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Abstract Cholangiocarcinoma, a malignant neoplasm of the biliary system, poses a significant challenge in clinical practice due to its increasing incidence and diagnostic and therapeutic complexity. This review addresses the epidemiological aspects, risk factors, and classification of this disease. We examine advances in histological diagnosis, highlighting essential criteria for accurate assessment. Additionally, we discuss standard treatment approaches and their efficacy, alongside the latest innovations in therapy, including emerging biomarkers and targeted therapies. By providing a comprehensive overview of these topics, this article aims to enhance understanding and guide the pathological diagnosis and clinical management of this devastating disease.

May Hagiwara,1 Victoria Divino,2 Swapna Munnangi,2 Mark Delegge,2 Suna Park,1 Ed G Marins,3 Kaili Ren,4 Charlie Strange5 1Global Evidence and Outcomes, Takeda Development Center Americas, Inc., Cambridge, MA, USA; 2Medical and Scientific Services, IQVIA Inc., Falls Church, VA, USA; 3Global Medical Affairs, Takeda Development Center Americas, Inc., Cambridge, MA, USA; 4Statistics and Quantitative Sciences, Takeda Development Center Americas, Inc., Cambridge, MA, USA; 5Department of Medicine, Medical University of South Carolina, Charleston, SC, USACorrespondence: May Hagiwara, Takeda Development Center Americas, Inc., 500 Kendall Street, Cambridge, MA, 02142, USA, Tel +1 781-482-0426, Email may.hagiwara@takeda.comBackground and Aims: Real-world analyses on burden of illness in patients with alpha-1 antitrypsin deficiency (AATD) are limited. We investigated the real-world burden of liver-related clinical events among adult and pediatric patients with AATD in the USA.Methods: This was a retrospective, observational analysis of administrative claims data from the IQVIA PharMetrics® Plus and Ambulatory Electronic Medical Records databases from 2011 to 2022. Patients had a diagnosis of liver and/or lung disease with ≥ 180 days of continuous enrollment in the IQVIA PharMetrics Plus database before and ≥ 90 days after their first diagnosis. Follow-up time was assigned to the AATD with liver disease health state or AATD with both liver and lung disease health state (for patients aged ≥ 18 years only). Baseline demographic characteristics and liver-related clinical events of interest were reported.Results: Of 5136 eligible patients, 771 adult and 123 pediatric patients contributed time to the AATD with liver disease health state; 541 adults contributed time to the AATD with both liver and lung disease health state. Among adults, patients with both liver and lung disease had higher rates of liver-related clinical events than patients with liver disease alone. Ascites was the most frequently observed clinical event among adults in both health states, and the median time to the composite of any liver-related clinical event was 26.5 days among all adults combined. Across all pediatric age groups, ascites, gastrointestinal bleed and hepatic encephalopathy were more common than spontaneous bacterial peritonitis and hepatocellular carcinoma, but median time to liver-related clinical event varied by age group at index date and type of event. No liver transplantations occurred in patients aged 6– 17 years.Conclusion: Diagnosed AATD with liver disease carries a substantial burden on adult and pediatric patients; new treatment options are warranted to avoid disease progression to decompensating events.Keywords: alpha-1 antitrypsin deficiency, genetic disease, liver disease, lung disease, pediatric, adult

Abstract Random mutagenesis, such as error-prone PCR (epPCR), is a technique capable of generating a wide variety of a single gene. However, epPCR can produce a large number of mutated gene variants, posing a challenge in ligating these mutated PCR products into plasmid vectors. Typically, the primers for mutagenic PCRs incorporate artificial restriction enzyme sites compatible with chosen plasmids. Products are cleaved and ligated to linearized plasmids, then recircularized by DNA ligase. However, this cut-and-paste method known as ligation-dependent process cloning (LDCP), has limited efficiency, as the loss of potential mutants is inevitable leading to a significant reduction in the library’s breadth. An alternative to LDCP is the circular polymerase extension cloning (CPEC) method. This technique involves a reaction where a high-fidelity DNA polymerase extends the overlapping regions between the insert and vector, forming a circular molecule. In this study, our objective was to compare the traditional cut-and-paste enzymatic method with CPEC in producing a variant library from the gene encoding the red fluorescent protein (DsRed2) obtained by epPCR. Our findings suggest that CPEC can accelerate the cloning process in gene library generation, enabling the acquisition of a greater number of gene variants compared to methods reliant on restriction enzymes.

