Normal Development Research Articles

Ti3C2 nanosheet-induced autophagy derails ovarian functions

BackgroundTwo-dimensional ultrathin Ti3C2 (MXene) nanosheets have gained significant attention in various biomedical applications. Although previous studies have described the accumulation and associated damage of Ti3C2 nanosheets in the testes and placenta. However, it is currently unclear whether Ti3C2 nanosheets can be translocated to the ovaries and cause ovarian damage, thereby impairing ovarian functions.ResultsWe established a mouse model with different doses (1.25, 2.5, and 5 mg/kg bw/d) of Ti3C2 nanosheets injected intravenously for three days. We demonstrated that Ti3C2 nanosheets can enter the ovaries and were internalized by granulosa cells, leading to a decrease in the number of primary, secondary and antral follicles. Furthermore, the decrease in follicles is closely associated with higher levels of FSH and LH, as well as increased level of E2 and P4, and decreased level of T in mouse ovary. In further studies, we found that exposure toTi3C2 nanosheets increased the levels of Beclin1, ATG5, and the ratio of LC3II/Ι, leading to autophagy activation. Additionally, the level of P62 increased, resulting in autophagic flux blockade. Ti3C2 nanosheets can activate autophagy through the PI3K/AKT/mTOR signaling pathway, with oxidative stress playing an important role in this process. Therefore, we chose the ovarian granulosa cell line (KGN cells) for in vitro validation of the impact of autophagy on the hormone secretion capability. The inhibition of autophagy initiation by 3-Methyladenine (3-MA) promoted smooth autophagic flow, thereby partially reduced the secretion of estradiol and progesterone by KGN cells; Whereas blocking autophagic flux by Rapamycin (RAPA) further exacerbated the secretion of estradiol and progesterone in cells.ConclusionTi3C2 nanosheet-induced increased secretion of hormones in the ovary is mediated through the activation of autophagy and impairment of autophagic flux, which disrupts normal follicular development. These results imply that autophagy dysfunction may be one of the underlying mechanisms of Ti3C2-induced damage to ovarian granulosa cells. Our findings further reveal the mechanism of female reproductive toxicity induced by Ti3C2 nanosheets.

[Retrospective analysis of diagnosis and treatment of tuberculosis in designated medical institutions in China from 2017 to 2022].

Objective: To understand the status of tuberculosis diagnosis and treatment capacity and the development and changes of tuberculosis diagnosis and treatment in provincial and municipal designated medical institutions in China from 2017 to 2022, so as to provide a basis for the formulation of relevant policies for the improvement and development of designated medical institutions for tuberculosis and the tuberculosis prevention and treatment service system, and to provide reasonable support for further strengthening the capacity of designated medical institutions for tuberculosis. Methods: This study was initiated and carried out by Beijing Chest Hospital affiliated to Capital Medical University/Clinical Center for Tuberculosis Prevention and Control of China CDC (hereinafter referred to as "Clinical Center") by means of questionnaire survey, and the investigation was carried out from March to November 2023. During this period, the clinical center distributed questionnaires to the hospital member units of "Beijing Tuberculosis Diagnosis and Treatment Technology Innovation Alliance", retrospectively collected their tuberculosis-related diagnosis and treatment data from 2017 to 2022, and used descriptive statistical methods to analyze the number of tuberculosis beds, outpatients and hospitalizations in medical institutions. The results were expressed in absolute numbers (percentages), and three-line tables, bar charts and line charts were drawn to describe the analysis results and changing trends. Results: The 54 medical institutions surveyed in this survey included 21 provincial-level designated medical institutions and 33 prefecture-level designated medical institutions. Most medical institutions have set up clinical departments, auxiliary departments and functional departments to undertake public health tasks of infectious diseases. The tuberculosis laboratory in the hospital has a comprehensive ability and has the detection technology needed for most tuberculosis diagnosis; The number of tuberculosis beds, children's tuberculosis beds and ICU beds all showed an increasing trend from 2017 to 2022. The proportion of tuberculosis beds in the hospital decreased slightly, from 39.31% in 2017 to 34.76% in 2022, showing a slight downward trend. Compared with the hospital surveyed, the number of tuberculosis outpatients in 2019 was 562 029, and the number of outpatients in 2020-2022 was 462 328, 519 630 and 424 069 respectively, which was significantly lower than that in 2019. The number of tuberculosis outpatients in medical institutions decreased significantly from 2020 to 2022. By analyzing the proportion of patients with different types of tuberculosis, the proportion of sensitive tuberculosis outpatients in 2017-2022 decreased from 84.49% in 2017 to 78.05% in 2022, showing a downward trend year by year. The proportion of patients with multidrug-resistant/ rifampin-resistant tuberculosis increased from 2.03% in 2017 to 7.18% in 2022. From 2017 to 2019, the total number of inpatients with tuberculosis showed an upward trend. Compared with 2019, the number of inpatients in 2020, 2021 and 2022 showed a downward trend, and the decline in 2020 was large (down 14.94% compared with 2019). Among the inpatients, the absolute number and proportion of patients with sensitive pulmonary tuberculosis remained relatively stable, and the number and proportion of inpatients with multidrug-resistant/rifampin-resistant pulmonary tuberculosis increased year by year. Conclusions: Most medical institutions have the capacity to carry out routine diagnosis and treatment of tuberculosis, but the public health function needs to be strengthened. The transformation of medical institutions requires proper guidance and adequate support. During 2019-2022, most medical institutions were affected by the COVID-19 epidemic, and their tuberculosis diagnosis and treatment work also changed to varying degrees. During this period, hospitals took various measures to overcome difficulties and tried their best to maintain the normal development of tuberculosis diagnosis and treatment, and the tuberculosis diagnosis and treatment work of various institutions gradually resumed in 2022.

