bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PD12-07: PD12-07 The effect of BMI on the pathological response after neoadjuvant systemic therapy in breast cancer patients: a nationwide retrospective study
Authors: Jansen Britt , Gielen Anke , Agteroff Mariette , van Maaren Marissa , Beijer Sandra , Moossdorff Martine , Smidt Marjolein , Postma Emily
Published: March 2023

Background: Neoadjuvant systemic therapy is increasingly applied in breast cancer patients to improve surgical and oncological outcomes. There is only limited data from clinical practice on the relevance of body mass index (BMI) on the pathologic complete response (pCR) rate following neoadjuvant systemic treatment (NST). We aimed to retrospectively analyze the impact of BMI on pCR after NST for Dutch breast cancer patients.

Methods: Patients diagnosed with invasive breast cancer between 2019 and 2021 who were treated with NST followed by a surgical procedure, were selected from the Netherlands Cancer Registry (NCR). Patients were divided into three groups based on BMI: patients with underweight/normal weight (BMI< 25 kg/m2), patients with overweight (BMI 25-29.9 kg/m2) and patients with obesity (BMI>30 kg/m2). Patients with unknown BMI, ER/PR/HER2 or pCR status were excluded for analysis. The primary outcome was pCR after NST. The association between BMI and pCR was estimated using logistic regression models with the expression of odds ratios (ORs).

Results: After applying in- and exclusion criteria, 4430 patients were included for analysis, statified into four molecular breast cancer subtypes; HR+/HER2- (n=2256), HR+/HER2- (n=722), HR-/HER2+ (n=405) and HR-/HER2- (n=1047). The predictors age, differentiation grade, histological type, clinical tumor (cT) and nodal (cN) stage and molecular breast cancer subtype were found siginificant for achieving pCR after NST. Multivariabele regression analysis identified differentiation grade, cT and cN stage and molecular subtype as independent predictors for pCR after NST. There was no association between pCR and (continuous or categorical) BMI. Above mentioned analyses performed by stratification according to molecular breast cancer subtype, also showed no statistically meaningful association between BMI and pCR.

Conclusion: In this nationwide retrospective cohort study, evaluating 3340 patients with invasive breast cancer, we found no evidence of BMI being a predictive factor for achieving pCR following NST in neither the whole cohort, nor stratified according to molecular breast cancer subtype.

Table 1. Multivariable regression analysis of the total cohort

Citation Format: Britt Jansen, Anke Gielen, Mariette Agteroff, Marissa van Maaren, Sandra Beijer, Martine Moossdorff, Marjolein Smidt, Emily Postma. PD12-07 The effect of BMI on the pathological response after neoadjuvant systemic therapy in breast cancer patients: a nationwide retrospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-07.
Abstract PD15-03: PD15-03 Incorporation of Repeated Core Needle Biopsy and Targeted Fine Needle Aspiration to Optimize Axillary Surgery After Neoadjuvant Chemotherapy in Node-positive Breast Cancer: A Prospective Feasibility Study
Authors: Wu Siyu , Li Jianwei , Zhang Ying , Hu Na , Liu Guangyu
Published: March 2023

Background: It is of substantial importance to tailor axillary surgery after neoadjuvant chemotherapy (NAC) based on tumor biology and response to treatment. This study aimed to determine the accuracy of repeated core needle biopsy (RCNB) in breast to predict nodal response after NAC.

Methods: Eligible patients with clip insertment into pathologically-proven positive node underwent RCNB during NAC. Targeted fine needle aspiration (TFNA) of clipped lymph node (CLN) was performed in a subset of patients after NAC. All patients ultimately underwent axillary surgery. RCNB and TFNA results were compared with surgical pathology.

Results: Data from 189 eligible patients were analyzed. The overall axillary pCR was 57.1%. The false-negative rate (FNR) of RCNB across the whole cohort was 12.1% (95% CI, 5.3%–18.9%), and exploratory subgroup analysis revealed an excellent ability to predict the presence of residual nodal disease in estrogen receptor-positive breast cancer with a low FNR of 1.6% (95% CI, 0.0%–4.9%) (Table 1). Adopting a strategy where only patients with negative RCNB undergo targeted axillary dissection (TAD) would potentially reduce the FNR of TAD from 9.3% to 2.3%. Furthermore, combination of RCNB and TFNA demonstrated a FNR of 2.2% (95% CI, 0.0%–6.6%), and negative predictive value of 94.1% (95% CI, 81.6%–100.0%) (N = 87) (Table 2). The proposed algorithm based on RCNB and TFNA is helpful in optimizing axillary surgery by avoiding 25 unnecessary attempts as well as 2 false-negative cases in TAD and conferring 10 patients omission of axillary surgery.

Conclusions: Combination of RCNB and TFNA allows for an accurate assessment of nodal response after NAC. These results may facilitate reliable identification of suitable candidates for de-escalation or elimination in axillary surgery.