End-to-end simulations play a key role in the analysis of any high-sensitivity cosmic microwave background (CMB) experiment, providing high-fidelity systematic error propagation capabilities that are unmatched by any other means. In this paper, we address an important issue regarding such simulations, namely, how to define the inputs in terms of sky model and instrument parameters. These may either be taken as a constrained realization derived from the data or as a random realization independent from the data. We refer to these as posterior and prior simulations, respectively. We show that the two options lead to significantly different correlation structures, as prior simulations (contrary to posterior simulations) effectively include cosmic variance, but they exclude realization-specific correlations from non-linear degeneracies. Consequently, they quantify fundamentally different types of uncertainties. We argue that as a result, they also have different and complementary scientific uses, even if this dichotomy is not absolute. In particular, posterior simulations are in general more convenient for parameter estimation studies, while prior simulations are generally more convenient for model testing. Before BEYONDPLANCK, most pipelines used a mix of constrained and random inputs and applied the same hybrid simulations for all applications, even though the statistical justification for this is not always evident. BEYONDPLANCK represents the first end-to-end CMB simulation framework that is able to generate both types of simulations and these new capabilities have brought this topic to the forefront. The BEYONDPLANCK posterior simulations and their uses are described extensively in a suite of companion papers. In this work, we consider one important applications of the corresponding prior simulations, namely, code validation. Specifically, we generated a set of one-year LFI 30 GHz prior simulations with known inputs and we used these to validate the core low-level BEYONDPLANCK algorithms dealing with gain estimation, correlated noise estimation, and mapmaking.

ObjectiveSpinal cord injury (SCI) is a serious condition that can lead to partial or complete paraplegia or tetraplegia. Currently, there are few therapeutic options for these conditions, which are mainly directed toward the acute phase, such as surgical intervention and high-dose steroid administration. Mesenchymal stromal cells (MSC) have been shown to improve neurological function following spinal cord injury. The aim of the study was to evaluate the safety, feasibility, and potential efficacy of MSC transplantation in patients with cervical traumatic SCI.MethodsWe included seven subjects with chronic traumatic SCI (> 1 year) at the cervical level, classified as American Spinal Cord Injury Association impairment scale (AIS) grade A. Subjects received two doses of autologous bone marrow derived MSC, the first by direct injection into the lesion site after hemilaminectomy and the second three months later by intrathecal injection. Neurologic evaluation, spinal magnetic resonance imaging (MRI), urodynamics, and life quality questionnaires were assessed before and after treatment.ResultsCell transplantation was safe without severe or moderate adverse effects, and the procedures were well tolerated. Neurological evaluation revealed discrete improvements in sensitivity below the lesion level, following treatment. Five subjects showed some degree of bilateral sensory improvement for both superficial and deep mechanical stimuli compared to the pretreatment profile. No significant alterations in bladder function were observed during this study.ConclusionTransplantation of autologous MSC in patients with chronic cervical SCI is a safe and feasible procedure. Further studies are required to confirm the efficacy of this therapeutic approach.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT02574572, identifier NCT02574572.

Abstract We aimed to find new therapeutic targets related to Cancer Stem Cell alterations in recurrent patients from two TCGA cohorts: Testicular Germ Cell Tumor (TGCT) and Uterine Corpus Endometrial Carcinoma (UCEC). Raw sequencing data were downloaded from the TCGA database. Datasets containing RNA expression and Methylation files were directly downloaded from cBioportal. Variant Call Format files (VCFs) were downloaded from the GDC portal. Gene enrichment analysis was performed using GSEA (Gene Set Enrichment Analysis) software. Transcriptome profiling, coexpression co-occurrence, networks, and survival analyses were performed using cBioportal tools, while mutational analysis of patients was processed using UNIX scripts. We found that cancer stem cell transcription factors were highly expressed in Testicular Germ Cell Tumor (TGCT) and Uterine Corpus Endometrial Carcinoma (UCEC) cohorts, compared to the other 29 cancer cohorts in TCGA. Patients presented a poorer diagnosis when the genes (POU5F1, NANOG, SOX2, SALL4, ABCB1, ABCC1, and ABCG2) were altered. In UCEC cohorts, recurrent patients showed the ABCG2 potentially phosphorylated by the PIM1 kinase. In the TGCT cohort, genes ABCB1 and ABCG2 only appeared in the phosphonetwork in recurrent patients potentially phosphorylated by the same kinase, PIM1, but also by PRKACA. Our data indicate that PRKACA and PIM1 may modulate POU5F1 phosphorylation.

Este estudo objetivou analisar as representações sociais dos orixás presentes nas letras de cantigas de Candomblé reconhecidamente adotadas por comunidades religiosas. Pesquisa qualitativa, descritiva, desenvolvida com o suporte teórico-metodológico da Teoria das Representações Sociais, em sua abordagem processual. Analisou letras em português de cantigas relativas a 13 orixás, tais como Exú, Ogun, Oxóssi, Ossain, Logun-Edé, Obaluaê, Oxumaré, Xangô, Oyá, Oxum, Iemanjá, Nanã e Oxalá, do livro Cantando para os Orixás, de Altair Bento de Oliveira. A análise lexical do material foi realizada através do software Alceste® 4.5, que gerou um dendograma com cinco classes e em três blocos distintos, evidenciando o papel das Iabás7 e o cuidado materno, o processo de destruição-criação e de manutenção da vida e da comunidade pelas características de Ogum, Oxóssi e Logun-Edé e a relação da comunidade com os orixás e os elementos naturais. As representações sociais dos orixás para a comunidade religiosa do Candomblé apreendidas nas letras das cantigas cantadas no cotidiano das roças e dos ilês8 se estruturam por complexos e antigos thêmatas9 comuns às divindades do ocidente. Observou-se a objetivação na formação de determinadas representações, como a de masculinidade para Ogum, bem como a ancoragem de Oxalá na ancestralidade, na sabedoria e na paciência.