a randomised clinical biomarker validation trial
Authors: Torp Nikolaj , Israelsen Mads , Coenraad Minneke , Papp Maria , Shawcross Debbie , Korenjak Marko , Angeli Paolo , Laleman Wim , Juanola Adria , Gines Pere , Trebicka Jonel , Krag Aleksander
Published: February 2024

Introduction

Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites.

Methods and analysis

ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis.

Ethics and dissemination

The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion.

Trial registration number

NCT05056220EU CT: 2022-501006-34-01
Quantifying non-adherence to anti-tuberculosis treatment due to early discontinuation: a systematic literature review of timings to loss to follow-up
Authors: Walker Elizabeth F , Flook Mary , Rodger Alison J , Fielding Katherine L , Stagg Helen R
Published: February 2024

Background

The burden of non-adherence to anti-tuberculosis (TB) treatment is poorly understood. One type is early discontinuation, that is, stopping treatment early. Given the implications of early discontinuation for treatment outcomes, we undertook a systematic review to estimate its burden, using the timing of loss to follow-up (LFU) as a proxy measure.

Methods

Web of Science, Embase and Medline were searched up to 14 January 2021 using terms covering LFU, TB and treatment. Studies of adults (≥ 18 years) on the standard regimen for drug-sensitive TB reporting the timing of LFU (WHO definition) were included. A narrative synthesis was conducted and quality assessment undertaken using an adapted version of Downs and Black. Papers were grouped by the percentage of those who were ultimately LFU who were LFU by 2 months. Three groups were created: <28.3% LFU by 2 months, ≥28.3–<38.3%, ≥38.3%). The percentage of dose-months missed due to early discontinuation among (1) those LFU, and (2) all patients was calculated.

Results

We found 40 relevant studies from 21 countries. The timing of LFU was variable within and between countries. 36/40 papers (90.0%) reported the percentage of patients LFU by the end of 2 months. 31/36 studies (86.1%) reported a higher than or as expected percentage of patients becoming LFU by 2 months. The percentage of dose-months missed by patients who became LFU ranged between 37% and 77% (equivalent to 2.2–4.6 months). Among all patients, the percentage of dose-months missed ranged between 1% and 22% (equivalent to 0.1–1.3 months).

Conclusions

A larger than expected percentage of patients became LFU within the first 2 months of treatment. These patients missed high percentages of dose months of treatment due to early discontinuation. Interventions to promote adherence and retain patients in care must not neglect the early months of treatment.

PROSPERO registration number

CRD42021218636.
Inversion points of the accretion flows onto super-spinning Kerr attractors
Authors: Pugliese D. , Stuchlík Z.
Published: February 2024

We study the accretion flows towards a central Kerr super-spinning attractor, discussing the formation of the flow inversion points, defined by condition $$u^{\phi }=0$$

u
ϕ

=
0

on the particles flow axial velocity. We locate two closed surfaces, defining inversion coronas (spherical shells), surrounding the central attractor. The coronas analysis highlights observational aspects distinguishing the central attractors and providing indications on their spin and the orbiting fluids. The inversion corona is a closed region, generally of small extension and thickness, which is for the counter-rotating flows of the order of $$\lesssim 1.4 M$$

≲
1.4
M

(central attractor mass) on the vertical rotational axis. There are no co-rotating inversion points (from co-rotating flows). The results point to strong signatures of the Kerr super-spinars, provided in both accretion and jet flows. With very narrow thickness, and varying little with the fluid initial conditions and the emission process details, inversion coronas can have remarkable observational significance for primordial Kerr super-spinars predicted by string theory. The corona region closest to the central attractor is the most observably recognizable and active part, distinguishing black holes solutions from super-spinars. Our analysis expounds the Lense–Thirring effects and repulsive gravity effects in the super-spinning ergoregions.
From isolated polyelectrolytes to star-like assemblies: the role of sequence heterogeneity on the statistical structure of the intrinsically disordered neurofilament-low tail domain
Authors: Kravikass Mathar , Koren Gil , Saleh Omar A. , Beck Roy
Published: February 2024