Schizencephaly: Etiopathogenesis, Classification, Therapeutic, and Rehabilitative Approach

AbstractSchizencephaly is an uncommon anomaly in neuronal migration characterized by complete clefts that extend from the pia mater to the ependymal surface of the ventricular system. These clefts are encompassed by displaced gray matter and filled with cerebrospinal fluid. Typically, they are found most often in the frontal lobe or the area around the lateral sulcus and can occur on one or both sides. The size, location, and type of these clefts carry significant clinical and prognostic implications. Moreover, they are frequently associated with other central nervous system malformations, including the absence of the septum pellucidum, septo-optic dysplasia, optic nerve hypoplasia, pachygyria, polymicrogyria, cortical dysplasia, heterotopia, and dysplasia of the corpus callosum. Occurrence of schizencephaly is almost always sporadic but its etiopathogenesis is yet to be fully understood. Most likely environmental factors, including exposure to teratogens, viral infections, and maternal factors, operate jointly with genetic defects. To date COL4A1, EMX2, SHH, and SIX3 are the genes identified as possible pathogenetic target. It is interesting to notice that schizencephaly is commonly seen in abandoned or adopted children, as proof of causative effect of intrautero insults. Clinical presentations widely vary and symptoms include a spectrum of cognitive impairment, limb paresis/tetraparesis, and epileptic seizures either with early or late onset; anyway, none of these symptoms is ever-present and patients with schizencephaly can also have normal neurocognitive and motor development. Diagnostic gold standard for schizencephaly is magnetic resonance imaging, which allows to identify and characterize typical clefts. Treatment of schizencephaly is symptomatic and supportive and depends on the severity of morbidity resulting from the malformation. Therapy includes antiepileptic drugs, psychomotor rehabilitation, and in selected cases surgical approach.

The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges.

In recent years, the potential of stem cells (SCs) to differentiate into various types of cells, including β-cells, has led to a significant boost in development. The efficiency of this differentiation process and the functionality of the cells post-transplantation are crucial factors for the success of stem cell therapy in diabetes. Herein, this article reviews the current advances and challenges faced by stem cell differentiation into functional β-cells for diabetes treatment. In vitro, researchers have sought to enhance the differentiation efficiency of functional β-cells by mimicking the normal pancreatic development process, using gene manipulation, pharmacological and culture conditions stimulation, three-dimensional (3D) and organoid culture, or sorting for functional β-cells based on mature islet cell markers. Furthermore, in vivo studies have also looked at suitable transplantation sites, the enhancement of the transplantation microenvironment, immune modulation, and vascular function reconstruction to improve the survival rate of functional β-cells, thereby enhancing the treatment of diabetes. Despite these advancements, developing stem cells to produce functional β-cells for efficacious diabetes treatment is a continuous research endeavor requiring significant multidisciplinary collaboration, for the stem-cell-derived beta cells to evolve into an effective cellular therapy.

