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This study aimed to comprehensively assess the pattern of cortical maturation by magnetic resonance imaging (MRI) in fetuses with unaffected and mildly affected CMV infection determined by ultrasound (US) and establish possible differences compared to healthy controls.Twenty-four CMV-infected fetuses (7 US unaffected, 17 US mildly affected) and 24 healthy controls between 27 and 36 weeks of gestation undergoing fetal MRI were included. Fetuses were considered unaffected or mildly affected according to prenatal US/MRI neuroimaging findings. We compared fetal sulci depth, Sylvian fissure depth, Sylvian fissure, and angle and cortical maturation grading of specific sulci and areas among study groups. Regression, parametric trend and intraclass correlation analysis were performed.Compared to controls, in the CMV-infected fetuses showed a significantly larger median (interquartile range: IQR) width of the lateral ventricles [right (mm): 3.9 (2.6-5.3) vs. 7.8 (5.9-9.9); left: 4.2 (3.2-5.3) vs. 7.5 (6.0-10.9)], significantly decreased parieto-occipital sulcus [right (mm): 15.9 (14.7-17.3) vs. 12.6 (11.3-13.5); left: 16.0 (13.3-17.5) vs. 12.3 (10.6-13.5)] and calcarine sulcus depth [right (mm): 17.5 (16.1-18.7) vs. 15.4 (14.4-16.3); left: 16.7 (15.6-18.9) vs. 14.6 (14.1-15.6)], p0.001; and a significantly larger upper and lower Sylvian fissure angle [upper, right (°): 42.8 (35.8-45.8) vs. 48.9 (38.4-64.7); left: 40.9 (34.2-45.8) vs. 48.2 (41.9-60.7)], [lower, right: 41.6 (34.4-49.2) vs. 48.9 (40.6-60.9); left: 42.2 (38.8-46.9) vs. 48.9 (39.5-57.5)]; p0.05. In addition, the infected fetuses had a significantly lower cortical-grading in the temporal and parietal areas, and the parieto-occipital and calcarine sulcus compared to healthy fetuses (p0.05). These differences persisted when adjusting for gestational age, ipsilateral atrium width, fetal gender and considering being small for gestational age as a confounding/interacting factor.Unaffected and mildly affected CMV-infected fetuses with mild sonographic involvement showed underdeveloped cortical maturation compared to healthy controls. These results suggest that congenital CMV-infection, even in non-severely affected fetuses, which are typically considered of good prognosis, could be related to altered brain cortical structure. Further research is warranted to better elucidate its correlation with neurodevelopmental outcomes. This article is protected by copyright. All rights reserved.

The Perseverance rover landed in Jezero crater, Mars, in February 2021. We used the Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument to perform deep-ultraviolet Raman and fluorescence spectroscopy of three rocks within the crater. We identify evidence for two distinct ancient aqueous environments at different times. Reactions with liquid water formed carbonates in an olivine-rich igneous rock. A sulfate-perchlorate mixture is present in the rocks, which probably formed by later modifications of the rocks by brine. Fluorescence signatures consistent with aromatic organic compounds occur throughout these rocks and are preserved in minerals related to both aqueous environments.

We compare the stable isotope compositions of Zn, S, and Cl for Apollo mare basalts to better constrain the sources and timescales of lunar volatile loss. Mare basalts have broadly elevated yet limited ranges in δ66Zn, δ34S, and δ37ClSBC+WSC values of 1.27 ± 0.71, 0.55 ± 0.18, and 4.1 ± 4.0‰, respectively, compared to the silicate Earth at 0.15, –1.28, and 0‰, respectively. We find that the Zn, S, and Cl isotope compositions are similar between the low- and high-Ti mare basalts, providing evidence of a geochemical signature in the mare basalt source region that is inherited from lunar formation and magma ocean crystallization. The uniformity of these compositions implies mixing following mantle overturn, as well as minimal changes associated with subsequent mare magmatism. Degassing of mare magmas and lavas did not contribute to the large variations in Zn, S, and Cl isotope compositions found in some lunar materials (i.e., 15‰ in δ66Zn, 60‰ in δ34S, and 30‰ in δ37Cl). This reflects magma sources that experienced minimal volatile loss due to high confining pressures that generally exceeded their equilibrium saturation pressures. Alternatively, these data indicate effective isotopic fractionation factors were near unity. Our observations of S isotope compositions in mare basalts contrast to those for picritic glasses (Saal and Hauri 2021), which vary widely in S isotope compositions from –14.0 to 1.3‰, explained by extensive degassing of picritic magmas under high-P/PSat values (>0.9) during pyroclastic eruptions. The difference in the isotope compositions of picritic glass beads and mare basalts may result from differences in effusive (mare) and explosive (picritic) eruption styles, wherein the high-gas contents necessary for magma fragmentation would result in large effective isotopic fractionation factors during degassing of picritic magmas. Additionally, in highly vesiculated basalts, the δ34S and δ37Cl values of apatite grains are higher and more variable than the corresponding bulk-rock values. The large isotopic range in the vesiculated samples is explained by late-stage low-pressure “vacuum” degassing (P/PSat ~ 0) of mare lavas wherein vesicle formation and apatite crystallization took place post-eruption. Bulk-rock mare basalts were seemingly unaffected by vacuum degassing. Degassing of mare lavas only became important in the final stages of crystallization recorded in apatite—potentially facilitated by cracks/fractures in the crystallizing flow. We conclude that samples with wide-ranging volatile element isotope compositions are likely explained by localized processes, which do not represent the bulk Moon.