Intrinsically disordered proteins (IDPs) are a subset of proteins that lack stable secondary structure. Given their polymeric nature, previous mean-field approximations have been used to describe the statistical structure of IDPs. However, the amino-acid sequence heterogeneity and complex intermolecular interaction network have significantly impeded the ability to get proper approximations. One such case is the intrinsically disordered tail domain of neurofilament low (NFLt), which comprises a 50 residue-long uncharged domain followed by a 96 residue-long negatively charged domain. Here, we measure two NFLt variants to identify the impact of the NFLt two main subdomains on its complex interactions and statistical structure. Using synchrotron small-angle x-ray scattering, we find that the uncharged domain of the NFLt induces attractive interactions that cause it to self-assemble into star-like polymer brushes. On the other hand, when the uncharged domain is truncated, the remaining charged N-terminal domains remain isolated in solution with typical polyelectrolyte characteristics. We further discuss how competing long- and short-ranged interactions within the polymer brushes dominate their ensemble structure and, in turn, their implications on previously observed phenomena in NFL native and diseased states.

Graphic abstract

Visual schematic of the SAXS measurement results of the Neurofilament-low tail domain IDP (NFLt). NFLts assemble into star-like brushes through their hydrophobic N-terminal domains (marked in blue). In increasing salinity, brush height (h) is initially increased following a decrease while gaining additional tails to their assembly. Isolating the charged sub-domain of the NFLt (marked in red) results in isolated polyelectrolytes
A Computer-Aided Design Tool for Muqarnas
Authors: Dinçer Sevde Gülizar , Korumaz Mustafa , Yazar Tuğrul
Published: February 2024

In numerous instances of Islamic architecture, the geometric arrangement of muqarnas was established using square-rhombus tessellations in their flat projections. Similarly, in Türkiye, square-rhombus projection schemes have been employed in muqarnas designs since the era of the Anatolian Seljuks. This study introduces a computer-aided design (CAD) tool called “Anatolian Muqarnas,” which aims to recreate muqarnas schemes with square-rhombus projections. The tool is built upon a novel geometric analysis approach specifically tailored for Anatolian Seljuks muqarnas, drawing inspiration from Ammann-Beenker tiling and supertiles. Users of Anatolian Muqarnas can easily simulate existing or new designs by following predetermined rules. This contribution is expected to enhance discussions regarding the geometric analysis of muqarnas and the interplay between computing and cultural heritage at large.
Differences in Heritage Tourism Experience between VR and AR: A Comparative Experimental Study Based on Presence and Authenticity
Authors: Guo Yuqing , Lu Shizhu , Shen Min , Huang Wei , Yi Xiaolie , Zhang Jifa
Published: February 2024

This study developed two distinct types of remote heritage virtual tourism programs, namely VR and AR. We utilized the Stimulus-Organism-Response (S-O-R) model to understand how users’ perceptions of vividness and interactivity in VR and AR influence their sense of presence and perceived authenticity. Furthermore, we explored how the sense of presence and perceived authenticity further impact tourists’ responses, including satisfaction and behavioral intention. The findings indicate differences between VR and AR in several aspects. To elaborate, in the context of VR, vividness significantly influences perceived authenticity, an effect not found within the AR setting. Furthermore, interactivity impacts the sense of presence in AR, but this is not the case in VR. Within an AR setting, a user's sense of presence directly influences their level of satisfaction, yet no corresponding impact was found in VR. Even though the results show varying influences of presence on user intention in VR and AR, no significant differences were discovered. By gaining an in-depth understanding of tourists’ actual perceptions of VR and AR applications, this study provides insights for heritage site managers on how to employ VR and AR to enhance the efficiency of virtual heritage experiences for tourists.
Contraction Decomposition in Unit Disk Graphs and Algorithmic Applications in Parameterized Complexity
Authors: Panolan Fahad , Saurabh Saket , Zehavi Meirav
Published: February 2024

We give a new decomposition theorem in unit disk graphs (UDGs) and demonstrate its applicability in the fields of Structural Graph Theory and Parameterized Complexity. First, our new decomposition theorem shows that the class of UDGs admits an “almost” Contraction Decomposition Theorem. Prior studies on this topic exhibited that the classes of planar graphs [Klein, SICOMP, 2008], graphs of bounded genus [Demaine, Hajiaghayi and Mohar, Combinatorica 2010], and
H
-minor free graphs [Demaine, Hajiaghayi and Kawarabayashi, STOC 2011] admit a Contraction Decomposition Theorem. Even
bounded-degree
UDGs can contain arbitrarily large cliques as minors, and therefore our result is a significant advance in the study of contraction decompositions. Additionally, this result answers an open question posed by Hajiaghayi (
www.youtube.com/watch?v=2Bq2gy1N01w
) regarding the existence of contraction decompositions for classes of graphs beyond
H
-minor free graphs though under a relaxation of the original formulation.