Table 1: Overall Cohort Diagnostic Accuracy of Repeated Core Needle Biopsy to Predict Nodal Response (N = 189) Abbreviations: ER, estrogen receptor; HER2, human epidermal factor receptor 2; NPV, negative predictive value; PPV, positive predictive value.

Table 2. Diagnostic Accuracy of Repeated Core Needle Biopsy in Breast, Targeted Fine Needle Aspiration and the Combination in Cohort 2 (N = 87) Abbreviations: NPV, negative predictive value; PPV, positive predictive value; RCNB, repeated core needle biopsy; TFNA, targeted fine needle aspiration.

Citation Format: Siyu Wu, Jianwei Li, Ying Zhang, Na Hu, Guangyu Liu. PD15-03 Incorporation of Repeated Core Needle Biopsy and Targeted Fine Needle Aspiration to Optimize Axillary Surgery After Neoadjuvant Chemotherapy in Node-positive Breast Cancer: A Prospective Feasibility Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-03.
Abstract PD2-01: Local and lymphoid immune surveillance mechanisms in “exceptional survivors” of stage 4 cancers following standard of care chemo- and targeted therapies
Authors: Kakkassery Helen , Alaguthurai Thanussuyah , Graham Rosalind , Carpenter Esme , Hossain Farhana , Keane Sean , Irshad Sheeba
Published: March 2023

Breast cancer patients with advanced metastatic disease can exhibit rapid disease progression, disease stabilisation or partial responses of varying duration. However, for reasons that are not fully elucidated, a small fraction of patients will elicit an exceptional durable response to standard anticancer treatments or survive significantly longer than patients with clinically comparable tumours. Here, we investigate the drivers of immune surveillance mechanisms across breast cancer subtypes in stage IV exceptional survivors (n=13) with matched control cohorts of stage IV typical responders (n=6), early breast cancer patients (n=5) and healthy volunteers (n=17). Peripheral blood mononuclear cells (PBMCs) from patients were stained with 8 panels providing 241 non-redundant immune parameters for flow cytometry analysis. Principle Component Analysis (PCA) showed distinct segregation of the exceptional survivors from the other control groups with an immune signature in exceptional survivors constituting of activated NK, CD8 T cells and gamma delta (gd) T cells pointing towards higher innate immunogenicity in these individuals. Specifically, although these metastatic exceptional responder patients possessed comparable NK cell frequencies, the proportion of NKG2D+CD56dimCD16+ NK cells were significantly enriched compared to the typical responders. Additionally, proportions of CD8+ central memory (CD45RA- CD27+) and effector memory (CD45RA- CD27-) gd T cells, were also seen to be significantly increased. Functional in vitro validation of these findings along with scRNA sequencing of lymph node and tumour tissue is currently underway. To our knowledge, this work is the first to explore in depth the immune signatures in the peripheral blood of exceptional survivors with metastatic breast cancer. Elucidating the immunological reasons for favourable atypical responses alongside functional tumour microenvironment analysis offers unique insights for predictive biomarker identification and discovery of axes that could be exploited therapeutically to benefit those with less favourable responses. Written informed consent was obtained from all individuals in accordance with the Declaration of Helsinki under the following research ethics committee; London-Chelsea approved study (REC ID 13/LO/1248).

Citation Format: Helen Kakkassery, Thanussuyah Alaguthurai, Rosalind Graham, Esme Carpenter, Farhana Hossain, Sean Keane, Sheeba Irshad. Local and lymphoid immune surveillance mechanisms in “exceptional survivors” of stage 4 cancers following standard of care chemo- and targeted therapies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-01.
Abstract PD4-03: PD4-03 Pelareorep primes the tumor for checkpoint inhibition therapy by activating the interferon-gamma signaling pathway and tumor inflammation signature in early breast cancer patients - results of the AWARE-1 trial
Authors: Loghmani Houra , Gavilá Joaquín , Manso Luis , Coffey Matt , Trauger Richard , Salvador Fernando , Pascual Tomás , Prat Aleix , Heineman Thomas
Published: March 2023

Background The status of the tumor microenvironment (TME) can profoundly affect the response to immune-based therapies for the treatment of cancer. Results previously reported from the AWARE-1 study in early breast cancer patients demonstrated that pelareorep (pela, an oncolytic reovirus), alone or in combination with checkpoint inhibitor (CPI) therapy, modified the inflammatory state of the TME. We also showed that many of pela’s effects on the TME were enhanced by the addition of checkpoint blockade. Here, we report the effect of treatment with pela on selected molecular markers associated with enhanced anti-tumor immunity. Methods Newly diagnosed HR+/HER2- early BC patients were enrolled into two cohorts: Cohort 1 (C1): pela + letrozole (n=10); and Cohort 2 (C2): pela + letrozole + atezolizumab (n=10). Pela was intravenously administered on days 1, 2 and 8, 9, and atezolizumab was given on day 3. For this analysis, tumor biopsies (FFPE samples) collected pre-treatment (D1) and on days 3 (D3, prior to the atezolizumab administration) were examined by GeoMx digital spatial profiling (DSP, using Nanostring’s Cancer Transcriptome Atlas [CTA]). Moreover, the expression of 770 immune-related genes was analyzed using a specific immune panel (n=20). Gene Set Enrichment Analysis (GSEA) (version 4.1.0) was used to assess pela-induced activation pathways. Results GeoMx DSP showed that pela therapy significantly activated IFN-gamma signaling and associated interferon response genes from D1 to D3 (Normalized Enrichment Score [NES] = 3.3, p-values < 0.02) in the cytokeratin-positive subset of the tumor samples. GSEA of the immune dataset (730 immune genes + 30 housekeeping genes) from the whole tissue also showed a significant upregulation of IFN-gamma signaling pathway genes (FDR < 25%, p-value< 0.001). Increases were also observed in genes reported to be associated with an enhanced tumor inflammatory signal (TIS) including PD-L1, IDO1, HLA-E and STAT1 (p-values < 0.005). Conclusions These results demonstrate that treatment with pela alters the TME to induce and enhance anti-tumor immunity. This enhancement of anti-tumor immunity may potentiate the TME for CPI therapy.

