Transient Appearance Research Articles

Circuit Modeling of the Impact of Heavy Charged Particles on Transient Processes in Bipolar Analog Microcircuits

One of the factors causing the failure of spacecraft integrated circuits is exposure to heavy charged particles. The entry of heavy charged particles into electronic devices leads to the appearance of single event transients (short current pulses), which in analog microcircuits manifest themselves in distortion of the output signal shape, and in digital microcircuits can cause a single event upset. The article discusses a technique for circuit mode-ling of the effect of heavy charged particles on bipolar analog microcircuits, including the developed equivalent electrical circuit of a bipolar transistor for LTSpice and the procedure for modeling transient processes. Despite the simplifications adopted, namely: failure to take into account the dependence of the duration of the rise and fall of the current pulse generated by a charged particle on the parameters of the transistor structure, the assumption that the entire charge is generated in the active base and the space charge regions of the emitter and collector junctions, an equivalent circuit has been developed made it possible to determine that the shape of the collector current pulse for circuit with a common emitter when exposed to a heavy charged particle is determined by the speed of the transistor and its operating mode. Using the developed methodology, the “critical” transistors of the two studied analog microcircuits were determined, and the need to bypass the current-setting resistors with a small capacitor was justified.

Prenatal Manifestation of Transient Abnormal Myelopoiesis: Case Report and Review of the Literature.

Background: Congenital malignancies are unusual fetal conditions, and therefore, the data on their prenatal manifestation are limited. Transient abnormal myelopoiesis (TAM) is a hematologic disorder characteristic for babies with trisomy 21 and based on the transient appearance of blast cells in peripheral blood. Methods: This paper presents prenatal manifestation of congenital TAM in a newborn with normal karyotype and reviews the literature on prenatal manifestation of this disorder. Results: A pregnant woman in her third pregnancy referred herself to the hospital for reduced fetal movements at 30 weeks of gestation. Admission's ultrasound scan showed an increased middle cerebral artery peak systolic velocity together with hepatomegaly. The patient was admitted to the labor ward for cardiotocography monitoring which showed acute fetal distress with repeated unprovoked decelerations. An emergency cesarean section was conducted and a phenotypically normal female newborn with low Apgar score was delivered. Further examination of the peripheral blood revealed anemia and leukocytosis with high blast proportion. A bone marrow aspirate revealed 70.2% of blasts in a sample with an abnormal karyotype of 47 XX+21. Cytogenetic analysis of the blasts with later microarray comparative genomic hybridization confirmed the presence of GATA1 mutation. However, the buccal smear showed a normal karyotype in the infant. The disease was classified as TAM. Conclusions: Our study demonstrates a rare case of prenatal manifestation of TAM in a neonate with a normal karyotype. Obstetricians should pay attention to symptoms like high MCA PSV and hepatosplenomegaly as possible causes of fetal hematological disorders and differentiate it with infection or isoimmunization.

Integration of metataxonomic data sets into microbial association networks highlights shared bacterial community dynamics in fermented vegetables.

Within the growing body of research on the bacterial communities involved in the fermentation of vegetables, there is particular interest in discovering the species or consortia that drive different fermentation steps. This integrative analysis demonstrates that the reuse and integration of public microbiome data sets can provide new insights into a little-known biotope. Our most important finding is the recurrent but transient appearance, at the beginning of vegetable fermentation, of amplicon sequence variants (ASVs) belonging to Enterobacterales and their associations with ASVs belonging to Lactobacillales. These findings could be applied to the design of new fermented products.

An Ayurveda Case Study on GTCS w.s.r to Apasmara Roga

The word ‘Epilepsy’ is derived from Greek meaning- ‘to seize upon’. The disease Apasmara is diagnosed based upon shrewd observation of the symptoms, with the main presenting feature of this disease as “Apaya (loss) of Smriti (memory)” i.e., ‘loss of memory/ consciousness’. Apasmara occurs due to an aberration of not only the physical bio-entities Vata, Pitta and Kapha dosha but also of the psychological (Manasika) attributes like Sattva (harmonious), Rajah (passion/activity), and Tamah (inertia/ignorance). It is presented with transient appearance of unconsciousness (Tamah Pravesha) with abhorrent activities like froth from mouth, abnormal postures of the body (Vibhatsa Cheshta, referring to the involuntary movements during the seizures) and psychological symptoms like perversion of memory and cognition (Smriti-buddhi Samplava). Here the case was pre diagnosed with GTCS (generalised toni-clonic seizures) having symptoms such as decreased memory, epileptic attack 3 months ago which impersonates with Vataja Apasmara. So, in this case study an effort is made to correct the cause and the epileptic attacks with other associated symptoms by giving oral medications having predominantly Vata Shamak properties as well as Shodhana Chikitsa (Nasya).

