bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical analysis plan for the TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation of potentially clinically significant prostate cancer) multicentre randomised controlled trial
Authors: Marian Ioana R. , Ooms Alexander , Holmes Jane , Parkes Matthew J. , Lamb Alastair D. , Bryant Richard J.
Published: June 2024

Background

The TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation) trial assesses the clinical and cost-effectiveness of two biopsy procedures in terms of detection of clinically significant prostate cancer (PCa). This article describes the statistical analysis plan (SAP) for the TRANSLATE randomised controlled trial (RCT).

Methods/design

TRANSLATE is a parallel, superiority, multicentre RCT. Biopsy-naïve men aged ≥ 18 years requiring a prostate biopsy for suspicion of possible PCa are randomised (computer-generated 1:1 allocation ratio) to one of two biopsy procedures: transrectal (TRUS) or local anaesthetic transperineal (LATP) biopsy. The primary outcome is the difference in detection rates of clinically significant PCa (defined as Gleason Grade Group ≥ 2, i.e. any Gleason pattern ≥ 4 disease) between the two biopsy procedures. Secondary outcome measures are th eProBE questionnaire (Perception Part and General Symptoms) and International Index of Erectile Function (IIEF, Domain A) scores, International Prostate Symptom Score (IPSS) values, EQ-5D-5L scores, resource use, infection rates, complications, and serious adverse events. We describe in detail the sample size calculation, statistical models used for the analysis, handling of missing data, and planned sensitivity and subgroup analyses. This SAP was pre-specified, written and submitted without prior knowledge of the trial results.

Discussion

Publication of the TRANSLATE trial SAP aims to increase the transparency of the data analysis and reduce the risk of outcome reporting bias. Any deviations from the current SAP will be described and justified in the final study report and results publication.

Trial registration

International Standard Randomised Controlled Trial Number ISRCTN98159689, registered on 28 January 2021 and registered on the ClinicalTrials.gov (NCT05179694) trials registry.
Effectiveness of some plant extracts in biocontrol of induced onion basal rot disease in greenhouse conditions
Authors: Hegazy Mohamed G. A. , Ahmed Abdel-Raddy M. , Yousef Ahmed Fathy , Ali Waleed M. , Nasr Alyaa , Elshazly Ezzat H. , Shalaby Mohamed E. , Teiba Islam I. , Al-Bedak Osama A. M.
Published: June 2024

One of Egypt’s most notable and historically significant vegetable crops is the Liliaceae plant, Allium cepa L. In this study, the effectiveness of methanolic extracts of Artemisia absinthium leaves, Calotropis procera latex, Moringa oleifera seeds, and Syzygium aromaticum clove was investigated in vitro and, in a greenhouse, setting against Fusarium oxysporum, the pathogen that causes onion basal rot in Assiut Governorate, Egypt. The S. aromaticum extract exhibited the inhibition peak (63.3%), whereas the A. absinthium extract had the lowest inhibition impact against F. oxysporum growth (41.1%). The gas chromatography-mass spectroscopy (GC–MS) analysis revealed that 82 important compounds, with abundances ranging from low to high, were present in the tested S. aromaticum’s methanolic extract. The primary components were acetaldehyde, hydroxy- and 2-propanone, 1,1,3,3-tetrachloro-(42.71%), 1,2-ethanediol, and methyl alcohol (34.01%). In comparison to the infected control, the disease severity was significantly reduced by 20% with the use of a plant extracts mixture and Dovex 50% and increased by 62.22% with the use of an extract from A. absinthium. When compared to the infected control, onion plant fresh weight and dry weight were considerably higher under the clove extract therapy. The plant extracts used in this study’s testing contain a number of active ingredients, including amino acids, vitamins, minerals, antioxidants, and enzymes, which is probably why they have such positive impacts. The application of a combination of plant extracts was suggested as a feasible strategy for improving the growth and productivity of onion plants by the study’s findings. More research is needed to comprehend the mechanisms by which plant extracts promote plant development and to optimize the concentration and timing of administration.
ALKBH5-mediated m6A demethylation of Runx2 mRNA promotes extracellular matrix degradation and intervertebral disc degeneration
Authors: Lei Yu , Zhan Enyu , Chen Chao , Hu Yaoquan , Lv Zhengpin , He Qicong , Wang Xuenan , Li Xingguo , Zhang Fan
Published: June 2024

Background

N6-methyladenosine (m6A) methylation is a prevalent RNA modification implicated in various diseases. However, its role in intervertebral disc degeneration (IDD), a common cause of low back pain, remains unclear.

