Processing and Visualization of Protec-Seq Data for the Generation of Calibrated, Genome-Wide Double Double-Strand Break (dDSB) Maps.

This chapter describes the computational pipeline for the processing and visualization of Protec-Seq data, a method for purification and genome-wide mapping of double-stranded DNA protected by a specific protein at both ends. In the published case, the protein of choice was Saccharomyces cerevisiae Spo11, a conserved topoisomerase-like enzyme that makes meiotic double-strand breaks (DSBs) to initiate homologous recombination, ensuring proper segregation of homologous chromosomes and fertility. The isolated DNA molecules were thus termed double DSB (dDSB) fragments and were found to represent 34 to several hundred base-pair long segments that are generated by Spo11 and are enriched at DSB hotspots, which are sites of topological stress. In order to allow quantitative comparisons between dDSB profiles across experiments, we implemented calibrated chromatin immunoprecipitation sequencing (ChIP-Seq) using the meiosis-competent yeast species Saccharomyces kudriavzevii as calibration strain. Here, we provide a detailed description of the computational methods for processing, analyzing, and visualizing Protec-Seq data, comprising the download of the raw data, the calibrated genome-wide alignments, and the scripted creation of either arc plots or Hi-C-style heatmaps for the illustration of chromosomal regions of interest. The workflow is based on Linux shell scripts (including wrappers for publicly available, open-source software) as well as R scripts and is highly customizable through its modular structure.

Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype.

BACKGROUND: Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty. RESULTS: We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene. CONCLUSION: This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

Impaired 11ß-HSD1 Activity in a Male Patient With Cushing Disease Resulting in Lack of the Full Cushingoid Phenotype.

We present a patient who had surgically confirmed CD but without the full cushingoid phenotype despite markedly elevated cortisol. Nonpathologic causes of elevated ACTH and cortisol were eliminated as were pathogenic variants in the glucocorticoid receptor gene. Further studies of urine metabolites, cortisol half-life, and the ratios of cortisone to cortisol conversion revealed impaired 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. There have only been 2 prior reports of impaired 11ß-HSD1 resulting in lack of classic cushingoid features in the past 2 decades. Our patient's presentation and previous reports demonstrate the key role of 11ß-HSD1 in modulating intracellular cortisol concentration, therefore shielding the peripheral tissues from the effects of excess cortisol. When patients present with markedly elevated cortisol but without classic cushingoid features, impaired 11ß-HSD1 should be considered in the differential diagnosis.

Therapeutic targeting of GDF11 in muscle atrophy: Insights and strategies.

The exploration of novel therapeutic avenues for skeletal muscle atrophy is imperative due to its significant health impact. Recent studies have spotlighted growth differentiation factor 11 (GDF11), a TGFß superfamily member, for its rejuvenating role in reversing age-related tissue dysfunction. This review synthesizes current findings on GDF11, elucidating its distinct biological functions and the ongoing debates regarding its efficacy in muscle homeostasis. By addressing discrepancies in current research outcomes and its ambiguous role due to its homological identity to myostatin, a negative regulator of muscle mass, this review aims to clarify the role of GDF11 in muscle homeostasis and its potential as a therapeutic target for muscle atrophy. Through a thorough examination of GDF11's mechanisms and effects, this review provides insights that could pave the way for innovative treatments for muscle atrophy, emphasizing the need and strategies to boost endogenous GDF11 levels for therapeutic potential.

Dual role of BCL11B in T-cell malignancies.

The zinc finger transcription factor B-cell CLL/lymphoma 11B gene (BCL11B, CTIP2) plays a crucial role in T-cell development, but its role in T-cell malignancies has not yet been definitively clarified. In the literature, 2 contradictory hypotheses on the function of BCL11B exist. One suggests that BCL11B functions as tumor suppressor gene, and the other suggests that BCL11B functions as oncogene. The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies, confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach, based on recent findings of the function of BCL11B in DNA damage repair. Decreased BCL11B expression, resulting in deficient DNA repair, may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements, thereby leading to malignant transformation. On the other hand, decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells. We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it. In those cases, targeted inhibition of BCL11B expression may have a therapeutic effect. The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells (ITNK). Therefore, there is an urgent need to develop a specific BCL11B inhibitor.