Abstract 4220: Combined light sheet and multispectral imaging facilitates the detection of tumor-associated tertiary lymphoid structures in the KP NSCLC model

Abstract Tertiary lymphoid structures (TLS) have recently emerged as a predictive biomarker in cancer immunotherapy. Their consideration in preclinical drug development is impeded by rare and transient appearance and random distribution, making them difficult to analyze with conventional sampling methods. We applied whole-organ tissue clearing and 3D staining of B and T cell clusters to comprehensively identify TLS in a KP GEMM of NSCLC using 3D Light Sheet Fluorescence Microscopy (3D LSFM). To further investigate cellular composition of TLS we performed 3D LSFM-educated sectioning of relevant ROIs and cyclic immunofluorescence of the same samples. 3D LSFM facilitated correlation of tumor features and location with T cell infiltration as well as the analysis of number, size and location of TLS. The majority of TLS were located in proximity to bronchi instead of intratumorally. LSFM-guided multiplex immunofluorescence revealed further details on cellular composition and maturation status of TLS. This combination of 3D and 2D imaging modalities offers a holistic approach for the identification of TLS in whole murine tumors or organs. The technology could help studying effects of immunotherapy on de novo formation or maturation of TLS. Citation Format: Nils O'Brien, Birte Appelt, Marie-Lena Moerbitz, Joerg P. Mueller, Frank Herting, Pablo Umaña, Claudio Murgia, Sara Colombetti, Thomas Pöschinger. Combined light sheet and multispectral imaging facilitates the detection of tumor-associated tertiary lymphoid structures in the KP NSCLC model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4220.

Persistence of dengue serotype 2 viral RNA in blood cells of a returned traveler with dengue fever

Dengue virus (DENV) is one of the most significant vector-borne pathogens worldwide. In this report, we describe clinical features and laboratory detection of dengue in a 45-year-old traveler to Nicaragua on return home to the United States in 2019. Clinical presentation was mild, with rash, headache, and fatigue, with only low-grade transient fever. Infection dynamics were documented by serology and PCR of serially collected body fluids. DENV serotype 2 was detected in whole blood 1 day after symptoms emerged, with viral RNA isolated to the red cell fraction, and remained detectable through day 89. DENV-2 RNA was detected in serum only on day 4, and IgM was undetectable on day 4 but evident by day 13. Viral RNA was also detected in urine. This report of DENV-2 RNA persistence in blood cells but only transient appearance in serum, supports the potential diagnostic value of whole blood over serum for PCR and opportunity of an expanded testing window. Informed testing approaches can improve diagnostic accuracy and inform strategies that preserve individual and public health.

Faint calcium-rich transient from a double detonation of a 0.6 M⊙ carbon-oxygen white dwarf star

We have computed a 3D hydrodynamic simulation of the merger between a massive (0.4 M⊙) helium white dwarf (He WD) and a low-mass (0.6 M⊙) carbon-oxygen white dwarf (CO WD). Despite the low mass of the primary, the merger triggers a thermonuclear explosion as a result of a double detonation, producing a faint transient and leaving no remnant behind. This type of event could also take place during common-envelope mergers whenever the companion is a CO WD and the core of the giant star has a sufficiently large He mass. The spectra show strong Ca lines during the first few weeks after the explosion. The explosion only yields < 0.01 M⊙ of 56Ni, resulting in a low-luminosity Type Ia supernova-like light curve that resembles the Ca-rich transients within this broad class of objects, with a peak magnitude of Mbol ≈ −15.7 mag and a rather slow decline rate of Δm15bol ≈ 1.5 mag. Both its light curve shape and spectral appearance resemble the appearance of Ca-rich transients, suggesting such mergers as a possible progenitor scenario for this class of events.

