Severe Elevated Bile Acids in Early Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) typically presents in the second half of pregnancy. Severe ICP is associated with increased risk of stillbirth. Little is known regarding elevated bile acids in the first trimester. We present a case of severely elevated bile acids in the first trimester, resistant to conservative management, in a patient with pre-existing cholestatic liver disease and aortic valve disease requiring anticoagulation. Therapeutic plasma exchange was used. In those with pre-existing cholestatic disease, early bile acid elevation is likely distinct from ICP, and conservative strategies may not be useful. In addition, therapeutic enoxaparin appears safe in therapeutic plasma exchange.

Utility of learning ratio scores from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Memory Test in distinguishing patterns of cognitive decline in veterans referred for neuropsychological evaluation.

Background: The Learning Ratio (LR) is a novel learning score that has shown improved utility over other learning metrics in detecting Alzheimer's disease (AD) across multiple memory tasks. However, its utility on the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD WLMT), a widely used list learning measure sensitive to decline in neurodegenerative disease, is unknown. The goal of the current study was to determine the utility of LR on the CERAD WLMT in differentiating between diagnostic (MiNCD vs MaNCD) and etiologic groups (VaD vs AD) in a veteran sample. Methods: Raw learning slope (RLS) and LR scores were examined in 168 veterans diagnosed with major neurocognitive disorder (MaNCD), mild neurocognitive disorder (MiNCD), or normal aging following neuropsychological evaluation. Patients with MaNCD were further classified by suspected etiology (i.e. microvascular disease vs AD). Results: Whereas RLS scores were not significantly different between MiNCD and MaNCD, LR scores were significantly different between all diagnostic groups (p's < .05). Those with AD had lower LR scores and RLS scores compared to those with VaD (p's < .05). LR classification accuracy was acceptable for MiNCD (AUC = .76), excellent for MaNCD (AUC = .86) and VaD (AUC = .81), and outstanding for AD (AUC = .91). Optimal cutoff scores for WLMT LR were derived from Youden's index. Conclusion: Results support the use of LR scores over RLS when interpreting the CERAD WLMT and highlight the clinical utility of LR in differentiating between diagnostic groups and identifying suspected etiology.

Perinatal Outcomes Associated With Management of Stage 1 Hypertension.

OBJECTIVE: To evaluate the association between maternal blood pressure (BP) below 130/80 mm Hg compared with 130-139/80-89 mm Hg and pregnancy outcomes. METHODS: We conducted a planned secondary analysis of CHAP (Chronic Hypertension and Pregnancy), an open label, multicenter, randomized controlled trial. Participants with mean BP below 140/90 mm Hg were grouped as below 130/80 mm Hg compared with 130-139/80-89 mm Hg by averaging postrandomization clinic BP throughout pregnancy. The primary composite outcome was preeclampsia with severe features, indicated preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The secondary outcome was small for gestational age (SGA). RESULTS: Of 2,408 patients in CHAP, 2,096 met study criteria; 1,328 had mean BP 130-139/80-89 mm Hg and 768 had mean BP below 130/80 mm Hg. Participants with mean BP below 130/80 mm Hg were more likely to be older, on antihypertensive medication, in the active treatment arm, and to have lower BP at enrollment. Mean clinic BP below 130/80 mm Hg was associated with lower frequency of the primary outcome (16.0% vs 35.8%, adjusted relative risk 0.45; 95% CI 0.38-0.54) as well as lower risk of severe preeclampsia and indicated birth before 35 weeks of gestation. There was no association with SGA. CONCLUSION: In pregnant patients with mild chronic hypertension, mean BP below 130/80 mm Hg was associated with improved pregnancy outcomes without increased risk of SGA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Association Between Time-of-Day of Immune Checkpoint Blockade Administration and Outcomes in Metastatic Renal Cell Carcinoma.

