bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA005: Therapeutic vulnerabilities of cohesin-mutant myeloid malignancies
Authors: Tothova Zuzana
Published: June 2024

Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in myeloid malignancies, including 15-20% of myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. I will discuss our recent findings identifying cohesin mutations as biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and describe the mechanism by which drug-induced alterations in splicing of DNA repair genes, such as BRCA1 and BRCA2, underlie this sensitivity. We have demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to PARP inhibitors and a panel of chemotherapeutic agents in vitro and in vivo, using AML cell lines and patient-derived xenograft models. Furthermore, we identified RAD51 foci formation as a predictive biomarker of sensitivity to SF3B1 splicing modulation alone or followed by sequential treatment with PARP inhibition and chemotherapy, and have identified additional non-cohesin mutant subtypes of MDS/AML and ovarian and breast cancer which are sensitive to this therapeutic approach. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML and we propose this as broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.

Citation Format: Zuzana Tothova. Therapeutic vulnerabilities of cohesin-mutant myeloid malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA005.
Abstract PR005: CX-5461 sensitizes DNA damage repair-proficient castrate-resistant prostate cancer to PARP inhibition
Authors: Lawrence Mitchell G. , Porter Laura H. , Choo Nicholas , Sanij Elaine , Taylor Renea , Pearson Richard , Simpson Kaylene J. , Hannan Ross D. , Sandhu Shahneen , Furic Luc
Published: June 2024

Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition. We have recently initiated a clinical trial combining CX-5461 with talazoparib in mCRPC patients (REPAIR trial, NCT05425862) to explore this combination in both HR proficient and deficient settings.

Citation Format: Mitchell G. Lawrence, Laura H. Porter, Nicholas Choo, Elaine Sanij, Renea Taylor, Richard Pearson, Kaylene J. Simpson, Ross D. Hannan, Shahneen Sandhu, Luc Furic. CX-5461 sensitizes DNA damage repair-proficient castrate-resistant prostate cancer to PARP inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR005.
Abstract PR008: Targeting mechanisms of dosage compensation to selectively kill aneuploid cancer cells
Authors: Okada Hajime , Sdeor Eran , Karmon Miriam , Levanon Erez , Ben-David Uri
Published: June 2024

Aneuploidy is an abnormal chromosome composition and a general hallmark of human cancer. Aneuploidy causes detrimental cellular stresses, but cancer cells evolve to cope with these stresses. Consequently, targeting such mitigation mechanisms is a promising potential therapeutic strategy. As an abnormal dosage of gene products from altered chromosomes can cause RNA and proteotoxic stress, dosage compensation (DC) of imbalanced gene products was reported to mitigate these stresses in aneuploid cells. However, the mechanisms that regulate DC remain elusive. To address these mechanisms, we focused on the role(s) of stress granules (SGs) and RNA binding proteins (RBPs) in aneuploid cancer cells. Our recent study revealed that aneuploid cancer cells preferentially depend on RNA and protein metabolism, and need to attenuate translation in order to cope with proteotoxic stress (Ippolito & Zerbib et al. bioRxiv 2023). In yeast, it has been previously reported that Ssd1, one of the RBPs localized in P-bodies, is indispensable to tolerating aneuploidy stress. Based on these findings, we set out to explore SGs as potential regulators of gene expression in aneuploid cancer cells. As expected, we revealed that SGs emerged in cells under acute aneuploidy stress induced by chromosome mis-segregation. These results imply that SGs are formed in cells during and right after aneuploidization, potentially as a way to mediate DC and ameliorate aneuploidy-induced cellular stress. To gain further insight into RNA regulation in aneuploid cells, we analyzed the essentiality of RBPs across cancer cell lines. We found that the RNA-editing enzyme ADAR, a suppressor of SG formation, is preferentially essential in aneuploid cancer cells. Remarkably, ADAR disruption synergized with acute aneuploidy stress to induce SGs, and ADAR exhibited increased RNA editing activity following chromosome mis-segregation. Our results suggest that SGs and their suppressor ADAR might contribute to ameliorating acute aneuploidy-induced stress. We are currently investigating the target RNAs regulated by SGs and ADAR and examining their functional role(s) in DC, with the goal of uncovering potential synthetic lethalities associated with aneuploidy in cancer cells.

