bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing multiplexed anti-ASFV CRISPR-Cas9 in reducing African swine fever virus
Authors: Zheng Zezhong , Xu Lei , Gao Yangbin , Dou Hongwei , Zhou Yixuan , Feng Xu , He Xiangjun , Tian Zhen , Song Lingling , Mo Guolong , Hu Jiapan , Zhao Hongye , Wei Hongjiang , Church George M. , Yang Luhan
Published: April 2024

African swine fever (ASF) is a highly fatal viral disease that poses a significant threat to domestic pigs and wild boars globally. In our study, we aimed to explore the potential of a multiplexed CRISPR-Cas system in suppressing ASFV replication and infection. By engineering CRISPR-Cas systems to target nine specific loci within the ASFV genome, we observed a substantial reduction in viral replication
in vitro
. This reduction was achieved through the concerted action of both Type II and Type III RNA polymerase-guided gRNA expression. To further evaluate its anti-viral function
in vivo
, we developed a pig strain expressing the multiplexable CRISPR-Cas-gRNA via germline genome editing. These transgenic pigs exhibited normal health with continuous expression of the CRISPR-Cas-gRNA system, and a subset displayed latent viral replication and delayed infection. However, the CRISPR-Cas9-engineered pigs did not exhibit a survival advantage upon exposure to ASFV. To our knowledge, this study represents the first instance of a living organism engineered via germline editing to assess resistance to ASFV infection using a CRISPR-Cas system. Our findings contribute valuable insights to guide the future design of enhanced viral immunity strategies.

IMPORTANCE

ASFV is currently a devastating disease with no effective vaccine or treatment available. Our study introduces a multiplexed CRISPR-Cas system targeting nine specific loci in the ASFV genome. This innovative approach successfully inhibits ASFV replication
in vitro
, and we have successfully engineered pig strains to express this anti-ASFV CRISPR-Cas system constitutively. Despite not observing survival advantages in these transgenic pigs upon ASFV challenges, we did note a delay in infection in some cases. To the best of our knowledge, this study constitutes the first example of a germline-edited animal with an anti-virus CRISPR-Cas system. These findings contribute to the advancement of future anti-viral strategies and the optimization of viral immunity technologies.
Refining taxonomic identification of microalgae through molecular and genetic evolution: a case study of
Prorocentrum lima
and
Prorocentrum arenarium
Authors: Zheng Danlin , Zou Ligong , Zou Jian , Li Qun , Lu Songhui
Published: April 2024

Species delimitation based on lineage definition has become increasingly popular. However, these methods have been limited, especially for species that lack genomic data and are morphologically similar. The trickiest part for the species identification is that the interspecific and intraspecific boundaries are vague. Taking
Prorocentrum
(Dinophyta) as an example, analysis of cell morphology, growth, and toxin synthesis in both species of
P. lima
and
P. arenarium
does not provide a reliable basis for species delineation. However, through phylogenetic and genetic distance analyses of their ITS and LSU sequences, establishment of evolutionary tree based on orthologous gene sequences, and combining the results of automatic barcode gap discovery and Poisson tree processes models, it was sustained that
P. arenarium
does not belong to the
P. lima
complex and should be considered as an independent species. Interspecies genetic evolution analysis revealed that
P. lima
and
P. arenarium
may contribute to evolutionary direction that favors combating reverse environmental factors. In
P. lima
, viral invasion may be one of the reasons for its large genome size. In the study,
P. lima
complex has been selected as an example to enhance the taxonomic identification of microalgae through molecular and genetic evolution, offering valuable insights into refining taxonomic identification and promoting microbial biodiversity research in other species.

IMPORTANCE

Microalgae, especially the species known as
Prorocentrum
, have received significant attention due to their ability to trigger harmful algal blooms and produce toxins. However, the boundaries between species and within species are ambiguous. Clear and comprehensive species delineation indicates that
Prorocentrum arenarium
should be considered as an independent species, separate from the
Prorocentrum lima
complex. Improving the classification and identification of microalgae through molecular and genetic evolution will provide reference points for other cryptic species.
Prorocentrum
occupy multiple ecological niches in marine environments, and studying their evolutionary direction contributes to understanding their ecological adaptations and community succession.
Unlocking the mechanism of action: a cost-effective flow cytometry approach for accelerating antimicrobial drug development
Authors: Mermans Fabian , De Baets Hanna , García-Timermans Cristina , Teughels Wim , Boon Nico
Published: April 2024