Second, we present a “parameteric version” of our new decomposition theorem. We prove that there is an algorithm that, given a UDG
G
and a positive integer
k
, runs in polynomial time and outputs a collection of

\(\mathcal {O}(k)\)

tree decompositions of
G
with the following properties. Each bag in any of these tree decompositions can be partitioned into

\(\mathcal {O}(k)\)

connected pieces (we call this measure the chunkiness of the tree decomposition). Moreover, for any subset
S
of at most
k
edges in
G
, there is a tree decomposition in the collection such that
S
is
well preserved
in the decomposition in the following sense. For any bag in the tree decomposition and any edge in
S
with both endpoints in the bag, either its endpoints lie in different pieces or they lie in a piece that is a clique. Having this decomposition at hand, we show that the design of parameterized algorithms for some cut problems becomes elementary. In particular, our algorithmic applications include single-exponential (or slightly super-exponential) algorithms for well-studied problems such as
Min Bisection
,
Steiner Cut
,

s
-Way Cut

, and
Edge Multiway Cut-Uncut
on UDGs; these algorithms are substantially faster than the best-known algorithms for these problems on general graphs.
Advances in Managing Chytridiomycosis for Australian Frogs: Gradarius Firmus Victoria
Authors: Berger Lee , Skerratt Lee F. , Kosch Tiffany A. , Brannelly Laura A. , Webb Rebecca J. , Waddle Anthony W.
Published: February 2024

Extensive knowledge gains from research worldwide over the 25 years since the discovery of chytridiomycosis can be used for improved management. Strategies that have saved populations in the short term and/or enabled recovery include captive breeding, translocation into disease refugia, translocation from resistant populations, disease-free exclosures, and preservation of disease refuges with connectivity to previous habitat, while antifungal treatments have reduced mortality rates in the wild. Increasing host resistance is the goal of many strategies under development, including vaccination and targeted genetic interventions. Pathogen-directed strategies may be more challenging but would have broad applicability. While the search for the silver bullet solution continues, we should value targeted local interventions that stop extinction and buy time for evolution of resistance or development of novel solutions. As for most invasive species and infectious diseases, we need to accept that ongoing management is necessary. For species continuing to decline, proactive deployment and assessment of promising interventions are more valid than a hands-off, do-no-harm approach that will likely allow further extinctions.
Development of optic disc edema during 30 days of hypercapnic head-down tilt bed rest is associated with short sleep duration and blunted temperature amplitude
Authors: Christian Kate H. , Petitti Carla , Oretga-Schwartz Kyra , Mulder Edwin , Noppe Alexandra , von der Wiesche Melanie , Stern Claudia , Young Millennia , Macias Brandon R. , Laurie Steven S. , Lovering Andrew T.
Published: February 2024

We determined that sleep and 24-h core body temperature were unaltered by 30 days exposure to the spaceflight analog strict 6° head-down tilt bed rest (HDTBR) in a 0.5% CO2 environment. However, shorter sleep duration, greater wake after sleep onset, and lower core temperature amplitude present throughout the study were associated with the development of optic disc edema, a key finding of spaceflight-associated neuro-ocular syndrome.
Effects of chronic alcohol intoxication on aerobic exercise-induced adaptations in female mice
Authors: Tice Abigail L. , Gordon Bradley S. , Fletcher Emma , McNeill Addison G. , Laskin Grant R. , Laudato Joseph A. , Rossetti Michael L. , Koutakis Panagiotis , Steiner Jennifer L.
Published: February 2024

Alcohol consumption during an aerobic exercise training period prevented training-induced increases in run to fatigue time and grip strength. Cessation of alcohol allowed for recovery of endurance performance within 2 wk. The worsened exercise performance after alcohol was unrelated to impairments in markers of mitochondrial health. Therefore, some adaptations to exercise training are impaired with alcohol use (endurance performance, muscle growth, and strength), while others remain mostly unaffected (mitochondrial health).
Effect of combined electrical stimulation and brief muscle lengthening on torque development
Authors: Pineau Antoine , Martin Alain , Lepers Romuald , Papaiordanidou Maria
Published: February 2024