Citation Format: Hajime Okada, Eran Sdeor, Miriam Karmon, Erez Levanon, Uri Ben-David. Targeting mechanisms of dosage compensation to selectively kill aneuploid cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR008.
Abstract PR010: CDK12 loss promotes prostate cancer development while exposing vulnerabilities to paralog-based synthetic lethality
Authors: Tien Jean C. , Chang Yu , Zhang Yuping , Chou Jonathan , Cheng Yunhui , Wang Xiaoju , Yang Jianzhang , Mannan Rahul , Shah Palak , Wang Xiao-Ming , Todd Abbey , Eyunni Sanjana , Cheng Caleb , Cao Xuhong , Bao Yi , Neiswender James , Brough Rachel , Pettitt Stephen , Labanca Estefania , Wang Yuzhuo , Cieslik Marcin , Lord Christopher J. , Ding Ke , Chinnaiyan Arul M.
Published: June 2024

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation—akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fidetumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

Citation Format: Jean C. Tien, Yu Chang, Yuping Zhang, Jonathan Chou, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Palak Shah, Xiao-Ming Wang, Abbey Todd, Sanjana Eyunni, Caleb Cheng, Xuhong Cao, Yi Bao, James Neiswender, Rachel Brough, Stephen Pettitt, Estefania Labanca, Yuzhuo Wang, Marcin Cieslik, Christopher J. Lord, Ke Ding, Arul M. Chinnaiyan. CDK12 loss promotes prostate cancer development while exposing vulnerabilities to paralog-based synthetic lethality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR010.
Abstract PR015: Discovery of LY4050784 (FHD-909), a selective BRM (SMARCA2) ATPase inhibitor for the treatment of BRG1(SMARCA4) mutant cancers
Authors: Lee Janice Y. , Brooks Nathan , Antonakos Brandon , Perria Bryan , Langan Candace , Jones Bonita D. , Flack Robert Stephen , Li Zhifang , Terry David , Wallace Ross , Bondi Robert , Sis Gereint , Baracani Ronee , McVean Maralee , Kolakowski Gabrielle , Osimboni Dayo , Wilson Kevin
Published: June 2024

BRM (SMARCA2) and BRG1 (SMARCA4) are highly homologous ATPases that are members of the BAF (also known as the mSWI/SNF) chromatin remodeling complex. BRM and BRG1 are mutually exclusive enzymatic subunits of BAF complexes, and functional genomic screens have shown a synthetic lethal relationship between the two genes. BRG1 is frequently mutated in cancer, including in approximately 10% of non-small cell lung carcinomas. Selective inhibition of BRM is a mechanism by which BRG1-mutated cancer cell growth would be affected by losing BRM function, while normal tissues should be spared as they still express functional BRG1. Given that the ATPase domains of BRM and BRG1 are 92% identical, the identification of selective enzymatic inhibitors of BRM has been challenging. Here, we report the discovery of a novel, highly potent compound that selectively inhibits BRM over BRG1 and that also possesses excellent oral pharmacokinetics. LY4050784 (aka FHD-909) inhibits BRM in cell-based transcriptional and proliferation assays and is greater than 30-fold selective over BRG1. It is also selective against other helicases and does not show any significant activity in off-target screening panels. Dosing of mice carrying BRG1-mutant xenografts causes target gene modulation that is correlated with compound exposure. Treatment of A549 and RERF-LC-AI xenografts with LY4050784 led to tumor growth inhibition of 87% and 96%, respectively, at well-tolerated doses, and significant tumor growth inhibition, including regression, was also achieved in BRG1-mutant models NCI-2126 and NCI-1793. The results suggest that our compound has first-in-class potential as a potent and selective BRM ATPase inhibitor for the treatment of BRG1-mutated cancers, and we are planning to file an IND in Q2 of 2024.

Citation Format: Janice Y. Lee, Nathan Brooks, Brandon Antonakos, Bryan Perria, Candace Langan, Bonita D. Jones, Robert Stephen Flack, Zhifang Li, David Terry, Ross Wallace, Robert Bondi, Gereint Sis, Ronee Baracani, Maralee McVean, Gabrielle Kolakowski, Dayo Osimboni, Kevin Wilson. Discovery of LY4050784 (FHD-909), a selective BRM (SMARCA2) ATPase inhibitor for the treatment of BRG1(SMARCA4) mutant cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR015.
Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma
Authors: Lai Thomas J. , Sun Lu , Li Kevin , Prins Terry J. , Treger Janet , Li Tie , Sun Matthew Z. , Nathanson David A. , Liau Linda M. , Lai Albert , Prins Robert M. , Everson Richard G.
Published: June 2024

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor–engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma.