BACKGROUND: Preclinical evidence demonstrating circadian rhythmicity within the immune system provides a rationale for hypothesis that immune checkpoint inhibitor (ICI) infusion time-of-day may serve as an actionable mechanism to improve outcomes. Herein, we explore the association between ICI time of infusion (TOI) and outcomes in metastatic renal cell carcinoma (mRCC). METHODS: Data from patients with mRCC who received nivolumab or nivolumab/ipilimumab, in first- or second-line were retrospectively collected. Patients who received < 20% of infusions after 16:30 were assigned to the early TOI sub-cohort, while the rest were assigned to the late TOI sub-cohort. Clinical outcomes were compared across the 2 groups. RESULTS: Among 135 patients included, 89 (65.9%) and 46 (34.1%) were assigned to early and late TOI sub-cohorts, respectively. Baseline characteristics were comparable across the 2 sub-cohorts. Objective response rate (ORR) was 36.0% with early TOI versus 29.5% with late TOI (P = .157). Median time to treatment failure (TTF) was 9.5 months in the early TOI sub-cohort versus 4.6 months in the late TOI sub-cohort with a hazard ratio (HR) of 1.405 (95% CI, 0.919-2.149; P = .11) in univariate analysis and 1.694 (95% CI, 1.064-2.698; P = .026) in multivariate analysis. Higher cut offs allocating patients into the late TOI sub-cohort yielded an incremental increase in the HR for TTF and overall survival (OS) that reached statistical significance. CONCLUSIONS: In patients with mRCC, early TOI yielded a numerical increase in ORR, TTF and OS, with the TTF difference reaching significance in multivariate analysis. Prospective randomized studies are warranted to examine the impact of chronomodulation on outcomes with ICIs in mRCC.

Anti-inflammatory Therapy Protects Spiral Ganglion Neurons After Aminoglycoside Antibiotic-Induced Hair Cell Loss.

Destruction of cochlear hair cells by aminoglycoside antibiotics leads to gradual death of the spiral ganglion neurons (SGNs) that relay auditory information to the brain, potentially limiting the efficacy of cochlear implants. Because the reasons for this cochlear neurodegeneration are unknown, there are no neuroprotective strategies for patients. To investigate this problem, we assessed transcriptomic changes in the rat spiral ganglion following aminoglycoside antibiotic (kanamycin)-induced hair cell destruction. We observed selectively increased expression of immune and inflammatory response genes and increased abundance of activated macrophages in spiral ganglia by postnatal day 32 in kanamycin-deafened rats, preceding significant SGN degeneration. Treatment with the anti-inflammatory medications dexamethasone and ibuprofen diminished long-term SGN degeneration. Ibuprofen and dexamethasone also diminished macrophage activation. Efficacy of ibuprofen treatment was augmented by co-administration of the nicotinamide adenine dinucleotide-stabilizing agent P7C3-A20. Our results support a critical role of neuroinflammation in SGN degeneration after aminoglycoside antibiotic-mediated cochlear hair cell loss, as well as a neuroprotective strategy that could improve cochlear implant efficacy.

Postpartum Maternal Hypothermia in an Adolescent Patient Following Spontaneous Vaginal Delivery.

Postpartum hypothermia, though rare after spontaneous vaginal delivery, can be life-threatening, warranting efficient workup and intervention. A 14-year-old primigravida developed postpartum hypothermia following spontaneous vaginal delivery. No clear etiology was identified despite extensive workup. Intervention with warmed fluids and application of forced air warming system resolved the hypothermia in less than 24 hours without relapse. Following negative workup, the most likely etiology was administration of chilled intravenous fluids in the setting of acute blood loss of delivery and physiologic vasodilation of pregnancy. This case demonstrates the importance of considering common and unusual causes of postpartum hypothermia and leads to a recommendation for routine postpartum temperature checks and hypothermia protocols that include warmed fluid replacement and a forced air warming system.

Comparing Detection of Alzheimer's and Vascular Disease-Related Cognitive Impairment With Brief Cognitive Screens.

Objectives: The study compared the accuracy of the Mini-Mental State Examination (MMSE) with its modified version (3MS) in distinguishing healthy older adults from adults with cognitive impairment due to suspected Alzheimer's disease (AD) or vascular disease (VaD). Method: Participants were 98 veterans who underwent comprehensive neuropsychological evaluation due to concern for cognitive decline. Participants were selected via retrospective chart review on the basis of diagnosis. They had diagnoses of mild or major neurocognitive disorder due to suspected AD (N=20), mild or major neurocognitive disorder due to suspected VaD (N=44), or no neurocognitive diagnosis (i.e., healthy adult comparisons; HC, N=34). Results: The 3MS demonstrated superior detection of cognitive impairment. The extent of this enhanced detection was influenced by the suspected etiology of cognitive impairment. The 3MS and MMSE had comparable discrimination of AD and HC. With respect to VaD, the 3MS showed superior discriminability compared to the MMSE. Conclusions: Overall, results support the adoption of the 3MS over that of the MMSE. The 3MS is a superior (and free) tool for detecting cognitive impairment in geriatric populations. Its use is recommended for first-line screening of cognitive symptoms in older adult populations, especially those with concern for VaD.

