bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence of aberrant anti-epstein-barr virus antibody response, though no viral reactivation, in people with post-stroke fatigue
Authors: Mouat Isobel C. , Zhu Li , Aslan Alperen , McColl Barry W. , Allan Stuart M. , Smith Craig J. , Buckwalter Marion S. , McCulloch Laura
Published: August 2024

Background

Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke.

Aims

We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue.

Methods

In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F < 40) and low fatigue (FACIT-F > 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher’s exact test for categorical data.

Results

We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288).

Conclusions

These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.
The role of lipid emulsions containing omega-3 fatty acids for medical and surgical critical care patients
Authors: Stoppe Christian , Martindale Robert G. , Klek Stanislaw , Calder Philip C. , Wischmeyer Paul E. , Patel Jayshil J.
Published: August 2024

In critical illness the regulation of inflammation and oxidative stress can improve patient outcomes, and thus omega-3 polyunsaturated fatty acids (PUFAs) have been used as part of parenteral nutrition (PN) owing to their potential anti-inflammatory effects. The international lipids in PN Summit, encompassed discussions and the production of consensus guidelines concerning PN intravenous lipid emulsion (ILE) use in critical care. The Lipid Summit participants agreed that the inclusion of fish oil in ILEs is associated with meaningful clinical benefits without signals of harm, based on a strong biological rationale and current clinical evidence. Decisions concerning ILE choice should be made based on current evidence, thus addressing clinical requirements for guidance, particularly as further definitive evidence seems unlikely to occur. In addition, a future of individualized ICU care is envisioned, yielding better clinical outcomes. This approach will require the greater use of intelligent study designs incorporating the use of biomarkers of omega-3 derivatives, inflammatory-resolving processes, and/or muscle protein breakdown.
READv2: advanced and user-friendly detection of biological relatedness in archaeogenomics
Authors: Alaçamlı Erkin , Naidoo Thijessen , Güler Merve N. , Sağlıcan Ekin , Aktürk Şevval , Mapelli Igor , Vural Kıvılcım Başak , Somel Mehmet , Malmström Helena , Günther Torsten
Published: August 2024

The advent of genome-wide ancient DNA analysis has revolutionized our understanding of prehistoric societies. However, studying biological relatedness in these groups requires tailored approaches due to the challenges of analyzing ancient DNA. READv2, an optimized Python3 implementation of the most widely used tool for this purpose, addresses these challenges while surpassing its predecessor in speed and accuracy. For sufficient amounts of data, it can classify up to third-degree relatedness and differentiate between the two types of first-degree relatedness, full siblings and parent-offspring. READv2 enables user-friendly, efficient, and nuanced analysis of biological relatedness, facilitating a deeper understanding of past social structures.
Silence is golden, but my measures still see—why cheaper-but-noisier outcome measures in large simple trials can be more cost-effective than gold standards
Authors: Woolf Benjamin , Pedder Hugo , Rodriguez-Broadbent Henry , Edwards Phil
Published: August 2024

Objective

To assess the cost-effectiveness of using cheaper-but-noisier outcome measures, such as a short questionnaire, for large simple clinical trials.

Background

To detect associations reliably, trials must avoid bias and random error. To reduce random error, we can increase the size of the trial and increase the accuracy of the outcome measurement process. However, with fixed resources, there is a trade-off between the number of participants a trial can enrol and the amount of information that can be collected on each participant during data collection.

Methods

To consider the effect on measurement error of using outcome scales with varying numbers of categories, we define and calculate the variance from categorisation that would be expected from using a category midpoint; define the analytic conditions under which such a measure is cost-effective; use meta-regression to estimate the impact of participant burden, defined as questionnaire length, on response rates; and develop an interactive web-app to allow researchers to explore the cost-effectiveness of using such a measure under plausible assumptions.

Results

An outcome scale with only a few categories greatly reduced the variance of non-measurement. For example, a scale with five categories reduced the variance of non-measurement by 96% for a uniform distribution. We show that a simple measure will be more cost-effective than a gold-standard measure if the relative increase in variance due to using it is less than the relative increase in cost from the gold standard, assuming it does not introduce bias in the measurement. We found an inverse power law relationship between participant burden and response rates such that a doubling the burden on participants reduces the response rate by around one third. Finally, we created an interactive web-app (https://benjiwoolf.shinyapps.io/cheapbutnoisymeasures/) to allow exploration of when using a cheap-but-noisy measure will be more cost-effective using realistic parameters.