Significance:

This study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting.
Pregnancy in Patients with Inflammatory Bowel Disease: A Narrative Review
Authors: Hecker Martin , Heihoff-Klose Anne , Mehdorn Matthias
Published: June 2024

Background: The incidence of inflammatory bowel diseases (IBDs) peaks in the fertile age of both women and men. There is a significant lack of knowledge regarding disease-specific aspects of guiding IBD patients through conception, pregnancy, and delivery in clinical routine. Summary: Patients with IBD often remain voluntarily childless, primarily due to a lack of knowledge. Fertility is generally unaffected in IBD patients, except in those with high disease activity or who have undergone specific abdominal surgeries that may lead to changes in the abdominal cavity, such as inflammatory or postoperative adhesions. Immunosuppressive and immunomodulatory medications are generally considered safe during pregnancy and should be continued to reduce the likelihood of relapses. If flares occur, close monitoring of the mother and the fetus is mandatory, and therapeutic options (conservative, interventional, surgical) have to be weighed thoroughly. Despite advances in treatment, IBD patients remain at increased risk of preterm labor, small-for-gestational-age newborns and are at risk of C-sections, although the current literature suggests vaginal delivery is possible for most patients. C-sections are recommended in patients with active perianal disease. Key Messages: Patients with IBD wishing to conceive should receive comprehensive preconception counseling about pregnancy-specific aspects of IBD management from an interdisciplinary team of specialists, including IBD gastroenterologists, obstetricians, and colorectal surgeons.
Multiple focal pulvinar projection fields in the macaque cortex
Authors: Froesel Mathilda , Clavagnier Simon , Goudard Quentin , Zhu Qi , Vanduffel Wim , Hamed Suliann Ben
Published: June 2024

The pulvinar, the largest nucleus of the thalamus, is functionally heterogeneous and involved in multiple cognitive functions. It has been proposed to act as a functional hub of cortical processes due to its extensive reciprocal connectivity with the cortex. However, its role in cognition is not fully understood yet. Here, we posit that an improved understanding of its functional connectivity with the cortex is needed to better capture the cognitive functions of this nucleus. To address this question, we characterize the pulvino-cortical functional connectivity along the ventro-dorsal, antero-posterior, and medio-lateral axes, using awake resting-state data from 10 adult macaques. We first report two global cortical functional connectivity gradients along the antero-posterior and ventro-dorsal pulvinar gradients that match remarkably well the structural connectivity gradients described by anatomical approaches. In addition to these global gradients, multiple local cortical pulvinar projection fields can be identified at the sulci level such as in the lateral sulcus (LS), the intraparietal sulcus (IPS), the principal sulci (PS), and the anterior cingulate cortex (ACC). For most sulci, we show that functional pulvino-cortical projection fields follow the major anatomical axis of these different sulci (e.g., the ventro-dorsal axis for the LS and the antero-posterior axis for the IPS). Other sulci, such as the superior temporal sulcus, the posterior cingulate cortex, or the central sulcus, display multiple projection fields from the pulvinar. Although substantial inter-individual differences exist, the general functional connectivity patterns are remarkably consistent across hemispheres and individuals. Overall, we propose that these multiple pulvinar projection fields correspond to a fundamental principle of pulvino-cortical connectivity and that a better understanding of this connectional organization will shed light on the function of pulvino-cortical interactions and the role of the pulvinar in cognition at large.
GPT-based normative models of brain sMRI correlate with dimensional psychopathology
Authors: Mendes Sergio Leonardo , Pinaya Walter Hugo Lopez , Pan Pedro Mario , Gadelha Ary , Belangero Sintia , Jackowski Andrea Parolin , Rohde Luis Augusto , Miguel Euripedes Constantino , Sato João Ricardo
Published: June 2024

Generative Pre-trained Transformer (GPT) models have been widely used for language tasks with surprising results. Furthermore, neuroimaging studies using deep generative normative modeling show promise in detecting brain abnormalities from brain structural MRI (sMRI). Meanwhile, psychiatric disorders are typically diagnosed through clinical assessment, which is particularly challenging in children and adolescents who present early symptoms or are in the early stages of the disease. Brain biomarkers research may contribute to the complex task of disentangling typical neurodevelopment from emergent psychiatric disorders. Here, we investigate whether a GPT-based normative architecture can detect psychiatric symptoms and disorders from brain sMRI of youths. The studied datasets contain measures of dimensional psychopathology: Brazilian High-Risk Cohort Study (BHRCS, n = 737) and Adolescent Brain Cognitive Development (ABCD, n = 11,031), and scores and diagnostic of psychiatric disorders: Attention Deficit Hyperactivity Disorder (ADHD-200, n = 922) and Autism Brain Imaging Data Exchange II (ABIDE-II, n = 580). We examined the associations of all brain regions with: the Child Behavior Checklist (CBCL) symptom groups, ADHD scores, and Autism Spectrum Disorder (ASD) diagnosis. Results showed the whole-brain typicality likelihood as correlated with social problems (ABCD test set) and ASD diagnosis (ABIDE-II dataset). Analysis by brain regions linked different areas to several CBCL scales, ADHD scores, and ASD diagnostic. This is the first successful study assessing all dimensional groups of CBCL symptoms, from all brain regions, based exclusively on sMRI. The normative models based on GPT are promising to investigate the gap between the phenotypes of psychiatric conditions and their neurobiological substrates.
Anaphora and Depictives Do Not Rule Out Small Clause Approaches to Argument Structure: A Reply to Bruening 2018
Authors: Hu Yehao , Cheng Gong
Published: June 2024