Results

In this investigation, we explored the involvement of m6A demethylation in the pathogenesis of IDD. Our findings revealed that ALKBH5 (alkylated DNA repair protein AlkB homolog 5), an m6A demethylase, exhibited upregulation in degenerative discs upon mild inflammatory stimulation. ALKBH5 facilitated m6A demethylation within the three prime untranslated region (3′-UTR) of Runx2 mRNA, consequently enhancing its mRNA stability in a YTHDF1 (YTH N6-methyladenosine RNA binding protein F1)-dependent manner. The subsequent elevation in Runx2 expression instigated the upregulation of ADAMTSs and MMPs, pivotal proteases implicated in extracellular matrix (ECM) degradation and IDD progression. In murine models, subcutaneous administration of recombinant Runx2 protein proximal to the lumbar disc in mice elicited complete degradation of intervertebral discs (IVDs). Injection of recombinant MMP1a and ADAMTS10 proteins individually induced mild to moderate degeneration of the IVDs, while co-administration of MMP1a and ADAMTS10 resulted in moderate to severe degeneration. Notably, concurrent injection of the Runx2 inhibitor CADD522 with recombinant Runx2 protein did not result in IVD degeneration in mice. Furthermore, genetic knockout of ALKBH5 and overexpression of YTHDF1 in mice, along with lipopolysaccharide (LPS) treatment to induce inflammation, did not alter the expression of Runx2, MMPs, and ADAMTSs, and no degeneration of the IVDs was observed.

Conclusion

Our study elucidates the role of ALKBH5-mediated m6A demethylation of Runx2 mRNA in activating MMPs and ADAMTSs, thereby facilitating ECM degradation and promoting the occurrence of IDD. Our findings suggest that targeting the ALKBH5/Runx2/MMPs/ADAMTSs axis may represent a promising therapeutic strategy for preventing IDD.
Impaired angiotensin II signaling in septic shock
Authors: Picod Adrien , Garcia Bruno , Van Lier Dirk , Pickkers Peter , Herpain Antoine , Mebazaa Alexandre , Azibani Feriel
Published: June 2024

Recent years have seen a resurgence of interest for the renin–angiotensin–aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II—angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin–angiotensin–aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin–angiotensin–aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin–angiotensin–aldosterone system alterations in septic shock should help to decipher patients’ phenotypes and to implement targeted interventions.
Protocol for a systematic review and network meta-analysis of the use of prophylactic antibiotics in hand trauma surgery
Authors: Zhang Chen , Yusuf Suraya Mohamed , Farag Soma , Wade Ryckie George , Wormald Justin Conrad Rosen
Published: June 2024

Background

The use of prophylactic antibiotics in surgery is contentious. With the rise in antimicrobial resistance, evidence-based antibiotic use should be followed. This systematic review and network meta-analysis will assess the effectiveness of different antibiotics on the prevention of surgical site infection (SSI) following hand trauma surgery.

Methods and analysis

The databases Embase, MEDLINE, CINAHL and CENTRAL, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform will be searched. Abstracts will be screened by two persons independently to identify eligible studies.

This systematic review will include both randomised and non-randomised prospective comparative studies in participants with hand and/or wrist injuries requiring surgery; bite injuries will be excluded. The network meta-analysis will compare the use of different prophylactic antibiotics against each other, placebo and/or no antibiotics on the development of SSI within 30 days of surgery (or 90 days if there is an implanted device).

The Cochrane risk-of-bias tool 2 will be used to assess the risk of methodological bias in randomised controlled trials, and the Newcastle-Ottowa scale (NOS) will be used to assess the risk of bias in non-randomised studies.

A random-effects network meta-analysis will be conducted along with subgroup analyses looking at antibiotic timing, injury type, and operation location. Sensitivity analyses including only low risk-of-bias studies will be conducted, and the confidence in the results will be assessed using Confidence in Network Meta‐Analysis (CINEMA).

Discussion

This systematic review and network meta-analysis aims to provide an up-to-date synthesis of the studies assessing the use of antibiotics following hand and wrist trauma to enable evidence-based peri-operative prescribing.

Systematic review registration

PROSPERO CRD42023429618.
Social distancing stress, anxiety/depression, COVID-19 diagnosis, gender identity, and immigration status
Authors: Adzrago David , Chiangong Jolyna , Ormiston Cameron K. , Dada Oluwabunmi M. , Jones Antwan , Williams Faustine
Published: June 2024

Background

Strict social distancing public health measures to decrease COVID-19 spread increased social distancing stress. However, differences in social distancing stress by anxiety/depression symptoms are understudied, especially based on COVID-19 diagnosis status, gender identity, and immigration status. We examined whether the association between social distancing stress and anxiety/depression symptoms was moderated by COVID-19 diagnosis status, gender identity, and immigration status. We further examined the associations of social distancing stress with anxiety/depression symptoms, gender identity, and immigration status among individuals with and without COVID-19.

Methods

We utilized data from a national cross-sectional survey among adults aged ≥ 18 years in the United States between May 13, 2021, and January 9, 2022 (n = 5,255). Multivariable logistic regression models were used to examine the associations.

Results

The prevalence of social distancing stress was higher among individuals with COVID-19 (79.23%) than among those without COVID-19 (67.51%). We observed significant associations between social distancing stress and anxiety/depression symptoms, moderated by COVID-19 diagnosis status, immigration status, and gender identity, respectively. Anxiety/depression symptoms were associated with social distancing stress among both individuals with and without COVID-19. Gender identity and immigration status were associated with social distancing stress among only individuals without COVID-19.