Same-day discharge (SDD) following left atrial appendage closure (LAAC) is increasingly common but predictors of successful SDD and 1-year clinical outcomes have not been described.The purpose of this study was to explore predictors of successful SDD and report 1-year outcomes in patients undergoing LAAC with SDD.A prospective analysis was performed over a 20-month period of 225 consecutive patients that underwent LAAC in a large, academic hospital. All patients included in the study underwent a SDD protocol. Baseline characteristics and 1-year outcomes of patients discharged same day of the procedure versus those that required at least one overnight stay were compared. Adverse events, procedural success, and procedure times were evaluated.One hundred and sixty-one patients (72%) of patients were discharged the same day and 64 patients (28%) required at least an overnight stay (non-SDD: NSDD). NSDD patients were older and more often female. Procedure time was also longer in the NSDD group than in the SDD (63.4 vs. 55.1 min; p = 0.01). While overall procedural success rates were similar between the SDD and NSDD groups (99.4% vs. 98.4%; p = 0.39), NSDD patients had more complications (9.4% vs. 0%; p = 0.01) and higher number of devices per procedure (1.2 vs. 1.0; p = 0.01) as compared to SDD. At 1 year, there were no significant difference between the SDD and NSDD groups in stroke (1.1% vs. 0%; log-rank p = 0.44) and all-cause mortality (3.9% vs. 4.7%; log-rank p = 0.70).In this single-center LAAC experience, female sex, older age, and longer procedure duration were associated with higher likelihood for need of overnight stay. At 1-year follow-up, there were no significant differences in stroke events and death rates between SDD and NSDD groups.

The Mars 2020 Perseverance rover landed in Jezero crater on 18 February 2021. After a 100‐sol period of commissioning and the Ingenuity Helicopter technology demonstration, Perseverance began its first science campaign to explore the enigmatic Jezero crater floor, whose igneous or sedimentary origins have been much debated in the scientific community. This paper describes the campaign plan developed to explore the crater floor's Máaz and Séítah formations and summarizes the results of the campaign between sols 100–379. By the end of the campaign, Perseverance had traversed more than 5 km, created seven abrasion patches, and sealed nine samples and a witness tube. Analysis of remote and proximity science observations show that the Máaz and Séítah formations are igneous in origin and composed of five and two geologic members, respectively. The Séítah formation represents the olivine‐rich cumulate formed from differentiation of a slowly cooling melt or magma body, and the Máaz formation likely represents a separate series of lava flows emplaced after Séítah. The Máaz and Séítah rocks also preserve evidence of multiple episodes of aqueous alteration in secondary minerals like carbonate, Fe/Mg phyllosilicates, sulfates, and perchlorate, and surficial coatings. Post‐emplacement processes tilted the rocks near the Máaz‐Séítah contact and substantial erosion modified the crater floor rocks to their present‐day expressions. Results from this crater floor campaign, including those obtained upon return of the collected samples, will help to build the geologic history of events that occurred in Jezero crater and provide time constraints on the formation of the Jezero delta.

The American Institute for Medical and Biological Engineering (AIMBE) hosted a virtual symposium titled “Diversifying Paths to Academic Leadership” on January 27 and 28, 2022. The symposium sought to educate the community on the opportunities for and impact of leadership by biomedical engineering faculty, to encourage and invite women faculty, especially women of color, to consider and prepare to pursue leadership roles, to educate faculty on the expectations and duties of these roles, and to highlight experiences and paths to leadership of women engineering leaders. Here we review the main outcomes of the symposium to provide perspective on (1) personal visioning and positioning for leadership, (2) negotiating for success in leadership positions, and (3) leadership strategies for success specific to women faculty and where applicable, faculty of color.

Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell cross-talk are largely unknown. We evaluated the role of integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counterreceptor for platelet glycoprotein (GP) Ibα. In a dynamic coincubation model, we observed interaction of human platelets with monocyte-derived DCs, but also that platelet activation induced a sharp increase in heterotypic cell binding. Inhibition of CD11b or GPIbα led to significant reduction of DC adhesion to platelets in vitro independent of GPIIbIIIa, which we confirmed using platelets from Glanzmann thrombasthenia patients and transgenic mouse lines on C57BL/6 background (GPIbα−/−, IL4R-GPIbα-tg, and muMac1 mice). In vivo, inhibition or genetic deletion of CD11b and GPIbα induced a significant reduction of platelet-mediated DC adhesion to the injured arterial wall. Interestingly, only intravascular antiCD11b inhibited DC recruitment, suggesting a dynamic DC–platelet interaction. Indeed, we could show that activated platelets induced CD11b upregulation on Mg2+-preactivated DCs, which was related to protein kinase B (Akt) and dependent on P-selectin and P-selectin glycoprotein ligand 1. Importantly, specific pharmacological targeting of the GPIbα–Mac-1 interaction site blocked DC–platelet interaction in vitro and in vivo. These results demonstrate that cross-talk of platelets with DCs is mediated by GPIbα and Mac-1, which is upregulated on DCs by activated platelets in a P-selectin glycoprotein ligand 1–dependent manner.

Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate–specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a prostate cancer xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients.Significance: The tyrosine kinase BMX is negatively regulated by androgen and contributes to castration-resistant prostate cancer by enhancing the phosphorylation and activation of multiple receptor tyrosine kinases following ADT. Cancer Res; 78(18); 5203–15. ©2018 AACR.

Figure S1. Inducible BMX knockdown suppresses CWR22RV1 tumor growth in vitro and in vivo; Figure S2. Schematic picture of BMX signaling pathway; Figure S3. The effect of BMX SiRNA smart pool on CWR22RV1 cell response to serum stimulation; Figure S4. The specificity of BMX antibody; Figure S5. Affymetrix microarray expression of BMX in PCa patients; Figure S6. BMX mRNA expression is repressed by DHT; Figure S7. BMX knockdown in CWR22RV1 cells; Figure S8. AR binding site sequence in BMX loci; Figure S9. DHT effect on expression of AR and associated proteins.

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Activation of lymphocyte function–associated antigen-1 (LFA-1) by chemokines is fine-tuned by inside-out signaling mechanisms responsible for integrin-mediated adhesion modulation. In the present study, we investigated the possibility of qualitative variability of signaling mechanisms controlling LFA-1 activation in chronic lymphocytic leukemia (CLL) cells. We pursued a multiplexed comparative analysis of the role of the recently described chemokine-triggered rho-signaling module in human normal versus CLL B-lymphocytes. We found that the rho-module of LFA-1 affinity triggering is functionally conserved in normal B-lymphocytes. In contrast, in malignant B-lymphocytes isolated from patients with B-CLL, the role of the rho-module was not maintained, showing remarkable differences and variability. Specifically, RhoA and phospholipase D1 were crucially involved in LFA-1 affinity triggering by CXCL12 in all analyzed patients. In contrast, Rac1 and CDC42 involvement displayed a consistent patient-by-patient variability, with a group of patients showing LFA-1 affinity modulation totally independent of Rac1 and CDC42 signaling activity. Finally, phosphatidylinositol-4-phosphate 5-kinase isoform 1γ (PIP5KC) was found without any regulatory role in all patients. The data imply that the neoplastic progression may completely bypass the regulatory role of Rac1, CDC42, and PIP5KC, and show a profound divergence in the signaling mechanisms controlling integrin activation in normal versus neoplastic lymphocytes, suggesting that patients with CLL can be more accurately evaluated on the basis of the analysis of signaling mechanisms controlling integrin activation. Our findings could potentially affect the diagnosis, prognosis, and therapy of CLL disorders. [Cancer Res 2009;69(24):9281–90]

Supplementary Table 1 from Comparative Analysis of Normal versus CLL B-Lymphocytes Reveals Patient-Specific Variability in Signaling Mechanisms Controlling LFA-1 Activation by Chemokines

The first samples collected by the Mars 2020 mission represent units exposed on the Jezero Crater floor, from the potentially oldest Séítah formation outcrops to the potentially youngest rocks of the heavily cratered Máaz formation. Surface investigations reveal landscape-to-microscopic textural, mineralogical, and geochemical evidence for igneous lithologies, some possibly emplaced as lava flows. The samples contain major rock-forming minerals such as pyroxene, olivine, and feldspar, accessory minerals including oxides and phosphates, and evidence for various degrees of aqueous activity in the form of water-soluble salt, carbonate, sulfate, iron oxide, and iron silicate minerals. Following sample return, the compositions and ages of these variably altered igneous rocks are expected to reveal the geophysical and geochemical nature of the planet’s interior at the time of emplacement, characterize martian magmatism, and place timing constraints on geologic processes, both in Jezero Crater and more widely on Mars. Petrographic observations and geochemical analyses, coupled with geochronology of secondary minerals, can also reveal the timing of aqueous activity as well as constrain the chemical and physical conditions of the environments in which these minerals precipitated, and the nature and composition of organic compounds preserved in association with these phases. Returned samples from these units will help constrain the crater chronology of Mars and the global evolution of the planet’s interior, for understanding the processes that formed Jezero Crater floor units, and for constraining the style and duration of aqueous activity in Jezero Crater, past habitability, and cycling of organic elements in Jezero Crater.