Polyploidy in Tissue Repair and Regeneration.

Polyploidy is defined as a cell with three or more whole genome sets and enables cell growth across the kingdoms of life. Studies in model organisms have revealed that polyploid cell growth can be required for optimal tissue repair and regeneration. In mammals, polyploid cell growth contributes to repair of many tissues, including the liver, heart, kidney, bladder, and eye, and similar strategies have been identified in Drosophila and zebrafish tissues. This review discusses the heterogeneity and versatility of polyploidy in tissue repair and regeneration. Polyploidy has been shown to restore tissue mass and maintain organ size as well as protect against oncogenic insults and genotoxic stress. Polyploid cells can also serve as a reservoir for new diploid cells in regeneration. The numerous mechanisms to generate polyploid cells provide an unlimited resource for tissues to exploit to undergo repair or regeneration.

Neuropsychology of COVID-19: Anticipated cognitive and mental health outcomes.

OBJECTIVE: Discuss anticipated patterns of cognitive and emotional dysfunction, prognostic indicators, and treatment considerations based on review of (a) neuroinvasive properties of prior human coronaviruses and (b) extensively researched disorders which share similar neurological mechanisms. METHOD: A web-based comprehensive search of peer-reviewed journals was conducted based on a variety of key terms (and variants of) including coronavirus, neuroinvasion, cognitive dysfunction, viral pandemics, respiratory illness, critical illness, and metabolic disease. Articles were chosen based on relevance to the current topic and ability to provide unique thematic information. Historical articles were included if these added scientific merit to recent literature. Review of information in widely disseminated news articles was followed-up with direct review of cited scientific literature. Databases searched included Google Scholar, PubMed, and Ovid Medline. RESULTS: Based on neuroinvasive properties of prior coronaviruses and existing research on similar neurophysiological conditions with detrimental cognitive effects, COVID-19-especially those with severe symptoms-are at risk for cognitive decline and significant psychiatric/behavioral sequela. CONCLUSIONS: There are few studies examining cognitive outcomes in COVID-19. This review argues that neuropsychological sequelae are to be expected in patients with COVID-19. Considerations for clinicians working with this unique population are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Mild Neonatal Acidemia is Associated with Neonatal Morbidity at Term.

OBJECTIVE: The aim of this study is to determine the association between mild acidemia (umbilical artery [UA] pH: 7.11-7.19) and neonatal morbidity in neonates at term. STUDY DESIGN: This is a secondary analysis of a prospective cohort of women admitted for labor at ≥37 weeks of gestation within a single institution from 2010 to 2015. Universal umbilical cord blood gas assessment was performed and validated. A composite neonatal morbidity index was created including respiratory distress, mechanical ventilation, meconium aspiration syndrome, suspected or confirmed sepsis, hypoxic-ischemic encephalopathy, need for therapeutic hypothermia, seizures and death. The cohort was stratified by UA pH into normal (≥7.20), mild acidemia (7.11-7.19), acidemia (7.00-7.10), and severe acidemia (≤7.00). A subanalysis was also performed where neonates with UA pH between 7.11 and 7.19 were further stratified into two groups (7.11-7.14 and 7.15-7.19) to determine if mildly acidotic infants at the lower end of the pH range were at increased risk of morbidity. Multivariable logistic regression was used to estimate the association between UA pH and neonatal morbidity. RESULTS: Among 6,341 participants, 614 (9.7%) had mild acidemia. These infants were more likely to experience morbidity compared with those with normal UA pH (adjusted odds ratio [aOR]: 2.14; [1.68-2.73]). Among neonates with mild acidemia, UA pH 7.11 to 7.14 was associated with increased risk of composite neonatal morbidity (aOR: 3.02; [1.89-4.82]), as well as respiratory distress and suspected or confirmed sepsis when compared with UA pH 7.15 to 7.19. CONCLUSION: These data demonstrate that term neonates with mild acidemia at birth are at higher odds for short-term morbidity compared with neonates with normal UA pH. Furthermore, among neonates with mild acidemia, those with lower UA pH had worse neonatal outcomes than those with higher UA pH. This suggests that closer evaluation of neonates with UA pH higher than traditionally used could allow for earlier detection of morbidity and possible intervention. KEY POINTS: · Neonates with mild acidemia (umbilical artery [UA] pH: 7.11-7.19) demonstrated an increased risk of composite morbidity compared with those with normal UA pH (≥7.20).. · Among neonates with mild acidemia, those with lower UA pH (7.11-7.14) had a greater risk of morbidity compared with those with higher UA pH (7.15-7.19), suggesting a progression of risk of morbidity as UA pH decreases.. · The majority of prior research has focused on severe acidemia (UA pH ≤ 7.00) using outcomes of severe neurologic morbidity and mortality. These data suggest that an increased risk of morbidity exists at higher pH values when more proximal and less severe outcomes are included, such as respiratory distress and neonatal sepsis..