Citation Format: Houra Loghmani, Joaquín Gavilá, Luis Manso, Matt Coffey, Richard Trauger, Fernando Salvador, Tomás Pascual, Aleix Prat, Thomas Heineman. PD4-03 Pelareorep primes the tumor for checkpoint inhibition therapy by activating the interferon-gamma signaling pathway and tumor inflammation signature in early breast cancer patients - results of the AWARE-1 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD4-03.
Abstract PD6-10: PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies
Authors: Haddad Philip A. , Zaheer Usman
Published: March 2023

Background/Rationale: Male breast cancer accounts for less than 1 percent of all cancer diagnoses in men. Because it is rare, it does not lend itself to large, randomized trials. In general, the approach to the treatment of early, non-metastatic male breast cancer has largely been extrapolated from female breast cancer trials. Specifically, the data on early-stage post mastectomy radiation therapy (PMRT) is limited, and its benefits remain unclear. Objectives: We conducted this meta-analysis to determine the impact of PMRT on clinical outcomes of men with breast cancer. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of invasive non-metastatic male breast cancer (MBC), comparative studies of PMRT versus none, and studies that reported the incidence of local and distant recurrences as well as survival data in the compared arms. A meta-analysis using the Mantel-Haenszel method for calculating the weighted pooled relative risk (RR) under the fixed effects model. Subsequently, the heterogeneity statistic gets incorporated to calculate the summary RR under the random effects model. Results: Ten retrospective comparative studies with 3912 patients were included and analyzed. Eight studies reported survival data. Six and three studies reported local and distant recurrence incidence, respectively. PMRT did not have an impact on overall survival or distant recurrences. However, PMRT significantly lowered the RR of locoregional recurrences (RR=0.53, 95%CI 0.31-0.92). In addition, when survival was analyzed by TNM stage and N status, PMRT was found to have a significant reduction in RR of death in stage III (RR=0.85, 95%CI 0.75-0.97), N1 (RR=0.77, 95%CI 0.61-0.98), and N2 (RR=0.61, 95%CI 0.49-0.78) disease. Conclusions: This is the first meta-analysis to show that PMRT is associated with a lower relative risk of death in stage III MBC as well as N1 and N2 disease. It also demonstrates a significant reduction in RR of locoregional recurrences. In the absence of randomized clinical trials, it represents the most compelling data supporting the use of PMRT in this MBC patient population.

Citation Format: Philip A. Haddad, Usman Zaheer. PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-10.
Abstract WS2-1: Drug-tolerant persister cells in cancer
Authors: Brugge Joan
Published: March 2023

Despite favorable initial response to therapy, many cancer patients develop recurrent disease and succumb to it within five years of diagnosis. While there has been much progress in characterizing the pathways that contribute to stable genetic drug resistance, non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer. In my presentation, I will discuss different types of non-genetic, reversible mechanisms that confer therapy resistance, those involving immediate adaptive responses to stresses associated with therapies, and the other states associated with longer term persistence. I will include a discussion of strategies to target the vulnerabilities associated with each of these adaptive responses.

Citation Format: Joan Brugge. Drug-tolerant persister cells in cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-1.
The Influence of Overminus Lens Therapy on Control of Intermittent Exotropia: A Meta-Analysis of Randomized Clinical Trials
Authors: Song Desheng , Li Jue , Qian Jing , Lou Bin , Chen Zhijun
Published: March 2023