Conclusions

Our findings revealed that the association between social distancing stress and anxiety/depression varied by COVID-19 diagnosis status, gender identity, and immigration status. The findings underscore the need for more targeted psychological distress strategies to reduce social distancing stress and anxiety/depression among diverse US populations, while considering the impacts of COVID-19 diagnosis status, gender identity, and immigration status.
Feasibility-sustainability study of power generation using solar energy at an industrial site: a case study from Egypt
Authors: Mostafa Noha A. , Aboelezz Amr
Published: June 2024

Background

Fossil fuel utilization is the biggest contributor to the emissions of greenhouse gases which are the main reason for global warming. Solar energy photovoltaic (PV) technology is one of the most rapidly rising technologies and is a sturdy candidate to replace fossil fuels due to its versatility. Egypt receives high solar intensity which makes it a perfect place for utilizing this technology. However, for the past years, the focus in Egypt was on using solar energy for residential applications, henceforth a research gap was identified in studying the feasibility of using solar energy for industrial applications in Egypt. To ensure the sustainability of this application, this feasibility study addresses technical, economic, environmental, and social aspects.

Results

A case study is investigated for utilizing solar PV panels for energy generation in Egypt at an industrial site. A food factory was studied under three scenarios. Scenario 1 is the baseline case for the other scenarios with fixed tilted PV panels and no storage, Scenario 2 is the same as Scenario 1 with difference in is the model of the PV panels with no tracking or storage system. Scenario 3 has a vertical axis tracking system. Software was used to simulate the performance of the three scenarios for 25 years. Results have shown that Scenario 1 and Scenario 2 had close values of the annual energy production. However, Scenario 3 produces 2047 MWh annually which is considerably higher. Finally, a sensitivity analysis is carried out to test the effect of some economic parameters on the financial feasibility.

Conclusions

All the three scenarios are found to be feasible. Scenario 1 has the shortest discounted payback period with a net present value of 414,110.12 USD, a nominal levelized cost of energy of 0.022 USD/kWh, and avoided CO2 emissions of 14,898.993 tons. Although Scenario 3 has higher costs, it has higher energy production and better impact on the environment with 18,891.435 tons of avoided CO2 emissions. The paper concluded that a generalization could be done about using solar PV systems in Egypt for energy generation to be sustainable and feasible technically, economically, and environmentally.
Environmental trade-offs of (de)centralized renewable electricity systems
Authors: Reutter F. , Lehmann P.
Published: June 2024

Background

Renewable energies are key to reduce CO2 emissions and other environmental impacts of fossil-fueled electricity generation. However, renewable energy systems can also cause negative environmental effects. In this paper, we analyze the potential environmental trade-offs associated with different spatio-technical (de)centralization options for a renewable electricity system. For this purpose, we first review the potential environmental life cycle impacts of key technologies for renewable electricity systems. Subsequently, we develop a framework identifying which factors determine actual environmental effects of renewable electricity systems. We apply the framework to four basic spatio-technical (de)centralization options for the future Germany electricity system.

Results

Our analysis shows that all (de)centralization options are associated with potential environmental trade-offs. We find that the (de)centralization of the system is a relevant factor determining these trade-offs. For instance, the two more centralized options considered have lower environmental impacts related to PV, whereas the two more decentralized options have lower environmental impacts related to grid infrastructure. However, we also find that the trade-offs depend on the specific way (de)centralization is pursued. For instance, only in one of the two considered more decentralized development options, there is a potential environmental trade-off between higher impacts related to battery storage and lower impacts related to offshore wind power.

Conclusions

Our analysis reveals that the spatio-technical (de)centralization of a renewable electricity system plays a role for its environmental trade-offs while further factors like the institutional and stakeholder management in place also shape the environmental trade-offs. Policy makers should acknowledge the identified potential environmental trade-offs and their influencing factors when making policies favoring certain spatio-technical (de)centralization options.
Ageism, welfare, and the energy transition: a comparative analysis of the perceptions among the elderly in Poland and Norway
Authors: Szulecki Kacper , Neerland Maria Aspen , Tomter Håkon , Wæringsaasen Cecilie A. Blomberg , Żuk Paweł , Żuk Piotr
Published: June 2024

Background

One of the potential dimensions on which exclusion and injustice may occur in energy transitions is age. Age-based patterns of exclusion—ageism—has recently been conceptualized in the context of decarbonization as energy ageism. This paper offers a comparative empirical analysis of the senior citizens’ outlook towards an imminent energy transition as well as the impact of energy poverty in two European countries: Norway and Poland.

Results

Drawing on interviews and focus groups with Polish and Norwegian seniors, we present the differences and similarities between the two countries, and the determinants of energy ageism, as well as the concept’s overall applicability and empirical usefulness. We find that socioeconomic conditions outweigh ageism, that is, the resilience of senior citizens in dealing with energy poverty during a transition is conditioned by their material standing and welfare state robustness rather than age based. An important factor is household heating technology, combined with economic vulnerability can push some individuals into energy poverty, while others using alternative sources of heat can navigate through energy crises unscathed.