Single-Cell Insights into Mouse Testicular Toxicity under Peripubertal Exposure to Di(2-ethylhexyl) phthalate.

Male fertility depends on normal pubertal development. Di(2-ethylhexyl) phthalate (DEHP) is a potent antiandrogen chemical, and exposure to DEHP during peripuberty can damage the developing male reproductive system, especially the testis. However, the specific cellular targets and differentiation processes affected by DEHP, which lead to testicular toxicity, remain poorly defined. Herein, we presented the first single-cell transcriptomic profile of the pubertal mouse testis following DEHP exposure. To carry out the experiment, two groups (n = 8 each) of three-week old male mice were orally administered 0.5% carboxymethylcellulose sodium salt or 100 mg/kg body weight DEHP daily from postnatal day 21 to 48, respectively. Using single-cell RNA sequencing, a total of 31 distinct cell populations were identified, notably, Sertoli and Leydig cells emerged as important targets of DEHP. DEHP exposure significantly decreased the proportions of Sertoli cell clusters expressing mature Sertoli markers (Sox9 and Ar), and selectively reduced the expression of testosterone synthesis genes in fetal Leydig cells. Through cell-cell interaction analyses, we observed changed numbers of interactions in Sertoli cells 1 (SCs1), Leydig cells 1 (LCs1) and interstitial macrophages (ITMs), and we also identified cell-specific ligand gene expressions in these clusters, such as Inha, Fyn, Vcam1, and Apoe. Complementary in vitro assays confirmed that DEHP directly reduced the expression of genes related to Sertoli cell adhesion and intercellular communication. In conclusion, peripubertal DEHP exposure reduced the number of mature Sertoli cells and may disrupt testicular steroidogenesis by affecting the testosterone synthesis genes in fetal Leydig cells rather than adult Leydig cells.

Multimodal deep learning-based drought monitoring research for winter wheat during critical growth stages

Wheat is a major grain crop in China, accounting for one-fifth of the national grain production. Drought stress severely affects the normal growth and development of wheat, leading to total crop failure, reduced yields, and quality. To address the lag and limitations inherent in traditional drought monitoring methods, this paper proposes a multimodal deep learning-based drought stress monitoring S-DNet model for winter wheat during its critical growth periods. Drought stress images of winter wheat during the Rise-Jointing, Heading-Flowering and Flowering-Maturity stages were acquired to establish a dataset corresponding to soil moisture monitoring data. The DenseNet-121 model was selected as the base network to extract drought features. Combining the drought phenotypic characteristics of wheat in the field with meteorological factors and IoT technology, the study integrated the meteorological drought index SPEI, based on WSN sensors, and deep image learning data to build a multimodal deep learning-based S-DNet model for monitoring drought stress in winter wheat. The results show that, compared to the single-modal DenseNet-121 model, the multimodal S-DNet model has higher robustness and generalization capability, with an average drought recognition accuracy reaching 96.4%. This effectively achieves non-destructive, accurate, and rapid monitoring of drought stress in winter wheat.

First-Trimester Ultrasound Screening in Routine Obstetric Practice

Technologic advances and ultrasonographer–physician experience in fetal imaging have led to significant improvements in our ability to distinguish between normal and abnormal fetal structural development in the latter part of the first trimester. As a critical component of pregnancy care, assessment of fetal anatomy at the end of the first trimester with a standardized imaging protocol should be offered to all pregnant patients regardless of aneuploidy screening results because it has been demonstrated to identify approximately half of fetal structural malformations. Early identification of abnormalities allows focused genetic counseling, timely diagnostic testing, and subspecialist consultation. In addition, a normal ultrasound examination result offers some degree of reassurance to most patients. Use of cell-free DNA alone for aneuploidy screening while foregoing an accompanying early anatomic evaluation of the fetus will result in many anomalies that are typically detected in the first trimester not being identified until later in pregnancy, thus potentially diminishing the quality of obstetric care for pregnant individuals and possibly limiting their reproductive options, including pregnancy termination.