Conclusion

Cheaper-but-noisier questionnaires containing just a few questions can be a cost-effective way of maximising power. However, their use requires a judgement on the trade-off between the potential increase in risk of information bias and the reduction in the potential of selection bias due to the expected higher response rates.
Eco-conscious potentiometric sensing: a multiwalled carbon nanotube-based platform for tulathromycin monitoring in livestock products
Authors: Hussein Omnia G. , Monir Hany H. , Zaazaa Hala E. , Galal Maha M.
Published: August 2024

Tulathromycin (TUL) is a widely used veterinary antibiotic for treating bovine and porcine respiratory infections. Consuming animal-derived food contaminated with this medication may jeopardize human health. This work adopted the first portable potentiometric platform for direct TUL sensing in pharmaceutical and food products. The sensor employed a plasticized PVC membrane on a glassy carbon electrode doped with calix[6]arene and multi-walled carbon nanotubes (MWCNT) in a single solid contact layer for selective binding and signal stability. Characterization via scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) confirmed the material’s integrity. The MWCNT-based sensor produced a stable Nernstian response (1.0 × 10−7 to 1.0 × 10−3 M) and a limit of detection (LOD) of 9.76 × 10–8 M with instantaneous response (8 ± 2 s). IUPAC validation revealed high selectivity for TUL against interfering ions, minimal drift (0.6 mV/h), and functionality over a broad pH range (2.0–7.0), allowing direct application to dosage form, spiked milk, and liver samples. Eco-Scale, AGREE, and Whiteness assessment proved the method's ecological sustainability, economic viability, and practical feasibility, surpassing traditional approaches.

Graphical Abstract
Infection prevention and control in 2030: a first qualitative survey by the Crystal Ball Initiative
Authors: Sax Hugo , Marschall Jonas ,   and the Crystal Ball Initiative, Barnes Sue , Boyce John M. , Bradley Suzanne F. , Fisher Dale , Grisold Andrea , Harbarth Stephan , Huis Anita , Larson Elaine , Lee Andie , Lee Grace , Longtin Yves , Lucet Jean-Christophe , Perencevich Eli , Scheithauer Simone , Storr Julie , Tetro Jason-Anthony , Tschirky Erich , Vilar-Compte Diana
Published: August 2024

Background

Healthcare delivery is undergoing radical changes that influence effective infection prevention and control (IPC). Futures research (short: Futures), the science of deliberating on multiple potential future states, is increasingly employed in many core societal fields. Futures might also be helpful in IPC to facilitate current education and organisational decisions. Hence, we conducted an initial survey as part of the IPC Crystal Ball Initiative.

Methods

In 2019, international IPC experts were invited to answer a 10-item online questionnaire, including demographics, housekeeping, and open-ended core questions (Q) on the “status of IPC in 2030” (Q1), “people in charge of IPC” (Q2), “necessary skills in IPC” (Q3), and “burning research questions” (Q4). The four core questions were submitted to a three-step inductive and deductive qualitative content analysis. A subsequent cross-case matrix produced overarching leitmotifs. Q1 statements were additionally coded for sentiment analysis (positive, neutral, or negative).

Results

Overall, 18 of 44 (41%) invited experts responded (from 11 countries; 12 physicians, four nurses, one manager, one microbiologist; all of them in senior positions). The emerging leitmotifs were “System integration”, “Beyond the hospital”, “Behaviour change and implementation”, “Automation and digitalisation”, and “Anticipated scientific progress and innovation”. The statements reflected an optimistic outlook in 66% of all codes of Q1.

Conclusions

The first exercise of the IPC Crystal Ball Initiative reflected an optimistic outlook on IPC in 2030, and participants envisioned leveraging technological and medical progress to increase IPC effectiveness, freeing IPC personnel from administrative tasks to be more present at the point of care and increasing IPC integration and expansion through the application of a broad range of skills. Enhancing participant immersion in future Crystal Ball Initiative exercises through simulation would likely further increase the authenticity and comprehensiveness of the envisioned futures.
A multidimensional tool to measure farm stressors: development and initial validation of the farmer stress assessment tool (FSAT)
Authors: Purc-Stephenson R. J. , Dedrick S. , Hood D.
Published: August 2024

Background

Farming is a stressful occupation, and a growing body of research shows that farm stressors are associated with poor mental health. To date, there are few methodologically sound surveys that assess farm stressors, and none have been validated for the Canadian context. Our study aimed to: (a) investigate the types of stressors experienced by farmers, (b) develop a farm stress assessment tool and test its factor structure and internal consistency, and (c) assess its criterion-related validity to self-reported levels of anxiety, depression, burnout, and resilience among farmers.

Methods

We developed a 20-item survey based on a review of the literature, examining existing farm stress surveys, and consulting 10 farmers and agricultural industry experts. Then, a convenience sample of farmers living in Alberta, Canada (Sample 1, N = 354) completed a questionnaire containing the 20-item farm stress survey and four validated measures that assessed depression, anxiety, burnout, and resilience. Sample 1 was used to assess the factor structure using exploratory factor analysis (EFA), internal consistency, and criterion-validity of the survey. Next, a convenience sample of farmers living outside of Alberta (Sample 2, N = 138) was used to evaluate the factor structure of the survey using confirmatory factor analysis (CFA).

