Embryology of the fat-tailed dunnart (Sminthopsis crassicaudata): A marsupial model for comparative mammalian developmental and evolutionary biology.

BACKGROUND: Marsupials are a diverse and unique group of mammals, but remain underutilized in developmental biology studies, hindering our understanding of mammalian diversity. This study focuses on establishing the fat-tailed dunnart (Sminthopsis crassicaudata) as an emerging laboratory model, providing reproductive monitoring methods and a detailed atlas of its embryonic development. RESULTS: We monitored the reproductive cycles of female dunnarts and established methods to confirm pregnancy and generate timed embryos. With this, we characterized dunnart embryo development from cleavage to birth, and provided detailed descriptions of its organogenesis and heterochronic growth patterns. Drawing stage-matched comparisons with other species, we highlight the dunnarts accelerated craniofacial and limb development, characteristic of marsupials. CONCLUSIONS: The fat-tailed dunnart is an exceptional marsupial model for developmental studies, where our detailed practices for reproductive monitoring and embryo collection enhance its accessibility in other laboratories. The accelerated developmental patterns observed in the Dunnart provide a valuable system for investigating molecular mechanisms underlying heterochrony. This study not only contributes to our understanding of marsupial development but also equips the scientific community with new resources for addressing biodiversity challenges and developing effective conservation strategies in marsupials.

Applying machine learning to international drug monitoring: classifying cannabis resin collected in Europe using cannabinoid concentrations.

In Europe, concentrations of ∆9-tetrahydrocannabinol (THC) in cannabis resin (also known as hash) have risen markedly in the past decade, potentially increasing risks of mental health disorders. Current approaches to international drug monitoring cannot distinguish between different types of cannabis resin which may have contrasting health effects due to THC and cannabidiol (CBD) content. Here, we compared concentrations of THC and CBD in different types of cannabis resin collected in Europe (either Moroccan-type, or Dutch-type). We then tested the ability of machine learning algorithms to classify the type of cannabis resin (either Moroccan-type, or Dutch-type) using routinely collected monitoring data on THC and CBD. Finally, we applied the optimal algorithm to new samples collected in countries where the type of cannabis resin was unknown, the UK and Denmark. Results showed that overall, Dutch-type samples had higher THC (Hedges' g = 2.39) and lower CBD (Hedges' g = 0.81) than Moroccan-type samples. A Support Vector Machine algorithm achieved classification accuracy exceeding 95%, with little variation in this estimate, good interpretability, and plausibility. It made contrasting predictions about the type of cannabis resin collected in the UK (94% Moroccan-type; 6% Dutch-type) and Denmark (36% Moroccan-type; 64% Dutch-type). In conclusion, we provide proof-of-concept evidence for the potential of machine learning to inform international drug monitoring. Our findings should not be interpreted as objective confirmatory evidence but suggest that Dutch-type cannabis resin has higher THC concentrations than Moroccan-type cannabis resin, which may contribute to variation in drug markets and health outcomes for people who use cannabis in Europe.

Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time.

BACKGROUND: Breast cancer is estimated to comprise about 290,560 new cases in 2022. Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive (ER+) breast carcinoma in postmenopausal women, which includes approximately two-thirds of all women with breast cancer. AIs inhibit the peripheral conversion of androgens to estrogen by deactivation of the aromatase enzyme, leading to a reduction in serum estrogen level in postmenopausal women with ER+ breast carcinoma. Estrogen is known for its cardiovascular (CV) protective properties through a variety of mechanisms including vasodilation of blood vessels and inhibition of vascular injury resulting in the prevention of atherosclerosis. In clinical trials and prospective cohorts, the long-term use of AIs can increase the risk for hypertension and hyperlipidemia. Studies demonstrate mixed results as to the impact of AIs on actual CV events and overall survival. METHODS: A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota (UMN). Subjects with a history of known tobacco use, hypertension, hyperlipidemia, and diabetes were excluded to eliminate potential confounding factors. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p = 0.045; Figure 1) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p = 0.91). There were no statistically significant changes in small or large arterial elasticity. CONCLUSIONS: We hypothesize that long-term use of AI can lead to persistent endothelial dysfunction, and further investigation is necessary. In our study, patients were on AI for approximately 5-10 years. As a result, we do not have data on whether these changes, such as EndoPAT® ratio and the elasticity of small and large arterial, are reversible with discontinuation of AI. These findings set the stage for a larger study to more conclusively determine the association between AI exposure and cardiovascular outcomes. Further studies should evaluate for multivariate associations withmodifiable risk factors for CV disease.