Modelling energy trilemma and economic growth on renewables in N11 economies: Do economic complexity matter?

Utilizing renewable energy is a necessity for accomplishing global agendas, including combating climate change and promoting sustainable development programs. Although much literature has investigated the nexus between energy sources and their affected regressors during the last few years, no appreciable emphasis is available in the previous studies respecting the influence of the energy trilemma index and economic expansion on the influence of the energy trilemma index and economic the renewables in N11 economies. Therefore, the current study analyzes the crucial influencing factors, including the energy trilemma, economic growth, economic complexity, financial development, and urban population, as drivers of renewable energy in N11 economics from 1990 to 2021 by utilizing a panel quantile regression approach. The empirical outcomes certify that renewable energy is positively connected with the energy trilemma, economic growth, financial development, and urban population, but not with economic complexity, which has the inverse result. As a result, legislators responsible for monitoring the deployment of renewables should stimulate their attempts to consider the energy trilemma dimensions into account when determining energy structural policies, increase the use of greener energy subsidies, pose high-carbon taxes, promote green financial innovation, and improve energy efficiency.

Unveiling the intricate role of S100A1 in regulating RyR1 activity: A commentary on "Structural insights into the regulation of RyR1 by S100A1".

S100A1, a calcium-binding protein, plays a crucial role in regulating Ca2+ signaling pathways in skeletal and cardiac myocytes via interactions with the ryanodine receptor (RyR) to affect Ca2+ release and contractile performance. Biophysical studies strongly suggest that S100A1 interacts with RyRs but have been inconclusive about both the nature of this interaction and its competition with another important calcium-binding protein, calmodulin (CaM). Thus, high-resolution cryo-EM studies of RyRs in the presence of S100A1, with or without additional CaM, were needed. The elegant work by Weninger et al. demonstrates the interaction between S100A1 and RyR1 through various experiments and confirms that S100A1 activates RyR1 at sub-micromolar Ca2+ concentrations, increasing the open probability of RyR1 channels.

MicroRNA Profiling as a Predictive Indicator for Time to First Treatment in Chronic Lymphocytic Leukemia: Insights from the O-CLL1 Prospective Study.

A "watch and wait" strategy, delaying treatment until active disease manifests, is adopted for most CLL cases; however, prognostic models incorporating biomarkers have shown to be useful to predict treatment requirement. In our prospective O-CLL1 study including 224 patients, we investigated the predictive role of 513 microRNAs (miRNAs) on time to first treatment (TTFT). In the context of this study, six well-established variables (i.e., Rai stage, beta-2-microglobulin levels, IGVH mutational status, del11q, del17p, and NOTCH1 mutations) maintained significant associations with TTFT in a basic multivariable model, collectively yielding a Harrell's C-index of 75% and explaining 45.4% of the variance in the prediction of TTFT. Concerning miRNAs, 73 out of 513 were significantly associated with TTFT in a univariable model; of these, 16 retained an independent relationship with the outcome in a multivariable analysis. For 8 of these (i.e., miR-582-3p, miR-33a-3p, miR-516a-5p, miR-99a-5p, and miR-296-3p, miR-502-5p, miR-625-5p, and miR-29c-3p), a lower expression correlated with a shorter TTFT, whereas in the remaining eight (i.e., miR-150-5p, miR-148a-3p, miR-28-5p, miR-144-5p, miR-671-5p, miR-1-3p, miR-193a-3p, and miR-124-3p), the higher expression was associated with shorter TTFT. Integrating these miRNAs into the basic model significantly enhanced predictive accuracy, raising the Harrell's C-index to 81.1% and the explained variation in TTFT to 63.3%. Moreover, the inclusion of the miRNA scores enhanced the integrated discrimination improvement (IDI) and the net reclassification index (NRI), underscoring the potential of miRNAs to refine CLL prognostic models and providing insights for clinical decision-making. In silico analyses on the differently expressed miRNAs revealed their potential regulatory functions of several pathways, including those involved in the therapeutic responses. To add a biological context to the clinical evidence, an miRNA-mRNA correlation analysis revealed at least one significant negative correlation between 15 of the identified miRNAs and a set of 50 artificial intelligence (AI)-selected genes, previously identified by us as relevant for TTFT prediction in the same cohort of CLL patients. In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