Lateral Decubitus Dynamic CT Myelography with Real-Time Bolus Tracking (dCTM-BT) for Evaluation of CSF-Venous Fistulas: Diagnostic Yield Stratified by Brain Imaging Findings.

CSF-venous fistulas (CVFs) associated with spontaneous intracranial hypotension (SIH) may have a transient appearance, relative to contrast arrival, which may influence the diagnostic performance of lateral decubitus CT myelography (CTM). We developed a dynamic CTM protocol using real-time bolus-tracking (dCTM-BT) to improve the temporal resolution and standardize the timing of CTM acquisitions post-intrathecal contrast administration. The purpose of our study was to evaluate the feasibility of the dCTM-BT technique and evaluate its diagnostic yield for CVF detection, stratified by brain MRI SIH findings. Patients with suspected SIH without extradural fluid collection on spine MRI who underwent dCTM-BT were retrospectively reviewed. CT bolus monitoring was performed at the upper thoracic level. Following the visualization of dense intrathecal contrast, at least 3 CTM acquisitions of the spine were obtained and reviewed by 2 neuroradiologists. The Bern SIH score was calculated on the brain MRI. The diagnostic yield for CVF detection was evaluated, stratified by Bern score categories and a receiver operating characteristic (ROC) analysis. Out of 48 patients, 23 (48%) had a CVF on dCTM-BT, located at T1-5 (n = 4), T6-12 (n = 18), L1 (n = 1), with 70% on the right. CVF was identified in 22/22 (100%) of patients who had a high Bern score, 1/7 (14%) of those who had an intermediate score, and 0/19 (0%) of those who had a low score. The area under the ROC curve was 0.99 (95% CI, 0.98-1.00). The optimal cutoff was a Bern score of ≥5 (96% sensitivity, 100% specificity). dCTM-BT is feasible and has excellent diagnostic performance for CVF identification/localization. The Bern score is strongly associated with CVF detection and may help inform who will benefit from dCTM-BT.

A transient wave of Bhlhe41+ resident macrophages enables remodeling of the developing infarcted myocardium

The immune system plays a critical role during myocardial injury, contributing to repair and remodeling post myocardial infarction (MI). The myocardial infarct and border zone exhibit high heterogeneity, in turn leading to reconstructing macrophage subsets and specific functions. Here we use a combination of single-cell RNA sequencing, spatial transcriptomes, and reporter mice to characterize temporal-spatial dynamics of cardiac macrophage subtype in response to MI. We identify that transient appearance of monocyte-derived Bhlhe41+ Mφs in the "developing" infarct zone peaked at day 7, while other monocyte-derived macrophages are identified in "old" infarct zone. Functional characterization by co-culture of Bhlhe41+ Mφs with cardiomyocytes and fibroblasts or depletion of Bhlhe41+ Mφs unveils a crucial contribution of Bhlhe41+ Mφs in suppression of myofibroblast activation. This work highlights the importance of Bhlhe41+ Mφ phenotype and plasticity in preventing excessive fibrosis and limiting the expansion of developing infarct area.

Intensive care unit sinks are persistently colonized with multidrug resistant bacteria and mobilizable, resistance-conferring plasmids.

Contamination of hospital sinks with microbial pathogens presents a serious potential threat to patients, but our understanding of sink colonization dynamics is largely based on infection outbreaks. Here, we investigate the colonization patterns of multidrug-resistant organisms (MDROs) in intensive care unit sinks and water from two hospitals in the USA and Pakistan collected over 27 months of prospective sampling. Using culture-based methods, we recovered 822 bacterial isolates representing 104 unique species and genomospecies. Genomic analyses revealed long-term colonization by Pseudomonas spp. and Serratia marcescens strains across multiple rooms. Nanopore sequencing uncovered examples of long-term persistence of resistance-conferring plasmids in unrelated hosts. These data indicate that antibiotic resistance (AR) in Pseudomonas spp. is maintained both by strain colonization and horizontal gene transfer (HGT), while HGT maintains AR within Acinetobacter spp. and Enterobacterales, independent of colonization. These results emphasize the importance of proactive, genomic-focused surveillance of built environments to mitigate MDRO spread. IMPORTANCE Hospital sinks are frequently linked to outbreaks of antibiotic-resistant bacteria. Here, we used whole-genome sequencing to track the long-term colonization patterns in intensive care unit (ICU) sinks and water from two hospitals in the USA and Pakistan collected over 27 months of prospective sampling. We analyzed 822 bacterial genomes, representing over 100 different species. We identified long-term contamination by opportunistic pathogens, as well as transient appearance of other common pathogens. We found that bacteria recovered from the ICU had more antibiotic resistance genes (ARGs) in their genomes compared to matched community spaces. We also found that many of these ARGs are harbored on mobilizable plasmids, which were found shared in the genomes of unrelated bacteria. Overall, this study provides an in-depth view of contamination patterns for common nosocomial pathogens and identifies specific targets for surveillance.