Antimicrobial resistance is one of the greatest challenges to global health. While the development of new antimicrobials can combat resistance, low profitability reduces the number of new compounds brought to market. Elucidating the mechanism of action is crucial for developing new antimicrobials. This can become expensive as there are no universally applicable pipelines. Phenotypic heterogeneity of microbial populations resulting from antimicrobial treatment can be captured through flow cytometric fingerprinting. Since antimicrobials are classified into limited groups, the mechanism of action of known compounds can be used for predictive modeling. We demonstrate a cost-effective flow cytometry approach for determining the mechanism of action of new compounds. Cultures of
Actinomyces viscosus
and
Fusobacterium nucleatum
were treated with different antimicrobials and measured by flow cytometry. A Gaussian mixture mask was applied over the data to construct phenotypic fingerprints. Fingerprints were used to assess statistical differences between mechanism of action groups and to train random forest classifiers. Classifiers were then used to predict the mechanism of action of cephalothin. Statistical differences were found among the different mechanisms of action groups. Pairwise comparison showed statistical differences for 35 out of 45 pairs for
A. viscosus
and for 32 out of 45 pairs for
F. nucleatum
after 3.5 h of treatment. The best-performing random forest classifier yielded a Matthews correlation coefficient of 0.92 and the mechanism of action of cephalothin could be successfully predicted. These findings suggest that flow cytometry can be a cheap and fast alternative for determining the mechanism of action of new antimicrobials.

IMPORTANCE

In the context of the emerging threat of antimicrobial resistance, the development of novel antimicrobials is a commonly employed strategy to combat resistance. Elucidating the mechanism of action of novel compounds is crucial in this development but can become expensive, as no universally applicable pipelines currently exist. We present a novel flow cytometry-based approach capable of determining the mechanism of action swiftly and cost-effectively. The workflow aims to accelerate drug discovery and could help facilitate a more targeted approach for antimicrobial treatment of patients.
Propargyl-Substituted Furazanoazepines: Synthesis, Structure, Enthalpy of Formation, Ballistic Efficiency
Authors: Lempert D. B. , Ignatieva E. L. , Stepanov A. I. , Dashko D. V. , Kazakov A. I. , Nabatova A. V. , Shilov G. V. , Lagodzinskaya G. V. , Korchagin D. V. , Aldoshin S. M.
Published: April 2024

7-propargyl-7H-difurazano[3,4-b:3',4'-f]furoxano[3",4"-d]azepine (Az(O)Prg) and 7-propargyl-7H-trifurazano[3,4-b:3',4'-d:3",4"-f]azepine (AzPrg) are synthesized as potential dispersants of solid fuels for gas-generator engines for the first time. Their molecular structure, enthalpies of combustion and formation are determined. The relative aircraft flight range is estimated when using Az(O)Prg and AzPrg as fuel dispersants.
Rapid progression from MDS to AML with gastric submucosal tumour as an extramedullary infiltration
Authors: Kobayashi Keigo , Umekawa Yasuhiro
Published: April 2024

We present a rare case of myeloid sarcoma in the stomach of an elderly woman initially diagnosed with anaemia. Myeloid sarcoma, an unusual extramedullary manifestation of acute myeloid leukaemia (AML), primarily affects lymph nodes, bones, spine and skin, with gastrointestinal involvement being infrequent. Despite normal results from the initial endoscopy, a follow-up examination after 4 months revealed multiple submucosal gastric tumours. These developments coincided with worsening of anaemia and an increase in peripheral myeloblasts. Pathological evaluation and immunohistochemical staining confirmed gastric extramedullary infiltration associated with AML. This case highlights the importance of comprehensive diagnostic processes when suspecting leukaemic transformations, especially in myelodysplastic syndrome (MDS). Due to financial constraints, additional critical studies such as cytogenetics and next-generation sequencing were not performed. Nonetheless, this rare case demonstrates the visual observation of rapid progression from MDS to AML and concurrent early myeloid sarcoma development in an elderly patient.
Gastric emptying during and following resolution of moderate diabetic ketoacidosis in type 1 diabetes: a case series
Authors: Jalleh Ryan J , Phillips Liza , Umapathysivam Mahesh M , Jones Karen L , Marathe Chinmay S , Watson Linda E , Bound Michelle , Rayner Christopher K , Horowitz Michael
Published: April 2024

Introduction

To use the ‘gold standard’ technique of scintigraphy to quantify gastric emptying (GE) as soon as practicable during an admission with diabetic ketoacidosis (DKA) and following its resolution at least 7 days later.

Research design and methods

Five patients with type 1 diabetes, age 29±12 years; Body Mass Index 23±3 kg/m2; hemoglobin A1c 11.3%±1.9%, were studied during an admission with DKA and following its resolution. Solid and liquid GE were measured using scintigraphy. Solid emptying was assessed via the percentage intragastric retention at 100 min and that of liquid by the 50% emptying time.

Results

There was no difference in either solid or liquid GE at the initial study compared with the follow-up. Median (IQR) solid retention was 47±20 versus 38%±33%, respectively; p=0.31, and time to empty 50% of liquid was 37±25 min versus 35±15 min, p=0.31, at the initial and follow-up GE study, respectively.