De novo and inherited micro-CNV at 16p13.11 in 21 Chinese patients with defective cardiac left-right patterning.

Objective: Copy number changes at Chromosomal 16p13.11 have been implicated in a variety of human diseases including congenital cardiac abnormalities. The clinical correlation of copy number variants (CNVs) in this region with developmental abnormalities remains controversial as most of the patients inherit the duplication from an unaffected parent. Methods: We performed CNV analysis on 164 patients with defective left-right (LR) patterning based on whole genome-exome sequencing (WG-ES) followed by multiplex ligation-dependent probe amplification (MLPA) validation. Most cases were accompanied with complex congenital heart disease (CHD). Results: CNVs at 16p13.11 were identified in a total of 21 cases, accounting for 12.80% (21/164) evaluated cases. We observed a marked overrepresentation of chromosome 16p13.11 duplications in cases when compared with healthy controls according to literature reports (15/164, 9.14% versus 0.09% in controls). Notably, in two independent family trios, de novo 16p13.11 micro-duplications were identified in two patients with laterality defects and CHD. Moreover, 16p13.11 micro-duplication was segregated with the disease in a family trio containing 2 affected individuals. Notably, five coding genes, NOMO1, PKD1P3, NPIPA1, PDXDC1, and NTAN1, were potentially affected by micro-CNV at 16p13.11 in these patients. Conclusion: Our study provides new family-trio based evidences to support 16p13.11 micro-duplications predispose individuals to defective cardiac left-right patterning and laterality disorder.

Evolution of the Cytomegalovirus RL11 gene family in Old World monkeys and Great Apes.

Cytomegalovirus (CMV) is a genus of herpesviruses, members of which share a long history of coevolution with their primate hosts including New World monkeys, Old World monkeys (OWMs), and Great Apes (GAs). These viruses are ubiquitous within their host populations and establish lifelong infection in most individuals. Although asymptomatic in healthy individuals, infection poses a significant risk to individuals with a weakened or underdeveloped immune system. The genome of human CMV is the largest among human-infecting viruses and comprises at least 15 separate gene families, which may have arisen by gene duplication. Within human CMV, the RL11 gene family is the largest. RL11 genes are nonessential in vitro but have immune evasion roles that are likely critical to persistence in vivo. These genes demonstrate an extreme level of inter-species and intra-strain sequence diversity, which makes it challenging to deduce the evolutionary relationships within this gene family. Understanding the evolutionary relationships of these genes, especially accurate ortholog identification, is essential for reconstructing ancestral genomes, deciphering gene repertoire and order, and enabling reliable functional analyses across the CMV species, thereby offering insights into evolutionary processes, genetic diversity, and the functional significance of genes. In this work, we combined in silico genome screening with sequence-based and structure-guided phylogenetic analysis to reconstruct the evolutionary history of the RL11 gene family. We confirmed that RL11 genes are unique to OWM and GA CMVs, showing that this gene family was formed by multiple early duplication events and later lineage-specific losses. We identified four main clades of RL11 genes and showed that their expansions were mainly lineage specific and happened independently in CMVs of GAs, African OWMs, and Asian OWMs. We also identified groups of orthologous genes across the CMV tree, showing that some human CMV-specific RL11 genes emerged before the divergence of human and chimpanzee CMVs but were subsequently lost in the latter. The extensive and dynamic species-specific evolution of this gene family suggests that their functions target elements of host immunity that have similarly coevolved during speciation.

11-Azaartemisinin derivatives bearing halogenated aromatic moieties: Potent anticancer agents with high tumor selectivity.