Background: Intermittent exotropia (IXT) is the most common type of strabismus, overminus lens (OML) therapy is frequently prescribed to treat IXT. Objectives: The purpose of this study was to compare the effectiveness of OML and observation in the treatment of IXT. Method: An exhaustive search of the literature in PubMed, Embase, Web of Science, and Cochrane Library databases was performed until July 2022. No language restrictions were used. The literature was rigorously screened according to eligibility criteria. Weighted mean differences and 95% confidence intervals (CIs) were calculated. Results: A total of 4 articles with 561 participants were included in this meta-analysis. Our pooled results showed that OML demonstrated superior outcomes compared with observation, with greater decreases in distance and near exodeviation control (MD = −1.08, 95% CI: −1.96 to −0.20, p = 0.02; MD, −0.64, 95% CI: −1.15 to −0.13, p < 0.001). Patients who received OML therapy had a greater decrease in the deviation at both distance and near (MD = −4.00, 95% CI: −7.03 to −0.98, p < 0.001; MD = −4.79, 95% CI: −6.29 to −3.30, p < 0.001). There was no statistical difference between the two groups in terms of post-treatment proximal stereopsis (MD, 0.00, 95% CI: −0.08 to 0.08, p = 1.00). Conclusions: The present meta-analysis indicated that OML therapy was effective in improving the control and decreasing exodeviation angle of IXT. However, it seemed not to be effective in improving the level of near stereopsis.
Bacterial Profile and Antibiotic Susceptibility Patterns of Urinary Tract Infection Among Children in Karbala Teaching Hospital
Authors:   University of kerbala, Al-Mousawi Masar , Hanoon Ameer ,   Department of Urology, Collage of Medicine, Kerbela University 56001, Iraq, Jasim Alaa ,   Department of Paediatric, Kerbela Health Director, Imam Al-Hassan AlMojtaba Teaching Hospital ,56001, Iraq, Alattab Alaa ,   Departmet of Microbiology, Collage of Medicine, Kerbela University, 56001, Iraq, Musafer Karar ,   Deparment of pharmacy, Al-Zahrawi University Collage, 56001, Iraq, Abdulzahraa Zahraa ,   Department of Paediatric, Kerbela Health Director, Imam Al-Hassan AlMojtaba Teaching Hospital ,56001, Iraq
Published: March 2023

Urinary tract infections (UTIs) are common diseases in pediatric age groups. The emergence of bacterial strains that exhibit resistance to specific antimicrobial agents has led to several therapeutic challenges. This study aimed to evaluate the frequency and antimicrobial susceptibility patterns of common types of bacteria isolated from urine samples of patients with urinary tract infections in Karbala Teaching Hospital for Children. The study was conducted between September 2021 and January 2022. The susceptibilities of antimicrobial agents were determined using the Kirby-Bauer disk diffusion technique. Positive cultures from 56 patients were included in the analysis. Escherichia coli and Proteus spp. were the most common organisms identified in pediatric patients suspected of a UTI (50% and 14.3%, respectively), while Raoutella ornithimolytics and Enterobacter sp. represented 7.14%. Other bacteria like Pseudomonas aeruginosa, Staphylococcus saprophyticus, Acinetobacter baumannii, Serratia spp., and Kluyvera spp. represented 3.6%. The sensitivity of E. coli isolates to imipenem, amikacin, and chloramphenicol were 92.9%, 85.7%, and 78.6%, respectively. Proteus spp. isolates solely exhibited susceptibility to amikacin and nalidixic acid. The current study concluded that E. coli was the most frequently arising underlying pathogen UTI in pediatric patients. In this clinical setting, the organisms identified exhibited high susceptibility to imipenem, amikacin, and chloramphenicol.
Applications of X-Chromosome Short Tandem Repeats for Human Identification: A Review
Authors:   Department of Chemistry, Faculty of Science, University Teknologi Malaysia, 81310 Skudai, Johor, Mahat Naji , Alwi Aedrianee ,   Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia (UTM), 81310 Johor Bahru, Johor, Malaysia., Salleh Faezah ,   Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia (UTM), 81310 Johor Bahru, Johor, Malaysia., Ishar Seri ,   Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), 43600 Bangi, Selangor, Malaysia, Kamaluddin Mohammad ,   Psychology and Human Well Being Research Centre, Faculty of Social Sciences and Humanities, Universiti Kebangsaan Malaysia (UKM), 43600 Bangi, Selangor, Malaysia., Rashid Mohd ,   Family Medicine Unit, Faculty of Medicine and Health Science, Universiti Sains Islam Malaysia (USIM), Bandar Baru Nilai 71800, Nilai, Negeri Sembilan, Malaysia
Published: March 2023

The forensic DNA profiling technique has tremendously contributed to forensic human identification, an important aspect in forensic investigations. In instances whereby comparison samples are unavailable, utilization of short tandem repeats of X chromosome (X-STRs) may prove useful to resolve complex kinship investigations involving missing persons and mass disasters. Despite such evidential values, the use of X-STRs during investigations remains scarce in many Southeast Asian countries including Malaysia, requiring concerted efforts for establishing forensic statistical support for its diverse populations (especially the admixture populations), standardizing core loci and procedure, improving the knowledge among practitioners as well as developing suitable standard operating procedure for incorporating X-STRs analysis in the overall DNA profiling framework. Hence, this review paper aims to highlight the developments, applications and population data of X-STRs, as well as its challenges and future insights for forensic casework.
The Thai species of the Polyrhachis (Myrmatopa) flavicornis Smith, 1857 species group, with description of a new species (Hymenoptera, Formicidae, Formicinae)
Authors: JAITRONG WEEYAWAT , YAMANE SEIKI , NOON-ANANT NAWEE
Published: March 2023