Conclusions

GE of solids and liquids is not affected by moderate DKA, inferring that earlier reintroduction of oral intake may be appropriate.
Modified sutureless and glue-free method versus conventional sutures for conjunctival autograft fixation in primary pterygium surgery: a systematic review and meta-analysis
Authors: Aljahdali Faisal , Khayyat Waleed , BinYamin Abdulelah T , Al-Qahtani Sultan A , Alghamdi Mohammed D , Alsudais Ali Saleh , Alalgum Husain A , Bin Helayel Halah , AlMutlak Mohammed
Published: April 2024

Background

Pterygium is a common ocular surface disorder that requires surgical intervention for treatment. Conjunctival autografts are preferred over simple excision due to lower recurrence rates. This systematic review and meta-analysis compared the modified sutureless glue-free (MSGF) method with conventional sutures (CS) for conjunctival autograft fixation in primary pterygium surgery.

Methods

A comprehensive search was conducted in MEDLINE, Embase, CENTRAL, Google Scholar and ClinicalTrials.gov for randomised controlled trials (RCTs) comparing MSGF and CS conjunctival autografts. Outcome measures included operation time, recurrence and postoperative complications. Standardised mean difference (SMD) and risk ratio (RR) were used for continuous and dichotomous outcomes, respectively.

Results

11 RCTs involving 833 participants were included. The analysis revealed that MSGF had a significantly shorter operation time compared with CS (SMD −3.704, 95% CI −5.122 to −2.287, p<0.001). CS was associated with a higher risk of foreign body sensation (RR 0.22, 95% CI 0.06 to 0.74, p=0.01). MSGF was associated with a higher risk of graft dehiscence (RR 9.01, 95% CI 2.74 to 29.68, p=0.000) and graft retraction (RR 2.37, 95% CI 1.17 to 4.77, p=0.02). No significant differences were found in recurrence, graft haemorrhage, granuloma, Dellen and conjunctival oedema.

Conclusion

Using the MSGF technique in conjunctival autograft fixation for pterygium surgery reduces operation time by relying solely on the patient’s blood for fixation. However, it increases the risk of graft dehiscence and retraction. However, CS is linked to a higher likelihood of experiencing foreign body sensations. Understanding the learning curve and surgeon familiarity with novel techniques is crucial for optimising patient care and surgical outcomes, while individualised decision-making is necessary considering the advantages and disadvantages of each approach. Further research is warranted to minimise complications and optimise surgical outcomes.
Recruitment and baseline characteristics of young adults at risk of early-onset knee osteoarthritis after ACL reconstruction in the SUPER-Knee trial
Authors: Culvenor Adam G , West Thomas J , Bruder Andrea M , Scholes Mark J , Barton Christian J , Roos Ewa M , Oei Edwin H G , McPhail Steven M , Souza Richard B , Lee Jusuk , Patterson Brooke E , Girdwood Michael A , Couch Jamon L , Crossley Kay M
Published: April 2024

Objectives

The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants.

Methods

The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18–40 years) with ongoing symptoms (ie, mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score subscales (KOOS4)) 9–36 months post-ACLR. The NNS was calculated as the number of prospective participants screened to enrol one person. At baseline, participants provided medical history, completed questionnaires (demographic, injury/surgery, rehabilitation characteristics) and underwent physical examination.

Results

1044 individuals were screened to identify 567 eligible people, from which 184 participants (63% male) enrolled. The sample of enrolled participants was multicultural (29% born outside Australia; 2% Indigenous Australians). The NNS was 5.7. For randomised participants, mean±SD age was 30±6 years. The mean body mass index was 27.3±5.2 kg/m2, with overweight (43%) and obesity (21%) common. Participants were, on average, 2.3 years post-ACLR. Over half completed <8 months of postoperative rehabilitation, with 56% having concurrent injury/surgery to meniscus and/or cartilage. The most affected KOOS (0=worst, 100=best) subscale was quality of life (mean 43.7±19.1).

Conclusion

Young adults post-ACLR were willing to participate in a secondary osteoarthritis prevention trial. Sample size calculations should be multiplied by at least 5.7 to provide an estimate of the NNS. The SUPER-Knee cohort is ideally positioned to monitor and intervene in the early development and trajectory of osteoarthritis.