While artemisinin and its derivatives, including 11-azaartemisinin-based compounds, have shown promising anticancer activity, the integration of halogens into aromatic structures can amplify drug potency, metabolic stability, and selectivity. Herein, we present the synthesis of new novel 11-azaartemisinin derivatives bearing halogenated aromatic moieties connected via 1,2,3-triazole bridges and evaluate their anticancer activities against three human tumor cell lines: epidermoid carcinoma (KB), hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). Among the synthesized compounds, six of them (8c-h) displayed good to excellent antiproliferative activity in the low micromolar range across all three human cancer cell lines. In general, the m-bromide (8c) and m-iodide (8d) compounds exhibited superior anticancer activities compared to their o- and p-analogs, as well as the m-chloride and m-fluoride compounds. The most promising m-Br compound (8c) displayed 50 % inhibition of KB, HepG2, and A549 cell growth at concentrations of 7.7, 42.5, and 15.5 µM, respectively. Notably, the m-Br compound (8c) exhibited approximately 32-, 6-, and 16-fold lower activity in normal cells (Hek293) compared to KB, HepG2, and A549 tumor cells, respectively, indicating a significant tumor-selectivity.

The deubiquitinating enzyme USP11 regulates breast cancer progression by stabilizing PGAM5.

Breast cancer is common worldwide. Phosphoglycerate mutase 5 (PGAM5) belongs to the phosphoglycerate mutase family and plays an important role in many cancers. However, research on its role in breast cancer remains unclear. The present investigation highlights the significant expression of PGAM5 in breast cancer and its essential role in cell proliferation, invasion, apoptosis and the regulation of ferroptosis in breast cancer cells. Overexpression or knockdown of ubiquitin-specific protease 11 (USP11) promotes or inhibits the growth and metastasis of breast cancer cells, respectively, in vitro and in vivo. Mechanistically, USP11 stabilizes PGAM5 via de-ubiquitination, protecting it from proteasome-mediated degradation. In addition, the USP11/PGAM5 complex promotes breast cancer progression by activating iron death-related proteins, indicating that the synergy between USP11 and PGAM5 may serve as a predictor of disease outcome and provide a new treatment strategy for breast cancer.

European Society of Immunodeficiencies guidelines for the management of patients with congenital athymia.

Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-B+NK+ immunophenotype with profound T lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency (SCID) and T lymphocytopaenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society of Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects, and offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification and management of congenital athymia, with the aim of improving patient outcomes.

Hearing Loss in Children with 22q11.2 Deletion Syndrome.

OBJECTIVES: Hearing loss is considered common in children with 22q11.2 deletion syndrome (22q11.2DS), with a few prior studies reporting a 32%-78% prevalence; mild-moderate conductive hearing loss has been reported most commonly. Overall, however, there remains a paucity of data regarding the frequency, type, age, and progression of hearing loss in children with 22q11.2DS. METHODS: Retrospective chart review was completed, and data combined for two large 22q centers. Inclusion criteria were children with 22q11.2DS and a documented audiogram. Data extracted included a laboratory-confirmed chromosome 22q11.2 deletion; co-morbidities; results of all audiograms and radiologic temporal bone imaging; and otologic surgical procedures. RESULTS: One thousand seven hundred sixty-nine charts were reviewed; 775 met inclusion criteria. Of these, 563 (73%) children had at least one abnormal audiogram demonstrating hearing loss. A total of 2,536 audiograms were reviewed; 74% of these showed abnormal hearing in at least one ear. Most of the hearing loss was conductive (right ear 76%; left ear 69%) and mild severity. For the children with SNHL, 90% of all follow-up audiograms were stable without progression. Hearing loss was identified across all pediatric age ranges. Ear tube placement occurred in 39% of children. CONCLUSION: This study confirms the high incidence of hearing loss for children with 22q11.2DS at some point in their childhood. In our cohort, hearing loss occurred in 73% of children and was most often conductive and mild in severity. The results highlight the importance of otolaryngology and audiology involvement in managing children with 22q11.2DS for timely diagnosis and treatment of hearing loss. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

UBR5 mediates colorectal cancer chemoresistance by attenuating ferroptosis via Lys 11 ubiquitin-dependent stabilization of Smad3-SLC7A11 signaling.