Conclusions

We note the importance of mainstreaming social inclusion considerations in energy policy and of targeted digital competence building which can enhance senior citizen integration in the energy transition. Lower levels of digital competences among senior citizens certainly play a role and need to be addressed with education programs to increase participation. In both countries, household heating is a major issue and heating sources are strong predictors of energy poverty and regulatory measures and subsidies should be designed at national, regional, and municipal level to assist vulnerable groups in this area.
Student entrepreneurship competency and mindset: examining the influence of education, role models, and gender
Authors: Alkaabi Khaula , Senghore Salieu
Published: June 2024

This research aims to explore the interplay among entrepreneurial education, role models, and gender on students' entrepreneurial competence and mindset. Using purposive sampling, 306 participants enrolled in entrepreneurship and innovation-related courses at UAEU completed an online survey. The research used statistical analyses, including Spearman's Rank Correlations, Cramer's V correlation, Mann–Whitney U, and multiple linear regression, to explore variable relationships. Findings indicate that access to entrepreneurial role models is associated with higher competence, emphasizing resource mobilization and fostering a growth mindset. Active engagement in entrepreneurship courses correlates with enhanced innovative thinking and networking. Despite gender-based disparities, statistical analysis indicates minimal impact on students' ability to generate novel business ideas. This study contributes insights to entrepreneurship education literature, offering practical implications for educators and institutions.
Bacteria of healthy periodontal tissues as candidates of probiotics: a systematic review
Authors: del Pilar Angarita-Díaz María , Fong Cristian , Medina Daniela
Published: June 2024

Objectives

The use of probiotics could promote the balance of the subgingival microbiota to contribute to periodontal health. This study aimed to identify the potential of bacteria commonly associated with healthy periodontal tissues as probiotic candidates.

Material and methods

A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, Scopus, Science Direct, ProQuest, and Ovid databases as well as the combination of Medical Subject Headings (MeSH) and non-MeSH terms. Based on the selection criteria, original studies published in English and identifying the microorganisms present in the periodontium of healthy individuals and patients with periodontitis using the high-throughput 16S ribosomal gene sequencing technique were included.

Results

Out of 659 articles, 12 met the criteria for this review. These articles were published from 2012 to 2020 and mainly originated from the United States, China, and Spain. Most of these studies reported adequate criteria for selecting participants, using standardized clinical criteria, and compliance with quality based on the tools used. In periodontal healthy tissue were identified species like Actinomyces viscosus, Actinomyces naeslundii, Haemophilus parainfluenzae, Rothia dentocariosa, Streptococcus sanguinis, Streptococcus mitis, Streptococcus oralis, Streptococcus gordonii, Streptococcus intermedius, and Prevotella nigrescens which have recognized strains with a capacity to inhibit periodontopathogens.

Conclusions

S. sanguinis, S. oralis, S. mitis, and S. gordonii are among the bacterial species proposed as potential probiotics because some strains can inhibit periodontopathogens and have been reported as safe for humans.
Associations between deep venous thrombosis and thyroid diseases: a two-sample bidirectional Mendelian randomization study
Authors: Zhang Lifeng , Li Kaibei , Yang Qifan , Lin Yao , Geng Caijuan , Huang Wei , Zeng Wei
Published: June 2024

Background

Some previous observational studies have linked deep venous thrombosis (DVT) to thyroid diseases; however, the findings were contradictory. This study aimed to investigate whether some common thyroid diseases can cause DVT using a two-sample Mendelian randomization (MR) approach.

Methods

This two-sample MR study used single nucleotide polymorphisms (SNPs) identified by the FinnGen genome-wide association studies (GWAS) to be highly associated with some common thyroid diseases, including autoimmune hyperthyroidism (962 cases and 172,976 controls), subacute thyroiditis (418 cases and 187,684 controls), hypothyroidism (26,342 cases and 59,827 controls), and malignant neoplasm of the thyroid gland (989 cases and 217,803 controls. These SNPs were used as instruments. Outcome datasets for the GWAS on DVT (6,767 cases and 330,392 controls) were selected from the UK Biobank data, which was obtained from the Integrative Epidemiology Unit (IEU) open GWAS project. The inverse variance weighted (IVW), MR-Egger and weighted median methods were used to estimate the causal association between DVT and thyroid diseases. The Cochran’s Q test was used to quantify the heterogeneity of the instrumental variables (IVs). MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) was used to detect horizontal pleiotropy. When the causal relationship was significant, bidirectional MR analysis was performed to determine any reverse causal relationships between exposures and outcomes.

Results

This MR study illustrated that autoimmune hyperthyroidism slightly increased the risk of DVT according to the IVW [odds ratio (OR) = 1.0009; p = 0.024] and weighted median methods [OR = 1.001; p = 0.028]. According to Cochran’s Q test, there was no evidence of heterogeneity in IVs. Additionally, MR-PRESSO did not detect horizontal pleiotropy (p = 0.972). However, no association was observed between other thyroid diseases and DVT using the IVW, weighted median, and MR-Egger regression methods.