Trial registration number

ACTRN12620001164987.
A narrative review exploring advances in interval training for endurance athletes
Authors: Mølmen Knut Sindre , Rønnestad Bent R.
Published: April 2024

Interval training is considered an essential training component in endurance athletes. Recently, there has been a focus on optimization of interval training characteristics to sustain a high fraction of maximal oxygen consumption (≥90% VO2max) to improve physiological adaptations and performance. Herein, we present a synopsis of the latest research exploring both acute and chronic studies in endurance athletes. Further, a decision flowchart was created for athletes and coaches to select the most appropriate interval training regime for specific individualized goals.
Reinforcing preloaded steel I-beams by considering welding heat effects and geometric imperfections
Authors: Mohammadzadeh Masoud , Bhowmick Anjan
Published: April 2024

Steel I-beams are often strengthened by welding steel cover plates to the bottom flanges of the beams. However, very limited studies have been conducted on the effect of welding heat on the behaviour of I-beams reinforced while under load. This paper presents a finite element (FE) analysis-based study on the behaviour of preloaded steel I-beams reinforced with cover plates welded to the bottom flanges of beams, considering welding procedure simulation. FE analysis is conducted to study the effects of welding heat, welding sequence, and weld length on the residual welding deformation and behaviour of steel I-beams reinforced while under load. It is observed that an appropriate welding sequence and weld length can reduce the residual lateral deformations induced from welding of a reinforcing plate to the bottom flange of the preloaded I-beam and thus control the unfavourable welding effects. Based on the analyses, a welding segment length of L/9, where L is the length of the beam, is recommended for practical applications. In addition, FE analysis shows that the direction and magnitude of the initial geometrical imperfection can change the value and direction of the residual deformation resulting from welding. Furthermore, it is observed that preloading does not have any significant effect on the behaviour and ultimate capacity of the I-beam reinforced at a preload level up to 50% of the strength of the unreinforced beam. Also, when compared with the current standards AISC 360-16 and CSA S16-9, FE analysis of reinforced steel I-beams considering welding simulation shows that the current standards significantly overpredict the moment capacities of the reinforced beams when the top flange loading effect is not considered.
Exploring the Complementary and Nonlinear Effects of Financial Development and ICT on Inclusive Growth in South Asia
Authors: Khalid Laila , Rasul Farhat , Asghar Nabila
Published: April 2024

The current research aims to examine the dynamics among financial development, renewable energy consumption, information and communication technology (ICT) and inclusive growth by focusing on the interaction of finance and ICT in South Asia from 1995 to 2019. The objectives of the study are obtained by using new and broad measures for inclusive growth and financial development. The panel co-integration tests confirm the long-run association between the selected variables. The existence of cross-sectional dependence and mixed order of integration of analyzed variables require the application of panel linear and nonlinear autoregressive distributed lag (ARDL). The findings of both techniques disclose that financial development and ICT individually are significant and vital contributors to inclusive growth in the long run. While their collaboration does not supplement inclusive growth during the same period which is an interesting and unique finding. The short-run outcomes also endorse this outcome. However, the individual impact of financial development remains insignificant while ICT enhances inclusive growth significantly in the short run. The panel nonlinear autoregressive distributed lag (NARDL) results have more explanatory powers than panel ARDL and endorse the assumptions of significant complementarity and nonlinearity between financial development-ICT and inclusive growth. Therefore, it is suggested to increase the access and efficiency of financial intermediaries to accelerate the participation of the masses in the economic growth process and its benefits. In addition, more investment in ICT infrastructure and education is needed so that the ICT sector can complement the financial sector efficiently to boost inclusive growth in South Asia.
EdgeCI: Distributed Workload Assignment and Model Partitioning for CNN Inference on Edge Clusters
Authors: Chen Yanming , Luo Tong , Fang Weiwei , Xiong Neal. N.
Published: April 2024

Deep learning technology has grown significantly in new application scenarios such as smart cities and driverless vehicles, but its deployment needs to consume a lot of resources. It is usually difficult to execute inference task solely on resource-constrained Intelligent Internet-of-Things (IoT) devices to meet strictly service delay requirements. CNN-based inference task is usually offloaded to the edge server or cloud. However, it may lead to unstable performance and privacy leaks. To address the above challenges, this article aims to design a low latency distributed inference framework, EdgeCI, which assigns inference tasks to locally idle, connected, and resource-constrained IoT device cluster networks. EdgeCI exploits two key optimization knobs, including: (1) Auction-based Workload Assignment Scheme (AWAS), which achieves the workload balance by assigning each workload partition to the more matching IoT device; (2) Fused-Layer parallelization strategy based on non-recursive Dynamic Programming (DPFL), which is aimed at further minimizing the inference time. We have implemented EdgeCI based on PyTorch and evaluated its performance with VGG-16 and ResNet-34 image recognition models. The experimental results prove that our proposed AWAS and DPFL outperform the typical state-of-the-art solutions. When they are well combined, EdgeCI can improve inference speed by 34.72% to 43.52%. EdgeCI outperforms the state-of-the art approaches on our edge cluster.
Emerging Theranostics for Prostate Cancer and a Model of Prostate-specific Membrane Antigen Therapy
Authors: Jewell Kerry , Hofman Michael S. , Ong Jeremy S. L. , Levy Sidney
Published: April 2024