Chemoresistance remains a principal culprit for the treatment failure in colorectal cancer (CRC), especially for patients with recurrent or metastatic disease. Deciphering the molecular basis of chemoresistance may lead to novel therapeutic strategies for this fatal disease. Here, UBR5, an E3 ubiquitin ligase frequently overexpressed in human CRC, is demonstrated to mediate chemoresistance principally by inhibiting ferroptosis. Paradoxically, UBR5 shields oxaliplatin-activated Smad3 from proteasome-dependent degradation via Lys 11-linked polyubiquitination. This novel chemical modification of Smad3 facilitates the transcriptional repression of ATF3, induction of SLC7A11 and inhibition of ferroptosis, contributing to chemoresistance. Consequently, targeting UBR5 in combination with a ferroptosis inducer synergistically sensitizes CRC to oxaliplatin-induced cell death and control of tumor growth. This study reveals, for the first time, a major clinically relevant chemoresistance mechanism in CRC mediated by UBR5 in sustaining TGFß-Smad3 signaling and tuning ferroptosis, unveiling its potential as a viable therapeutic target for chemosensitization.

Multiple routes to fungicide resistance: Interaction of Cyp51 gene sequences, copy number and expression.

We examined the molecular basis of triazole resistance in Blumeria graminis f. sp. tritici (wheat mildew, Bgt), a model organism among powdery mildews. Four genetic models for responses to triazole fungicides were identified among US and UK isolates, involving multiple genetic mechanisms. Firstly, only two amino acid substitutions in CYP51B lanosterol demethylase, the target of triazoles, were associated with resistance, Y136F and S509T (homologous to Y137F and S524T in the reference fungus Zymoseptoria tritici). As sequence variation did not explain the wide range of resistance, we also investigated Cyp51B copy number and expression, the latter using both reverse transcription-quantitative PCR and RNA-seq. The second model for resistance involved higher copy number and expression in isolates with a resistance allele; thirdly, however, moderate resistance was associated with higher copy number of wild-type Cyp51B in some US isolates. A fourth mechanism was heteroallelism with multiple alleles of Cyp51B. UK isolates, with significantly higher mean resistance than their US counterparts, had higher mean copy number, a high frequency of the S509T substitution, which was absent from the United States, and in the most resistant isolates, heteroallelism involving both sensitivity residues Y136+S509 and resistance residues F136+T509. Some US isolates were heteroallelic for Y136+S509 and F136+S509, but this was not associated with higher resistance. The obligate biotrophy of Bgt may constrain the tertiary structure and thus the sequence of CYP51B, so other variation that increases resistance may have a selective advantage. We describe a process by which heteroallelism may be adaptive when Bgt is intermittently exposed to triazoles.

ARL11 knockdown alleviates spinal cord injury by inhibiting neuroinflammation and M1 activation of microglia in mice.

Spinal cord injury (SCI) is a severe central nervous system injury and microglia are major participants in neuroinflammation after injury. ADP-ribosylation factor-like GTPase 11 (ARL11) is a GTP-binding protein. Whether ARL11 is involved in the SCI progression is unknown. In the impactor-induced moderate SCI mouse model, ARL11 protein and mRNA expression were significantly increased in the injury site. LPS (100 ng/mL) and IFN-γ (20 ng/mL) were incubated with BV2 cells (immortalized mouse microglial cell line) to drive them into an M1-like phenotype. ARL11 up-regulation was also observed in activated microglia in SCI mice and LPS and IFN-γ treated BV2 cells. Basso Mouse Scale scores and inclined plate test revealed that ARL11 deletion promoted motor function recovery in SCI mice. Pathological examination showed ARL11 knockdown reduced spinal cord tissue damage, increased neuron numbers, and inhibited neuronal apoptosis in SCI mice. ARL11 knockdown notably inhibited IL-1ß and IL-6 production in vivo and in vitro. Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression in vivo and in vitro, and COX-2 expression in vivo. Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression in vitro. ELF1 acted as a transcription activator in regulating ARL11 expression by binding to the promoter. In conclusion, ARL11 knockdown protects neurons by inhibiting M1 microglia-induced neuroinflammation, thereby promoting motor functional recovery in SCI mice. This may occur in part under the regulation of ELF1. Our study provides a new molecular target for SCI treatment.