Translation of nonclinical to clinical safety findings for 27 biotherapeutics.

Human adverse drug reactions (ADRs), and in vivo nonclinical adverse and nonadverse findings, were identified in 27 biotherapeutic programs and placed into organ categories to determine translation. The sensitivity of detecting human ADRs was 30.8% with a positive predictive value (PPV) of 53.3% for nonclinical adverse findings; sensitivity increased to 67.3% and PPV fell to 35.0% when including nonadverse findings. Nonclinical findings were associated with a greater likelihood of a human ADR in that organ category, especially for adverse findings [positive likelihood ratio (LR+) >10 (lower 95% confidence interval [CI] of >5)]. The specificity and negative predictive value (NPV) were very high (>85%). A lack of nonclinical findings in an organ category was associated with a lower likelihood of a human ADR in that organ category. About 40-50% of human ADRs and nonclinical adverse findings, and about 30% of nonclinical nonadverse findings, were attributed to pharmacology. Slightly more than half of the human ADRs with a translating nonclinical finding had findings in animals that could be considered very similar. Overall, 38% of nonclinical findings translated to a human ADR at the organ category level. When nonclinical findings did not translate to humans, the cause was usually higher exposures or longer dosing in animals. All programs with human ADRs attributed to immunogenicity also had nonclinical adverse or nonadverse findings related to immunogenicity. Overall, nonclinical adverse and nonadverse findings were useful in predicting human ADRs, especially at an organ category level, and the majority of human ADRs were predicted by nonclinical toxicity studies.

Impact of body mass index on pathological response after neoadjuvant chemotherapy: results from the I-SPY 2 trial.

PURPOSE: Increased body mass index (BMI) has been associated with poor outcomes in women with breast cancer. We evaluated the association between BMI and pathological complete response (pCR) in the I-SPY 2 trial. METHODS: 978 patients enrolled in the I-SPY 2 trial 3/2010-11/2016 and had a recorded baseline BMI prior to treatment were included in the analysis. Tumor subtypes were defined by hormone receptor and HER2 status. Pretreatment BMI was categorized as obese (BMI ≥ 30 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and normal/underweight (< 25 kg/m2). pCR was defined as elimination of detectable invasive cancer in the breast and lymph nodes (ypT0/Tis and ypN0) at the time of surgery. Logistic regression analysis was used to determine associations between BMI and pCR. Event-free survival (EFS) and overall survival (OS) between different BMI categories were examined using Cox proportional hazards regression. RESULTS: The median age in the study population was 49 years. pCR rates were 32.8% in normal/underweight, 31.4% in overweight, and 32.5% in obese patients. In univariable analysis, there was no significant difference in pCR with BMI. In multivariable analysis adjusted for race/ethnicity, age, menopausal status, breast cancer subtype, and clinical stage, there was no significant difference in pCR after neoadjuvant chemotherapy for obese compared with normal/underweight patients (OR = 1.1, 95% CI 0.68-1.63, P = 0.83), and for overweight compared with normal/underweight (OR = 1, 95% CI 0.64-1.47, P = 0.88). We tested for potential interaction between BMI and breast cancer subtype; however, the interaction was not significant in the multivariable model (P = 0.09). Multivariate Cox regression showed there was no difference in EFS (P = 0.81) or OS (P = 0.52) between obese, overweight, and normal/underweight breast cancer patients with a median follow-up time of 3.8 years. CONCLUSION: We found no difference in pCR rates by BMI with actual body weight-based neoadjuvant chemotherapy in this biologically high-risk breast cancer population in the I-SPY2 trial.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Development of an International Virtual Multidisciplinary Tumor Board for Breast Cancer in Mongolia.