Bruening (2018) uses the facts of anaphora and depictive modification to justify non-small-clause analyses of resultative constructions, caused-motion constructions, verb-particle constructions, and double object constructions: these constructions behave differently from canonical small clause constructions in terms of anaphora and depictive modification. In this reply, we argue against treating these tests as reliable diagnostics of small clauses. For one thing, we show that small clauses may have two different kinds of interpretations: they can be either semantically complete or incomplete. For another, Bruening’s (2018) arguments rely on some particular assumptions about anaphora and depictive modification that, we argue, are not without problems. If we adopt another set of reasonable assumptions, those facts of anaphora and depictive modification can be accounted for via the two kinds of interpretations for small clauses and thus do not argue in favor of non-small-clause analyses of the relevant constructions.
Subword Representations Successfully Decode Brain Responses to Morphologically Complex Written Words
Authors: Hakala Tero , Lindh-Knuutila Tiina , Hultén Annika , Lehtonen Minna , Salmelin Riitta
Published: June 2024

This study extends the idea of decoding word-evoked brain activations using a corpus-semantic vector space to multimorphemic words in the agglutinative Finnish language. The corpus-semantic models are trained on word segments, and decoding is carried out with word vectors that are composed of these segments. We tested several alternative vector-space models using different segmentations: no segmentation (whole word), linguistic morphemes, statistical morphemes, random segmentation, and character-level 1-, 2- and 3-grams, and paired them with recorded MEG responses to multimorphemic words in a visual word recognition task. For all variants, the decoding accuracy exceeded the standard word-label permutation-based significance thresholds at 350–500 ms after stimulus onset. However, the critical segment-label permutation test revealed that only those segmentations that were morphologically aware reached significance in the brain decoding task. The results suggest that both whole-word forms and morphemes are represented in the brain and show that neural decoding using corpus-semantic word representations derived from compositional subword segments is applicable also for multimorphemic word forms. This is especially relevant for languages with complex morphology, because a large proportion of word forms are rare and it can be difficult to find statistically reliable surface representations for them in any large corpus.
On the Relation between Thermohaline Anomalies and Water Mass Transformation in the Eastern Subpolar North Atlantic
Authors: Passos Leilane , Langehaug Helene R. , Årthun Marius , Straneo Fiammetta
Published: June 2024

Decadal thermohaline anomalies carried northward by the North Atlantic Current are an important source of predictability in the North Atlantic region. Here, we investigate whether these thermohaline anomalies influence surface-forced water mass transformation (SFWMT) in the eastern subpolar gyre using the reanalyses EN4.2.2 for the ocean and the ERA5 for the atmosphere. In addition, we follow the propagation of thermohaline anomalies along two paths: in the subpolar North Atlantic and the Norwegian Sea. We use observation-based datasets (HadISST, EN4.2.2, and Ishii) between 1947 and 2021 and apply complex empirical orthogonal functions. Our results show that when a warm anomaly enters the eastern subpolar gyre, more SFWMT occurs in light-density classes (27.0–27.2 kg m−3). In contrast, when a cold anomaly enters the eastern subpolar gyre, more SFWMT occurs in denser classes (27.4–27.5 kg m−3). Following the thermohaline anomalies in both paths, we find alternating warm–salty and cold–fresh subsurface anomalies, repeating throughout the 74-yr-long record with four warm–salty and cold–fresh periods after the 1950s. The cold–fresh anomaly periods happen simultaneously with the Great Salinity Anomaly events. Moreover, the propagation of thermohaline anomalies is faster in the subpolar North Atlantic (SPNA) than in the Norwegian Sea, especially for temperature anomalies. These findings might have implications for our understanding of the decadal variability of the lower limb of the Atlantic meridional overturning circulation and predictability in the North Atlantic region.