Introduction:Neutrophil transmigration is multifactorial and primarily driven by selectins and β2-integrins (CD11b/CD18), whose expression are dependent on the underlying stimulus. Ventilator-induced lung injury (VILI) results in a predominantly CD18-independent mechanism of neutrophil recruitment, while direct endotoxin-induced lung injury results from a CD18-dependent mechanism. We previously observed that lack of NADPH oxidases DUOX1 and DUOX2 resulted in reduced neutrophil influx in a VILI model of lung injury but had no influence on neutrophil influx after LPS exposure. Based on these observations, we hypothesized that DUOX1/DUOX2 are an important component of CD18-independent mechanisms of neutrophil recruitment in the lung.Methods:We exposedDuoxa−/−(KO) mice andDuoxa+/+(WT) mice to either an intratracheal exposure of lipopolysaccharide (LPS/endotoxin)-or high tidal volume ventilation and compared expression of neutrophil markers between groups. WT mice (129S6/SvEvTac) were obtained from Taconic Biosciences (One Discovery Drive Suite 304; Rensselaer, NY 1244) and were allowed to acclimatize for one week prior to study enrollment. KO mice were generated as previously described [Grasberger 2012] and bred in-house on a 129S6 background. We provided positive-pressure ventilation at a tidal volume of 10 ml/kg with 2 cmH20 positive end-expiratory pressure (PEEP). Mice were assigned to groups consisting of KO (n = 5) and WT (n = 5) in each group and divided into non-ventilated, positive-pressure ventilation, or LPS IT exposure groups. Positive-pressure ventilation was instituted for 4-h using a FlexiVent (Flexiware 8.1, Scireq, Montreal, QC, Canada). Lipopolysaccharide (Salmonella enterica serotype tryphimurium L6143, Millipore Sigma) was administered via an intratracheal (IT) route at a dose of 0.1 mg/kg. Mice were humanely euthanized at 4-h post-injection consistent with the UC Davis IAUCAC-approved protocol.Results:As previously observed, neutrophilic influx into the airways was significantly impaired in theDuoxa−/−(KO) mice after VILI, but not after LPS exposure. LPS-induced lung injury resulted in upregulation of CD11b+neutrophils and shedding of CD62L and CD162 regardless of DUOX expression, whereas VILI resulted in upregulation of CD49+neutrophils in theDuoxa+/+(WT) mice but not theDuoxa−/−(KO) mice.Conclusion:Our data suggest DUOX is required for CD18-independent mechanisms of neutrophil recruitment in the lung induced by acute lung injury, but not for canonical CD18depedent mechanisms after LPS exposure.

The epidural space is commonly accessed via an interlaminar or transforaminal approach to administer corticosteroids for radicular pain. An alternative is a transarticular approach, which may be considered when conventional access to the epidural space is either not desired or contraindicated. This approach has been described in the cervical spine using computed tomography guidance but not fluoroscopic guidance. We describe a cervical transarticular approach to the epidural space under fluoroscopy and review the computed tomography-guided literature. The risks of transarticular epidural injections are likely low given that when performed prudently, they avoid direct contact with the vertebral artery, spinal medullary arteries, venous plexus, spinal cord, and nerve roots.

Clinically used inhibitors of mammalian target of rapamycin (mTOR) negatively impacts endothelial-dependent vasodilatation (EDD) through unidentified mechanisms. Here we show that either the endothelium-specific deletion of Mtor to inhibit both mTOR complexes, or depletion of Raptor or Rictor to disrupt mTORC1 or mTORC2, causes impaired EDD, accompanied by reduced NO in the serum of mice. Consistently, inhibition of mTOR decreases NO production by human and mouse EC. Specifically, inhibition of mTORC1 suppresses eNOS gene expression, due to impairment in p70S6K-mediated posttranscriptional regulation of the transcription factor KLF2 expression. In contrast to mTORC1 inhibition, a positive-feedback between MAPK (p38 and JNK) activation and Nox2 upregulation contributes to the excessive generation of reactive oxygen species (ROS), which causes eNOS uncoupling and decreased NO bioavailability in mTORC2-inhibited EC. Adeno-associated virus-mediated EC-specific overexpression of KLF2 or suppression of Nox2 restores EDD function in endothelial mTORC1- or mTORC2-inhibited mice.

Recognition of integrins by CD62P has not been reported and this motivated a docking simulation using integrin αvβ3 as a target. We predicted that the C-type lectin domain of CD62P functions as a potential integrin ligand and observed that it specifically bound to soluble β3 and β1 integrins. Known inhibitors of the interaction between CD62P–PSGL-1 did not suppress the binding, whereas the disintegrin domain of ADAM-15, a known integrin ligand, suppressed recognition by the lectin domain. Furthermore, an R16E/K17E mutation in the predicted integrin-binding interface located outside of the glycan-binding site within the lectin domain, strongly inhibited CD62P binding to integrins. In contrast, the E88D mutation that strongly disrupts glycan binding only slightly affected CD62P-integrin recognition, indicating that the glycan and integrin-binding sites are distinct. Notably, the lectin domain allosterically activated integrins by binding to the allosteric site 2. We conclude that CD62P-integrin binding may function to promote a diverse set of cell–cell adhesive interactions given that β3 and β1 integrins are more widely expressed than PSGL-1 that is limited to leukocytes.