Prostate-specific membrane antigen theranostics for care of patients with advanced prostate cancer is rapidly advancing and, as the field continues to progress, strong multidisciplinary collaboration with leadership from medical imaging specialists will be necessary to ensure the utmost level of patient management and care.
Comparison of Four Diagnostic Guidelines for Hepatocellular Carcinoma Using Gadoxetic Acid–enhanced Liver MRI
Authors: Yoon Jeong Hee , Kim Young Kon , Kim Jeong Woo , Chang Won , Choi Joon-Il , Park Beom Jin , Choi Jin-Young , Kim Seung-seob , Park Hee Sun , Lee Eun Sun , Yu Jeong-Sik , Park Seong Jin , You Myung-Won , Lee Chang Hee , Lee Jeong Min
Published: April 2024

Among four hepatocellular carcinoma diagnosis guidelines and by using MRI with hepatobiliary contrast agent, Eastern guidelines offered higher sensitivity whereas Western guidelines provided higher specificity in patients with cirrhosis and in those with chronic hepatitis B.
Websites of Note - Spring 2024
Authors: Suroviec Alice
Published: April 2024

Websites of Note selected for you by Alice Suroviec
Electrochemical Separations for Sustainability
Authors: Arges Christopher G. , Xu Hui
Published: April 2024

This special issue of Interface comprises three articles that articulate the importance of electrochemical separations for sustainability. The articles emphasize electrochemical separations for industrial applications, such as gas purification (e.g., CO2 concentration, hydrogen purification, and ammonia compression), critical minerals refining, and nutrient and organic acid recovery. Electrochemical separations are a powerful tool for securing critical minerals and materials for the growing electrification of energy production and transmission while being more environmentally friendly (e.g., using renewable electrons and less solvent). For nutrient recovery, it is meaningful to capture and recycle phosphate from waste streams, as we are diminishing our phosphorus rock reserves. Plus, the energy intensive Haber-Bosch process contributes significantly to CO2 emissions. Recovering nitrate from wastewater and transforming nitrate back into ammonia can reduce the need for virgin ammonia from the Haber-Bosch process and the CO2 footprint for manufacturing fertilizers. Although water purification is an important sustainability topic in which electrochemical processes play an important role, water desalination by electrodialysis and other electrochemical platforms is not the focus of the articles in this issue due to the maturity of this technology.
Intestinal perfusion of unacylated ghrelin alleviated metabolically associated fatty liver disease in rats via a central glucagon-like peptide-1 pathway
Authors: Lv Pengfei , Li Hongzeng , Li Xiangbo , Wang Xueyuying , Yu Jiantong , Gong Yanling
Published: April 2024

Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.
The Essential Oils Compounds of Lippia multiflora Moldenke and Cymbopogon schoenanthus (L.) Spreng Repel and Affect the Survival of the Maize Pest Spodoptera frugiperda (Lepidoptera: Noctuidae) Larvae
Authors: Wangrawa Dimitri Wendgida , Waongo Antoine , Traore Fousséni , Sanou Drissa , Lahondere Chloé , Sané Abdoul Razac , Borovsky Dov , Ouédraogo Sylvain Nafita , Sanon Antoine
Published: April 2024

Plant-derived insecticides, such as essential oils, can be an effective alternative to replace synthetic chemical insecticides against Spodoptera frugiperda, which becomes increasingly resistant to synthetic products. This study aims to evaluate essential oils (EOs) effects on larval growth and development following feeding inhibition, growth regulation, and repellency of EOs of Lippia multiflora (Verbenaceae), Cymbopogon schoenanthus (Poaceae), and their combination. Topical application of EOs was used on S. frugiperda larvae for larvicidal effect or treating filter paper with the EOs to find repellency. The effect of EOs on food intake and larval growth was also evaluated. Several types of compounds have been identified in the EOs, mainly monoterpenes with the appearance of new compounds in the 1 : 1 combination. Bioassay results show that individuals and combinations of EOs significantly influenced S. frugiperda larval development. L. multiflora caused 100% mortality of L2 larvae within 24 hours at 3%. The Lm + Cs (1 : 1) EOs combination was the most effective with LC50 and LC90 of 1.02% and 1.92%, respectively. Lm + Cs (1/4 : 3/4) EOs caused the highest inhibition of food consumption, 0.0160 g consumed after food was treated with 2.2% concentration compared to food consumption of 0.0602 g for the control group at 24 hours. Lower food consumption caused the inhibition of larval growth and weight loss of 0.0005 g/day at the 2.2% EOs concentration. The highest repellency effect of the EOs was found in EOs of L. multiflora, exhibiting a repulsion of 83.33% of the larvae after 3 hours of exposure. This diversity in the biological actions of the EOs tested on S. frugiperda represents valuable options for contributing to integrated pest management and an alternative to synthetic chemical insecticides.
Prevalence and Risk Factors for Newborn Anemia in Southwestern Uganda: A Cross-Sectional Study
Authors: Ngonzi Joseph , Tibaijuka Leevan , Mwanje Kintu Timothy , Kihumuro Raymond Bernard , Ahabwe Onesmus , Byamukama Onesmus , Salongo Wasswa , Adong Julian , Boatin Adeline A. , Bebell Lisa M.
Published: April 2024