Narrative review of value frameworks in urothelial carcinoma and positioning of enfortumab vedotin.

AIMS: Evaluate existing oncology value frameworks in terms of their methodology, structure, characteristics, and functionality using the example of enfortumab vedotin, an approved therapy for urothelial carcinoma. METHODS: A search of PubMed, grey literature, and official websites of relevant international organizations was performed from January 2022 to March 2023. RESULTS: Six frameworks were identified and analyzed, including the American Society of Clinical Oncology's assessment framework, European Society for Medical Oncology's Magnitude of Clinical Benefit Scale, the National Comprehensive Cancer Network's Evidence Blocks, Memorial Sloan Kettering Cancer Center's DrugAbacus, Institute for Clinical and Economic Review's assessment framework, and the Drug Assessment Framework. Comparisons across frameworks were challenging, owing to differing approaches, objectives, perspectives, methodology, and criteria. Based on the results of the EV-301 study (NCT03474107), the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale assigned a score of 4 out of 5 to enfortumab vedotin administered after chemotherapy and immunotherapy. The National Comprehensive Cancer Network's Evidence Blocks enabled assessment of enfortumab vedotin compared with other treatments for locally advanced or metastatic urothelial carcinoma, resulting in the positioning of enfortumab vedotin as a preferred regimen after chemotherapy and immunotherapy. CONCLUSIONS: Application of value frameworks in oncology can contribute to informed value-based decision-making. However, comparisons across frameworks should be made with caution and limited to the same lines of treatment. Enfortumab vedotin may contribute to optimizing outcomes in patients previously treated with chemotherapy and immunotherapy for locally advanced or metastatic urothelial carcinoma.

Real-time continuous glucose monitoring vs. self-monitoring of blood glucose: cost-utility in South Korean type 2 diabetes patients on intensive insulin.

AIMS: This study investigated the cost-utility of real-time continuous glucose monitoring (rt-CGM) versus self-monitoring of blood glucose (SMBG) in people with type 2 diabetes (T2D) receiving intensive insulin therapy in South Korea. METHODS: The IQVIA Core Diabetes Model (CDM v9.5) was used, with clinical effectiveness data obtained from a large-scale real world study. Costs were obtained from South Korean sources and inflated to 2022 South Korean Won (KRW). A South Korean payer perspective was adopted over a lifetime horizon, with future costs and effects discounted at 4.5% per annum. Baseline characteristics included a mean baseline HbA1c level of 8.6% (71 mmol/mol), and a mean age of 64.4 years. A willingness-to-pay (WTP) threshold of KRW 46.0 million was used. RESULTS: Rt-CGM led to an increase of 0.683 quality-adjusted life years (QALYs) versus SMBG (7.526 QALYs for rt-CGM versus 6.843 QALYs for SMBG). An increase in costs of KRW 16.4 million (from KRW 90.4 million to KRW 106.8 million) was associated with rt-CGM. The incremental cost-utility ratio was KRW 24.0 million per QALY gained, significantly lower than the KRW 46 million threshold. CONCLUSIONS: For individuals with T2D managed by intensive insulin therapy in South Korea, rt-CGM is cost-effective relative to SMBG.

Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses.

BACKGROUND: Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear. METHODS: We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n = 52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls). FINDINGS: In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration) = 1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk. INTERPRETATION: Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis. FUNDING: Funding for IIG_FULL_2021_008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA_15849 was obtained from Institut National du Cancer (INCa).