Professor Teruo Inoue and his collaborators are exploring repair from vascular and myocardial injury in the context of stem cell biology in work that is set to make waves in regenerative medicine. This research involves endothelial progenitor cells (EPCs) for vascular repair, adipose-derived regenerative cells (ADRCs) for angiogenesis and multilineage differentiating stress enduring cell (Muse) cells for myocardial repair. Inoue and his collaborators are also investigating the 'wound repair priming' phenomenon with a view to overcoming the challenge of the inconsistent capacities of angiogenesis due to individual differences in cell quality. The researchers found that the ADRCs (also called adipose-derived stromal fractions: SVFs) obtained from subcutaneous fat after manipulation caused by surgical injury as well as ischaemia showed higher angiogenetic ability. The researchers plan to pharmacologically reproduce wound repair priming in order to facilitate more consistent cell therapy using ADRCs. The team is also exploring other promising functional analysis methods for stem cells, including comprehensive gene analysis using single cell RNA sequence (scRNA seq), which the researchers plan to apply to Muse cells. In addition to Muse cell research targeting myocardial repair, the team will also conduct Muse cell vascular research as they believe that Muse cell treatment holds great promise for the repair of injured-vessel sites. Ultimately, Inoue and his collaborators hope their work will significantly impact medical research and clinical medicine.

Radiculopathy is diagnosed using a combination of history, physical examination, and imaging. Unfortunately, well-established dermatomal and myotomal maps are an oversimplification of the convoluted nature of spinal sensory and motor innervation. When clinical presentation and imaging seemingly contradict one another, it is important to consider variant innervation patterns. This article presents three patients with objective dermatomal and/or myotomal deficits due to disc herniations whose clinical presentations are "textbook" for nerve root pathology that is adjacent to the nerve root that is actually compromised. In addition, the literature is reviewed to discuss the history of dermatomal and myotomal maps, the effectiveness of a clinician's ability to determine the precise pathologic disc and nerve root level in patients presenting with radiculopathy, and anatomical explanations as to why inconsistencies such as those seen in the patients in these cases exist.

Prior studies have suggested significant underutilization of statins in women and worse cardiovascular outcomes. Data examining the impact of real-world coronary artery calcium (CAC) scoring to improve utilization of preventive therapies and outcomes is limited.In a prospective registry study of low cost or no-cost CAC scoring between 2014 and 19 (CLARIFY Study, Clinicaltrials.gov NCT04075162), we sought to study the association of CAC scoring on statin utilization, blood lipids (LDL, total cholesterol, triglycerides), downstream ischemic testing (coronary angiography and stress testing), coronary revascularization and outcomes (MI, stroke, death) in women compared with men. Eligibility for statin initiation was defined as atherosclerotic cardiovascular disease pooled cohort equation (ASCVD-PCE) ≥ 7.5% and CAC≥100/≥75th percentile.A total of 52,151 patients (26,336 women and 25,815 men) were enrolled. Women were more likely to have CAC 0 (51% vs 30%,CAC scoring primarily served to downgrade statin eligibility in women compared with men. Women had similar CAC risk-guided reductions in LDL cholesterol compared with men.

Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including surveillance, salvage radiation, androgen deprivation therapy (ADT), and clinical trials. This article reviews the current approaches to radiation therapy, ADT, and molecular imaging in men with biochemically recurrent prostate cancer. First, radiation therapy, including selection of field, dose, and use of concurrent antiandrogen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease. Finally, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.

Outgoing

Male reproductive maladaptive responses are becoming a global health concern and also a social issue. Polychlorinated biphenyls (PCBs) are a member of halogenated aromatic environmental pollutants with diverse environmental matrices. This study was conducted to explore the mechanisms of PCBs-induced testicular maladaptive responses and the potential reversal effects of d-ribose- l-cysteine (DRLC) on testicular injury induced by administration of PCBs (2 mg/kg) for 30 days. DRLC (50 mg/kg) was administered orally for 15 days starting from Days 16 to 30 after the initial 15 days of treatment with PCB. All assays were carried out using established protocols. Administration of DRLC at 50 mg/kg after treatment with PCBs enhances body and testicular weights, gonadotropins (luteinizing hormone and follicle-stimulating hormone), testosterone and poor sperm quality. DRLC also reduced testicular injury score, improved spermatogenesis scoring, reduced oxidative stress biomarkers (malondialdehyde), as well as restored the reduced activities of antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) and decreases pro-inflammatory response (tumor necrosis factor-alpha and NO). More so, DRLC treatment abrogates testicular DNA fragmentation and downregulated p53 and caspase 3 activities and upregulated the concentration of autophagy-related protein (mammalian target of rapamycin [mTOR] and Atg7). DRLC abates testicular deficit induced by PCBs intoxicated rats via activation of the mTOR signaling pathway mediating inhibition of apoptosis, Inflammation and oxidative flux.

Intermediate monocytes (iMo; CD14+CD16+) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity β2-integrin (CD11c/CD18) that activates β1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk– and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-κB and production of IL-1β+. We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.