A Drosophila Model to Study Wound-induced Polyploidization.

Polyploidy is a frequent phenomenon whose impact on organismal health and disease is still poorly understood. A cell is defined as polyploid if it contains more than the diploid copy of its chromosomes, which is a result of endoreplication or cell fusion. In tissue repair, wound-induced polyploidization (WIP) has been found to be a conserved healing strategy from fruit flies to vertebrates. WIP has several advantages over cell proliferation, including resistance to oncogenic growth and genotoxic stress. The challenge has been to identify why polyploid cells arise and how these unique cells function. Provided is a detailed protocol to study WIP in the adult fruit fly epithelium where polyploid cells are generated within 2 days after a puncture wound. Taking advantage of D. melanogaster's extensive genetic tool kit, the genes required to initiate and regulate WIP, including Myc, have begun to be identified. Continued studies using this method can reveal how other genetic and physiological variables including sex, diet, and age regulate and influence WIP's function.

Overcoming Barriers: Evidence-Based Strategies to Increase Enrollment of Underrepresented Populations in Cancer Therapeutic Clinical Trials-a Narrative Review.

Disparities in cancer incidence and mortality rates among racial and ethnic minorities (African Americans, Asian Americans, Pacific Islanders, American Indians, and Latinos/Hispanic Americans) in the USA are well documented. Enrollment of underrepresented populations in cancer therapeutic clinical trials, however, is very low. This is true despite federal mandates to ensure accrual rates adequate for analyses and the evidence that the effectiveness of specific therapies and medications varies across ethnic and racial groups. Consequently, cancer clinical decision-making is based on research studies where the majority of research participants are white males, despite the disproportionate cancer burden in racial and ethnic minority groups. To date, there have been multiple reviews detailing the barriers to enrollment for these populations in cancer clinical trials, but a notable lack of research on possible strategies to overcome them. The aim of this narrative review is to summarize the current evidence for effective approaches to increase enrollment of underrepresented minorities in cancer therapeutic clinical trials. These approaches include (1) cultural and linguistic adaptations of marketing materials, (2) the use of patient navigators, and (3) building ongoing community partnerships. The majority of studies reviewed employ multiple improvement strategies simultaneously. Identifying effective approaches to increase enrollment of underrepresented populations in cancer clinical trials is a critical step in reducing persistent disparities in cancer incidence and mortality among racial and ethnic populations.

Older Adults' Awareness and Knowledge of Beans in Relation to Their Nutrient Content and Role in Chronic Disease Risk.