Density and phase-purity of α-TCP obtained by sintering of nano-crystalline powder

Dense and polished samples are sometimes used to test the in vitro biological response of biomaterials. However, their production can be challenging, for example for α-tricalcium phosphate (α-TCP), a commonly-used bone graft substitute. In this particular case, the ideal sintering conditions are in a temperature range close to the β-α-TCP phase transition (1125 °C). This phase transition is characterized by a 7 % volume increase which typically leads to the formation of cracks. Additionally, the production of a powder suitable for ceramic processing is difficult because α-TCP can only be produced via a thermal process. The initial aim of this study was to produce dense and polished α-TCP samples using an innovative method to produce nano-crystalline α-TCP. However, after observing the formation of β-TCP phase above the β-α-TCP phase transition (1125 °C), the focus of this study was shifted towards this unexpected phenomenon. Specifically, uniaxially compressed bulk samples were sintered at between 1160 and 1240 °C for different durations up to one week. The resulting density reached up to 95 % and was positively associated with green body density and sintering time, while being initially highest when sintered at the lowest temperature. A transient appearance of up to 6 wt% β-TCP was observed during sintering. The higher the sintering temperature was, the shorter and the smaller this transient appearance was. This behavior was attributed to the intrinsic pressure occurring within the material during sintering and which favoured the denser β-TCP phase.

The behaviour and deformation mechanisms for 316L stainless steel deformed at cryogenic temperatures

The microstructural evolution and deformation mechanisms of 316L stainless steel (SS) have been investigated at 297, 173, 50 and 15 K by in situ neutron diffraction during tensile loading and correlative transmission electron microscopy (TEM). The yield strength and ultimate tensile strength of 316L stainless steel are significantly improved at cryogenic temperatures. In contrast to room temperature, deformation-induced martensitic transformation was observed at all cryogenic temperatures. The γ-austenite (FCC) content decreases and α′-martensite (BCC) increases with increasing strain, a fraction of this γ to α′ transformation is accompanied by the transient appearance of ε-martensite (HCP) as an intermediate phase. The maximum volume fraction of ε-martensite increases with decreasing deformation temperature and reaches 13% for deformation at 15 K. TEM results confirm that γ → ε → α′ and γ → α′ martensitic transformations occur during cryogenic deformation, while mechanical twins were observed only at 173 K. The evolution of lattice strain, phase volume fraction, stacking fault probability (SFP) and stacking fault energy (SFE) were quantified to investigate the correlation between deformation mechanisms and mechanical behaviour of 316L SS as a function of deformation temperature.

Assessment of Enterovirus Antibodies during Early Childhood Using a Multiplex Immunoassay.