INTRODUCTION: Breast cancer is the most diagnosed cancer among Mongolian women and mortality rates are high. We describe a virtual multi-institutional and multidisciplinary tumor board (MTB) for breast cancer created to assist the National Cancer Center of Mongolia. MATERIALS AND METHODS: A virtual MTB for breast cancer was conducted with participation of two United States and 1 Mongolian cancer centers. A standardized template for presentations was developed. Recommendations were summarized and shared with participants. Collected data included patient demographics, tumor characteristics, stage, imaging and treatments performed, and recommendations. Questions were categorized as treatment, diagnosis, or palliative questions. RESULTS: Fifteen patients were evaluated. Median age was 39 y. 86.7% of breast cancers were invasive ductal cancers and 13.3% were metaplastic carcinomas. 53.3% were estrogen and progesterone receptor positive (ER+/PR+), 60% were HER2+, 13.3% were triple negative, and 26.7% were recurrent. 40% of patients were evaluated with mammography. 6% received positron emission tomography scans for metastatic evaluation. 66.7% of surgical patients received neoadjuvant chemotherapy. Herceptin was administered to 55.6% of patients with Her2+ cancers. Modified radical mastectomy was most commonly performed and reconstruction was rare. Sentinel lymph node biopsy was not performed. 66.7% of ER+/PR+ patients received endocrine therapy. 6.7% of patients received radiation. 75% of MTB questions pertained to treatment. Recommendations were related to systemic therapy (40%), surgical management (33.3%), pathology (13.3%), and imaging (13.3%). CONCLUSIONS: This study illustrates the development of an international, virtual, multi-institutional breast cancer MTB and provides insight into challenges and potential interventions to improve breast cancer care in Mongolia.

Impact of Body Mass Index on Pathological Response after Neoadjuvant Chemotherapy: Results from the I-SPY 2 trial.

Purpose: Increased body mass index (BMI) has been associated with poor outcomes in women with breast cancer. We evaluated the association between BMI and pathological complete response (pCR) in the I-SPY 2 trial. Methods: 978 patientsenrolled in the I-SPY 2 trial 3/2010-11/2016 and had a recorded baseline BMI prior to treatment were included in the analysis. Tumor subtypes were defined by hormone receptor and HER2 status. Pretreatment BMI was categorized as obese (BMI≥30 kg/m2), overweight (25≤BMI < 30 kg/m2), and normal/underweight (< 25 kg/m2). pCR was defined as elimination of detectable invasive cancer in the breast and lymph nodes (ypT0/Tis and ypN0) at the time of surgery. Logistic regression analysis was used to determine associations between BMI and pCR. Event-free survival (EFS) and overall survival (OS) between different BMI categories were examined using Cox proportional hazards regression. Results: The median age in the study population was 49 years. pCR rates were 32.8% in normal/underweight, 31.4% in overweight, and 32.5% in obese patients. In univariable analysis, there was no significant difference in pCR with BMI. In multivariable analysis adjusted for race/ethnicity, age, menopausal status, breast cancer subtype, and clinical stage, there was no significant difference in pCR after neoadjuvant chemotherapy for obese compared with normal/underweight patients (OR = 1.1, 95% CI: 0.68-1.63, p = 0.83), and for overweight compared with normal/underweight (OR = 1, 95% CI: 0.64-1.47, p = 0.88). We tested for potential interaction between BMI and breast cancer subtype; however, the interaction was not significant in the multivariable model (p = 0.09). Multivariate Cox regression showed there was no difference in EFS (p = 0.81) or OS (p = 0.52) between obese, overweight, and normal/underweight breast cancer patients with a median follow-up time of 3.8 years. Conclusions: We found no difference in pCR rates by BMI with actual body weight based neoadjuvant chemotherapy in this biologically high-risk breast cancer population in the I-SPY2 trial.

Endothelial Dysfunction in Breast Cancer Survivors on Aromatase Inhibitors: Changes over Time.

Background: Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive breast carcinoma in postmenopausal women. Studies demonstrate mixed results as to the impact of AIs on cardiovascular (CV) events and overall survival. With the increasing number of pre- and postmenopausal women on AIs for five to ten years, understanding the long-term impact of AIs on blood vessels and CV risk in cancer survivors is vital. Methods: A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota. Subjects with a history of tobacco use, hypertension, or hyperlipidemia were excluded. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Pro ling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Results: After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p=0.045) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p=0.91). There were no statistically significant changes in small or large arterial elasticity. Conclusion: Endovascular dysfunction is an early sign for atherosclerosis and vascular impairment. This study suggests that postmenopausal breast cancer survivors on aromatase inhibitor therapy develop endothelial dysfunction as early as six months which is a predictor of adverse CV disease. We hypothesize that long-term use of AIs can lead to persistent endothelial dysfunction. It is unclear if these changes are reversible once AI use is discontinued and further investigation is necessary.