Significance Statement

Anomalously warm–salty or cold–fresh water, carried by the North Atlantic Current toward the Arctic, is a source of climate predictability. In this study, we investigate 1) how these ocean anomalies influence the transformation of water masses in the eastern subpolar gyre and 2) their subsequent propagation poleward and northwestward. The key findings reveal that anomalously warm waters entering the eastern subpolar gyre lead to increased transformation in lighter water masses, while cold anomalies affect denser water masses. These anomalies propagate more than 2 times faster toward the Greenland coast (northwestward) than toward the Arctic (poleward). Our findings contribute to enhancing the understanding of decadal predictability in the northern North Atlantic, including its influence on the Atlantic meridional overturning circulation.
The invisible cohort: Reporting of students with disability in the national assessment program for literacy and numeracy
Authors: Richardson Kathryn , Rollo Greta
Published: June 2024

The National Assessment Program for Literacy and Numeracy (NAPLAN) is intended to assess all Australian students in Years 3, 5, 7 and 9 to ensure equity and inclusion. This paper explores the extent to which equity and inclusion are achieved for students with disability through NAPLAN reporting. Document analysis of publicly accessible NAPLAN reports, technical reports, handbooks and protocols was conducted to evaluate how this cohort is represented in NAPLAN reports. This paper demonstrates the paucity of NAPLAN reporting about students with disability. It highlights opportunities for NAPLAN data from this cohort to be reported and used to inform educational decisions at all levels (teachers, schools, systems and parents) for students with disability.
Middle and High School Students with Visual Impairments Describe Their Experiences in Learning a New Braille Code for Mathematics and Science
Authors: Herzberg Tina S. , McBride C. Rett
Published: June 2024

Introduction: When the United States adopted Nemeth Code within Unified English Braille (UEB) Contexts and UEB Math/Science in 2016, students who were using braille had to learn a new code for science, technology, engineering, and mathematics (STEM). In late 2016, Bell and Silverman surveyed students about their initial experiences transitioning to a new braille code. However, to date there has not been additional research that includes students’ perspectives regarding the long-term effect of the transition to a new braille code on their ability to learn. The purpose of this study was to learn about students’ experiences in transitioning to a new braille code, whether students receive STEM braille materials in a timely manner, the technology students use in STEM, and what advice students have for teachers of students with visual impairments. Methods: In the spring of 2021, 11 middle and high school students who use braille for STEM classes participated in one of three focus groups. The data were analyzed using open-coding methods. Results: All participants had initially learned the Nemeth Braille Code for Mathematics and Science Notation and subsequently transitioned to one of the new braille codes. Students typically characterized learning a new braille code as easy. Most of the students had experienced delays in receiving braille materials, which sometimes negatively affected their ability to learn. Students reported using a variety of mainstream and assistive technologies. Discussion: Students should have consistent access to high-quality STEM materials in a timely manner in the braille code that they prefer. The students in this study articulated their preferences and were willing to advocate for themselves to overcome learning challenges in their STEM courses. Implications for Practitioners: Teachers of students with visual impairments can partner with general education STEM teachers and administrators to resolve persistent issues. Teachers can encourage students to voice their preferences and assist students in developing strategies before challenges arise.
Use of carbon dioxide fractional laser in the management of lower limb ischemia in patients with diabetes: a case report
Authors: Xing Dan-Lei , Zhu Yuan-Qiang , Sun Wei , Fang Xiao , Zhuang Zhi-Wei , Qiu Le , Chen Xu-Lin
Published: June 2024

Treatment of lower limb ischemia in patients with diabetes is challenging because of the location of the ulcers and the complexity of their pathogenesis. Carbon dioxide fractional laser (CO2FL) therapy in conjunction with tibial periosteum distraction could become a substitute for conventional methods. We herein describe a patient diagnosed with ischemic diabetic foot with a complex ulcer in the upper third of the tibia. Laser irradiation (Deep FX mode with 30 mJ of energy and 10% density) was applied to the entire region of skin below the knee after surface anesthesia, and this treatment was performed twice a week until the ulcer healed. Computed tomography angiography showed successful establishment of a blood supply to the back of the right foot after treatment. Skin grafting was successfully performed, with only a few wounds remaining on the foot 8 months after treatment. The pain score was significantly decreased at the last follow-up. No complications occurred. This case report provides guidance for the performance of CO2FL, a fast, easy, accurate treatment in patients with diabetes. CO2FL can target lower limb arterial occlusive disease accompanied by refractory ulcers, addressing the underlying vascular occlusion and dysfunction as well as promoting microcirculation and wound healing.
Hard to Soft Tissue Profile Changes in Skeletal Class III Dentofacial Deformities After Maxillary Advancement and Mandibular Setback Orthognathic Surgery
Authors: Sharma Rupesh , Verma Sanjeev , Kumar Vinay , Verma Raj Kumar , Singh Satinder Pal , Rattan Vidya
Published: June 2024

Objective

To correlate the sagittal hard tissue movement and soft tissue changes among patients with skeletal class III malocclusion following bimaxillary orthognathic surgery.

Material and Methods

Fifty-nine subjects with skeletal class III malocclusion treated consecutively with maxillary advancement and mandibular setback were assessed for skeletal and soft tissue linear changes using presurgical (T1) and post-treatment (T2) lateral cephalograms. Pearson’s correlation coefficient test was used to correlate hard and soft tissue parameters.