Results

The results of the EFA revealed five underlying dimensions of farm stressors: Unexpected work disruptions, Agricultural hazards, Farm and financial planning, Isolation, and Regulations and public pressure. The subscales accounted for 61.6% of the variance, and the internal consistency (Cronbach’s alpha) ranged from 0.66 to.75. Subscale correlations were below 0.44, indicating evidence of discriminant validity. Correlations between the five subscales and the four mental health outcome variables supported the criterion-related validity of the survey. The results of the CFA indicated that the data fit the model, and fit was further improved by correlating one pair of error terms.

Conclusions

Preliminary analysis of our Farmer Stress Assessment Tool (FSAT) suggests it is a reliable and valid instrument for measuring a range of stressors farmers face. Implications for policy and community-based mental health interventions that help farmers manage the enduring stressors of agriculture is discussed.
KAT6A/YAP/TEAD4 pathway modulates osteoclastogenesis by regulating the RANKL/OPG ratio on the compression side during orthodontic tooth movement
Authors: Tan Kuang , Wang Jiayi , Su Xinyu , Zheng Yunfei , Li Weiran
Published: August 2024

Background

Orthodontic tooth movement (OTM) is a dynamic equilibrium of bone remodeling, involving the osteogenesis of new bone and the osteoclastogenesis of old bone, which is mediated by mechanical force. Periodontal ligament stem cells (PDLCSs) in the periodontal ligament (PDL) space can transmit mechanical signals and regulate osteoclastogenesis during OTM. KAT6A is a histone acetyltransferase that plays a part in the differentiation of stem cells. However, whether KAT6A is involved in the regulation of osteoclastogenesis by PDLSCs remains unclear.

Results

In this study, we used the force-induced OTM model and observed that KAT6A was increased on the compression side of PDL during OTM, and also increased in PDLSCs under compression force in vitro. Repression of KAT6A by WM1119, a KAT6A inhibitor, markedly decreased the distance of OTM. Knockdown of KAT6A in PDLSCs decreased the RANKL/OPG ratio and osteoclastogenesis of THP-1. Mechanistically, KAT6A promoted osteoclastogenesis by binding and acetylating YAP, simultaneously regulating the YAP/TEAD axis and increasing the RANKL/OPG ratio in PDLSCs. TED-347, a YAP-TEAD4 interaction inhibitor, partly attenuated the elevation of the RANKL/OPG ratio induced by mechanical force.

Conclusion

Our study showed that the PDLSCs modulated osteoclastogenesis and increased the RANKL/OPG ratio under mechanical force through the KAT6A/YAP/TEAD4 pathway. KAT6A might be a novel target to accelerate OTM.
Expansive learning in the learning assistant model: how instructors’ goals lead to differences in implementation and development of LAs’ practices
Authors: Karch Jessica M. , Mashhour Sedrah , Koss Micah P. , Caspari-Gnann Ira
Published: August 2024

Background

The learning assistant (LA) model supports student success in undergraduate science courses; however, variation in outcomes has led to a call for more work investigating how the LA model is implemented. In this research, we used cultural historical activity theory (CHAT) to characterize how three different instructors set up LA-facilitated classrooms and how LAs’ understanding and development of their practices was shaped by the classroom activity. CHAT is a sociocultural framework that provides a structured approach to studying complex activity systems directed toward specific objects. It conceptualizes change within these systems as expansive learning, in which experiencing a contradiction leads to internalization and critical self-reflection, and then externalization and a search for solutions and change.

Results

Through analyzing two semi-structured retrospective interviews from three professors and eleven LAs, we found that how the LA model was implemented differed based on STEM instructors’ pedagogical practices and goals. Each instructor leveraged LA-facilitated interactions to further learning and tasked LAs with emotionally supporting students to grapple with content and confusions in a safe environment; however, all three had different rules and divisions of labor that were influenced by their perspectives on learning and their objects for the class. For LAs, we found that they had multiple, sometimes conflicting, motives that can be described as either practical, what they described as their day-to-day job, or sense-making, how they made sense of the reason for their work. How these motives were integrated/separated or aligned/misaligned with the collective course object influenced LAs’ learning in practice through either a mechanism of consonance or contradiction. We found that each LA developed unique practices that reciprocally shaped and were shaped by the activity system in which they worked.