Introduction. The global prevalence of maternal anemia is about 42%, and in sub-Saharan Africa, the prevalence of newborn anemia ranges from 25% to 30%. Anemia in newborn babies may cause complications such as delayed brain maturation and arrested growth. However, there is limited data on the prevalence of newborn anemia and its risk factors in people living in resource-limited settings. Objectives. We determined the prevalence and risk factors for newborn anemia and its correlation with maternal anemia in southwestern Uganda. Methods. This was a cross sectional study of 352 pregnant women presenting to the Mbarara Regional Referral Hospital for delivery. We collected maternal blood in labor and umbilical cord blood from the placental vein. We measured hemoglobin using a point-of-care Hemocue machine. We used summary statistics to characterize the study participants and compared demographic characteristics and outcomes using chi-square, t-test, and Wilcoxon rank sum analyses. We defined newborn anemia as umbilical cord hemoglobin <13 g/dl and measured the relationship between maternal and umbilical cord hemoglobin using linear regression analysis. Results. The prevalence of newborn anemia was 17%. Maternal parity was significantly higher for anemic than nonanemic newborns (3 versus 2, P=0.01). The mean age in years (SD) was significantly lower for participants with umbilical cord hemoglobin <13 g/dl than those ≥13 g/dl (26 years [5.6] versus 28 [6.3], P=0.01). In multivariable linear regression analysis, a 1-point decrease in maternal hemoglobin was associated with a 0.14-point decrease in umbilical cord hemoglobin (P=0.02). Each one-unit increase in parity was associated with a 0.25-point decrease in umbilical cord hemoglobin (P=0.01). Cesarean delivery was associated with a 0.46-point lower umbilical cord hemoglobin level compared with vaginal delivery (P=0.03). Conclusions. We found a significant association between maternal and newborn hemoglobin, underscoring the importance of preventing and correcting maternal anemia in pregnancy. Furthermore, maternal anemia should be considered a risk factor for neonatal anemia.
The VEGF-Hypoxia Signature Is Upregulated in Basal-like Breast Tumors from Women of African Ancestry and Associated with Poor Outcomes in Breast Cancer
Authors: Han Yoo Jane , Liu Siyao , Hardeman Ashley , Rajagopal Padma Sheila , Mueller Jeffrey , Khramtsova Galina , Sanni Ayodele , Ajani Mustapha , Clayton Wendy , Hurley Ian W. , Yoshimatsu Toshio F. , Zheng Yonglan , Parker Joel , Perou Charles M. , Olopade Olufunmilayo I.
Published: April 2024

Purpose:

Black women experience the highest breast cancer mortality rate compared with women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry.

Experimental Design:

We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n = 182) and the University of Chicago (Chicago, IL; n = 161). We also analyzed RNA sequencing data from Nigeria (n = 84) and The Cancer Genome Atlas (TCGA) datasets (n = 863). Patient prognosis was analyzed using multiple datasets.

Results:

The VEGF-hypoxia signature was highest in the basal-like subtype compared with other subtypes, with greater expression in Black women compared with White women. In TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared with non-necrosis tumors (P < 0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation, and necrosis. T-cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in TCGA dataset. Finally, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (P < 0.0001) and SCAN-B datasets (P = 0.002).

Conclusions:

These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.
Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine
Authors: Mouillet-Richard Sophie , Cazelles Antoine , Sroussi Marine , Gallois Claire , Taieb Julien , Laurent-Puig Pierre
Published: April 2024