The Polyrhachis (Myrmatopa) flavicornis species group in Thailand is reviewed. Four species are recognized, of which one species closely related to Polyrhachis constructor Smith, 1857 is described and illustrated as new to science based on the worker caste under the name Polyrhachis longipilosa sp. nov. The queens of P. flavicornis Smith, 1857 and P. constructor, and the males of P. flavicornis and P. varicolor Viehmeyer, 1916 are described. The new species is distributed in western Thailand in the area north of the Isthmus of Kra, while P. constructor is distributed in Malaysia (West Malaysia and Sabah), Indonesia, Singapore, southern and western Thailand. Polyrhachis piliventris Smith, 1857 and Polyrhachis elii Emery, 1900 are synonymized with P. constructor. A key to the Thai species of the Polyrhachis flavicornis species group is given. The type series of P. longipilosa was collected from the canopy of a dry evergreen forest.
A new species in the genus Precis Hübner, [1819] (Lepidoptera: Nymphalidae: Nymphalinae), another surprising discovery in the Nimba Mountains, Guinea and the broader Guinea Highlands in West Africa
Authors: SÁFIÁN SZABOLCS , FLORCZYK KLAUDIA , TAKANO HITOSHI
Published: March 2023

A new species in the genus Precis (Papilionoidea, Nymphalidae, Nymphalinae), described in this paper as P. koivoguii sp. n., was discovered in the Nimba Mountains, Guinea, West Africa, and specimens were also identified from the neighbouring mountainous area in Ivory Coast in the broader Guinea Highlands. In appearance the species is similar to some wet season forms of the widely distributed P. pelarga and the Madagascan P. andremiaja, but in size and wingshape, it also resembles P. ceryne, and could have been a natural hybrid between this latter species and P. pelarga. The specific distinction from these taxa was confirmed by marked differences in male genitalia and constant phenotypic characteristics. Based on the type series, it was thought that the new species might be endemic to mid- and high-altitude habitats, particularly forest-scrub-grassland edges or wetlands in the broader Guinea Highlands but a new photographic record from western Ghana suggests a much wider distribution in suitable habitats of the Upper Guinean forest zone.
Southern Ocean Surface Temperatures and Cloud Biases in Climate Models Connected to the Representation of Glacial Deep Ocean Circulation
Authors: Sherriff-Tadano Sam , Abe-Ouchi Ayako , Yoshimori Masakazu , Ohgaito Rumi , Vadsaria Tristan , Chan Wing-Le , Hotta Haruka , Kikuchi Maki , Kodama Takanori , Oka Akira , Suzuki Kentaroh
Published: March 2023

Simulating and reproducing the past Atlantic meridional overturning circulation (AMOC) with comprehensive climate models are essential to understanding past climate changes as well as to testing the ability of the models in simulating different climates. At the Last Glacial Maximum (LGM), reconstructions show a shoaling of the AMOC compared to modern climate. However, almost all state-of-the-art climate models simulate a deeper LGM AMOC. Here, it is shown that this paleodata–model discrepancy is partly related to the climate model biases in modern sea surface temperatures (SST) over the Southern Ocean (70°–45°S). Analysis of model outputs from three phases of the Paleoclimate Model Intercomparison Project shows that models with warm Southern Ocean SST biases tend to simulate a deepening of the LGM AMOC, while the opposite is observed in models with cold SST biases. As a result, a positive correlation of 0.41 is found between SST biases and LGM AMOC depth anomalies. Using sensitivity experiments with a climate model, we show, as an example, that changes in parameters associated with the fraction of cloud thermodynamic phase in a climate model reduce the biases in the warm SST over the modern Southern Ocean. The less biased versions of the model then reproduce a colder Southern Ocean at the LGM, which increases formation of Antarctic Bottom Water and causes shoaling of the LGM AMOC, without affecting the LGM climate in other regions. The results highlight the importance of sea surface conditions and clouds over the Southern Ocean in simulating past and future global climates.

Significance Statement

To test the ability of comprehensive climate models, simulations of the Last Glacial Maximum (LGM) have been conducted. However, most models simulated a deeper Atlantic meridional overturning circulation (AMOC) in the LGM, which contradicts paleodata suggesting a shallower AMOC. Here, using multimodel analysis and sensitivity experiments with a climate model, we show that this paleodata–model discrepancy is partly related to model biases in the modern Southern Ocean. Improvements in Southern Ocean surface temperatures and clouds reproduce a colder climate over the Southern Ocean at the LGM, which causes an intense shoaling of the AMOC due to increased formation of Antarctic Bottom Water. These results demonstrate the important effect of model biases over the Southern Ocean on simulating past climates.
Pacific Meridional Mode Does Not Induce Strong Positive SST Anomalies in the Central Equatorial Pacific
Authors: Hu Ruikun , Lian Tao , Feng Jie , Chen Dake
Published: March 2023