This study showed, for the first time, that the combined application of a brief muscle lengthening and wide-pulse neuromuscular electrical stimulation (NMES) delivered over the posterior tibial nerve can entail increased torque production as compared with the sole application of NMES. This observation, present only for high stimulation frequencies (100 Hz) and independently of the lengthening speed, is attributed to neural mechanisms, most probably related to increased afferents’ solicitation, although muscular phenomena cannot be excluded.
Physiological and muscle histochemical assessment of men and women 10 km runners matched for race performance or training volume
Authors: Engelbrecht Lize , Rawlins Maia , Kohn Tertius A. , Wilson Robyn L. , Eksteen Gabriël J. , Myburgh Kathryn H.
Published: February 2024

When subelite women 10 km runners were matched with male counterparts for 10 km race performance, inherent differences in % body fat, V̇o2max, Hct, and peak treadmill speed were counteracted by significantly higher training volume, more time training at higher %HRmax and consequently, higher %HRmax and %PTS at race pace. Citrate synthase activity and muscle fiber types did not differ. When women and men matched for training, 10 km performance of men was 10.5% faster.
Knowledge, Awareness, and Practices toward Colorectal Cancer and Its Dietary and Lifestyle-Related Risk Factors among Jordanian University Students: A Cross-Sectional Study
Authors: Khraiwesh Husam , Abdelrahim Dana N. , Mahmoud Iman F. , Faris MoezAlIslam
Published: February 2024

Background. Globally, colorectal cancer (CRC) incidence is rising, and it is a leading cause of mortality, with greater death rates pronounced in developing countries, including Jordan. Understanding knowledge and awareness of etiologic factors, unhealthy lifestyles, and dietary patterns is crucial for combating ailments. Hence, this study is aimed at investigating the level of knowledge and awareness of CRC-related risk factors, practices, and possible associations of studied variables among young Jordanians. Methodology. A cross-sectional, observational study was conducted using an online self-reported assessment of anthropometrics, knowledge, awareness, and dietary and lifestyle practices toward CRC and its related risk factors. Results. A study of 795 Jordanian university students found that 93.8% were Jordanians, 73.0% were female, aged 18-24, and single. Most participants were from medical and science schools (69.4%). The vast majority (about 84%) were found to have good knowledge and awareness of CRC and its risk factors, but this was not reflected in their dietary practices. There are significant differences in physical activity, smoking, vegetable consumption, and serving sizes of red meat and processed meats between the sexes. Academic study specialties significantly impact knowledge and awareness. Conclusion. The study reveals that while young Jordanian university students have good knowledge and awareness about CRC and its risk factors, these levels are not reflected in their dietary behaviors and food choices for CRC prevention, highlighting the need for national programs to improve these practices, particularly in the younger population.
Salidroside Alleviates Myocardial Ischemia Reperfusion by Balancing Mitochondrial Homeostasis via Nrf2
Authors: Yan Tingxu , Li Xu , Wang Xin , He Bosai , Jia Ying , Xiao Wei
Published: February 2024

Salidroside (SAL), a phenylpropanoid glycoside compound mainly from Rhodiola rosea, showed potential effects on myocardial ischemia reperfusion (MIRI) in our previous studies. The primary objective of this investigation was to study the mechanism by which SAL preserves mitochondrial homeostasis in order to provide protection against MIRI. The impact of SAL on the hypoxia/reoxygenation (H/R)-induced H9c2 cells was detected by using CCK-8, LDH, and AST. The number, function, and morphology of mitochondria were examined by TEM, RT-qPCR, and western blot. The binding ability between SAL and Nrf2 was explored through molecular docking and the cell thermal shift assay. Combined with the Nrf2 inhibitor ML385, our results demonstrated that SAL promotes mitochondrial protection by activating Nrf2, decreasing oxidative stress, and altering the AMPK/PGC-1α/PPARα pathway. In addition, SAL elevates ATP levels and improves mitochondrial dynamics imbalance by inducing both autophagy and mitophagy. These findings highlight the potential therapeutic benefits of SAL for cardiac health and the mitigation of MIRI.
Supplementary Table S4 from FAM3C in Cancer-Associated Adipocytes Promotes Breast Cancer Cell Survival and Metastasis
Authors: Kim Sahee , Oh Jiyoung , Park Chanho , Kim Min , Jo Woobeen , Kim Chu-Sook , Cho Sun Wook , Park Jiyoung
Published: February 2024