Over the past decade, our understanding of the diversity of colorectal cancer has expanded significantly, raising hopes of tailoring treatments more precisely for individual patients. A key achievement in this direction was the establishment of the consensus molecular classification, particularly identifying the challenging consensus molecular subtype (CMS) CMS4 associated with poor prognosis. Because of its aggressive nature, extensive research is dedicated to the CMS4 subgroup. Recent years have unveiled molecular and microenvironmental features at the tissue level specific to CMS4 colorectal cancer. This has paved the way for mechanistic studies and the development of preclinical models. Simultaneously, efforts have been made to easily identify patients with CMS4 colorectal cancer. Reassessing clinical trial results through the CMS classification lens has improved our understanding of the therapeutic challenges linked to this subtype. Exploration of the biology of CMS4 colorectal cancer is yielding potential biomarkers and novel treatment approaches. This overview aims to provide insights into the clinico-biological characteristics of the CMS4 subgroup, the molecular pathways driving this subtype, and available diagnostic options. We also emphasize the therapeutic challenges associated with this subtype, offering potential explanations. Finally, we summarize the current tailored treatments for CMS4 colorectal cancer emerging from fundamental and preclinical studies.
An Integrated Cancer Prevention Strategy: the Viewpoint of the Leon Berard Comprehensive Cancer Center Lyon, France
Authors: Fervers Beatrice , Pérol Olivia , Lasset Christine , Moumjid Nora , Vidican Pauline , Saintigny Pierre , Tardy Juliette , Biaudet Julien , Bonadona Valérie , Triviaux Dominique , Marijnen Philippe , Mongondry Rodolf , Cattey-Javouhey Anne , Buono Romain , Bertrand Amandine , Marec-Bérard Perrine , Rousset-Jablonski Christine , Pilleul Frank , Christophe Veronique , Girodet Magali , Praud Delphine , Solodky Marie-Laure , Crochet Hugo , Achache Abdel , Michallet Mauricette , Galvez Christelle , Miermont Anne , Sebileau Damien , Zrounba Philippe , Beaupère Sophie , Philip Thierry , Blay Jean-Yves
Published: April 2024

This article describes some of the key prevention services in the Leon Berard Comprehensive Cancer Center (CLB) Lyon, France, which are based on clinical prevention services, outreach activities, and collaboration with professional and territorial health communities. In addition, research is embedded at all stages of the prevention continuum, from understanding cancer causes through to the implementation of prevention interventions during and after cancer. Health promotion activities in the community and dedicated outpatient primary cancer prevention services for individuals at increased risk have been implemented. The CLB's experience illustrates how prevention can be integrated into the comprehensive mission of cancer centers, and how in turn, the cancer centers may contribute to bridging the current fragmentation between cancer care and the different components of primary, secondary, and tertiary prevention. With increasing cancer incidence, the shift toward integrated prevention-centered cancer care is not only key for improving population health, but this may also provide a response to the shortage of hospital staff and overcrowding in cancer services, as well as offer opportunities to reduce carbon emissions from cancer care.
Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors
Authors: Pecci Federica , Nakazawa Seshiru , Ricciuti Biagio , Harada Guilherme , Lee Jessica K. , Alessi Joao V. , Barrichello Adriana , Vaz Victor R. , Lamberti Giuseppe , Di Federico Alessandro , Gandhi Malini M. , Gazgalis Dimitris , Feng William W. , Jiang Jie , Baldacci Simon , Locquet Marie-Anaïs , Gottlieb Felix H. , Chen Monica F. , Lee Elinton , Haradon Danielle , Smokovich Anna , Voligny Emma , Nguyen Tom , Goel Vikas K. , Zimmerman Zachary , Atwal Sumandeep , Wang Xinan , Bahcall Magda , Heist Rebecca S. , Iqbal Sumaiya , Gandhi Nishant , Elliott Andrew , Vanderwalde Ari M. , Ma Patrick C. , Halmos Balazs , Liu Stephen V. , Che Jianwei , Schrock Alexa B. , Drilon Alexander , Jänne Pasi A. , Awad Mark M.
Published: April 2024

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
CD8-Targeted IL2 Unleashes Tumor-Specific Immunity in Human Cancer Tissue by Reviving the Dysfunctional T-cell Pool
Authors: Kaptein Paulien , Slingerland Nadine , Metoikidou Christina , Prinz Felix , Brokamp Simone , Machuca-Ostos Mercedes , de Roo Guido , Schumacher Ton N.M. , Yeung Yik A. , Moynihan Kelly D. , Djuretic Ivana M. , Thommen Daniela S.
Published: April 2024

Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune-checkpoint blockade can restore antitumor T-cell function in some patients; however, most do not respond to this therapy, often despite T-cell infiltration in their tumors. We here explored a CD8-targeted IL2 fusion molecule (CD8–IL2) to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments. Treatment with CD8–IL2 broadly armed intratumoral CD8+ T cells with enhanced effector capacity, thereby specifically enabling reinvigoration of the dysfunctional T-cell pool to elicit potent immune activity. Notably, the revival of dysfunctional T cells to mediate effector activity by CD8–IL2 depended on simultaneous antigen recognition and was quantitatively and qualitatively superior to that achieved by PD-1 blockade. Finally, CD8–IL2 was able to functionally reinvigorate T cells in tumors resistant to anti–PD-1, underscoring its potential as a novel treatment strategy for patients with cancer.

Significance: Reinvigorating T cells is crucial for response to checkpoint blockade therapy. However, emerging evidence suggests that the PD-1/PD-L1 axis is not the sole impediment for activating T cells within tumors. Selectively targeting cytokines toward specific T-cell subsets might overcome these barriers and stimulate T cells within resistant tumors.