Awareness and knowledge of nutrient-dense foods are important for older adults to help them make dietary choices that support a food-first approach to healthy aging. This is especially important since age is a major risk factor for chronic disease and the proportion of older adults in North America is increasing. Beans can contribute to a food-first approach to healthy aging as they are nutrient-dense and can reduce the risk of chronic diseases. However, studies exploring awareness and knowledge of beans in older adults are lacking. Therefore, the aim of this study was to explore older adults' awareness of beans in relation to their nutrient content and role in chronic disease risk. Community-dwelling older adults (≥65 years old) were recruited and completed a validated researcher-administered questionnaire (n = 250), which was followed by 10 focus groups (n = 49). Results showed that the majority of older adults considered beans as a healthy food and thought consuming them could improve their health (99.2% and 98.0%, respectively); however, only 51.2% were bean consumers. While the majority (83.6%) of older adults were aware that a serving of beans is high in dietary fibre, bean consumers were significantly more likely to think that consuming beans could improve health areas related to dietary fibre including body weight management and constipation. Furthermore, most (84.8%) older adults thought consuming beans could improve heart health; however, bean consumers were significantly more likely to be aware that one serving of beans is low in nutrients relevant to heart health including total fat, saturated and trans fat as well as cholesterol. This research can help to inform healthcare professionals and public health agencies to create specific dietary strategies focusing on increasing older adults' awareness and knowledge of beans in relation to their nutrient profile and role in promoting health.

NAD+ improves neuromuscular development in a zebrafish model of FKRP-associated dystroglycanopathy.

BACKGROUND: Secondary dystroglycanopathies are muscular dystrophies that result from mutations in genes that participate in Dystroglycan glycosylation. Glycosylation of Dystroglycan is essential for muscle fibers to adhere to the muscle extracellular matrix (myomatrix). Although the myomatrix is disrupted in a number of secondary dystroglycanopathies, it is unknown whether improving the myomatrix is beneficial for these conditions. We previously determined that either NAD+ supplementation or overexpression of Paxillin are sufficient to improve muscle structure and the myomatrix in a zebrafish model of primary dystroglycanopathy. Here, we investigate how these modulations affect neuromuscular phenotypes in zebrafish fukutin-related protein (fkrp) morphants modeling FKRP-associated secondary dystroglycanopathy. RESULTS: We found that NAD+ supplementation prior to muscle development improved muscle structure, myotendinous junction structure, and muscle function in fkrp morphants. However, Paxillin overexpression did not improve any of these parameters in fkrp morphants. As movement also requires neuromuscular junction formation, we examined early neuromuscular junction development in fkrp morphants. The length of neuromuscular junctions was disrupted in fkrp morphants. NAD+ supplementation prior to neuromuscular junction development improved length. We investigated NMJ formation in dystroglycan (dag1) morphants and found that although NMJ morphology is disrupted in dag1 morphants, NAD+ is not sufficient to improve NMJ morphology in dag1 morphants. Ubiquitous overexpression of Fkrp rescued the fkrp morphant phenotype but muscle-specific overexpression only improved myotendinous junction structure. CONCLUSIONS: These data indicate that Fkrp plays an early and essential role in muscle, myotendinous junction, and neuromuscular junction development. These data also indicate that, at least in the zebrafish model, FKRP-associated dystroglycanopathy does not exactly phenocopy DG-deficiency. Paxillin overexpression improves muscle structure in dag1 morphants but not fkrp morphants. In contrast, NAD+ supplementation improves NMJ morphology in fkrp morphants but not dag1 morphants. Finally, these data show that muscle-specific expression of Fkrp is insufficient to rescue muscle development and homeostasis.

Motivators, Barriers and Other Factors Related to Bean Consumption in Older Adults.

Beans are nutrient-dense and can reduce risk of chronic diseases. This is relevant to older adults who can benefit from consuming beans to reduce their elevated chronic disease risk. This study explored bean consumption in older adults (≥65 years) using mixed-methods including a researcher-administered questionnaire (n = 250) and focus groups (n = 49). Prevalence of bean consumption (daily or weekly) was 51.2%. Motivators to bean consumption were significantly more likely among bean consumers with the top three including nutritional value, taste/texture and versatility, which were also predictors of consuming beans (OR = 3.54, 2.72, and 4.24, respectively). Conversely, barriers to bean consumption were significantly more likely among bean non-consumers with the top three including not part of traditional diet/do not think to include beans in meals, flatulence/abdominal discomfort and lack of knowledge about preparation/cooking, which were also predictors of not consuming beans (OR = 3.85, 2.26, and 5.08, respectively). This research will inform dietary strategies to increase bean consumption.