Electrophysiological signatures of reward learning in the rodent touchscreen-based Probabilistic Reward Task.

Blunted reward learning and reward-related activation within the corticostriatal-midbrain circuitry have been implicated in the pathophysiology of anhedonia and depression. Unfortunately, the search for more efficacious interventions for anhedonic behaviors has been hampered by the use of vastly different preclinical and clinical assays. In a first step in addressing this gap, in the current study, we used event-related potentials and spectral analyses in conjunction with a touchscreen version of the rodent Probabilistic Reward Task (PRT) to identify the electrophysiological signatures of reward learning in rats. We trained 11 rats (5 females and 6 males) on the rodent touchscreen-based PRT and subsequently implanted them with deep electrodes in the anterior cingulate cortex (ACC) and nucleus accumbens (NAc) for local field potentials recordings during the PRT. Behaviorally, the expected responsivity-to-reward profile was observed. At the electrophysiological level, we identified a negative amplitude deflection 250-500 ms after feedback in the ACC and NAc electrodes, as well as power increase in feedback-locked delta (1-5 Hz) and alpha/beta (9-17 Hz) bands in both electrodes for rewarded trials. Using a reverse-translational approach, we identified electrophysiological signatures of reward learning in rats similar to those described in humans. These findings and approaches might provide a useful translational platform to efficiently evaluate novel therapeutics targeting anhedonia.

Nonclinical Safety Signals in PharmaPendium Improve the Predictability of Human Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a leading cause of candidate attrition during drug development in the pharmaceutical industry. This study evaluated liver toxicity signals for 249 approved drugs (114 of "most-DILI concern" and 135 of "no-DILI concern") using PharmaPendium and assessed the association between nonclinical and clinical injuries using contingency table analysis. All animal liver findings were combined into eight toxicity categories based on nature and severity. Together, these analyses revealed that cholestasis [odds ratio (OR): 5.02; 95% confidence interval (CI) 1.04-24.03] or liver aminotransferase increases (OR: 1.86; 95% CI 1.09-3.09) in rats and steatosis (OR-1.9; 95% CI 1.03-3.49) or liver aminotransferase increases (OR-2.57; 95% CI 1.4-4.7) in dogs were significant predictors of human liver injury. The predictive value further improved when the liver injury categories were combined into less severe (steatosis, cholestasis, liver aminotransferase increase, hyperbilirubinemia, or jaundice) and more-severe (liver necrosis, acute liver failure, or hepatotoxicity) injuries. In particular, less-severe liver injuries in the following pairs of species predicted human hepatotoxicity {[dog and mouse] (OR: 2.70; 95% CI 1.25-5.84), [dog and rat] (OR-2.61; 95% CI 1.48-4.59), [monkey and mouse] (OR-4.22; 95% CI 1.33-13.32), and [monkey and rat] (OR-2.45; 95% CI 1.15-5.21)} were predictive of human hepatotoxicity. Meanwhile, severe liver injuries in both [dog and rat] (OR-1.9; 95% CI 1.04-3.49) were significant predictors of human liver toxicity. Therefore, we concluded that the occurrence of DILI in humans is highly likely if liver injuries are observed in one rodent and one nonrodent species and that liver aminotransferase increases in dogs and rats can predict DILI in humans. Together, these findings indicate that the liver safety signals observed in animal toxicity studies indicate potential DILI risk in humans and could therefore be used to prioritize small molecules with less potential to cause DILI in humans.

Efficient neutralization of daratumumab in pretransfusion samples using a novel recombinant monoclonal anti-idiotype antibody.