Conclusions

This study helps bridge the bodies of research that focus on outcomes from the LA model and LA learning and development by describing how LA learning mechanisms are shaped by their context. We also show that variation in the LA model can be described both by classroom objects and by LAs’ development in dialogue with those objects. This work can be used to start to develop a deeper understanding of how students, instructors, and LAs experience the LA model.
Implications of using administrative healthcare data to identify risk of motor vehicle crash-related injury: the importance of distinguishing crash from crash-related injury
Authors: Joyce Nina R. , Lombardi Leah R. , Pfeiffer Melissa R. , Curry Allison E. , Margolis Seth A. , Ott Brian R. , Zullo Andrew R.
Published: August 2024

Background

Administrative healthcare databases, such as Medicare, are increasingly used to identify groups at risk of a crash. However, they only contain information on crash-related injuries, not all crashes. If the driver characteristics associated with crash and crash-related injury differ, conflating the two may result in ineffective or imprecise policy interventions.

Methods

We linked 10 years (2008–2017) of Medicare claims to New Jersey police crash reports to compare the demographics, clinical diagnoses, and prescription drug dispensings for crash-involved drivers ≥ 68 years with a police-reported crash to those with a claim for a crash-related injury. We calculated standardized mean differences to compare characteristics between groups.

Results

Crash-involved drivers with a Medicare claim for an injury were more likely than those with a police-reported crash to be female (62.4% vs. 51.8%, standardized mean difference [SMD] = 0.30), had more clinical diagnoses including Alzheimer’s disease and related dementias (13.0% vs. 9.2%, SMD = 0.20) and rheumatoid arthritis/osteoarthritis (69.5% vs 61.4%, SMD = 0.20), and a higher rate of dispensing for opioids (33.8% vs 27.6%, SMD = 0.18) and antiepileptics (12.9% vs 9.6%, SMD = 0.14) prior to the crash. Despite documented inconsistencies in coding practices, findings were robust when restricted to claims indicating the injured party was the driver or was left unspecified.

Conclusions

To identify effective mechanisms for reducing morbidity and mortality from crashes, researchers should consider augmenting administrative datasets with information from police crash reports, and vice versa. When those data are not available, we caution researchers and policymakers against the tendency to conflate crash and crash-related injury when interpreting their findings.
A comprehensive expedition of tauopathies in subacute sclerosing panencephalitis (SSPE): a narrative review
Authors: Pandey Nikhil , Srivastava Niraj Kumar , Kumar Anand , Hussain Ibrahim , Joshi Deepika
Published: August 2024

Introduction

Tauopathies are a class of neurodegenerative disorders characterized by the abnormal accumulation of hyperphosphorylated tau protein in the brain. Subacute sclerosing panencephalitis (SSPE) caused by a latent aberrant measles virus infection, is characterized by extensive inflammation and neuronal impairment. A prominent pathological hallmark of SSPE described recently is the accumulation of abnormal tau protein possibly resulting from diffuse brain inflammation triggered by measles virus infection.

Short summary

Understanding the role of tau pathophysiology in SSPE is crucial for improving the diagnosis and management of this debilitating condition. Current research suggests that persistent measles virus infection in the brain leads to chronic inflammation, which in turn triggers abnormal tau phosphorylation and accumulation. Further elucidating the precise mechanisms linking measles virus infection, neuro-inflammation, and tauopathy in SSPE is essential for developing targeted therapies.

Conclusion

This narrative review provides valuable insights for both researchers and clinicians in understanding the pathological mechanisms underlying SSPE which is crucial for developing effective treatment strategies. These might include antiviral drugs to combat persistent infection, anti-inflammatory agents to reduce neuro-inflammation, or even treatments targeting tau pathology directly. Collaborative efforts among researchers, clinicians, and public health authorities are crucial for advancing our understanding of SSPE to combat this devastating disorder.
Cognitive assessment of a sample of Egyptian patients with amyotrophic lateral sclerosis
Authors: Belal Nourhan , Soliman Radwa , ElSerafy Doha Moustafa , Okasha Tarek , Fahmy Nagia
Published: August 2024

Background

Cognitive and behavioral changes in ALS are featured as an integral part of the disease. A noticeable proportion of ALS patients present with a full-blown picture of frontotemporal dementia, which is considered the most common form of cognitive impairment in ALS.

Results

A total of 30 ALS cases and 30 sex, age and education matched healthy controls were enrolled; their sociodemographic data were statistically insignificant as regards (age, sex, education). Regarding cognitive and behavioral assessment using the ECAS-EG, both ECAS mean total score and subdomains mean scores were significantly lower in ALS patients compared to controls (p-value < 0.001), with statistically significant relation between ALS clinical staging and ECAS total scores (p-value < 0.001). Furthermore, it was found that mean scores of nearly all ECAS domains are lower in early-onset group with longer duration of illness than late onset with short duration of illness but with a non-statistically significant difference.