Conclusions

This study revealed that autoimmune hyperthyroidism may cause DVT; however, more evidence and larger sample sizes are required to draw more precise conclusions.
Investigating the association between blood oxidative stress markers and dementia in Egyptian elderly women
Authors: Ebrahim Lamyaa Kamel , Adel Sherihan , Hamza Sarah A. , Alsadany Mohamad A. , Ali Suzan Mounir
Published: June 2024

Background

The predicted increase in the senior population will have a substantial impact on mental health and dementia development, emphasizing the need to study the biochemical components related to the pathogenesis of dementia. Oxidative stress is caused by an imbalance between the production of reactive oxygen species and the antioxidant balance of the body. The brain is particularly vulnerable to oxidative stress because of the relatively low levels of antioxidants in the brain, high levels of polyunsaturated fatty acids, and increased oxygen needs. The increase of reactive oxygen species leads to the accumulation of protein oxidation by-products which has a key role in dementia pathogenesis. The aim of the study is to investigate the link between oxidative stress and dementia in Egyptian older women and its possible effect on dementia severity and types. A case–control study was conducted involving 40 elderly women with dementia, and another 40 cognitively intact controls. All participants were subjected to a comprehensive geriatric evaluation, which included cognitive assessment, depression screening, and functional assessment. Blood levels of malondialdehyde (an oxidative stress marker), glutathione peroxidase enzyme and total antioxidant capacity (an antioxidant markers) were measured.

Results

Malondialdehyde’s blood level was significantly higher in dementia cases (p < 0.001), indicating a higher oxidative stress status in dementia cases. While blood levels of both glutathione peroxidase enzyme and total antioxidant capacity were significantly lower in dementia cases (p < 0.001), indicating a lower antioxidant activity in dementia cases. We found that glutathione peroxidase enzyme at a cutoff point ≤ 122 mu/ml, total antioxidant capacity at a cutoff point ≤ 39.1 mm/l, and malondialdehyde at a cutoff point > 95 nmol/ml had perfect diagnostic value for identifying patients with dementia.

Conclusion

Oxidative stress showed a significant role in the pathogenesis of dementia, with the presence of higher levels of oxidative damage by-products and lower levels of antioxidant status. So, the role of oxidative stress in dementia should not be neglected, and more effort should be directed to prevent unnecessary exposure to oxidative stress in older adults to contribute towards dementia prevention.
Alpha-lipoic acid induced insulin autoimmune antibody syndrome
Authors: Baburaj Karthik , MP Jabir , MV Vimal
Published: June 2024

Background

Insulin autoimmune antibody syndrome is an uncommon cause of hypoglycemia in non-diabetic individuals. We report a case of alpha-lipoic acid-induced insulin autoimmune antibody syndrome.

Case report

A 40-year-old non-diabetic female presented with unresponsiveness due to severe hypoglycemia. Investigations revealed high fasting insulin levels, elevated C-peptide, and positive anti-insulin antibodies. Further history revealed recent ingestion of alpha-lipoic acid supplements. She was diagnosed with alpha-lipoic acid-induced insulin autoimmune antibody syndrome and managed with symptomatic measures and steroids.

Conclusions

This case highlights the importance of recognizing drug-induced insulin autoimmune antibody syndrome as a potential cause of hypoglycemia in non-diabetic individuals, especially in the context of recent supplement or medication use.
Unraveling the hidden relationships between seismic multiattributes, well-dynamic data, and Brazilian pre-salt carbonate reservoirs productivity: A shallow versus deep machine-learning approach
Authors: Maas Marcus Vinicius Rodrigues , Bedle Heather , Ballinas Mario Ricardo , Castro de Matos Marcilio
Published: June 2024

During the initial phases of an E&P project, the most reliable data on the reservoir’s deliverability are acquired via drill stem tests (DST), which provide the productivity per flow unit whenever production logging tool data are available. However, DSTs are restricted to a few kilometers, whereas seismic data cover large areas. The integration of these data has been challenging, particularly due to the difference in scale between them. So, a new workflow to determine the relationship between poststack seismic attributes and reservoir productivity using classic supervised (shallow) and deep-learning regression algorithms was developed. The DST parameters were predicted over the entire seismic cube, which can be extremely valuable for the decision-making process. The data set is from the Brazilian deep-water presalt carbonate reservoirs of the Mero Field, which is a well-explored area with a plethora of test and production data. It is adjacent to an underexplored Central Libra appraisal plan area, which is covered by the same seismic survey. Thus, any relationships between seismic attributes and well productivity data observed at the Mero Field are extrapolated to the adjacent underexplored area. Ten seismic attributes and DST data from 10 wells of the Mero Field were used to train shallow and deep-learning supervised regression algorithms for the prediction of flow capacity and productivity index seismic cubes. Twenty development wells (blind tests) were used for the assessment of our predictive models. The highest percentage of correct predictions at the blind test wells (85%) was obtained with random forest regression using six attributes derived from a spectrally balanced full-stack volume, and neither amplitude-variation-with-offset nor inversion data were needed. Deep learning provided lower performance (75%) at a higher computational cost. It demonstrated a new reservoir derisking tool that can be used for project optimization in areas covered by the same seismic survey.
Distribution and mutational landscape of inherited cancer susceptibility syndromes in central nervous system tumors.
Authors: Gong Jie , Wang Chuanwei , Luo Ningning , Han Tiantian , Yin Xiangyu , Chen Dong-sheng
Published: June 2024