Enteroviruses are a group of positive single-stranded viruses that belong to the Picornaviridae family. They regularly infect humans and cause symptoms ranging from the common cold and hand-foot-and-mouth disease to life-threatening conditions, such as dilated cardiomyopathy and poliomyelitis. Enteroviruses have also been associated with chronic immune-mediated diseases, such as type 1 diabetes, celiac disease, and asthma. Studying these disease-pathogen connections is challenging due to the high prevalence of enterovirus infections in the population and the transient appearance of the virus during the acute infection phase, which limit the identification of the causative agent via methods based on the virus genome. Serological assays can detect the antibodies induced by acute and past infections, which is useful when direct virus detection is not possible. We describe in this immuno-epidemiological study how the antibody levels against VP1 proteins from eight different enterovirus types, representing all seven of the human infecting enterovirus species, vary over time. VP1 responses first significantly (P < 0.001) decline until 6 months of age, reflecting maternal antibodies, and they then start to increase as the infections accumulate and the immune system develops. All 58 children in this study were selected from the DiabImmnune cohort for having PCR-confirmed enterovirus infections. Additionally, we show that there is great, although not complete, cross-reactivity of VP1 proteins from different enteroviruses and that the response against 3C-pro could reasonably well reflect the recent Enterovirus infection history (ρ = 0.94, P = 0.017). The serological analysis of enterovirus antibodies in sera from children paves the way for the development of tools for monitoring the Enterovirus epidemics and associated diseases. IMPORTANCE Enteroviruses cause a wide variety of symptoms ranging from a mild rash and the common cold to paralyzing poliomyelitis. While enteroviruses are among the most common human pathogens, there is a need for new, affordable serological assays with which to study pathogen-disease connections in large cohorts, as enteroviruses have been linked to several chronic illnesses, such as type 1 diabetes mellitus and asthma exacerbations. However, proving causality remains an issue. In this study, we describe the use of an easily customizable multiplexed assay that is based on structural and nonstructural enterovirus proteins to study antibody responses in a cohort of 58 children from birth to 3 years of age. We demonstrate how declining maternal antibody levels can obscure the serological detection of enteroviruses before the age of six months and how antibody responses to nonstructural enterovirus proteins could be interesting targets for serodiagnosis.

Apicosome: Newly identified cell-type-specific organelle in mouse cochlear and vestibular hair cells

Cochlear and vestibular hair cells are highly specialized sensory receptors for hearing and balance. Here, we report a serendipitous identification of a hair-cell-specific organelle in neonatal mouse inner ear, which we name "apicosome." The apicosome is ∼500nm in diameter and shows itinerant nature and transient appearance during development in cochlear hair cells. In contrast to cochlear hair cells, the apicosome persists in vestibular hair cells even in adult. The timing of apicosome translocation and disappearance in cochlear hair cells during development is correlated with kinocilium development and maintenance. The apicosome is not seen in supporting cells despite the fact that nascent supporting cells have microvilli and a primary cilium. Interestingly, transdifferentiated hair cells from supporting cells also contain apicosome, suggesting that it is unique to hair cells. Thus, our study identifies a previously undescribed organelle in hair cells and lays the foundation for further characterization of this specialized structure.

Compound I Formation and Reactivity in Dimeric Chlorite Dismutase: Impact of pH and the Dynamics of the Catalytic Arginine.

The heme enzyme chlorite dismutase (Cld) catalyzes the degradation of chlorite to chloride and dioxygen. Many questions about the molecular reaction mechanism of this iron protein have remained unanswered, including the electronic nature of the catalytically relevant oxoiron(IV) intermediate and its interaction with the distal, flexible, and catalytically active arginine. Here, we have investigated the dimeric Cld from Cyanothece sp. PCC7425 (CCld) and two variants having the catalytic arginine R127 (i) hydrogen-bonded to glutamine Q74 (wild-type CCld), (ii) arrested in a salt bridge with a glutamate (Q74E), or (iii) being fully flexible (Q74V). Presented stopped-flow spectroscopic studies demonstrate the initial and transient appearance of Compound I in the reaction between CCld and chlorite at pH 5.0 and 7.0 and the dominance of spectral features of an oxoiron(IV) species (418, 528, and 551 nm) during most of the chlorite degradation period at neutral and alkaline pH. Arresting the R127 in a salt bridge delays chlorite decomposition, whereas increased flexibility accelerates the reaction. The dynamics of R127 does not affect the formation of Compound I mediated by hypochlorite but has an influence on Compound I stability, which decreases rapidly with increasing pH. The decrease in activity is accompanied by the formation of protein-based amino acid radicals. Compound I is demonstrated to oxidize iodide, chlorite, and serotonin but not hypochlorite. Serotonin is able to dampen oxidative damage and inactivation of CCld at neutral and alkaline pH. Presented data are discussed with respect to the molecular mechanism of Cld and the pronounced pH dependence of chlorite degradation.