Conclusion

ALS causes significant cognitive impairment, with relation between functional status and clinical staging of the disease with the severity of cognitive and behavioral dysfunctions and although early-onset cases had lower score on ECAS compared to those with late onset, but it was non-significant.
Retraction Note: Shapley-based interpretation of deep learning models for wildfire spread rate prediction
Authors: Qayyum Faiza , Samee Nagwan Abdel , Alabdulhafith Maali , Aziz Ahmed , Hijjawi Mohammad
Published: August 2024

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s42408-023-00242-y.
Retraction Note: Wildfire risk exploration: leveraging SHAP and TabNet for precise factor analysis
Authors: Qayyum Faiza , Jamil Harun , Alsboui Tariq , Hijjawi Mohammad
Published: August 2024

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s42408-023-00236-w.
Development of functional bioflavor based on Indonesian indigenous microbial fermentation products
Authors: Setiarto R. Haryo Bimo , Octaviana Senlie , Perwitasari Urip , Juanssilfero Ario Betha , Suprapedi Suprapedi
Published: August 2024

Bioflavor and fermented foods in Indonesian cuisine were interesting for studying the relationship between fermentation products, microbial aspects, functional implications and biotechnological applications. The methodology employed in the literature review, including the sources used and inclusion criteria, demonstrates a meticulous approach to gathering and synthesizing information. Additionally, the factors influencing the perception of flavors on the tongue provide valuable insights into the complexities of taste perception, encompassing the role of specific amino acids and alkaloid compounds. The discussions on flavor production through microbial fermentation and the application of recombinant DNA technology in microbial flavor production showcase the strides made in biotechnology and their profound impact on flavor development. The escalating significance of natural ingredients and biocatalyst processes in producing flavor compounds aligns with consumer preferences for natural and sustainable options. Moreover, safety considerations for bioflavor products derived from biotechnology underscore the critical importance of ensuring consumer-friendly and safe products in this field. Functional bioflavor constraints provide practical considerations for developing and applying functional flavors, emphasizing the necessity for natural, safe and stable alternatives to conventional food additives. Overall, it offers a comprehensive and in-depth exploration of the multifaceted realm of flavor, integrating scientific, cultural and technological perspectives. It is an invaluable resource for researchers, industry professionals and enthusiasts engaged in flavor science and technology.
A prospective analysis of the correlation between ultrasonic B-lines, cardiac tissue doppler signals and left ventricular end-diastolic pressure in patients with severe aortic stenosis
Authors: Bitar Zouheir Ibrahim , Maadarani Ossama , Dashti Hussien , Alenezi Abdullah , Almerri Khaled
Published: August 2024

Background

The development of heart failure is a turning point in the natural course of aortic stenosis (AS). Pulmonary oedema and elevated left ventricular pressure (LVP) are cardinal features of heart failure. Evaluating pulmonary oedema by lung ultrasound involves taking the upper hand with a bedside noninvasive tool that may reflect LVP.

Aim

We sought to assess the correlation between sonographic pulmonary congestion, invasive LV pre-A pressure, and echocardiographic LV end-diastolic pressure (LVEDP) in symptomatic AS patients receiving transcatheter aortic valve replacement.

Methods

Forty-eight consecutive patients with severe AS and planned transcatheter aortic valve implantation (TAVI) were enrolled. LVEDP was estimated to be normal or elevated using the ASE/EACVI algorithm and transmitral Doppler indices, the E/A ratio, the E/e′, and the left atrial volume index. Invasive LV pre-A pressure was used as a reference, with > 12 mm Hg defined as elevated.

Results

Forty-eight patients (25 women (52%), mean age 75 years, standard deviation (SD) ± 7.7 years) were enrolled in the study. We detected severe B-lines (≥ 30) in 13 (27%) patients and moderate B-lines (15–30) in 33 (68.6%) patients. The number of B-lines increased significantly with the severity of New York Heart Association (NYHA) functional classes (Fig. 1). The B-line count was 14 ± 13 in NYHA class I patients, 20 ± 20 in class II patients, and 44 ± 35 in class III patients (p < 0.05, rho = 0.384). The number of B-lines was correlated with the E/E’ ratio (R = 0.664, p < 0.0001) and the proBNP level (R = 0. 882, p < 0.008). We found no significant correlation with the LVEDP or LVEF. The LVEDP correlated well with the E/E’ ratio (R = 0.491, p < 0.001) but not at all with E/A, DT, or LAVI. All patients had an elevated LVEDP > 12, with a mean pressure of 26 mmHg, a minimum of 13 mmHg, and a maximum of 45 mmHg, with an SD of 7.85.