The positive phase of the Pacific meridional mode (PMM) is closely related to the onset of El Niño. Previous studies have indicated that positive sea surface temperature anomalies (SSTAs) in the central equatorial Pacific (CEP) during the spring and summer of positive PMM years primarily originate from the northeastern tropical Pacific (NETP) via positive wind–evaporation–SST feedback. We review the evolution of PMM and find weak evidence to support such a linkage. Coupled model experiments show that the positive PMM-regressed SSTAs in the NETP only account for ∼24% of those in the CEP from winter to spring, illustrating the principle that correlation does not necessarily mean causality. The strongest positive PMM SSTAs in the NETP and CEP increase El Niño intensity by 1.07°C, whereas that in the NETP alone increase El Niño intensity by 0.69°C. When the composite SSTAs in the NETP during positive PMM years are used, however, the El Niño intensity is increased merely by 0.17°C. The change in the subsurface temperature in the equatorial Pacific is curtailed for the NETP SSTAs to trigger El Niño, while the wind–evaporation–SST feedback plays a less important role. Our results indicate that the impact of PMM on El Niño might be overestimated by ∼55%. Moreover, a comprehensive understanding about the role of the tropical North Pacific on El Niño can be obtained only when the impact from the western North Pacific is considered.
Cryo-EM structure of coagulation factor V short
Authors: Mohammed Bassem M. , Pelc Leslie A , Rau Michael J , Di Cera Enrico
Published: March 2023

Coagulation factor V (fV) is the inactive precursor of fVa, an essential component of the prothrombinase complex required for rapid activation of prothrombin in the penultimate step of the coagulation cascade. In addition, fV regulates the tissue factor pathway inhibitor α (TFPIα) and protein C pathways that inhibit the coagulation response. A recent cryogenic electron microscopy (cryo-EM) structure of fV has revealed the architecture of its A1-A2-B-A3-C1-C2 assembly but left the mechanism that keeps fV in its inactive state unresolved due to intrinsic disorder in the B domain. A splice variant of fV, fV short, carries a large deletion of the B domain that produces constitutive fVa-like activity and unmasks epitopes for binding of TFPIα. The cryo-EM structure of fV short was solved at 3.2 Å resolution and reveals the arrangement of the entire A1-A2-B-A3-C1-C2 assembly for the first time. The shorter B domain stretches across the entire width of the protein, making contacts with the A1, A2 and A3 domains but suspended over the C1 and C2 domains. In the portion distal to the splice site, several hydrophobic clusters and acidic residues provide a likely binding site for the basic C-terminal end of TFPIα. In fV, these epitopes may bind intramolecularly the basic region of the B domain. The cryo-EM structure reported in this study advances our understanding of the mechanism that keeps fV in its inactive state, provides new targets for mutagenesis and facilitates future structural analysis of fV short in complex with TFPIα, protein S and fXa.
Analysis of structural variation among inbred mouse strains
Authors: Arslan Ahmed , Fang Zhuoqing , Wang Meiyue , Tan Yalun , Cheng Zhuanfen , Chen Xinyu , Guan Yuan , J. Pisani Laura , Yoo Boyoung , Bejerano Gill , Peltz Gary
Published: March 2023

Background

‘Long read’ sequencing methods have been used to identify previously uncharacterized structural variants that cause human genetic diseases. Therefore, we investigated whether long read sequencing could facilitate genetic analysis of murine models for human diseases.

Results

The genomes of six inbred strains (BTBR T + Itpr3tf/J, 129Sv1/J, C57BL/6/J, Balb/c/J, A/J, SJL/J) were analyzed using long read sequencing. Our results revealed that (i) Structural variants are very abundant within the genome of inbred strains (4.8 per gene) and (ii) that we cannot accurately infer whether structural variants are present using conventional short read genomic sequence data, even when nearby SNP alleles are known. The advantage of having a more complete map was demonstrated by analyzing the genomic sequence of BTBR mice. Based upon this analysis, knockin mice were generated and used to characterize a BTBR-unique 8-bp deletion within Draxin that contributes to the BTBR neuroanatomic abnormalities, which resemble human autism spectrum disorder.

Conclusion

A more complete map of the pattern of genetic variation among inbred strains, which is produced by long read genomic sequencing of the genomes of additional inbred strains, could facilitate genetic discovery when murine models of human diseases are analyzed.
Construct of qualitative diagnostic biomarkers specific for glioma by pairing serum microRNAs
Authors: Li Hongdong , Ma Liyuan , Luo Fengyuan , Liu Wenkai , Li Na , Hu Tao , Zhong Haijian , Guo You , Hong Guini
Published: March 2023

Background

Serum microRNAs (miRNAs) are promising non-invasive biomarkers for diagnosing glioma. However, most reported predictive models are constructed without a large enough sample size, and quantitative expression levels of their constituent serum miRNAs are susceptible to batch effects, decreasing their clinical applicability.