Sexual experiences and behaviours in the offspring generation of the Avon Longitudinal Study of Parents and Childhood

Previous research on child/teenage sexual experiences has largely focussed on negative outcomes such as teen pregnancy or acquiring sexually transmitted infections and are mainly cross-sectional. Longitudinal research is required to assess normal sexual development and the attainment of psychologically healthy attitudes towards sexuality. The Avon Longitudinal Study of Parents and Children (ALSPAC) has administered questions on relationships and sexual experiences from the age of 11 years to the index children. This data note describes these data.

FGF12 copy number variant associated with epileptic encephalopathy.

FGF12 related epilepsy presents with variable phenotypes. We report another patient with a duplication involving the FGF12 gene who presented similar to other published cases having normal early development and responded to phenytoin.

Acetate Alleviates Gut Microbiota Depletion-Induced Retardation of Skeletal Muscle Growth and Development in Young Mice

The normal growth and development of skeletal muscle is essential for the health of the body. The regulation of skeletal muscle by intestinal microorganisms and their metabolites has been continuously demonstrated. Acetate is the predominant short-chain fatty acids synthesized by gut microbiota through the fermentation of dietary fiber; however, the underlying molecular mechanisms governing the interaction between acetate and skeletal muscle during the rapid growth stage remains to be further elucidated. Herein, specific pathogen-free (SPF) mice, germ-free (GF) mice, and germ-free mice supplemented with sodium acetate (GS) were used to evaluate the effects of acetate on the skeletal muscle growth and development of young mice with gut microbiota deficiency. We found that the concentration of serum acetate, body mass gain, succinate dehydrogenase activity, and expression of the myogenesis maker gene of skeletal muscle in the GS group were higher than those in the GF group, following sodium acetate supplementation. Furthermore, the transcriptome analysis revealed that acetate activated the biological processes that regulate skeletal muscle growth and development in the GF group, which are otherwise inhibited due to a gut microbiota deficiency. The in vitro experiment showed that acetate up-regulated Gm16062 to promote skeletal muscle cell differentiation. Overall, our findings proved that acetate promotes skeletal muscle growth and development in young mice via increasing Gm16062 expression.

Joint association of overweight/obesity, high electronic screen time, and low physical activity time with early pubertal development in girls: a case–control study

To examine the joint association of electronic screen time (EST), moderate-to-vigorous physical activity time (MVPA) and overweight/obesity with early pubertal development (EPD) in girls. A case–control study of 177 EPD girls and 354 girls with normal pubertal development was conducted between October 2019 and August 2022. Overweight/obesity was defined as body mass index ≥ 85th percentiles for age and sex. We found a non-significant increase of EPD risk among girls with high EST alone [OR: 2.75 (0.65–11.58)] or low MVPA alone [OR: 2.54 (0.74–8.69)], but a significant increase of EPD risk among girls with overweight/obesity alone [OR: 4.91 (1.01–23.92)], compared to girls without any of the three risk factors (low MVPA, high EST and overweight/obesity). Girls with any two of the three risk factors faced increased risk of EPD, and girls with all three risk factors faced the highest risk of EPD [OR and 95% CI: 26.10 (6.40–106.45)]. Being overweight/obesity might be more important than having low MVPA or high EST as a correlate of EPD compared to girls without any of the three risk factors, but the co-presence of low MVPA, high EST and overweight/obesity would largely increase the risk of EPD in girls.

Hydroxylated polychlorinated biphenyls may affect the thyroid hormone-induced brain development during metamorphosis of Xenopus laevis by disturbing the expression of matrix metalloproteinases.