Conclusion

Assessing lung ultrasonic B-lines is a straightforward and practical approach to identifying pulmonary oedema in AS patients. The number of B-lines correlated with the E/E’ ratio and the functional status of patients but did not correlate with invasive LVEDP or LVEF. All patients had elevated LVEDP that correlated with E/E’.
Therapeutic response and outcomes with uncommon breast cancer subtypes in the I-SPY trial 2010-2022.
Authors: Thomas Alexandra , Wolf Denise M. , Balassanian Ronald , Chen Yunn-Yi , Ye Julia , Vohra Poonam , Gulbahce Evin H. , Borowsky Alexander D. , Brown Swigart Lamorna , Hirst Gillian L. , Venters Sara , Nanda Rita , Shatsky Rebecca Arielle , D'Agostino Ralph , Mukhtar Rita A. , Hatcher Sarah , Yau Christina , DeMichele Angela , van 't Veer Laura , Esserman Laura
Published: August 2024

1

Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients [Wolf et al, Cancer Cell 2022]. We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized; and EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCS. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. Clinical trial information: NCT01042379 .[Table: see text]
A pan-tumor description of the genomic, transcriptomic, and immunological landscape of sodium-glucose cotransporter-2 (SGLT2) and association with clinical outcomes.
Authors: Tan Heng , Kareff Samuel A. , Krause Harris Benjamin , Elliott Andrew , Liu Stephen V. , Ma Patrick C. , Gerchman Fernando , Spiazzi Bernardo , Antonarakis Emmanuel S. , Vanderwalde Ari M. , Radovich Milan , Lopes Gilberto
Published: August 2024

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Background: SGLT2 has been identified as being overexpressed in a diverse set of cancers. Retrospective data has demonstrated a correlation between the use of SGLT2 inhibitors and a reduced incidence of lung cancer. We explored the association of SGLT2-coding gene SLC5A2 with the transcriptomic, genomic, immunological landscape and outcomes in a subset of solid tumors. Methods: Breast ([N = 5623], HR+HER2- [6044] or TNBC [3040]), Colorectal carcinoma (CRC, 15425), NSCLC ([21603], Adenocarcinoma [AC, 8180] or Squamous Cell Carcinoma [SCC, 3579]), Pancreatic (Panc: 5488) and Prostate (PC: 5500) tumors were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1+ (22C3: TPS 1% for lung or SP142: 2+, 5% all other), Her2/Neu (+: ≥3+ and > 10%) and HR (ER or PR+: ≥1+ and ≥1%) expression was assessed by IHC. Mutations were defined as pathogenic SNVs/indels (-Mt). SLC5A2-H and -L expression (transcripts per million, TPM) was defined by cancer type as top and bottom quartile, respectively. Cell infiltration was estimated by QuantiSEQ. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed). The Mann-Whitney U test was applied as appropriate (p < .05, adjusted for multiple comparisons). Real-world overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined patients. Results: SLC5A2 expression varied across cohorts (TNBC: 1.2 TPM, HR+HER2-BC: 1.7, CRC: 2.2, AC: 1.8, SCC: 1.3, Panc: 1.7, PC: 1.7, p < .05). SLC5A2-H had a higher prevalence of FGF3 amplifications in HR+HER2- BC (17.4% -H v 10.4 -L), CRC (1.4 v .45) and PC (4.4 v .89, p < .05 all). KRAS-Mt was more prevalent in SLC5A2-L CRC (41% v 53) as was BRAF-Mt (6 v 14, p < .05 all). There was a lower prevalence of PDL1+ in SLC5A2-H for HR+HER- BC (14% -H v 24 -L), CRC (2 v 6), AC (47 v 68), SCC (50 v 66) and Panc (10 v 19, p < .05 all). All SLC5A2-H tumors had increased Neutrophil, B, NK cell infiltrate (Table) and an increased prevalence of T cell-inflamed tumors (p < .05, all). SLC5A2-H had longer OS v -L in CRC (HR .82 [.76-.88], p <.001), PC (HR .85 [.74-.99], p =.03), HR+HER2- BC (HR .79 [.68-.91], p < .001) and AC (HR .79 [.73-.85], p < .001). Conclusions: SCL5A2-H across all investigated tumors was associated with increased immune infiltrate and a T cell-inflamed phenotype in addition to improved survival in multiple cancer types. Future research on SGLT2 should delineate its role in cancer formation versus its association as a potential positive prognostic marker. [Table: see text]
Detailed pathological characteristics and survival prognosis of patients with penile cancer from a high-capacity tertiary referral centre over a 20-year period.
Authors: Liu Zhicheng , Tan Xingliang , Wang Yanjun , Wei Wensu , Zhou Qianghua , Yuan Gangjun , Yao Kai
Published: August 2024