The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron-carbohydrate administration.

Many disorders of iron homeostasis (e.g., iron overload) are associated with the dynamic kinetic profiles of multiple non-transferrin bound iron (NTBI) species, chronic exposure to which is associated with deleterious end-organ effects. Here we discuss the chemical nature of NTBI species, challenges with measuring NTBI in plasma, and the clinical relevance of NTBI exposure based on source (iron overload disorder vs. intravenous iron-carbohydrate complex administration). NTBI is not a single entity but consists of multiple, often poorly characterized species, some of which are kinetically non-exchangeable while others are relatively exchangeable. Prolonged presence of plasma NTBI is associated with excessive tissue iron accumulation in susceptible tissues, with consequences, such as endocrinopathy and heart failure. In contrast, intravenous iron-carbohydrate nanomedicines administration leads only to transient NTBI appearance and lacks evidence for association with adverse clinical outcomes. Assays to measure plasma NTBI are typically technically complex and remain chiefly a research tool. There have been two general approaches to estimating NTBI: capture assays and redox-activity assays. Early assays could not avoid capturing some iron from transferrin, thus overestimating NTBI. By contrast, some later assays may have promoted the donation of NTBI species to transferrin during the assay procedure, potentially underestimating NTBI levels. The levels of transferrin saturation at which NTBI species have been detectable have varied between different methodologies and between patient populations studied.

Feohromocitom kao potencijalni uzrok napada epilepsije

Epileptic seizures are defined as the transient appearance of signs or symptoms due to excessive or synchronous neuronal activity in the cerebral cortex. Pheochromocytomas and paragangliomas (PPGL) are tumors of chromaffin cells that arise from the medulla of the adrenal gland in 80-85% of patients and from the extra-adrenal sympathetic tissue of the abdomen, pelvis and chest in 10-20% of patients. The clinical picture of PPGL is variable and ranges from the absence of symptoms to severe clinical picture, depending on the biochemical profile. They are most often manifested by paroxysmal hypertension, followed by episodes of severe headache or diaphoresis, while epileptic attacks are rare. Neurological symptoms are present in many patients with PPGL. Also, paroxysmal neurological conditions such as vasodilating headache, intracranial tumors, diencephalic-autonomic epilepsy, hypertensive encephalopathy, focal arterial disease of the brain and anxiety state have been described, which may have similar clinical manifestations with pheochromocytomas. We present a 44-year-old woman, who has been diagnosed with pheochromocytoma as possible etiological basis of epileptic seizures. Pheochromocytoma, with its low incidence and "chameleon" clinical spectrum, should be considered as a potential etiological factor of convulsions.

Transient Increase in the Terminal Negative Deflection of the P Wave in Lead V1 during Treadmill Testing Identifies Exercise Induced Aggravated Left Ventricular Dysfunction

Terminal negative deflection of the P wave in lead V1 is produced by posteriorly directed depolarization of the left atrium. A value of more than 0.04 mm sec suggests increase in left atrial pressure. Transient new appearance of this finding during treadmill testing suggests transient exercise induced increase in left atrial pressure. Indirectly it suggests transient exercise induced/aggravated increase in left ventricular end diastolic pressure. In presence of clinical and/or electrocardiographic findings of myocardial ischemia, this finding suggest ischemia induced left ventricular dysfunction. Earlier this finding appears during exercise and longer it lasts during recovery, more severe is the left ventricular dysfunction.

Exploring the Impact of Humoral Immunogenicity with Tabelecleucel for the Treatment of EBV+ PTLD Following HCT and SOT