Results

The sagittal hard tissue movement and soft tissue changes for all the parameters assessed in maxilla and mandible showed statistically significant correlations. The ratios of changes for the maxillary protrusion [N-A (HP)] to horizontal subnasale (Sn), superior labial sulcus (Sls), and labrale superioris (Ls) were 0.574:1, 0.703:1, and 0.721:1 respectively. The ratio of horizontal labrale inferioris (Li), mentolabial fold (Mlf), and soft tissue (Pg′) to mandibular protrusion [N-B (HP)] were 0.992:1, 0.970:1, and 0.590:1 respectively and to chin protrusion [N-Pg (HP)] were 1.293:1, 1.252:1, and 1.001:1, respectively. The ratios were different for males and females in maxilla and mandible.

Conclusion

Sagittal hard tissue movement and soft tissue changes are significantly correlated. The soft tissue movement in the mandible were more proportionate compared to the maxilla. The sagittal hard tissue to soft tissues movement ratios were greater in maxilla and lesser at pogonion and mentolabial sulcus in females compared to males. The ratios obtained can be used for predicting postsurgical soft tissue changes.
Numerical study on steel flow dynamic behaviour in a round mould under the effect of a swirling flow brick design in tundish
Authors: Geng Lijin , Fu Shizheng , Xie Qinghua , Ersson Mikael , Ni Peiyuan
Published: June 2024

Swirling flow submerged entry nozzle technology is one of the important methods to optimise the continuous casting of steel. In this study, a novel swirling flow brick design in tundish was proposed to achieve a swirling flow submerged entry nozzle. Numerical simulations were carried out to investigate steel flow dynamic behaviour in a round mould under the effect of new designs. The results showed that a rotational steel flow was generated inside the submerged entry nozzle by using both two-inlet and three-inlet brick designs. Due to the rotational flow momentum, molten steel from the submerged entry nozzle outlet moved towards the mould wall. Such a flow pattern eliminated the impinging flow in mould, which was generally formed in conventional single-port submerged entry nozzle casting. When using swirling flow brick designs, the whole flow field in the submerged entry nozzle and mould exhibited a dynamic change. As the side-inlet number of bricks decreased from three-inlet to two-inlet, the velocity fluctuation range was reduced from ± 63.3% to ± 8.9%. Moreover, the swirling flow intensity in the submerged entry nozzle was decreased by about 40%. In addition, a high-pressure region above atmospheric pressure was obtained near the submerged entry nozzle wall by using new designs, which is helpful to prevent air from being sucked into the submerged entry nozzle.
Short-term Outcomes After Hip Arthroscopic Surgery in Patients Participating in Formal Physical Therapy Versus a Home Exercise Program: A Prospectively Enrolled Cohort Analysis
Authors: Hobson Taylor E. , Metz Allan K. , Bellendir Trina R. , Froerer Devin L. , Rosenthal Reece M. , Hunter Collin D.R. , Featherall Joseph , Maak Travis G. , Aoki Stephen K.
Published: June 2024

Background:

Physical therapy is frequently utilized in the postoperative care of femoroacetabular impingement syndrome (FAIS). There has been limited research into the efficacy of a structured home exercise program (HEP) compared with formal physical therapy (FPT) in this patient population.

Purpose/Hypothesis:

The purpose was to evaluate the short-term outcomes of patients utilizing FPT versus an HEP after hip arthroscopic surgery for FAIS. It was hypothesized that both groups would show similar improvements regarding outcome scores, which would improve significantly compared with their preoperative scores.

Study Design:

Cohort study; Level of evidence, 2.

Methods:

Patients undergoing hip arthroscopic surgery for FAIS at a single center between October 2020 and October 2021 were prospectively enrolled. Patients were allowed to self-select FPT or an HEP and were administered a survey preoperatively and at 1 month, 3 months, 6 months, and 12 months postoperatively. The survey included the Single Assessment Numeric Evaluation, visual analog scale for pain, 12-item International Hip Outcome Tool, Patient-Reported Outcomes Measurement Information System Physical Function, and patient satisfaction with physical therapy and overall care. Statistical analysis was conducted between the 2 groups and within groups to compare preoperative and postoperative scores.

Results:

The patients’ mean age was 32.6 ± 10.4 years, with 47.2% being female and 57.4% choosing the HEP. At 12 months postoperatively, no significant differences were reported between the FPT and HEP groups regarding the Single Assessment Numeric Evaluation score ( P = .795), visual analog scale for pain score ( P > .05), Patient-Reported Outcomes Measurement Information System Physical Function T-score ( P = .699), 12-item International Hip Outcome Tool score ( P = .582), and patient satisfaction ( P > .05). Outcome scores at 12 months postoperatively were significantly improved from the preoperative scores across all measures in both groups ( P < .001).