CD55 Is Essential for CD103+ Dendritic Cell Tolerogenic Responses that Protect against Autoimmunity.

Recent studies traced inflammatory bowel disease in some patients to deficiency of CD55 [decay-accelerating factor (DAF)], but the mechanism underlying the linkage remained unclear. Herein, we studied the importance of DAF in enabling processes that program tolerance in the gut and the eye, two immune-privileged sites where immunosuppressive responses are continuously elicited. Unlike oral feeding or ocular injection of ovalbumin in wild-type (WT) mice, which induced dominant immune tolerance, identical treatment of DAF-/- mice or DAF-/- to WT bone marrow chimeras did not. While 10% to 30% of mesenteric and submandibular lymph node CD4+ cells became robust T-regulatory cells (Tregs) in WT forkhead box P3 (Foxp3)-green fluorescent protein mice, few in either site became Tregs with little suppressor activity in DAF-/- Foxp3-green fluorescent protein mice. Phenotyping of CD103+ dendritic cells (DCs) from the ovalbumin-fed DAF-/- mice showed impaired expression of inducer of costimulation (ICOS) ligand, programmed death receptor 1-ligand 1 (PD1-L1), CxxxC chemokine receptor 1 (Cx3CR1), CCR7, and CCR9. Analyses of elicited DAF-/- Foxp3+ Tregs showed reduced expression of interferon regulatory factor 8 (IRF-8)/aldehyde dehydrogenase 1 family member A2 (Aldh1a2) and glycoprotein A repetitions predominant/latency-associated protein associated with Treg transforming growth factor-ß production and presentation, as well as integrin ß6/integrin ß8 associated with Treg and CD103+ DC transforming growth factor-ß release. Thus, DAF is required for the properties of CD103+ DCs and their naïve CD4+ cell partners that together program tolerance.

Health claims and information sources in relation to bean consumption in older adults.

Bean consumption can reduce chronic disease risk and improve diet quality; however, bean consumption among North Americans is low. Since health claims and other information sources could increase bean consumption, their exploration is warranted, particularly among older adults, a population well positioned to benefit. The purpose of this study was to explore bean consumption among older adults (≥65 years old) in relation to health claims and other information sources. A mixed-methods explanatory sequential study design utilizing a between strategy data collection approach was used. Community-dwelling older adults (n = 250; 76.0% female) completed a validated researcher-administered questionnaire to explore bean consumption, awareness and reading of health claims, the likelihood of health claims influencing bean consumption, and current and preferred sources of nutrition and/or health information regarding beans. The questionnaire was followed up with 10 semi-structured focus groups (n = 46; 76.1% female). Awareness of nutrient content, nutrient function, therapeutic and disease risk reduction claims was reported by 94.4%, 64.0%, 79.6% and 77.2% of participants, respectively. Among those aware, these health claims were read by 91.5%, 85.6%, 87.9% and 88.6% of participants, respectively. The prevalence of bean consumption was 51.2% and participants (46.8%) most frequently indicated that all health claims would equally increase their likelihood of bean consumption. Participants (72.0%) reported that they would like more information about the nutrition and/or health properties of beans, with their most common preferred sources including food labels (54.8%), brochures (51.2%) and the internet (47.2%). This research advances the literature on how health claims relate to eating behaviour and can inform regulatory and food industry scientists about consumer perception to bean health claims, and healthcare professionals about preferred information sources for their clients.

Studies Into ß-Glucan Recognition in Fish Suggests a Key Role for the C-Type Lectin Pathway.