2051

Background: Inherited cancer susceptibility syndromes (ICSS) caused approximately 5%–10% of malignancies. The fifth edition of the World Health Organization Classification of Tumors emphasized that central nervous system (CNS) tumors are associated with various ICSS. Our understanding of CNS tumors, both at the systemic and germline levels, has significantly improved with the increasing popularity of next-generation sequencing (NGS) testing. Recognizing individuals with ICSS in primary CNS tumors is crucial for optimizing proper genetic counseling and improving therapeutics and clinical care, and may further directly enhance patient outcomes. Methods: We retrospectively analyzed the ICSS of 4,828 patients with CNS tumors in a Chinese cohort, including age, cancer type, and sex distribution, and further investigated the somatic and germline mutations of cancer-related genes. Additionally, we examined the molecular characteristics of CNS tumors with ICSS and their clinical significance for diagnostic and therapeutic purposes. Results: Our study identified 258 (5.34%) patients with ICSS among 4,828 patients with CNS tumors with 265 germline P/LP variants, and identified 34 categories of ICSS, including 20 types of ICSS occurring in 28% (72/258) of patients not listed in the WHO CNS 5 classification. The gene with the highest germline P/LP mutation frequency was TP53 (9.69%), followed by MSH2 (9.30%), NF1(8.91%), and BRCA2 (7.75%). These ICSS-associated genes were significantly enriched in the DNA repair and genomic stability signaling pathways (67%, 178/265). The two-hit events mainly focused on NF1, MSH6, and MSH2. The genes with the top five somatic mutation frequencies were TP53 (42.25%), TERT (30.23%), CDKN2A (28.68%), CDKN2B (27.52%), and PTEN (25.58%). The top five ICSS in CNS tumors were Lynch syndrome, BRCA-related cancer predisposition syndrome, Li-Fraumeni syndrome, Fanconi anemia, and neurofibromatosis type 1. ICSS analysis reclassifies CNS tumors of “NOS” and 53.88% (139/258) of patients diagnosed with ICSS harboring potential precision oncology therapy target mutations. Conclusions: Our study is the first to include a large-scale cohort of patients with CNS tumors with ICSS and analyze the clinical and genomic features as well as their clinical significance. Results in our study of CNS tumors with ICSS are expected to improve disease entire process management, which is an important application of DNA-based NGS in ICSS evaluation and management and provides a reference direction for the future design of clinical trials.
Investigating peripheral blood biomarkers of immune checkpoint inhibitor associated fatigue.
Authors: Li Howard Liu , Charmsaz Soren , Alden Stephanie Leigh , Brancati Madelena , Warner Aanika , Munjal Kabeer , Tsai Hua-Ling , Gross Nicole E. , Thoburn Christopher , Lipson Evan J. , Ged Yasser , Garonce-Hediger Rachel , Bansal Sanjay , Tang Laura , Jaffee Elizabeth M. , Chandler G Scott , Mohindra Rajat , Ho Won Jin , Yarchoan Mark , Kao Chester
Published: June 2024

2571

Background: Fatigue is the most common side effect of immune checkpoint inhibitor (ICI) therapy. Despite its prevalence, the mechanisms underlying ICI-associated fatigue are poorly understood. In this study, we characterized dynamic changes in peripheral immune cell populations and cytokines to identify biomarkers and mechanisms of ICI-associated fatigue. Methods: We prospectively collected clinical data and blood samples from patients with solid tumors at a single institution who received ICIs between July 2021 and November 2023. Blood samples were collected at baseline, early-on-treatment (month 1-2), and later-on-treatment (month 4-6). Patients were contacted on-treatment to query for worsening of fatigue compared to treatment baseline. We analyzed peripheral lymphocyte populations by Cytometry by Time-of-Flight (CyTOF) and peripheral levels of 39 cytokines with Luminex multiplex assay. Tumor response was characterized by RECIST v1.1. False discovery rate (FDR) was used for multi-testing adjustment. Results: 53 patients received ICI therapy and had fatigue assessment performed. Thirty-one patients (58.5%) reported worsening fatigue, and 22 (41.5%) did not. In patients with worsened fatigue, a cluster of cytotoxic effector CD8+CD28+TIGIT+ T-cells was significantly increased from baseline to early-on-treatment (Wilcoxon Signed-rank Test FDR adjusted p<.05). Early-on-treatment fold changes in Type 1 cytokines (IFN-gamma, IL-2, IL-12) were increased in patients with worsened fatigue compared to patients with no fatigue (Wilcoxon Rank-sum Test unadjusted p<.05; Table). There was no association between increase in fatigue and objective response to ICI therapy, although numerically high rates of fatigue were observed both in patients experiencing disease progression as well as complete responses. After excluding patients with tumor progression to account for tumor-related fatigue, early-on-treatment fold changes in IL-2 and IL-12 were still increased in worsened fatigued compared to non-fatigued patients (unadjusted p<.05). However, in patients with disease progression, changes in Type 1 cytokines were not associated with worsening fatigue. Conclusions: In a pan-tumor cohort treated with ICIs, increases in a cluster of cytotoxic effector CD8+ T cells in parallel with related Type 1 cytokines were associated with fatigue, implicating fatigue as a marker of immune activation in this population. [Table: see text]
Phase 1 dose escalation and cohort expansion study evaluating safety, PK, PD and clinical activity of STC-15, a METTL-3 inhibitor, in patients with advanced malignancies.
Authors: Moser Justin C , Papadopoulos Kyriakos P. , Rodon Ahnert Jordi , Ofir-Rosenfeld Yaara , Holz Josefin-Beate ,   STC15-22101 Study Team
Published: June 2024