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Background: Penile cancer is a rare cancer that affects 0.1-1 per 100,000 men in developed countries. However, data on this cancer in developing countries, particularly in Asian populations, are lacking. A retrospective study is needed to determine the characteristics of penile cancer patients, tumor-related treatments, and prognosis. The objective of our study was to present statistical results that are applicable to an Asian population under the most recent staging system. Additionally, we aimed to report on the pathological characteristics and prognosis of a large sample of patients with penile cancer who underwent long-term follow-up with the standard extent of radical dissection. Methods: This study retrospectively analyzed clinical and pathological data from 1017 patients who were diagnosed with penile cancer at Sun Yat-sen University Cancer Center between October 2001 and October 2023. The primary study endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Survival curves were plotted using the Kaplan‒Meier method, and differences were compared using the log-rank test. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with tumor survival. Results: The average follow-up time was 50 months (range: 0.6-232.8 months). The 5- and 10-year OS rates were 67.3% and 62.7%, respectively, and the 5- and 10-year PFS rates were 63.9% and 61.1%, respectively. After excluding 127 Tx patients and 23 TIS stage patients, the 10-year OS rates of pTa stage (29 patients), pT1 (305 patients), pT2 stage (217 patients), pT3 stage (271 patients), and pT4 stage (45 patients) patients were 96.3%, 80.1%, 61.7%, 55.4%, and 14.2%, respectively. A total of 690 patients underwent standard lymph node dissection. The 10-year OS rates of pN0 (376 patients), pN1 (111 patients), pN2 (78 patients), and pN3 (125 patients) patients were 92.7%, 62.5%, 48.1% and 31.3%, respectively. The results of the multifactorial analysis revealed that T stage (T4 stage versus Ta-T1 stage: HR=2.38, 95% CI: 1.00~5.66, P=0.05), pathological grade (G3~4 grade versus G1~2 grade: HR=1.63, 95% CI: 1.05~2.53, P=0.027), N stage (pN+ versus pN0: HR=14.11, 95% CI: 7.83~25.43, P<0.001), and white blood cell count (WBC>8.5: HR=1.71, 95% CI: 1.17~2.51, P=0.006) were independent prognostic factors in penile cancer patients. Conclusions: Patients with penile cancer had better long-term OS after standard lymph node dissection. The adverse factors were T stage, pathological grade, extent of lymph node metastasis, and preoperative WBC count. Identifying high-risk patients through preoperative evaluation can improve long-term survival rates. Radical lymph node dissection in the early stage has more curative value, and adjuvant therapy should be provided in patients with advanced-stage disease after surgery.
Effect of ZCRB1 on the glycolysis via PKM2-HIF1α axis and promotion of immune tolerance in nasopharyngeal carcinoma.
Authors: Hong Gengde , Wang Meng-Yao , Chen Dong-ping
Published: August 2024

130

Background: Nasopharyngeal carcinoma (NPC) is characterized by abundant lymphocyte infiltration. The failure of immune checkpoint inhibitors in NPC may be related to immune tolerance. Methods: Bioinformatics analysis was performed to identify the correlation between the ZCRB1 mRNA level and immune cell infiltration in NPC tissues. Quantitative real time PCR and immunoblotting were used to determine the mRNA and protein expression, respectively. Functional experiments (CCK8, colony formation assay, cell migration assay and tumor xenograft) were used to explore the effect of ZCRB1 on the malignant phenotype in NPC cells. Glucose and lactate measurement assays as well as Seahorse XF glycolysis stress assay, were conducted to investigate the effects of ZCRB1 on glycolysis in NPC cells. RNA sequencing, QPCR and minigene analysis were used to confirm the splicing switch between PKM1 and PKM2. Luciferase assay was performed to detect the transcription activity of HIF1-α. Finally, correlation analysis between the ZCRB1 expression and glycolysis level was performed to in NPC samples. Results: The expression of ZCRB1 was negatively correlated with checkpoint-related genes and immune regulation-related gene sets in head and neck cancer. Likewise, in NPC, the expression of ZCRB1 was negatively correlated with lymphocyte infiltration, tumor immune microenvironment score and tumor-infiltrating CD4+ T cells, CD8+ T cells, and dendritic cells. Low expression of ZCRB1 was associated with better prognosis. Functional assays demonstrated that ZCRB1 significantly promoted NPC cells growth, clonogenicity, migratory capacity and glycolysis. Mechanistically, ZCRB1 was mainly involved in the hypoxic signaling pathway. Cells with ZCRB1 downregulation downregulated glycolysis-related genes and significantly reduced the transcriptional activity of HIF-1α. Moreover, minigene assays showed that the intron 9 region spliced by PKM in cells with ZCRB1 downregulation. Finally, bioinformatics analysis showed that the mRNA expression of ZCRB1 was positively correlated with the immune infiltration score significantly during glycolysis. Conclusions: ZCRB1 promotes the growth and migration of nasopharyngeal carcinoma cells and is associated with immune tolerance. Further, ZCRB1 accelerates the glycolysis via enhancing the transcriptional activity of HIF-1α through increasing PKM2 isoform splicing, providing a scientific basis for tumor metabolic reprogramming to reshape the immune microenvironment.
Effect of tumor-immune microenvironment (TIME) on disparate ascending (A) and descending (D) subtypes of nasopharyngeal carcinoma (NPC).
Authors: Yeo Eugenia Li Ling , Ong Enya , Hong Boon Hao , Lim Darren Wan-Teck , Yeong Joe , Tan Sze Huey , Chua Melvin L.K. , Hwang Jacqueline Siok Gek , Lu Tianzhu
Published: August 2024