Methods

We propose a general method for detecting qualitative serum predictive biomarkers using a large cohort of miRNA-profiled serum samples (n = 15,460) based on the within-sample relative expression orderings of miRNAs.

Results

Two panels of miRNA pairs (miRPairs) were developed. The first was composed of five serum miRPairs (5-miRPairs), reaching 100% diagnostic accuracy in three validation sets for distinguishing glioma and non-cancer controls (n = 436: glioma = 236, non-cancers = 200). An additional validation set without glioma samples (non-cancers = 2611) showed a predictive accuracy of 95.9%. The second panel included 32 serum miRPairs (32-miRPairs), reaching 100% diagnostic performance in training set on specifically discriminating glioma from other cancer types (sensitivity = 100%, specificity = 100%, accuracy = 100%), which was reproducible in five validation datasets (n = 3387: glioma = 236, non-glioma cancers = 3151, sensitivity> 97.9%, specificity> 99.5%, accuracy> 95.7%). In other brain diseases, the 5-miRPairs classified all non-neoplastic samples as non-cancer, including stroke (n = 165), Alzheimer’s disease (n = 973), and healthy samples (n = 1820), and all neoplastic samples as cancer, including meningioma (n = 16), and primary central nervous system lymphoma samples (n = 39). The 32-miRPairs predicted 82.2 and 92.3% of the two kinds of neoplastic samples as positive, respectively. Based on the Human miRNA tissue atlas database, the glioma-specific 32-miRPairs were significantly enriched in the spinal cord (p = 0.013) and brain (p = 0.015).

Conclusions

The identified 5-miRPairs and 32-miRPairs provide potential population screening and cancer-specific biomarkers for glioma clinical practice.
Composition, structure, and functional shifts of prokaryotic communities in response to co-composting of various nitrogenous green feedstocks
Authors: Matheri Felix , Kambura Anne Kelly , Mwangi Maina , Ongeso Nehemiah , Karanja Edward , Adamtey Noah , Mwangi Elias Kihara , Mwangi Edwin , Tanga Chrysantus , Musyoka Martha Wangu , Runo Steven
Published: March 2023

Background

Thermophilic composting is a promising method of sanitizing pathogens in manure and a source of agriculturally important thermostable enzymes and microorganisms from organic wastes. Despite the extensive studies on compost prokaryotes, shifts in microbial profiles under the influence of various green materials and composting days are still not well understood, considering the complexity of the green material sources. Here, the effect of regimens of green composting material on the diversity, abundance, and metabolic capacity of prokaryotic communities in a thermophilic compost environment was examined.

Methods

Total community 16S rRNA was recovered from triplicate compost samples of Lantana-based, Tithonia-based, Grass-based, and mixed (Lantana + Tithonia + Grass)- based at 21, 42, 63, and 84 days of composting. The 16S rRNA was sequenced using the Illumina Miseq platform. Bioinformatics analysis was done using Divisive Amplicon Denoising Algorithm version 2 (DADA2) R version 4.1 and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States version 2 (PICRUSt2) pipelines for community structure and metabolic profiles, respectively. In DADA2, prokaryotic classification was done using the Refseq-ribosomal database project (RDP) and SILVA version 138 databases.

Results

Our results showed apparent differences in prokaryotic community structure for total diversity and abundance within the four compost regimens and composting days. The study showed that the most prevalent phyla during composting included Acidobacteriota, Actinobacteriota, Bacteroidota, Chloroflexi, and Proteobacteria. Additionally, there were differences in the overall diversity of metabolic pathways but no significant differences among the various compost treatments on major metabolic pathways like carbohydrate biosynthesis, carbohydrate degradation, and nitrogen biosynthesis.

Conclusion

Various sources of green material affect the succession of compost nutrients and prokaryotic communities. The similarity of amounts of nutrients, such as total Nitrogen, at the end of the composting process, despite differences in feedstock material, indicates a significant influence of composting days on the stability of nutrients during composting.
Analysis of an Indian colorectal cancer faecal microbiome collection demonstrates universal colorectal cancer-associated patterns, but closest correlation with other Indian cohorts
Authors: Bose Mayilvahanan , Wood Henry M. , Young Caroline ,   International C. R. C. Microbiome Network (AMS/CRUK), Van Nang Pham , Van Doi Mai , Vaccaro Carlos , Piñero Tamara Alejandra , Arguero Julieta , Melendez Luis Contreras , Valladares Camilo Tapia , Quirke Philip , Seshadri Ramakrishan Ayloor
Published: March 2023

It is increasingly being recognised that changes in the gut microbiome have either a causative or associative relationship with colorectal cancer (CRC). However, most of this research has been carried out in a small number of developed countries with high CRC incidence. It is unknown if lower incidence countries such as India have similar microbial associations.

Having previously established protocols to facilitate microbiome research in regions with developing research infrastructure, we have now collected and sequenced microbial samples from a larger cohort study of 46 Indian CRC patients and 43 healthy volunteers.