Background Red cell distribution width (RDW), a measure of anisocytosis, is observed in chronic inflammation and is a prognostic marker in critically ill patients without COVID-19, but data in COVID-19 are limited. Methods Between March 12 and April 19, 2020, 282 individuals with confirmed COVID-19 and RDW available within 7 days prior to COVID-19 confirmation were evaluated. Individuals were grouped by quartiles of RDW. Association between quartiles of RDW and mortality was assessed using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. The association between RDW and all-cause mortality was further assessed using a Cox proportional hazards model. Plasma cytokine levels in uninfected ambulatory adults without cardiovascular disease (n=38) were measured and bivariate Spearman correlations and principle components analysis were used to identify relationships between cytokine concentrations with RDW. Results After adjusting for age, sex, race, cardiovascular disease, and hemoglobin, there was an association between RDW and mortality (Quartile 4 vs Quartile 1: HR 4.04 [1.08-15.07]), with each 1% increment in RDW associated with a 39% increased rate of mortality (HR 1.39 [1.21-1.59]). Remote RDW was also associated with mortality after COVID-19 infection. Among uninfected ambulatory adults without cardiovascular disease, RDW was associated with elevated pro-inflammatory cytokines (TNF- α , IL8, IL6, IL1b), but not regulatory cytokines (TGFb). Conclusions Anisocytosis predicts short-term mortality in COVID-19 patients, often predates viral exposure, and may be related to a pro-inflammatory phenotype. Additional study of whether the RDW can assist in the early identification of pending cytokine storm is warranted.

Lunar mare basalts are depleted in F and Cl by approximately an order of magnitude relative to mid-ocean ridge basalts and contain two Cl-bearing components with elevated isotopic compositions relative to the bulk-Earth value of ∼0‰. The first is a water-soluble chloride constituting 65 ± 10% of total Cl with δ(37)Cl values averaging 3.0 ± 4.3‰. The second is structurally bound chloride with δ(37)Cl values averaging 7.3 ± 3.5‰. These high and distinctly different isotopic values are inconsistent with equilibrium fractionation processes and instead suggest early and extensive degassing of an isotopically light vapor. No relationship is observed between F/Cl ratios and δ(37)Cl values, which suggests that lunar halogen depletion largely resulted from the Moon-forming Giant Impact. The δ(37)Cl values of apatite are generally higher than the structurally bound Cl, and ubiquitously higher than the calculated bulk δ(37)Cl values of 4.1 ± 4.0‰. The apatite grains are not representative of the bulk rock, and instead record localized degassing during the final stages of lunar magma ocean (LMO) or later melt crystallization. The large variability in the δ(37)Cl values of apatite within individual thin sections further supports this conclusion. While urKREEP (primeval KREEP [potassium/rare-earth elements/phosphorus]) has been proposed to be the source of the Moon’s high Cl isotope values, the ferroan anorthosites (FANs) have the highest δ(37)Cl values and have a positive correlation with Cl content, and yet do not contain apatite, nor evidence of a KREEP component. The high δ(37)Cl values in this lithology are explained by the incorporation of a >30‰ HCl vapor from a highly evolved LMO.

Background Inadvertent intravascular injection has been suggested as the most probable mechanism behind serious neurological complications during transforaminal epidural steroid injections. Authors believe a smaller gauge needle may lead to less intravascular uptake and less pain. Theoretically, there is less chance for a smaller gauge needle to encounter a blood vessel during an injection compared to a larger gauge needle. Studies have also shown smaller gauge needle to cause less pain. The aim of the study was to quantify the difference between a 22-gauge needle and 25-gauge needle during lumbosacral transforaminal epidural steroid injection in regards to intravascular uptake and pain perception. Methods This was a prospective single blind randomized clinical trial performed at outpatient spine practice locations of two academic institutions. One hundred sixty-two consecutive patients undergoing lumbosacral transforaminal epidural injections from February 2018 to June 2019 were recruited and randomized to each arm of the study – 84 patients were randomized to the 22-gauge needle arm and 78 patients to 25-gauge arm. Each transforaminal injection level was considered a separate incidence, hence total number of incidence was 249 (136 in 22-gauge arm and 113 in 25-gauge arm). The primary outcome measure was intravascular uptake during live fluoroscopy and/or blood aspiration. The secondary outcome measure was patient reported pain during the procedure on the numerical rating scale. Results Fisher exact test was used to detect differences between 2 groups in regards to intravascular uptake and paired t-tests were used to detect differences in pain scores. The incidence of intravascular uptake for a 22-gauge needle was 5.9% (95% confidence interval: 1.9 to 9.8%) and for a 25-gauge needle, 7.1% (95% confidence interval: 2.4 to 11.8%) [p = 0.701]. Average numerical rating scale scores during the initial needle entry for 22-gauge and 25-gauge needle was 3.46 (95% confidence interval: 2.94 to 3.98) and 3.13 (95% confidence interval: 2.57 to 3.69) respectively [p = 0.375]. Conclusions The study showed no statistically significant difference in intravascular uptake or pain perception between a 22-gauge needle and 25-gauge needle during lumbosacral transforaminal epidural steroid injections. Trial registration ClinicalTrials.gov NCT04350307. Registered 4/17/2020. (Retrospectively registered).