2586

Background: RNA modifications are involved in cancer initiation and progression. The most abundant modification of mRNA is m6A generated by METTL3. Inhibition of METTL3 causes double-stranded RNA formation and activation of cellular T1 IFN response. IFN signaling induces IFN-stimulated gene families i.e. IFIT and OAS, characteristic of an anti-viral response, and secretion of cytokines and chemokines. STC-15, a first in class small molecule inhibitor of METTL3 developed by Storm Therapeutics, demonstrated in pre-clinical models, activation of IFN signaling and remodeling of the TME towards pro-inflammatory state. We report the dose escalation results from a FIH trial in patients with advanced malignancies. Methods: This is a multi-center, open-label, dose escalation study. STC-15 oral capsules are administered daily or t.i.w. in 21-d treatment cycles. Dose escalation follows 3+3 modified Fibonacci regimen. Primary objectives are safety and PK. Secondary objectives are preliminary evidence of anticancer activity and RP2D. Exploratory objectives are PD (i.e. target engagement and immune activation biomarkers) and correlation of primary pharmacology with observed clinical efficacy. Results: As of 02/01/2024, 31 patients enrolled across 4 dose levels and 5 cohorts: 60mg QD (6 pats), 60mg t.i.w. (3 pats), 100mg t.i.w. (14 pats), 160 mg t.i.w. (5 pats) and 200mg t.i.w. (3 pats). PK profile supports t.i.w. dosing. A total of 169 AEs were observed with 45 AEs attributed to STC-15 treatment. AEs were manageable, mostly hematology (thrombocytopenia 31%; 4% Grade 3), skin (pruritis, rash 14% G1/2) and GI (N/V and diarrhea 14% G1/2). 12 SAEs occurred; 1 pt (60mg QD) had DLT with G3 pneumonitis. Of 14 patients with at least 1 on-treatment scan, DCR is 78% with 2 confirmed PR ongoing in angiosarcoma (60mg, 32 weeks) and IO-refractory NSCLC (100mg, 33 weeks) and 9 SD. An average of 63% reduction in m6A on mRNA in peripheral blood within the first 24h post dosing was observed in 60mg cohorts, confirming target engagement. Whole blood Nanostring and pathway analysis of gene expression confirms upregulation of innate immune pathways (i.e. T1,2 IFN activation and anti-viral responses) as early as 8h after first dose and throughout the treatment cycle. Updated PK/PD and clinical data will be presented. Conclusions: Treatment with STC-15 is well tolerated across pharmacologically active dose range with encouraging signs of clinical activity. Early biomarker data provide proof of mechanism in target engagement, strong activation of innate immune responses and correlation of pharmacological activity with clinical response. The study is ongoing and expansion cohorts are underway to further evaluate PK/PD, safety and clinical efficacy at optimized pharmacologically active doses. Clinical trial information: NCT05584111 .
Safety and preliminary efficacy of EIK1001 in combination with atezolizumab in participants with advanced solid tumors.
Authors: Patel Manish R. , Rasco Drew W. , Johnson Melissa Lynne , Hamid Omid , Sommerhalder David , Cho Carolyn , Wang Meihua , Kurland Etah
Published: June 2024

2618

Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-102 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 combined with atezolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with atezolizumab (1200 mg Q3W). Results: Forty-one pts (median age 65 years [range = 32 to 79]) with multiple, distinct histological tumor types and a median of 3 prior Rx regimens were enrolled. Overall, a total of 28/41 (68.3%) receiving EIK1001 + atezolizumab experienced a treatment-related adverse event (TRAE). Of these, 4/41 (9.8%) experienced a ≥ Grade 3 TRAE, including fatigue, nausea, hyponatremia, and lymphedema. Only 1/41 (2.4%) experienced manageable cytokine release syndrome. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 37), complete response (CR) or partial response (PR) was observed for 3/37 (8.1%). Disease control (including CR, PR, or stable disease) was observed in 19/37 (51.4%). The median duration of response (DOR) was 13 months (range = 10 to 27). One responder was PD-L1 negative yet had a > 12-month DOR; another had a history of prior anti-PD-1 Rx yet experienced a 10-month DOR on comb Rx. EIK1001 PK was linear and dose-proportional, and was not affected by combination with atezolizumab. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with atezolizumab. Responses were observed even in pts not anticipated to respond to atezolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT04196530 .
Impact of body mass index (BMI) on survival outcomes in patients with cancer treated with immune checkpoint inhibitors (ICPI): A systematic review and meta analysis.
Authors: Mishra Rahul , Sukaina Mahnoor , Batra Nitya , Kumar Madhan Srinivasan , Walia Kamalpreet Singh , Chahal Rutvi , Khosla Atulya Aman , Singh Rohit , Ahmed Shahid Sattar , Jatwani Karan
Published: June 2024