145

Background: Endemic NPC is invariably linked to Epstein-Barr virus infection, and often presents as locoregionally-advanced (LA-) disease. Nonetheless, it is acknowledged that LA-NPC is clinically heterogeneous, with disparate clinical presentations of ascending (A) and descending (D) subtypes that are characterized by T3-4N0-1 and T1-2N2-3 disease, respectively. Here, we investigated the TIME between these distinct NPC phenotypes using whole transcriptome sequencing and digital pathology. Methods: We utilized a cohort of 111 patients with NPC from 2 institutions – NCCS (n=68) and JXCH (n=43) as test and validation datasets, respectively. Whole transcriptome profiling using RNAseq (Illumina, CA) was performed in the NCCS cohort, while spatial analyses of hematoxylin and eosin-stained whole slide images (WSIs) were undertaken in the NCCS cohort (35 A- and 33 D-subtypes), and validated in the JXCH cohort (26 A- and 17 D-subtypes). A customized pipeline was developed to analyze the spatial relationships between tumor-rich and immune-rich regions (tiles) within the WSIs. Mean distances between each tumor-rich and its nearest immune-rich tiles were computed for each WSI. Highest and lowest quartiles of the mean distances in the test cohort were used as thresholds to classify NPC tumors into 3 immune classes of differing immune cell density. Results: Transcriptomic profiling revealed an enrichment of immune-related genesets and differentially expressed genes in D- relative to A-subtype tumors. This corresponded to observations of higher overall immune, T and B cell scores in D- than A-subtypes by deconvolution analyses (ESTIMATE and CIBERSORT). Through spatial analyses of our WSIs, we defined three immune classes – immune-dense, -sparse, and -desert, which corresponded to mean distances of <88 μm, 88-208 μm, and >208 μm between tumour- to immune-rich tiles, respectively. D-subtype NPC had significantly more immune-rich regions compared with A-subtypes in both NCCS and JXCH cohorts ( P=0.02 [NCCS]; P=0.01 [JXCH]). This corresponded to shorter median distances between tumor-rich to immune-rich tiles in D- than A-subtypes (103 μm vs 200 μm, P=0.01 [NCCS]; 123 μm vs250 μm, P=0.01 [JXCH]). Based on our novel spatial-based classification, we observed a higher proportion of immune dense tumors in D- than A-subtypes in the NCCS cohort, with only 3/33 (9%) D-subtypes being classified as immune desert. Using the same distance thresholds, we derived a consistent trend in the JXCH cohort, where a higher proportion of D-subtypes were classified as immune dense and sparse than A-subtypes (59% vs 31%, P=0.01). Conclusions: Our results support a model where the TIME delineates the biology underpinning the disparate clinical presentations of distinct A- and D-subtypes of LA-NPC.
Cost-effectiveness of liquid biopsy for molecular profiling of newly diagnosed advanced non-squamous NSCLC in an Asian population.
Authors: Tan Aaron C. , Liu Sibo , Graves Nicholas
Published: August 2024

178

Background: Liquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example. Methods: A decision tree and partitioned-survival model was developed from the Singapore healthcare system’s perspective to evaluate the cost-effectiveness of five molecular profiling strategies: either tissue or plasma next-generation sequencing (NGS) alone, a concurrent, and two sequential approaches. Model inputs were informed by local data or published literature. Sensitivity analyses and scenario analyses were undertaken to understand the robustness of the conclusions for decision making. The optimal strategy at different willingness-to-pay (WTP) thresholds was presented by cost-effectiveness acceptability frontier and the expected loss curve. Results: The sequential tissue-plasma NGS approach revealed an additional 0.0981 quality adjusted life years (QALYs) for an extra cost of S$3,074 over a 20-year time horizon compared to tissue NGS alone, resulting in an incremental cost-effectiveness ratio (ICER) of S$31,318/QALY and an incremental net monetary benefit of S$1,343 per patient. The findings were sensitive to the costs of pembrolizumab and osimertinib and the probabilities of re-biopsy after tissue NGS. Sequential plasma-tissue NGS and plasma NGS alone were more costly and less effective than alternatives. Conclusions: The sequential tissue-plasma NGS approach generated the highest net monetary benefit and was the optimal testing strategy when WTP was S$45,000/QALY. It retained superiority but understandably with a higher ICER when expensive, non-first line treatments were included. Overall, its routine clinical practice should be proactively considered for newly diagnosed advanced non-squamous NSCLC in an Asian population.