Thyroid hormones are primarily responsible for the brain development in perinatal mammals. However, this process can be inhibited by external factors such as environmental chemicals. Perinatal mammals are viviparous, which makes direct fetal examination difficult. We used metamorphic amphibians, which exhibit many similarities to perinatal mammals, as an experimental system. Therefore, using metamorphic amphibians, we characterized the gene expression of matrix metalloproteinases, which play an important role in brain development. The expression of many matrix metalloproteinases (mmps) was characteristically induced during metamorphosis. We also found that the expression of many mmps was induced by T3 and markedly inhibited by hydroxylated polychlorinated biphenyls (PCBs). Overall, our findings suggest that hydroxylated PCBs disrupt normal brain development by disturbingthe gene expression of mmps.

Prenatal aripiprazole induces alterations of rat placenta: a histological, immunohistochemical and ultrastructural study.

Antipsychotic drugs (APDs) are used to treat many psychiatric illnesses as schizophrenia. Typical antipsychotic drugs (TAPDs) are being used; however, they have many side effects. Atypical antipsychotic drugs (AAPDs) are newer medications with known fewer side effects. Aripiprazole (ARI) is an AAPD, recommended by healthcare providers, even during pregnancy. It can cross the placental barrier and enter fetal circulation, so it might be possible that ARI can adversely impair normal placental development and growth, if it is given prenatally. ARI was applied orally to pregnant female rats in two doses (3& 6mg/kg body weight). On gestation day 20, the mothers were sacrificed, and the placentas were removed and processed for general histological and electron microscopic evaluations. Immunohistochemistry was done using anti-PCNA (proliferating cell nuclear antigen), anti-Bax (for apoptosis) and anti-vascular endothelial growth factor alpha (VEGFA). Morphological evaluation revealed degenerative changes in the placenta as dark nuclei, vacuolization, and cyst formation. Ultra-structurally, there was degeneration of cellular components including organelles and nuclei. These changes were found in different cells of the basal and labyrinth zones and were dose dependent. Immunohistochemistry revealed upregulation of Bax and VEGFA and downregulation of PCNA. Prenatal administration of the AAPD, ARI to pregnant female rats resulted in histological changes in the placenta. Additionally, there was a decrease in cellular proliferation and increase in apoptosis, and vascular impairment. This indicates placental atrophy and dysgenesis and might suggest possible teratogenic effects to ARI, which needs further evaluation.

Initiating PeriCBD to probe perinatal influences on neurodevelopment during 3–10 years in China

Adverse perinatal factors can interfere with the normal development of the brain, potentially resulting in long-term effects on the comprehensive development of children. Presently, the understanding of cognitive and neurodevelopmental processes under conditions of adverse perinatal factors is substantially limited. There is a critical need for an open resource that integrates various perinatal factors with the development of the brain and mental health to facilitate a deeper understanding of these developmental trajectories. In this Data Descriptor, we introduce a multicenter database containing information on perinatal factors that can potentially influence children’s brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development associated with perinatal factors among children aged 3–10 years. Ultimately, our goal is to help understand how different adverse perinatal factors specifically impact cognitive development and neurodevelopment. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD.

Increased Vasoactive Intestinal Peptide (VIP) in polycystic ovary syndrome patients undergoing IVF

IntroductionPolycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis.MethodsELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis.ResultsOur ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing in vitro fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids.ConclusionVIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.

Morphogenesis-coupled DNA repair - in mammalian embryogenesis, morphogenesis and DNA double strand break (DSB) repair are carried out simultaneously to ensure normal development.

Morphogenesis-coupled DNA repair - in mammalian embryogenesis, morphogenesis and DNA double strand break (DSB) repair are carried out simultaneously to ensure normal development.