2624

Background: With the increased adoption of ICPI in treating various cancers, there is active exploration of individual-level factors that could predict treatment responses. A high-body mass index (BMI) induces a chronic inflammatory state and could drive T-cell dysfunction through high leptin levels, which may confer better outcomes with ICPI usage. However, there are conflicting outcomes in different studies. We performed this systematic review and meta-analysis to evaluate survival outcomes with ICPI in patients with BMI ≥25 vs <25 Kg/m2. Methods: A comprehensive search was conducted across PubMed, Embase, Scopus, and web of science databases. The original studies evaluating response [overall survival (OS) and progression free survival (PFS)], to ICPI-based therapies among adult cancer patients, stratified by BMI groups (high, BMI ≥25Kg/m2 or low, BMI <25Kg/m2), were included. RevMan version 5.4.1 was used for statistical analysis. A random effect model with inverse variance as the statistical method was used for hazard ratio (HR) and 95% confidence interval (CI). Results: Of 1215 identified studies, 22 observational studies, comprising 5859 patients (60.3% males) met the inclusion criteria. ECOG performance score was reported as 0-1 for 40.3% patients, and ≥2 for 7.1% patients. In 12-studies only PD-1 and/or PD-L1 inhibitors were administered, but no CTLA-4 inhibitor. Most frequently reported cancers were non-small cell cancer of lung (40.9%), melanoma (36.6%), and renal cell cancer (31.8%) in advanced/metastatic stages. Higher BMI, compared to low BMI, favored significant improvement in PFS [HR 0.86; 95% CI (0.76, 0.99), P= 0.03, I2 47%], and OS [ HR 0.73; 95% CI (0.62, 0.85), P< 0.0001, I2 53%] with any ICPI-based regimens. Similar findings were noted for patients treated with PD-1/PDL1 inhibitors [Table]. Conclusions: This study contributes to the evidence that BMI of 25 kg/m2 or higher exerts a beneficial impact on PFS and OS among cancer patients treated with ICPI. The favorable impact underscores the significance of considering BMI as a potential prognostic factor in ICPI therapy. However, the precise underlying mechanisms responsible for this observation warrant further investigation to deepen our understanding and potentially optimize therapeutic strategies in this patient population. [Table: see text]
First-in-human study of simmitinib, a novel tyrosine kinase inhibitor targeting FGFR1-3, KDR and CSF-1R.
Authors: Yang Sheng , Zhang Yanqiao , Zhang Mingjun , Wu Yongzhong , Li Yongsheng , Wang Feng , Tian Xin , Luo Suxia , Sun Yuping , Wang Linlin , Li Jiancheng , Jiang Da , Wang Mingxia , Huang Yunchao , Shi Huaqiu , Yang Haiyu , Liu Xiaowen , Ji Wei , Pu Weiqing , Shi Yuankai
Published: June 2024

3109

Background: Simmitinib, a potent tyrosine kinase inhibitor targeting FGFR1-3, KDR and CSF-1R, was evaluated in a phase I study in patients with advanced solid tumors. Methods: The study included dose-escalation cohorts and dose-expansion cohorts. In the dose-escalation cohorts, patients received simmitinib at doses from 1 to 9 mg orally. The DLT observation period consisted of a single dose over 7 days and multiple doses over 28 consecutive days. Patients were assessed for safety, pharmacokinetics, and efficacy. Results: As of October 31, 2023, 98 patients with a median age of 60 years (range 27-70) were enrolled. 24 patients were enrolled in the dose-escalation cohorts and 74 in the dose-expansion cohorts. One DLT was reported in the 9 mg group (grade 3 hypertension lasted for more than 3 days). The maximum tolerated dose (MTD) was not achieved. Furthermore, 4 mg QD, 6 mg QD and 6 mg 3 weeks on 1 week off dosing regimens were employed for expansion. Treatment-related adverse events (TRAEs) were reported in 88 patients (89.8%); detailed TRAEs of any grade occurring in ≥ 10% patients are listed in the table below. The incidence of TRAEs in the 6 mg 3 weeks on 1 week off group was the lowest among all the dosing regimens, with TRAEs any grade and grade ≥ 3 reported in 18 patients (66.7%) and 4 patients (14.8%), respectively. Of 56 patients with pretreated esophageal squamous carcinoma, the ORR was 16.1% (95% CI, 7.6-28.3%) with DCR of 46.4% (95% CI, 33.0-60.3%) and median PFS of 5.7 months (95% CI, 3.5-6.7); the ORRs for 4 mg QD, 6 mg QD, 6 mg 3 weeks on 1 week off, and 9 mg QD groups were 0 (0/6), 13.6% (3/22, 95% CI, 2.9-34.9%), 19.2% (5/26, 95% CI, 6.6-39.4%) and 50.0% (1/2, 95% CI, 1.3-98.7%), respectively. Based on the results of safety and efficacy, 6 mg 3 weeks on 1 week off was selected as recommended phase Ⅱ dose (RP2D). Statistical analysis using a power model for ln-transformed exposures (Cmax and AUC0-∞) suggested dose proportionality from 1 to 9 mg (95% CI of the slope estimate included the value of 1). Higher copy numbers of FGF3, FGF4, or FGF19 appeared to be associated with durable disease control in preliminary biomarker analysis, and further exploration is ongoing. Conclusions: Simmitinib showed manageable toxicity in the study and encouraging activity in esophageal squamous carcinoma. Accordingly, 6 mg 3 weeks on 1 week off was recommended for phase Ⅱ trials. Clinical trial information: NCT04058587 . [Table: see text]