Conclusion:

There were no significant differences regarding patient outcomes between FPT and the HEP at 1-year follow-up after hip arthroscopic surgery for FAIS when patients selected their own treatment, with both groups demonstrating significant improvements in their outcome scores from their preoperative values. These findings suggest that a structured HEP may be a viable alternative to FPT after hip arthroscopic surgery in patients who prefer a self-directed rehabilitation program.
Presence of Auditory Pathway Abnormalities in Children With Neurofibromatosis Type 1 With Brainstem Focal Areas of Abnormal Signal Intensity: Diffusion Tensor Imaging Features
Authors: Cesme Dilek Hacer , Atasoy Bahar , Alkan Gokberk , Peker Abdusselim Adil , Yilmaz Temel Fatih , Yurtsever Ismail , Iscan Akin , Alkan Alpay
Published: June 2024

Background: To investigate whether there is a difference in mean diffusivity (MD) and fractional anisotropy (FA) values in the auditory pathways of neurofibromatosis type 1 patients with and without focal areas of abnormal signal intensity (FASI) compared to healthy controls by using diffusion tensor imaging (DTI). Methods: Patients were classified as group 1 with focal areas of abnormal signal intensity in the brainstem, group 2 without focal areas of abnormal signal intensity, and healthy control group 3 according to the MRI findings. Mean diffusivity and fractional anisotropy values of lateral lemniscus, inferior colliculus, corpus geniculatum mediale, Heschl gyrus, and brainstem were compared between groups. The correlation between mean diffusivity and fractional anisotropy values of auditory pathways and age was investigated. Results: There was a significant difference between group 1 and group 2 in terms of mean diffusivity and fractional anisotropy values at lateral lemniscus, inferior colliculus, corpus geniculatum mediale, and Heschl gyrus. Increased mean diffusivity and decreased fractional anisotropy values at brainstem were found in group 1. There was a significant difference between group 1 and group 3 in terms of mean diffusivity values at all auditory pathways. Fractional anisotropy values obtained from lateral lemniscus, inferior colliculus, and Heschl gyrus decreased in group 1 compared with group 3. There was a negative correlation between mean diffusivity values and positive correlation between fractional anisotropy values at lateral lemniscus, inferior colliculus, Heschl gyrus, and age. Conclusions: Our diffusion tensor imaging findings show that the neuronal integrity of the auditory pathways is affected in neurofibromatosis type 1 patients with brainstem focal areas of abnormal signal intensity. We think that the disappearance of brainstem focal areas of abnormal signal intensity associated with myelin repair and the regression of diffusion tensor imaging changes in the auditory pathways occur simultaneously with advancing age in patients with neurofibromatosis type 1.
Conceptualizing the Commercialization of Human Milk: A Concept Analysis
Authors: Rusi Heather Christine , Grummer-Strawn Laurence , Perrin Maryanne Tigchelaar , Risling Tracie , Brockway Meredith Lee
Published: June 2024

Background:

Donor human milk is recommended when infants are unable to be fed their mother’s own milk or require supplementation. For-profit companies use technologies to create human milk products for infants in the neonatal intensive care setting without consistent guidelines and regulatory frameworks in place. This commercialization of human milk is inadequately conceptualized and ill-defined.

Research Aims:

The aim of this study is to conceptualize and define the commercialization of human milk and discuss the need for policy guidelines and regulations.

Method:

Using a concept analysis framework, we reviewed the literature on the commercialization of human milk, analyzed the antecedents and potential consequences of the industry, and developed a conceptual definition. The literature review resulted in 13 relevant articles.

Results:

There has been a surge in the development and availability of human milk products for vulnerable infants developed by for-profit companies. Commercialized human milk can be defined as the packaging and sale of human milk and human milk components for financial gain. Factors contributing to the commercialization of human milk include an increased demand for human milk, and consequences include potential undermining of breastfeeding. The lack of guidelines and regulations raises concerns of equity, ethics, and safety.

Conclusion:

The industry is rapidly growing, resulting in an urgent need for consistent guidelines and regulatory frameworks. If left unaddressed, there could be potential risks for donor milk banking, the future of breastfeeding, and infant and maternal health.
The question of an alleged resurrection in Jubilees 23:29–31
Authors: Granger Cook John
Published: June 2024

The scholarly community has generally concluded that Jub. 23:29–31 does not envision a resurrection of the dead. There are those who doubt the consensus, however. The question has implications for the debate over the existence of a so-called spiritual (non-bodily) resurrection in Second Temple Judaism. There is a fundamental distinction in the text between the Lord’s servants (ʾ agbertihu) who have long lives on the earth and the righteous ( s.ādeqān) whose bones rest in the earth while their spirits observe the servants. Consequently, any attempt to isolate a spiritual resurrection in Jub. 23:29–31 fails.
Kings from the Sun: Usages of an Eastern title in the Sibylline Oracles and related material
Authors: Dobroruka Vicente
Published: June 2024