Immune-modulatory effects of ß-glucans are generally considered beneficial to fish health. Despite the frequent application of ß-glucans in aquaculture practice, the exact receptors and downstream signalling remains to be described for fish. In mammals, Dectin-1 is a member of the C-type lectin receptor (CLR) family and the best-described receptor for ß-glucans. In fish genomes, no clear homologue of Dectin-1 could be identified so far. Yet, in previous studies we could activate carp macrophages with curdlan, considered a Dectin-1-specific ß-(1,3)-glucan ligand in mammals. It was therefore proposed that immune-modulatory effects of ß-glucan in carp macrophages could be triggered by a member of the CLR family activating the classical CLR signalling pathway, different from Dectin-1. In the current study, we used primary macrophages of common carp to examine immune modulation by ß-glucans using transcriptome analysis of RNA isolated 6 h after stimulation with two different ß-glucan preparations. Pathway analysis of differentially expressed genes (DEGs) showed that both ß-glucans regulate a comparable signalling pathway typical of CLR activation. Carp genome analysis identified 239 genes encoding for proteins with at least one C-type Lectin Domains (CTLD). Narrowing the search for candidate ß-glucan receptors, based on the presence of a conserved glucan-binding motif, identified 13 genes encoding a WxH sugar-binding motif in their CTLD. These genes, however, were not expressed in macrophages. Instead, among the ß-glucan-stimulated DEGs, a total of six CTLD-encoding genes were significantly regulated, all of which were down-regulated in carp macrophages. Several candidates had a protein architecture similar to Dectin-1, therefore potential conservation of synteny of the mammalian Dectin-1 region was investigated by mining the zebrafish genome. Partial conservation of synteny with a region on the zebrafish chromosome 16 highlighted two genes as candidate ß-glucan receptor. Altogether, the regulation of a gene expression profile typical of a signalling pathway associated with CLR activation and, the identification of several candidate ß-glucan receptors, suggest that immune-modulatory effects of ß-glucan in carp macrophages could be a result of signalling mediated by a member of the CLR family.

Evolution of the genomic landscape of circulating tumor DNA (ctDNA) in metastatic prostate cancer over treatment and time.

BACKGROUND: Targeted therapies have shown promise for men with metastatic castration-resistant prostate cancer (mCRPC). Due to the difficulty with obtaining tumor tissue in bony metastases, liquid biopsies are a promising alternative to guide treatment selection. While concurrent tissue next-generation sequencing (tNGS) and liquid biopsy has high concordance, it is unknown whether the genomic landscape of metastatic prostate cancer (mPC) changes over time or treatment. Herein, we hypothesize that the genomic landscape of mPC evolves with new treatments and/or time between tests. PATIENTS AND METHODS: Men with mPC from the University of Utah with matched tNGS and liquid biopsy were included. Clinical data was collected retrospectively. Exonic regions from 69 genes covered by both platforms were included for analysis. Paired t tests were used to assess number of genomic alterations (GAs) between testing platforms. Number of alterations was assessed by time and number of treatments between testing by multivariate nonparametric trend tests. RESULTS: 101 men with mPC were eligible and included. In men with no new treatments and ≤ 1 year between tests, a similar number of GAs were detected in both tests (2.0 vs. 2.2). In contrast, men with ≥ 1 new treatment between tests had significantly more GAs after treatment (5.0 vs. 2.4, p = 0.005). Total number of GAs was correlated with number of new treatments between testing (p = 0.003) and not time between testing (p = 0.76). CONCLUSION: The genomic landscape of mPC evolves with subsequent therapies. This finding suggests that contemporary tumor genomic profile upon disease progression may optimize guidance towards subsequent therapy selection.

Targeting Bacteroides in Stool Microbiome and Response to Treatment With First-Line VEGF Tyrosine Kinase Inhibitors in Metastatic Renal-Cell Carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for metastatic renal-cell carcinoma. Stool microbiome composition is predictive of response to immunotherapy and cytotoxic chemotherapy. We sought to investigate whether antibiotics targeting Bacteroides species affect progression-free survival (PFS) while receiving first-line VEGF-TKI therapy. PATIENTS AND METHODS: Using a retrospective cohort of intermediate- and poor-risk metastatic renal-cell carcinoma patients from the University of Utah, we categorized patients receiving first-line VEGF-TKIs by receipt of antibiotics (Bacteroides spp., non-Bacteroides spp., or none) and assessed PFS by Kaplan-Meier and Cox proportional hazard models. RESULTS: Of 145 patients, 17 received antibiotics with Bacteroides spp. coverage and 32 patients received antibiotics without Bacteroides spp. coverage. When compared to patients not receiving antibiotics, improved PFS was seen with each additional day antibiotics were prescribed with Bacteroides spp. coverage (hazard ratio = 0.92; 95% confidence interval, 0.83-0.99; P = .04). CONCLUSION: Targeting stool Bacteroides spp. with antibiotics improves PFS in patients receiving first-line VEGF-TKIs in a duration-dependent manner.