Background: Tabelecleucel is a non-genetically modified, allogeneic Epstein-Barr virus (EBV)-T-cell immunotherapy which targets and eliminates EBV-expressing cells in an HLA-restricted manner to treat patients (pts) with EBV+ post-transplant lymphoproliferative disease (PTLD) following hematopoietic stem cell transplantation (HCT) or solid organ transplantation (SOT). The theoretical risk of invoking a humoral or cell-mediated immune response against tabelecleucel is limited to the partially mismatched HLA allele. Tabelecleucel has proven to be safe and effective, with no confirmed evidence for clinical manifestation of immunogenicity in association with tabelecleucel. However, the theoretical consequences of eliciting an immune reaction against the mismatched HLA range from transient appearance of anti-HLA antibodies without any manifestation of clinically significant effects to the development of severe life-threatening conditions, which may include the potential for organ rejection. Therefore, evaluating the potential risk of immunogenicity against an allogeneic cell therapy like tabelecleucel is an important step in assessing the safety profile of the therapeutic agent. In this study we will assess the potential impact of humoral immunogenicity against tabelecleucel in pts with EBV+ PTLD after failure of rituximab or rituximab and chemotherapy enrolled in the ALLELE (NCT03394365) clinical study. Methods: Humoral immunogenicity was assessed through two methods of anti-HLA antibody detection that evaluated a total of 28 pts on study. The primary approach evaluated 9 pts by a pan anti-HLA detection method that provides a positive or negative result. In this approach evaluable pts must have a negative result in pre-treatment measurement and have at least one post-treatment measurement. Results are coupled with the pt's clinical safety profile to assess treatment related immunogenicity. The secondary approach evaluated 24 pts in a single-antigen bead method that provides not just a positive or negative result but also defines the specificity and strength of the positive result. Cross referencing the allele specificity of the Class I or Class II anti-HLA antibodies with the HLA type of the pt, the transplant and the infusion product aids in elucidating the source of the anti-HLA antibodies in these pts. Results: Two of the nine pts tested using the pan anti-HLA antibody detection approach had detection of anti-HLA antibodies in their pre-treatment sample. The remaining 7 evaluable pts had a median of 1 post-treatment measurement (min, max: 1, 3) and the median time post-treatment evaluated was 113 days (min, max: 40, 179). Six out of the 7 evaluable pts did not develop any anti-HLA antibodies post-treatment. One pt in the SOT cohort did develop anti-HLA antibodies 40 days after initial dosing on cycle 2 day 1. No treatment-emergent serious adverse events were reported for this pt, and only one adverse event of grade 1 fever was assessed as possibly related per investigator. The pt received additional doses of tabelecleucel yet did not manifest any subsequent events of fever or any signs of organ rejection. The second, single-antigen bead-based approach evaluated 24 pts. Four had anti-HLA antibodies present prior to tabelecleucel infusion. None of the pts evaluated had any incidence of de novo anti-HLA antibodies emerging post-treatment. For the 4 pts with pre-existing anti-HLA antibodies, evaluation of their safety profile and comparison to the total HLA immune profile of the pt is currently underway and will be reported at the time of presentation. Conclusions: To date, there has been no confirmed evidence for clinical manifestation of immunogenicity in association with tabelecleucel. Only 1 pt (tested using the pan anti-HLA method) out of 28 pts (tested using either method) had de novo emergence of anti-HLA antibodies post-infusion. This pt did not experience any severe events potentially reflecting immunogenicity such as hypersensitivity or SOT rejection. Taken together, these results reaffirm the low potential risk of developing humoral immunogenicity following tabelecleucel administration in HCT or SOT recipients with EBV+ PTLD after failure of rituximab or rituximab and chemotherapy.

A Potential Role of Keratinocyte-Derived Bilirubin in Human Skin Yellowness and Its Amelioration by Sucrose Laurate/Dilaurate.

Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin may be synthesized in other cells/organs, including the skin. We found human keratinocytes express the transcripts involved in bilirubin biosynthesis. In parallel, we also found human keratinocytes could indeed synthesize bilirubin in monolayer keratinocytes and in a 3D human skin-equivalent model. The synthesized amount was substantial enough to contribute to skin yellowness. In addition, oxidative stress enhanced bilirubin production. Using UnaG, a protein that forms a fluorescent species upon binding to bilirubin, we also visualized the intracellular expression of bilirubin in keratinocytes. Finally, we screened a compound library and discovered that the sucrose laurate/dilaurate (SDL) combination significantly reduced bilirubin levels, as well as bilirubin-mediated yellowness. In conclusion, bilirubin is indeed synthesized in epidermal keratinocytes and can be upregulated by oxidative stress, which could contribute to chronic or transient yellow skin tone appearance. Application of SDL diminishes bilirubin generation and may be a potential solution to mitigate yellowish and/or dull skin appearance.