Abstract PO4-28-06: A Singleminded-2s/Sirtuin interac4on in the regula4on of mitochondrial dynamics across normal mammary development and ER+ BC progression

Abstract Characterizing the mechanisms underlying the regulation of cellular differentiation and mitochondrial dynamics are critical to understanding normal development and breast cancer in the mammary gland. Our previous studies have highlighted the significance of Singleminded-2s (Sim2s), a member of the bHLH/PAS family, in regulating mitochondrial dynamics during mammary gland development and the progression of estrogen receptor-positive (ER+) breast cancer. Sim2s is temporally regulated, with maximal expression occurring during mid-lactation. Cross-fostered pups nursed by miceover-expressing Sim2s under the mouse mammary tumor virus (MMTV-Sim2s) display significantly higher weights by mid-lactation compared to pups nursed by control dams. Overexpression of Sim2s leads to alterations in mitochondrial morphology and dynamics, characterized by increased OPA1 expression and decreased DRP1 levels, resulting in enhanced mitochondrial fusion and elongation. Furthermore, we have extended our investigations to an ER+ breast cancer cell line (MCF7). We have identified SIM2s as a tumor suppressor expressed in mammary epithelial cells, known to inhibit epithelial-mesenchymal transition (EMT) and metastasis. In our previous studies, we discovered that loss of SIM2s expression in the MCF7 cell line promotes mitochondrial fragmentation, as evidenced by a decrease in OPA1 expression and an increase in DRP1 levels. In conjunction with these findings, literature suggests that sirtuins also play a role in the regulation of mitochondrial dynamics similar to Sim2s. Specifically, there is an upregulation of Sirtuin 1 in cancer when Sim2 is lost, while Sirtuin 3 increases during differentiation and normal development progression. Therefore, our aim is to elucidate the potential interaction between Singleminded-2s and sirtuins, a family of NAD+-dependent deacetylases, in the regulation of mitochondrial dynamics. We hypothesize that Sim2s may modulate mitochondrial function through its association with sirtuins, thereby influencing normal mammary gland development and breast cancer progression. Citation Format: Hannah Carter. A Singleminded-2s/Sirtuin interac4on in the regula4on of mitochondrial dynamics across normal mammary development and ER+ BC progression [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-28-06.

Abstract PO2-19-01: A Single-Arm Prospective Study of the Neurocognitive Changes Occurring in Breast Cancer Patients on Aromatase Inhibitors. Is There a Difference Between Objective and Perceived Neurocognition?

Abstract Background: Estrogen (ER) and Progesterone (PR) receptors are rich in regions of the brain involved in cognitive functions, like the hippocampus and cerebral cortex. Animal models have shown that estradiol regulates neurocognition and plays an important role in the normal brain development. Hormone positive (HR+) breast cancers (BC) comprise 70% of the disease and the standard of care in the post-menopausal group is the use of Aromatase Inhibitors (AI) for at least 5 years. While “chemo brain” is a well-recognized term, neurocognitive changes from estrogen inhibition by AI have not been clearly defined. As neurocognition is multi-faceted, information on specific aspects affected by AI use is unclear. We hope to answer this through our trial. Design: The study is a single arm, self-controlled prospective observational cohort study in which, post-menopausal BC patients who are to be started on AIs will undergo a battery of neurocognitive tests just before starting AI, at 6 months and at 12 months after being on AI. The changes at 6 and 12 months will be compared to baseline. The tests will involve objective [Hopkins verbal learning test revised (HVLT), Controlled Oral Word Association Test from Multilingual Aphasia Examination, Trial Making Test A and B, and Recall and Recognition of Word List encoded from the HVLT] and subjective/patient-reported [The Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)] components. Tests for anxiety [Generalized Anxiety Disorder (GAD)–7], depression [Patient Health Questionnaire (PHQ)-9] and working memory (Working Memory Tasks from the Wechsler Adult Intelligence Scale) will also be assessed. While the objective tests involve providing patients with specific instructions and asking them to complete the tasks, the FACT Cog questionnaire uses a self-reported 37-item questionnaire enabling assessment of their perceived symptoms. The tests have been summarized in the table. Eligibility criteria: ER/PR+ post-menopausal BC and DCIS patients who are English speaking and are planning to start AIs will be included. Patients who have received hormonal therapy or chemotherapy in the past, those who are scheduled to receive chemotherapy, those who have undergone Whole brain Radiation therapy (RT), those with a premenopausal status, and those having comorbid conditions that could affect cognitive functioning (like any form of dementia or brain metastasis) will be excluded. Specific aims: Our aim is to see if there are progressive neurocognitive changes compared to an age-appropriate baseline and to see if changes to both objective and perceived cognitive changes occur over the course of AI use, in post-menopausal HR+ BC patients. Statistical methods: The T-test and McNemer test will be used. The normal values provided from the test may be used as a standard to justify normal or abnormal values from the collected data. Therefore, a percentage of normal (or abnormal) subjects in each time point can be derived and compared using the McNemar's test. Present accrual and target accrual: 4 patients have been accrued as of June 2023 with a target accrual of 80 patients [80% power to detect a significant change, at a p of 0.05]. Contact information for people with a specific interest in the trial: Dr Abirami Sivapiragasam (abisiva2019@yahoo.com), Dr Sam Benjamin (benjamis@upstate.edu), Dr Prashanth Ashok Kumar (ashokkup@upstate.edu), Amy Bubb (bubbam@upstate.edu). Summary of the neurocognitive tests employed in the trial. Citation Format: Prashanth Ashok Kumar, Erinn McDowell, Amy Bubb, Danning Huang, Susan Sperry, Sam Benjamin, Abirami Sivapiragasam. A Single-Arm Prospective Study of the Neurocognitive Changes Occurring in Breast Cancer Patients on Aromatase Inhibitors. Is There a Difference Between Objective and Perceived Neurocognition? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-01.