Supplementary Table S4
Supplementary File S1 from Deep Learning–Based 3D Single-Cell Imaging Analysis Pipeline Enables Quantification of Cell–Cell Interaction Dynamics in the Tumor Microenvironment
Authors: Liu Bodong , Zhu Yanting , Yang Zhenye , Yan Helen H.N. , Leung Suet Yi , Shi Jue
Published: February 2024

User manual for SiQ-3D.
Figure S9 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S9
Table S3 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

List of plasmids
Data from FAM3C in Cancer-Associated Adipocytes Promotes Breast Cancer Cell Survival and Metastasis
Authors: Kim Sahee , Oh Jiyoung , Park Chanho , Kim Min , Jo Woobeen , Kim Chu-Sook , Cho Sun Wook , Park Jiyoung
Published: February 2024

Abstract
Adipose tissue within the tumor microenvironment (TME) plays a critical role in supporting breast cancer progression. In this study, we identified FAM3 metabolism-regulating signaling molecule C (FAM3C) produced by cancer-associated adipocytes (CAA) as a key regulator of tumor progression. FAM3C overexpression in cultured adipocytes significantly reduced cell death in both adipocytes and cocultured breast cancer cells while suppressing markers of fibrosis. Conversely, FAM3C depletion in CAAs resulted in adipocyte–mesenchymal transition (AMT) and increased fibrosis within the TME. Adipocyte FAM3C expression was driven by TGFβ signaling from breast cancer cells and was reduced upon treatment with a TGFβ-neutralizing antibody. FAM3C knockdown in CAAs early in tumorigenesis in a genetically engineered mouse model of breast cancer significantly inhibited primary and metastatic tumor growth. Circulating FAM3C levels were elevated in patients with metastatic breast cancer compared with those with nonmetastatic breast cancer. These results suggest that therapeutic inhibition of FAM3C expression levels in CAAs during early tumor development could be a promising approach in the treatment of patients with breast cancer.
Significance:
High FAM3C levels in cancer-associated adipocytes contribute to tumor-supportive niches and are tightly associated with metastatic growth, indicating that FAM3C inhibition could be beneficial for treating patients with breast cancer.
ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina
Published: February 2024

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors.

Significance:

Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance.

See related commentary by Rumde and Burns, p. 1188
Macrophages Under the Influence of Tumor Mesothelin Weaken Host Defenses against Pancreatic Cancer Metastasis
Authors: Alewine Christine
Published: February 2024

Although pancreatic cancer is a systemic disease that metastasizes early in its course, the signaling systems that promote this behavior remain incompletely understood. In this issue of Cancer Research, Luckett and colleagues identify a paracrine signaling pathway between cancer cells and macrophages that promotes pancreatic cancer metastasis. The authors used immunocompetent murine pancreatic cancer models with high versus low metastatic potential, genetic knockout and complementation strategies, and The Cancer Genome Atlas human data to demonstrate that tumor-secreted mesothelin repolarizes tumor and lung macrophages to a tumor-supportive phenotype. The repolarized macrophages increase secretion of VEGF and S100A9, raising local concentrations. In turn, VEGF enhances colony formation of cancer cells, while S100A9 promotes the recruitment of neutrophils to the lungs and the formation of neutrophil extracellular traps that support tumor metastasis. Together, these findings reveal a systemic signaling pathway that promotes pancreatic cancer metastasis by co-opting macrophages typically protective against cancer to instead promote its spread.

See related article by Luckett et al., p. 527
Prognostic Value of Pretreatment Plasma C-Reactive Protein in Patients with Early-Stage Breast Cancer
Authors: Andersen Høgni H. , Bojesen Stig E. , Johansen Julia S. , Ejlertsen Bent , Berg Tobias , Tuxen Malgorzata , Madsen Kasper , Danø Hella , Flyger Henrik , Jensen Maj-Britt , Nielsen Dorte L.
Published: February 2024

Background:

Breast cancer incidence is now the highest among all cancers and accountable for 6.6% of all cancer-related deaths worldwide. Studies of the prognostic utility of plasma C-reactive protein (CRP) measurement in early-stage breast cancer have given discrepant results.

Methods:

We identified 6,942 patients in the Danish Breast Cancer Cooperative Group database with early-stage breast cancer diagnosed between 2002 and 2016 who had a measure of pretreatment plasma CRP. Outcomes were recurrence-free interval and survival for a period up to 10 years. We analyzed associations with plasma CRP using Fine-Gray proportional subdistribution hazards model with recurrence-free interval. Data on plasma CRP were analyzed per doubling of concentration and in relation to CRP levels of <3 mg/L, 3 to 10 mg/L, and >10 mg/L and stratified according to standard clinical parameters in sensitivity analyses.