BACKGROUND: Anti-CD38 antibodies such as daratumumab (DARA) are critical therapies for multiple myeloma and other diseases. Unfortunately, anti-CD38 antibodies cause panreactivity in indirect antiglobulin tests (IATs), complicating blood compatibility testing. The anti-CD38 interference is most often mitigated by treating reagent red blood cells (RBCs) with dithiothreitol (DTT). However, when using the DTT method, not all RBC antibody specificities can be detected (e.g., anti-K), and the DTT method is impractical for some transfusion services. We evaluated the ability of a new anti-idiotype antibody to neutralize DARA in vitro and eliminate the anti-CD38 interference. STUDY DESIGN AND METHODS: A recombinant monoclonal rabbit anti-DARA idiotype antibody ("anti-DARA") was generated. The ratio of anti-DARA required to neutralize DARA in spiked samples was evaluated in IATs performed in gel. IATs performed in tube were used to demonstrate that anti-DARA allows alloantibody detection in the presence of DARA. Plasma samples from 29 patients receiving DARA were treated with a fixed quantity of anti-DARA (120 µg) before performing antibody detection tests (screens) in tube. RESULTS: Anti-DARA used at or above a 1:1 ratio with DARA eliminated the DARA interference with IATs. Anti-DARA allowed detection of both alloanti-E and alloanti-K in the presence of DARA. In 27/29 (93.1%) clinical samples, 120 µg anti-DARA was sufficient to neutralize the DARA in 100 µl patient plasma. DISCUSSION: An anti-DARA:DARA ratio as low as 1:1 is sufficient to neutralize DARA in solution. A fixed amount of anti-DARA eliminates the anti-CD38 interference in most patient samples.

Unraveling the Kinematics of Sperm Motion by Reconstructing the Flagellar Wave Motion in 3D.

Sperm swim through the female reproductive tract by propagating a 3D flagellar wave that is self-regulatory in nature and driven by dynein motors. Traditional microscopy methods fail to capture the full dynamics of sperm flagellar activity as they only image and analyze sperm motility in 2D. Here, an automated platform to analyze sperm swimming behavior in 3D by using thin-lens approximation and high-speed dark field microscopy to reconstruct the flagellar waveform in 3D is presented. It is found that head-tethered mouse sperm exhibit a rolling beating behavior in 3D with the beating frequency of 6.2 Hz using spectral analysis. The flagellar waveform bends in 3D, particularly in the distal regions, but is only weakly nonplanar and ambidextrous in nature, with the local helicity along the flagellum fluctuating between clockwise and counterclockwise handedness. These findings suggest a nonpersistent flagellar helicity. This method provides new opportunities for the accurate measurement of the full motion of eukaryotic flagella and cilia which is essential for a biophysical understanding of their activation by dynein motors.

The 70-gene signature test as a prognostic and predictive biomarker in patients with invasive lobular breast cancer.

PURPOSE: Genomic expression assays provide prognostic information and guide adjuvant chemotherapy decisions for patients with estrogen receptor (ER)-positive breast cancer. Few studies have evaluated the utility of such assays for invasive lobular carcinoma (ILC). The objective of this study is to evaluate the 70-gene signature test (ST) as a prognostic and predictive tool for ILC using a national cancer database. METHODS: We identified patients diagnosed with stage I-III ER-positive ILC from 2004 to 2016 using the National Cancer Database. All patients underwent 70-gene ST testing. We used the Kaplan-Meier method and Cox proportional hazard analyses to determine overall survival based on genomic risk classification. We also determined the benefit of adjuvant chemotherapy for patients with high-genomic risk ILC based on 70-gene ST testing. RESULTS: We identified 2610 patients with ILC who underwent 70-gene ST testing; 280 (11%) were classified as high genomic risk. Five-year overall survival rates were significantly worse for patients classified as high risk (83%) as compared with those classified as low risk (94%, p < 0.05). In Cox models, high genomic risk was independently associated with a significantly increased hazard of death. In our Cox models of patients who were high genomic risk, adjuvant chemotherapy was not significantly associated with improved overall survival. CONCLUSION: In this large database study, we found that the genomic risk category determined by the 70-gene ST was significantly associated with survival outcomes for patients with ILC. However, the 70-gene ST failed to predict the benefit of adjuvant chemotherapy for patients with high genomic risk.

Focus Attracts Attachment.

There is growing evidence that pitch accents as well as prosodic boundaries can affect syntactic attachment. But is this an effect of their perceptual salience (the Salience Hypothesis), or is it because accents mark the position of focus (the Focus Attraction Hypothesis)? A pair of auditory comprehension experiments shows that focus position, as indicated by preceding wh-questions instead of by pitch accents, affects attachment by drawing the ambiguous phrase to the focus. This supports the Focus Attraction Hypothesis (or a pragmatic version of salience) for both these results and previous results of accents on attachment. These experiments show that information structure, as indicated with prosody or other means, influences sentence interpretation, and suggests a view on which modifiers are drawn to the most important information in a sentence.