Abstract PO5-25-02: Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes

Abstract The tumour microenvironment (TME) includes physical forces from interstitial fluid flow and cell-cell interactions that modulate cancer development and progression through activation of multiple oncogenic pathways leading to tumor growth and metastatic spreading. We previously reported on the role of physical forces on epithelial to mesenchymal transition (EMT) and S100 gene family expression and cell to cell adhesion properties with implications to normal breast development and cancer. Signals from the tumor exit the local tumor environment through interstitial fluid transport and cell migration where they can be found in the blood stream. We developed a whole blood RNA gene expression biomarker panel coupled with proprietary software capable of identifying the presence of an active breast cancer signature at early stages of disease with clinical study results previously reported. Here we report on results from transcriptomic and function studies with cell interaction models. Cancer cells can influence immune cells through direct contact or via secreted molecules causing the immune cells to undergo functional changes. To investigate mechanisms involved in the induction of these alterations in a model system, we performed co-culture studies with human monocytic cells and breast cancer cells. Interaction of human monocytic cells with the breast cancer cells caused significant changes in both behavior and transcriptomes. Moreover, using RNAseq and pathway analysis we demonstrated that the changes induced through the exposure to the more aggressive triple negative (TNBC) phenotype were distinct from the alterations triggered upon contact with an ER+ breast cancer cell line. We also show that cancer-immune crosstalk triggers EMT as well as activation of multiple oncogenic pathways associated with cell migration and invasion, cell chemotaxis and cell-to-cell interactions. As the interplay between cancer and immune cells plays an important role in cancer progression, these findings provide important insight into key mechanisms controlling these outcomes. Citation Format: Karen Norek, Jacob Kennard, Kenneth Fuh, Robert Shepherd, Kristina Rinker, Olesya Kharenko. Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-02.

BAP31 Plays an Essential Role in Mouse B Cell Development via Regulation of BCR Signaling.

B cell receptor-associated protein 31 (BAP31) is a transmembrane protein that is widely expressed and primarily located in the endoplasmic reticulum (ER). B cells play a crucial role in the immune system, and BAP31 significantly contributes to the functions of various immune cells. However, the specific role of BAP31 in B lymphocytes development remains unknown. In this study, we utilized a mouse model with BAP31 deleted from B cells to investigate its effects. Our findings reveal a block in early B cell development in the bone marrow and a significant decrease in the number of B cells in peripheral lymphoid organs taken from BAP31 B cell conditional knockout (BAP31-BCKO) mice. B cell receptor (BCR) signaling is crucial for the normal development and differentiation of B lymphocytes. BAP31, an endoplasmic reticulum membrane protein, directly regulates the BCR signaling pathway and was shown to be significantly positively correlated with B cell activation and proliferation. These findings establish BAP31 as a crucial regulator of early B cell development.