Results:

A doubling of the plasma CRP concentration was associated with increased risk of recurrence (multivariate adjusted HR, 1.05; 95% CI, 1.01–1.08) and shorter survival (HR, 1.13; 95% CI, 1.09–1.16) in multivariate analyses. Survival was shorter in patients with plasma CRP levels of 3 to 10 and >10 mg/L versus <3 mg/L, with multivariate adjusted HRs of 1.30; 95% CI, 1.17–1.45 and 1.65; 95% CI, 1.39–1.95, respectively.

Conclusions:

Elevated plasma CRP measured before treatment in patients with early-stage breast cancer is an independent biomarker of increased risk of recurrence and early death.

Impact:

CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.
Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts
Authors: DiPeri Timothy P. , Evans Kurt W. , Wang Bailiang , Zhao Ming , Akcakanat Argun , Raso Maria Gabriela , Rizvi Yasmeen Q. , Zheng Xiaofeng , Korkut Anil , Varadarajan Kaushik , Uzunparmak Burak , Dumbrava Ecaterina E. , Pant Shubham , Ajani Jaffer A. , Pohlmann Paula R. , Jensen V. Behrana , Javle Milind , Rodon Jordi , Meric-Bernstam Funda
Published: February 2024

Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance.

Significance:

We demonstrate that PDXs can be developed from pretreatment and postprogression biopsies in clinical trials and may represent a powerful preclinical tool. We identified amplification of MET as a potential mechanism of acquired resistance to the HER2 inhibitor zanidatamab and MET inhibitors alone and in combination as a therapeutic strategy.

This article is featured in Selected Articles from This Issue, p. 695
TR(i)P Goes On: Auxiliary TRP Channel Subunits?
Authors: Flockerzi Veit , Fakler Bernd
Published: February 2024

Transient receptor potential (TRP) cation channels are a diverse family of channels whose members play prominent roles as cellular sensors and effectors. The important role of TRP channels (and mechanosensitive piezo channels) in the complex interaction of our senses with the environment was underlined by the award of the Nobel Prize in Physiology or Medicine to 2 pioneers in this field, David Julius and Ardem Patapoutian. There are many competent and comprehensive reviews on many aspects of the TRP channels, and there is no intention to expand on them. Rather, after an introduction to the nomenclature, the molecular architecture of native TRP channel/protein complexes in vivo will be summarized using TRP channels of the canonical transient receptor potential subfamily as an example. This molecular architecture provides the basis for the signatures of native canonical transient receptor potential currents and their control by endogenous modulators and potential drugs.
Information, Coding, and Biological Function: The Dynamics of
Life
Authors: Cartwright Julyan H. E. , Čejková Jitka , Fimmel Elena , Giannerini Simone , Gonzalez Diego Luis , Goracci Greta , Grácio Clara , Houwing-Duistermaat Jeanine , Matić Dragan , Mišić Nataša , Mulder Frans A. A. , Piro Oreste
Published: February 2024

In the mid-20th century, two new scientific disciplines emerged forcefully: molecular biology and information-communication theory. At the beginning, cross-fertilization was so deep that the term genetic code was universally accepted for describing the meaning of triplets of mRNA (codons) as amino acids. However, today, such synergy has not taken advantage of the vertiginous advances in the two disciplines and presents more challenges than answers. These challenges not only are of great theoretical relevance but also represent unavoidable milestones for next-generation biology: from personalized genetic therapy and diagnosis to Artificial Life to the production of biologically active proteins. Moreover, the matter is intimately connected to a paradigm shift needed in theoretical biology, pioneered a long time ago, that requires combined contributions from disciplines well beyond the biological realm. The use of information as a conceptual metaphor needs to be turned into quantitative and predictive models that can be tested empirically and integrated in a unified view. Successfully achieving these tasks requires a wide multidisciplinary approach, including Artificial Life researchers, to address such an endeavour.
Taxonomic revision of the jumping spider genus Tullgrenella Mello-Leitão, 1941 (Araneae: Salticidae: Freyina)
Authors: MARTA KIMBERLY S. , BUSTAMANTE ABEL A. , HAGOPIÁN DAMIÁN , TEIXEIRA RENATO A. , BRESCOVIT ANTONIO D. , VALIATI VICTOR H. , RODRIGUES EVERTON N. L.
Published: February 2024