Lymphadenopathy after the third Covid-19 vaccine.

Axillary lymphadenopathy ipsilateral to the vaccination site has been clinically and radiologically reported after administration of COVID-19 vaccines. This can be an important diagnostic dilemma, particularly in cancer patients who are being staged or re-staged, as this benign entity may mimic metastasis, cause unnecessary biopsies and changes in therapy. Here we present a breast cancer patient and a patient with squamous cell carcinoma of the head and neck, who had already received the first two doses of mRNA type COVID-19 vaccines before, now presenting with new hypermetabolic reactive lymphadenopathy on FDG PET/CT after the third booster dose.

CRISPs Function to Boost Sperm Power Output and Motility.

Fertilization requires sperm to travel long distances through the complex environment of the female reproductive tract. Despite the strong association between poor motility and infertility, the kinetics of sperm tail movement and the role individual proteins play in this process is poorly understood. Here, we use a high spatiotemporal sperm imaging system and an analysis protocol to define the role of CRISPs in the mechanobiology of sperm function. Each of CRISP1, CRISP2, and CRISP4 is required to optimize sperm flagellum waveform. Each plays an autonomous role in defining beat frequency, flexibility, and power dissipation. We thus posit that the expansion of the CRISP family from one member in basal vertebrates, to three in most mammals, and four in numerous rodents, represents an example of neofunctionalization wherein proteins with a common core function, boosting power output, have evolved to optimize different aspects of sperm tail performance.

Concurrent electrophysiological recording and cognitive testing in a rodent touchscreen environment.

Challenges in therapeutics development for neuropsychiatric disorders can be attributed, in part, to a paucity of translational models capable of capturing relevant phenotypes across clinical populations and laboratory animals. Touch-sensitive procedures are increasingly used to develop innovative animal models that better align with testing conditions used in human participants. In addition, advances in electrophysiological techniques have identified neurophysiological signatures associated with characteristics of neuropsychiatric illness. The present studies integrated these methodologies by developing a rat flanker task with electrophysiological recordings based on reverse-translated protocols used in human electroencephalogram (EEG) studies of cognitive control. Various touchscreen-based stimuli were evaluated for their ability to efficiently gain stimulus control and advance to flanker test sessions. Optimized stimuli were then examined for their elicitation of prototypical visual evoked potentials (VEPs) across local field potential (LFP) wires and EEG skull screws. Of the stimuli evaluated, purple and green photographic stimuli were associated with efficient training and expected flanker interference effects. Orderly stimulus-locked outcomes were also observed in VEPs across LFP and EEG recordings. These studies along with others verify the feasibility of concurrent electrophysiological recordings and rodent touchscreen-based cognitive testing and encourage future use of this integrated approach in therapeutics development.

A Neoadjuvant Chemotherapy Trial for Early Breast Cancer is Impacted by COVID-19: Addressing Vaccination and Cancer Trials Through Education, Equity, and Outcomes.

While COVID-19 vaccine distribution has addressed vulnerabilities related to age and comorbidities, there is a need to ensure vaccination of patients with cancer receiving experimental and routine treatment, where interruption of treatment by infection is likely to result in inferior outcomes. Among patients with cancer, those undergoing neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (Adj chemo) for early breast cancer (EBC) are at particularly high risk for inferior outcomes, in part, because optimal timing of chemotherapy is essential for promoting distant disease-free survival. COVID-19 data from the ongoing multicenter I-SPY 2 trial of NAC for EBC provides a window into the magnitude of the problem of treatment interruption, not only for the trial itself but also for routine Adj chemo. In the I-SPY 2 trial, 4.5% of patients had disruption of therapy by COVID-19, prior to wide vaccine availability, suggesting that nationally up to 5,700 patients with EBC were at risk for adverse outcomes from COVID-19 infection in 2020. To address this problem, vaccine education and public engagement are essential to overcome hesitancy, while equity of distribution is needed to address access. To accomplish these goals, healthcare organizations (HCO) need to not only call out disinformation but also engage the public with vaccine education and find common ground for vaccine acceptance, while partnering with state/local governments to improve efficiency of vaccine distribution. These approaches are important to improve trial access and to reduce susceptibility to COVID-19, as the pandemic could continue to impact access to clinical trials and routine cancer treatment.