Objectives The aim of this study was to develop and validate a risk prediction model for high-grade atrioventricular block requiring cardiac implantable electronic device (CIED) implantation after transcatheter aortic valve replacement (TAVR). Background High-grade atrioventricular block requiring CIED remains a significant sequelae following TAVR. Although several pre-operative characteristics have been associated with the risk of post-operative CIED implantation, an accurate and validated risk prediction model is not established yet. Methods This was a single center, retrospective study of consecutive patients who underwent TAVR from March 10, 2011, to October 8, 2018. This cohort sample was randomly divided into a derivation cohort (group A) and a validation cohort (group B). A scoring system for risk prediction of post-TAVR CIED implantation was devised using logistic regression estimates in group A and the calibration and validation were done in group B. Results A total of 1,071 patients underwent TAVR during the study period. After excluding pre-existing CIED, a total of 888 cases were analyzed (group A: 507 and group B: 381). Independent predictive variables were as follows: self-expanding valve (1 point), hypertension (1 point), pre-existing first-degree atrioventricular block (1 point), and right bundle branch block (2 points). The resulting score was calculated from the total points. The internal validation in group B showed an ideal linear relationship in calibration plot (R2 = 0.933) and a good predictive accuracy (area under the curve: 0.693; 95% confidence interval: 0.627 to 0.759). Conclusions This prediction model accurately predicts post-operative risk of CIED implantation with simple pre-operative parameters.

Aims Mammalian target of rapamycin (mTOR) inhibitors used in drug-eluting stents (DES) to control restenosis have been found to delay endothelialization and increase incidence of late-stent thrombosis through mechanisms not completely understood. We revealed that mTOR inhibition (mTORi) upregulated the expression of cell growth suppressor IRF-1 in primary human arterial endothelial cells (HAEC). This study aimed to examine how mTOR-regulated IRF-1 expression contributes to the suppressive effect of mTORi on arterial endothelial proliferation. Methods and results Western blotting, quantitative PCR, and a dual-luciferase reporter assay indicated that mTOR inhibitors rapamycin and torin 1 upregulated IRF-1 expression and increased its transcriptional activity. IRF-1 in turn contributed to the suppressive effect of mTORi by mediating HAEC apoptosis and cell cycle arrest in part through upregulation of caspase 1 and downregulation of cyclin D3, as revealed by CCK-8 assay, Annexin V binding assay, measurement of activated caspase 3, BrdU incorporation assay, and matrigel tube formation assay. In a mouse model of femoral artery wire injury, administration of rapamycin inhibited EC recovery, an effect alleviated by EC deficiency of IRF-1. Chromatin immunoprecipitation assay with HAEC and rescue expression of wild type or dominant-negative IRF-1 in EC isolated from Irf1−/− mice confirmed transcriptional regulation of IRF-1 on the expression of CASP1 and CCND3. Furthermore, mTORi activated multiple PKC members, among which PKCζ was responsible for the growth-inhibitory effect on HAEC. Activated PKCζ increased IRF1 transcription through JAK/STAT-1 and NF-κB signaling. Finally, overexpression of wild type or mutant raptor incapable of binding mTOR indicated that mTOR-free raptor contributed to PKCζ activation in mTOR-inhibited HAEC. Conclusions The study reveals an IRF-1-mediated mechanism that contributes to the suppressive effects of mTORi on HAEC proliferation. Further study may facilitate the development of effective strategies to reduce the side effects of DES used in coronary interventions.

The absence of septum pellucidum (ASP) is a rare disease, which affects the structure of the brain. It is either isolated or associated with various congenital brain malformations. The diagnosis of ASP can be performed by second‐trimester ultrasound. When the ASP is isolated, prenatal counseling is optimistic regarding neurological outcome, but there is a 20% risk of septo‐optic dysplasia in the neonate.

Objective: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr –/– mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr –/– mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c + foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin–coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c + macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. Conclusions: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr –/– mice.

Percutaneous left atrial appendage occlusion (LAAO) with the Watchman device is FDA approved for stroke prevention in patients with nonvalvular atrial fibrillation who have an appropriate indication. During the COVID-19 pandemic, a same-day discharge protocol (SDDP) was employed to improve resource utilization, relieve hospital occupation, and reduce the possible risk of in-hospital virus transmission.We sought to analyze the safety, feasibility, and cost effectiveness for SDDP in patients receiving LAAO.A prospective analysis of 142 consecutive patients, 119 treated prior to SDDP and 23 who underwent SDDP following LAAO with cardiac computed tomography angiography (CTA)-guided pre-procedural planning and intracardiac echocardiogram (ICE). Procedures were performed in a single, large academic hospital in the United States. In-hospital and 45-day procedural success, adverse events, length of procedure, and length-of-stay were evaluated.Baseline patient characteristics including mean CHA2DS2VASc scores and mean HAS-BLED scores were similar in both groups. All procedures were successful. There was no significant difference in rates of procedural complications or in-hospital adverse events. The mean procedure time in the SDDP group was 11 minutes longer than in the conventional group (62.1 ± 5.9 vs 51.1 ± 21; P=.01). Outcomes at 45-day follow-up were similar. SDDP was associated with a reduced length of stay compared with conventional strategy and a 15% reduction in total costs.Same-day discharge strategy for LAAO appears safe, feasible and could become the new standard approach for LAAO. A protocol including CTA pre-procedural planning, ICE-guided deployment and conscious sedation reduces hospital occupation and lowers costs.