The title “King from the Sun”—in the sense of a deliverance royal figure that will come from the Sun—appears repeatedly within apocalyptic literature throughout varied historic periods, albeit in slightly different depictions. We shall consider for this analysis how coming “from the Sun” and “from the East” are not synonymous and how the personalities, so to speak, of these anointed kings in the sources differ from one another. The present article examines and compares the usage and significance of the title in the Sibylline Oracles (Sib. Or. 3.652-656 and Sib. Or. 13.147-171) and in other oracular texts from the Hellenistic and the Roman periods (the Oracle of the Potter, which is Egyptian and Apoc. El. (C) 2.44-46, which is not a Sib. Or. passage). This parallel is drawn not only due to the fact that we are dealing with different primary materials, but also because in each case a different referent is intended—the “King from the Sun” is a different savior in each of the texts examined.
Pedernales-5: An enclave for flamingo (Phoenicopteridae) exploitation during the Early Holocene in the Chilean southern Puna (26°S-69°W)
Authors: Mendoza Patricio López , Loyola Rodrigo , Carrasco Carlos , Solís Constanza Roa , Varas Daniel , Santana-Sagredo Francisca , Méndez Víctor , Bravo Gabriela , Latorre Elvira , Sáez Alina , Orrego Vanessa , Sperling Ariel
Published: June 2024

We present the results of an interdisciplinary study conducted at the Pedernales-5 site, situated in the Salar de Pedernales basin (26°S; 3356 masl), dated from 10,510−10,749 to 11,201−11,612 cal. BP. Unlike other Late Pleistocene and Holocene sites in the Andean Puna, where vicuñas ( Vicugna vicugna) were the primary prey, at Pedernales-5, the zooarcheological assemblage consists almost exclusively of flamingo (Phoenicopteridae) and bird remains. Through the analysis of lithic and bone artifacts, archeobotanical remains, pigment composition, and paleoenvironmental data, we propose that the emphasis on flamingo exploitation cannot be solely explained by alimentary consumption but also served cultural and symbolic purposes related to the acquisition of feathers, hides, and bones. The unique archeological context of Pedernales-5 offers a distinctive perspective on human dynamics in the Andean highlands during the Early Holocene.
Insights Into the Impacts of Guerrilla Violence in Shaping War-Time Relationships in Rural Zimbabwe, 1966–1979
Authors: Mutanda Darlington
Published: June 2024

Using Zaka, a district located in Masvingo province, this study scrutinises the nature and dynamics of Zimbabwe's liberation war in the countryside. It focuses on the memories of the liberation war in Zaka to demonstrate how guerrilla violence defined guerrilla–civilian relations in rural Zimbabwe. The study shows that the liberation war in the countryside was a struggle for power, domination and influence right from the peasants, chimbwidos and mujibhas (young female and male guerrilla assistants respectively) to the lowest-ranked guerrilla up to the top general.
Retaining Healing Hands: A Transnational Study on Job Retention Interventions for the Healthcare Workforce
Authors: Boone Anke , Lavreysen Olivia , De Vries Neeltje , De Winter Peter , Mazzucco Walter , Matranga Domenica , Maniscalco Laura , Miceli Silvana , Savatteri Alessandra , Kowalska Małgorzata , Szemik Szymon , Baranski Kamil , Godderis Lode
Published: June 2024

Healthcare organizations worldwide face challenges in retaining their healthcare workforce, with individual and organizational factors influencing their intentions to leave. This study conducted eight online co-creation workshops and four Delphi sessions to gain qualitative and in-depth insights into job retention interventions, involving healthcare workers, hospital managers, and policymakers. A thematic analysis was conducted, resulting in multiple interventions that were clustered in four pre-defined themes: professional and personal support, education, financial incentives, and regulatory measures. Professional and personal support interventions included regular interprofessional team meetings, leadership training programs, self-scheduling and sabbaticals, support for administrative and non-clinical work, and the provision of psychological counselling. Educational interventions encompassed facilitating development opportunities, periodic evaluations, onboarding, mentorship programs, and peer support groups. Financial incentives included the provision of competitive salaries, adequate infrastructure, extra benefits, transport possibilities, and permanent employment contracts. Regulatory measures addressed the need for complementary legislation across various levels, fixed healthcare worker-to-patient ratio, and instruments to monitor workload. To optimize retention strategies, healthcare organizations should tailor these interventions to address the unique factors influencing their workforce’s intentions to leave within their specific context. The study concludes that combining personal and professional support, educational opportunities, financial incentives, and regulatory measures is necessary because there is no one-size-fits-all solution.