See related article by Moynihan et al., p. 1206 (32).
Lifileucel, an Autologous Tumor-Infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non–Small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors
Authors: Schoenfeld Adam J. , Lee Sylvia M. , Doger de Spéville Bernard , Gettinger Scott N. , Häfliger Simon , Sukari Ammar , Papa Sophie , Rodríguez-Moreno Juan F. , Graf Finckenstein Friedrich , Fiaz Rana , Catlett Melissa , Chen Guang , Qi Rongsu , Masteller Emma L. , Gontcharova Viktoria , He Kai
Published: April 2024

In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non–small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1–6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1–negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1−negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy.

Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non–small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy.

See related commentary by Lotze et al., p. 1366
Phosphocreatine Promotes Epigenetic Reprogramming to Facilitate Glioblastoma Growth Through Stabilizing BRD2
Authors: Chen Lishu , Qi Qinghui , Jiang Xiaoqing , Wu Jin , Li Yuanyuan , Liu Zhaodan , Cai Yan , Ran Haowen , Zhang Songyang , Zhang Cheng , Wu Huiran , Cao Shuailiang , Mi Lanjuan , Xiao Dake , Huang Haohao , Jiang Shuai , Wu Jiaqi , Li Bohan , Xie Jiong , Qi Ji , Li Fangye , Liang Panpan , Han Qiuying , Wu Min , Zhou Wenchao , Wang Chenhui , Zhang Weina , Jiang Xin , Zhang Kun , Li Huiyan , Zhang Xuemin , Li Ailing , Zhou Tao , Man Jianghong
Published: April 2024

Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase, mediated by Zinc finger E-box binding homeobox 1. PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine (cCr) leads to BRD2 degradation and a decrease in its targets’ transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment.

Significance: Glioblastoma (GBM) exhibits an adaptable metabolism crucial for survival and therapy resistance. We demonstrate that GBM stem cells modify their epigenetics by producing phosphocreatine (PCr), which prevents bromodomain containing protein 2 (BRD2) degradation and promotes accurate chromosome segregation. Disrupting PCr biosynthesis impedes tumor growth and improves the efficacy of BRD2 inhibitors in mouse GBM models.
Cell Salvage Using the Autotransfusion Device CATSmart®: A Randomized Controlled Bicentric Trial Evaluating the Quality of Two New Flex Wash Programs
Authors: Arends Sven , Thomas Michael , Nosch Michael , Droll Thomas , Zwanziger Denise , Brenner Thorsten , Haddad Ali
Published: April 2024

Background: The use of cell salvage and autologous blood transfusion is an important and widespread method of blood conservation during surgeries with expected high blood loss. The continuous autotransfusion device CATSmart® (Fresenius Kabi, Germany) contains two new washing programs on the device called Flex wash 3 and Flex wash 5. To the best of our knowledge, there are no published clinical data regarding the performance of the two new washing programs. Methods: In total, 69 patients undergoing cardiac or orthopedic surgery were included in this randomized, controlled, bicentric trial to validate the red cell separation process and washout quality of Flex wash 3 compared to Flex wash 5. After washing, the primary quality target was to determine hematocrit value, recovery rate, albumin, and total protein elimination rate in the packed red cells (PRCs). The secondary objective was to assess the elimination of heparin by measuring the factor anti-Xa activity by a 1- and 2-stage assay in PRC after washing. Results: In the whole cohort of patients, hematocrit was 16.00% [9.15%; 21.30%] (median [Q1; Q3]) in the wound blood and 69.90% [51.10%; 80.90%] in the PRC resulting in a recovery rate of 63.92% [47.06%; 88.13%]. The albumin elimination rate was 98.77% [97.94%; 99.27%], and the total protein elimination rate was 98.85% [97.76%; 99.42%]. The heparin elimination rate was 99.95% [99.90%; 99.97%] in the 1-stage assay and 99.70% [99.41%; 99.87%] in the 2-stage assay. There was no difference between Flex wash 3 and Flex wash 5 washing procedure regarding the recovery rate 63.75% [46.64%; 78.65%] versus 67.89% [47.20%; 92.69%] (p = 0.85), albumin elimination rate 98.74% [97.67%; 99.27%] versus 98.78% [98.10%; 99.28%] (p = 0.97), protein elimination rate 98.79% [97.94%; 99.47%] versus 98.92% [97.58%; 99.42%] (p = 0.88), and anti-Xa elimination rate in the 1-stage assay 99.94% [99.79%; 99.97%] versus 99.95% [99.92%; 99.97%] (p = 0.24) and in 2-stage assay 99.66% [99.20%; 99.86%] versus 99.77% [99.47%; 99.90%] (p = 0.23). Conclusions: The two new washing procedures, Flex wash 3 and Flex wash 5, enable sufficient and comparable red cell separation and washout quality of albumin, total protein, as well as heparin.