This paper presents a taxonomic revision of the genus Tullgrenella Mello-Leitão, 1941. Four new species are described: Tullgrenella aisenbergae Marta, sp. nov. (Brazil) (♂♀), T. legalissima Marta & Hagopián sp. nov. (Uruguay) (♀), T. galianoae Marta, sp. nov. (Brazil) (♂♀) and T. sciosciae Marta & Bustamante sp. nov. (Brazil) (♂♀). The males of T. corrugata Galiano, 1981 and T. peniaflorensis Galiano, 1970, and the female of T. selenita Galiano, 1970 are described for the first time. An updated diagnosis for the genus is provided based on the detailed comparative morphological studies. In addition, we present a proposal and discussion about the species groups of Tullgrenella based on the putative synapomorphies as well as the updated distribution of the genus in South America.
Evaluation of Combined Serum C-Peptide and Glycated Hemoglobin in the Clinical Diagnosis of Diabetes
Authors: Huang Zhumei , Luo Xiao
Published: February 2024

This study investigates the application effectiveness of combined serum C-peptide and glycated hemoglobin testing in the clinical diagnosis of diabetes. The research involved 80 diabetic patients treated at our hospital between January 2022 and January 2023, meeting the inclusion criteria.
Additionally, 80 individuals undergoing health examinations during the same period constituted the healthy control group. Blood glucose indicators were measured in both groups, and complications were recorded. Serum C-peptide and glycated hemoglobin were individually and jointly tested, with
an analysis of sensitivity, specificity, and other diagnostic indicators for diabetes. General participant data in the patient and healthy control groups were comparable (P > 0.05). In the patient group, C-peptide (C-PR), fasting blood glucose (FBG), and 2-hour postprandial blood
glucose (2 h PBG) levels were higher than those in the control group, while glycated hemoglobin (HbA1c) levels were lower (P < 0.05). Those in the patient group with low C-PR levels and HbA1c levels >7.5% showed a higher incidence of complications (P < 0.05). The combined
test of serum C-peptide and glycated hemoglobin in the patient group demonstrated higher accuracy, sensitivity, and specificity compared to individual diagnostic tests (P < 0.05). The combined test proves to be effective in the clinical diagnosis of diabetes, offering elevated accuracy,
sensitivity, and specificity compared to singleindicator testing. This approach bears substantial clinical significance.
Efficacy of 3D-Printing Additive Manufacturing in Comparison to CAD-CAM, and Conventional Method for Fabrication of Interim Crowns: A Systematic Review and Meta-Analysis
Authors: Alqahtani Abdulaziz S.
Published: February 2024

Objective: The present systematic review and meta-analysis aimed to determine the marginal and internal fit of the interim crowns fabricated utilizing the 3DP technique as compared with milling and molding methods. Methods: An electronic search was conducted in PubMed
(MEDLINE), Scopus, and Web of Science on 14th October 2023 without any restriction on language and year of publication to answer the following focused question based on the PICO format: “Do interim crowns (P) fabricated using 3DP approaches (I) have better marginal and/or internal
fit (O) as compared to conventionally fabricated (molding) and CAD-CAM (milled) interim crowns (O)?”. The study employed the inverse variance statistical method using a fixed-effect model with standard mean difference (SMD) due to varied recording scales. Results were expressed with
a 95% confidence interval (CI), and heterogeneity was measured using chi-square and I2. Statistical significance was set at p < 0.05. Result: The meta-analysis revealed the presence of statistically significant differences in the marginal fit between interim crowns
fabricated using 3DP and milling techniques (SMD: −0.48; 95% CI: −0.70 to −0.27; p < 0.0001) as well as molding techniques (SMD: −0.80; 95% CI: −1.10 to −0.49; p < 0.00001). Similarly, the presence of statistically significant differences
in the internal fit was observed using 3DP and milling techniques (SMD: −0.63; 95% CI: −0.87 to −0.39; p < 0.00001). All included studies were graded as ‘medium’ quality. Conclusion: Significant differences were revealed between the marginal and
internal fit of interim crowns fabricated using the 3DP approach as compared with the milling and molding techniques. Hence, the 3DP approach can be used as an alternative to the CAD-CAM milled and conventionally fabricated interim crowns. However, clinical trials with diverse cases are required,
considering cost, esthetics, and mechanics for broader applications.