When comparing to previous global collections, these samples resemble other Asian samples, with relatively high levels of Prevotella. Predicting cancer status between cohorts shows good concordance. When compared to a previous collection of Indian CRC patients, there was similar concordance, despite different sequencing technologies between cohorts.

These results show that there does seem to be a global CRC microbiome, and that some inference between studies is reasonable. However, we also demonstrate that there is definite regional variation, with more similarities between location-matched comparisons. This emphasises the importance of developing protocols and advancing infrastructure to allow as many countries as possible to contribute to microbiome studies of their own populations.
Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum – a systematic review with implications for the function of the oxytocinergic system
Authors: Buckley Sarah , Uvnäs-Moberg Kerstin , Pajalic Zada , Luegmair Karolina , Ekström-Bergström Anette , Dencker Anna , Massarotti Claudia , Kotlowska Alicja , Callaway Leonie , Morano Sandra , Olza Ibone , Magistretti Claudia Meier
Published: March 2023

Background

The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding.

Aim

To systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems.

Methods

Systematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables.

Results

Infusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2–3 times physiological levels.

Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher.

Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus.

Conclusions

Synthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2–3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress.
A harmonized analysis of five Canadian pregnancy cohort studies: exploring the characteristics and pregnancy outcomes associated with prenatal alcohol exposure
Authors: Schmidt Rose A. , Wey Tina W. , Harding Kelly D. , Fortier Isabel , Atkinson Stephanie , Tough Suzanne , Letourneau Nicole , Knight Julia A. , Fraser William D. , Bocking Alan
Published: March 2023

Background

As a teratogen, alcohol exposure during pregnancy can impact fetal development and result in adverse birth outcomes. Despite the clinical and social importance of prenatal alcohol use, limited routinely collected information or epidemiological data exists in Canada. The aim of this study was to pool data from multiple Canadian cohort studies to identify sociodemographic characteristics before and during pregnancy that were associated with alcohol consumption during pregnancy and to assess the impact of different patterns of alcohol use on birth outcomes.

Methods

We harmonized information collected (e.g., pregnant women’s alcohol intake, infants' gestational age and birth weight) from five Canadian pregnancy cohort studies to consolidate a large sample (n = 11,448). Risk factors for any alcohol use during pregnancy, including any alcohol use prior to pregnancy recognition, and binge drinking, were estimated using binomial regressions including fixed effects of pregnancy cohort membership and multiple maternal risk factors. Impacts of alcohol use during pregnancy on birth outcomes (preterm birth and low birth weight for gestational) were also estimated using binomial regression models.

Results

In analyses adjusting for multiple risk factors, women’s alcohol use during pregnancy, both any use and any binge drinking, was associated with drinking prior to pregnancy, smoking during pregnancy, and white ethnicity. Higher income level was associated with any drinking during pregnancy. Neither drinking during pregnancy nor binge drinking during pregnancy was significantly associated with preterm delivery or low birth weight for gestational age in our sample.

Conclusions

Pooling data across pregnancy cohort studies allowed us to create a large sample of Canadian women and investigate the risk factors for alcohol consumption during pregnancy. We suggest that future pregnancy and birth cohorts should always include questions related to the frequency and amount of alcohol consumed before and during pregnancy that are prospectively harmonized to support data reusability and collaborative research.
Integrated transcriptional analysis reveals macrophage heterogeneity and macrophage-tumor cell interactions in the progression of pancreatic ductal adenocarcinoma
Authors: Yang Kaidi , Yang Tongxin , Yu Jian , Li Fang , Zhao Xiang
Published: March 2023

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease harboring significant microenvironment heterogeneity, especially for the macrophages. Tumor-associated macrophages (TAMs) orchestrate PDAC malignancy, but their dynamics during disease progression remains poorly understood. There is a pressing need to identify the molecular mechanism underlying tumor-macrophage interactions and thus design novel therapeutic strategies.

Methods

Herein, we developed an insilico computational method incorporating bulk and single-cell transcriptome profiling to characterize macrophage heterogeneity. CellPhoneDB algorithm was applied to infer macrophage-tumor interaction networks, whereas pseudotime trajectory for dissecting cell evolution and dynamics.

Results

We demonstrated myeloid compartment was an interactive hub of tumor microenvironment (TME) essential for PDAC progression. Dimensionality reduction classified seven clusters within the myeloid cells wherein five subsets of macrophages were characterized by diverse cell states and functionality. Remarkably, tissue-resident macrophages and inflammatory monocyte were identified as potential sources of TAMs. Further, we uncovered several ligand-receptor pairs lining tumor cells and macrophages. Among them, HBEGF-CD44, HBEGF-EGFR, LGALS9-CD44, LGALS9-MET, and GRN-EGFR were correlated with worse overall survival. Notably, as in vitro experiments indicated, TAM-derived HBEGF promoted proliferation and invasion of the pancreatic cancer cell line.

Conclusion

Together, our work deciphered a comprehensive single-cell atlas of the macrophage compartment of PDAC and provided novel macrophage-tumor interaction features with potential value in developing targeted immunotherapies and molecular diagnostics for predicting patient outcome.