Aims Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signaling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signaling. Methods and results Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store operated Ca2+ entry (SOCE) through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signaling, thereby preventing cellular spreading, adhesion strengthening and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of E.coli particles by neutrophils in the absence of KV1.3. Conclusion We show that the voltage gated potassium channel KV1.3 is critical for Ca2+ signaling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signaling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration. Translational perspective Neutrophils exert important immune functions during tissue injury or bacterial infection through leaving the vasculature and extravasate into affected tissues. Conversely, neutrophils trigger the pathogenesis of acute and chronic inflammatory disorders and are involved in the development and maintenance of various autoimmune diseases. Within this study, we show that the voltage-gated potassium channel KV1.3 is functionally expressed on neutrophils and affects calcium signaling thereby regulating neutrophil effector functions during immune responses. Hence, KV1.3 represents an interesting potential new target to treat unwanted excessive neutrophil invasion in various disorders ranging from autoinflammatory disorders to ischemic tissue injury.

Songklanakarin Journal of Science an Technology (SJST), 44, 6, 1473-1480

467 Background: Neuroendocrine, small cell, or large cell carcinoma originating from the urothelium (uro-NE/SCC/LCC) is rare. Outcomes for metastatic disease are dismal. Treatment is extrapolated from small cell lung cancer, for which immune checkpoint inhibitors (ICIs) have modest activity. Preliminary activity has been reported with ICI for uro-NE. We aimed to compare real-world progression-free survival (PFS) and overall survival (OS) between ICI-containing and non-ICI-containing regimens in the first line (1L) metastatic setting for uro-NE/SCC/LCC. Methods: We performed a retrospective study at 11 cancer centers. Patients (pts) who received systemic therapy (2011-2021) for biopsy confirmed metastatic uro-NE/SCC/LCC were included. Pts with metastasis within 6 months of (neo)adjuvant chemotherapy (CT) (n=16) were excluded from 1L analyses. Results: 102 pts with metastatic uro-NE/SCC/LCC were evaluable. 17 (16.7%) had NE histology, 81 (79.4%) SCC, and 4 (3.9%) LCC. NE/SCC/LCC was mixed with urothelial histology in 19 (18.6%). Primary tumors were most often in the bladder (84.3%, n=86), less frequently upper tract (11.8%, n=12) or urethra (3.9%, n=4). 42 pts (41.2%) were previously treated for localized disease, the rest were de novo metastatic (n=60, 58.8%). Pts who received an ICI in any line (n=61) had significantly longer OS (p=0.038) than pts that never received an ICI (n=41). As shown in the table, in the 1L, ICI-containing regimens (n=33) resulted in significantly longer PFS, but not OS or ORR compared to non-ICI regimens (n=53). Subdividing 1L regimens into ICI without CT (n=14), CT without ICI (n=53), or ICI + CT (n=19), both PFS and OS were significantly different with similar ORR. ICI w/o CT had the longest median PFS and OS with an ORR 57.1% comparable to CT regimens. Of 61 pts that received ICI in any line, 14 (23.0%) had an immune-related adverse event of any grade; 11 (18.0%) received steroids. Conclusions: This is the largest ever report of ICI for metastatic uro-NE/SCC/LCC. ICIs were associated with improved outcomes with expected added toxicity. Further prospective investigation of ICI regimens is warranted. [Table: see text]

492 Background: The development and selection of treatments for locally advanced or metastatic urothelial carcinoma (la/mUC) have historically focused on clinical outcomes while stakeholder preferences are often considered less frequently. To facilitate the consideration of various perspectives, this study explored factors that may influence preferences of patients, caregivers, and physicians around aspects of la/mUC treatments. Methods: Interview guides elicited perspectives on disease impact (symptoms, health-related quality of life [HRQOL], survival), therapy goals and unmet needs and were conducted with patients with la/mUC, their caregivers, and medical oncologists in the US. Qualitative semi-structured data were collected on symptoms, treatment expectations, and hypothetical treatments that required trade-offs between overall survival (OS), progression-free survival (PFS), cancer pain, and the risk of severe adverse events (SAEs). Participant’s willingness to accept AEs was also explored. Results: Thirty participants, including: 10 patients (mean age 58 years; 60% female, ineligible for cisplatin: 50%), 10 caregivers (mean age 50 years; 70% female), and 10 physicians (mean 17 years treating la/mUC; 30% female) were interviewed. The most frequently reported symptom at diagnosis was pain (patients 90%, caregivers 90%) and blood in urine (physicians 100%). All three groups reported emotional impacts with depression/sadness the most common. Patients (n=7) and caregivers (n=7) relied on physicians for decision-making but felt that alternative treatments were not discussed (patients: n=5; caregivers: n=3). All groups were willing to accept some level of risk of experiencing an AE, but the accepted risk of SAEs varied (patients: 0-50% risk of SAEs; caregivers: 5-100%; physicians: 3-30%). Physicians focused treatment discussions on AEs (n=8), and overall response rate (ORR; n=6), and rarely discussed survival (n=3). All three groups described PFS and treatment response as very or most relevant to them. In the hypothetical choice tasks, all would make trade-offs between OS, PFS, pain reduction and risk of SAEs; consistent with an approach that weighs benefits and risks in treatment selection. Conclusions: Patients likely may benefit from shared, informed decision-making to identify the most appropriate treatment option for them based on clinical outcomes, AEs, HRQOL, and pain control. All groups were willing to make benefit-risk trade-offs but preferences were heterogeneous. While this study included a relatively small number of patients, planned research informed by these results will expand and further identify which treatment attributes are most important to patients.