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The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Abstract Our recently published K1N2-score robustly predicts KEAP1/NFE2L2-mutations and pathway activation status, while its accessibility might be limited. We tested if the RNA expression data of six pathway-related genes and NQO1-IHC might be a reliable alternative using 348 KEAP1/NFE2L2 mutation-enriched NSCLC. While TXNRD1 RNA testing was the best-performing single-gene test, the combination of single-gene screening and validation with the K1N2-score achieved the highest performance when predicting mutation status or pathway activation.

Abstract Objective There is a shortage of established prognostic biomarkers in bladder cancer. One candidate is tumour protein 63 (p63), a transcription factor of the p53 gene family that is expressed in the normal urothelium. Recently proposed RNA expression‐based molecular classifiers of bladder cancer identified high p63 expression as a component of a basal/squamous subtype linked to poor patient prognosis. Methods In this study, p63 protein expression was analysed by immunohistochemistry on more than 2500 urothelial bladder carcinomas in a tissue microarray format to determine its relationship with clinicopathological parameters of disease progression and patient outcome. Results Nuclear p63 staining was seen in all cells of normal urothelium and at elevated levels in pTaG2 tumours. The rate of p63 positive cases and the staining intensity was lower in pTaG3 tumours (93.2%, p

Abstract Background Spores produced by the filamentous fungus Aspergillus niger are abundant in a variety of environments. The proliferation of this fungus in indoor environments has been associated to health risks and its conidia can cause allergic reaction and severe invasive disease in animals and humans. Therefore, the detection and monitoring of Aspergillus conidia is of utmost importance to prevent serious fungal infections and contaminations. Among others, aptamers could serve as biosensors for the specific detection of fungal spores. Results In this study, DNA aptamers specific to conidia of A. niger were developed by optimizing a whole-cell SELEX approach. Three whole-cells SELEX experiments were performed in parallel with similar conditions. Quantification of recovered ssDNA and melting curve analyses were applied to monitor the ongoing SELEX process. Next-generation sequencing was performed on selected recovered ssDNA pools, allowing the identification of DNA aptamers which bind with high affinity to the target cells. The developed aptamers were shown to be species-specific, being able to bind to A. niger but not to A. tubingensis or to A. nidulans. The binding affinity of two aptamers (AN01-R9-006 and AN02-R9-185) was measured to be 58.97 nM and 138.71 nM, respectively, which is in the range of previously developed aptamers. Conclusions This study demonstrates that species-specific aptamers can be successfully developed via whole-cell SELEX to distinguish different Aspergillus species and opens up new opportunities in the field of diagnostics of fungal infections.

Abstract The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Abstract Upon stimulation of membrane receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) is formed as second messenger within seconds and evokes Ca2+ signaling in many different cell types. Here, to directly stimulate NAADP signaling, MASTER-NAADP, a Membrane permeAble, STabilized, bio-rEversibly pRotected precursor of NAADP is synthesized and release of its active NAADP mimetic, benzoic acid C-nucleoside, 2’-phospho-3’F-adenosine-diphosphate, by esterase digestion is confirmed. In the presence of NAADP receptor HN1L/JPT2 (hematological and neurological expressed 1-like protein, HN1L, also known as Jupiter microtubule-associated homolog 2, JPT2), this active NAADP mimetic releases Ca2+ and increases the open probability of type 1 ryanodine receptor. When added to intact cells, MASTER-NAADP initially evokes single local Ca2+ signals of low amplitude. Subsequently, also global Ca2+ signaling is observed in T cells, natural killer cells, and Neuro2A cells. In contrast, control compound MASTER-NADP does not stimulate Ca2+ signaling. Likewise, in cells devoid of HN1L/JPT2, MASTER-NAADP does not affect Ca2+ signaling, confirming that the product released from MASTER-NAADP is a bona fide NAADP mimetic.

Abstract Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.

Abstract Background Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells. Methods To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p = 0.0005), blood vessel infiltration (p = 0.0037), and lymph vessel infiltration (p

Abstract Objectives Carcinoembryonic antigen (CEA) is a cell surface glycoprotein that represents a promising therapeutic target. Serum measurement of shedded CEA can be utilized for monitoring of cancer patients. Material and Methods To evaluate the potential clinical significance of CEA expression in urothelial bladder neoplasms, CEA was analysed by immunohistochemistry in more than 2500 urothelial bladder carcinomas in a tissue microarray format. Results CEA staining was largely absent in normal urothelial cells but was observed in 30.4% of urothelial bladder carcinomas including 406 (16.7%) with weak, 140 (5.8%) with moderate, and 192 (7.9%) with strong staining. CEA positivity occurred in 10.9% of 411 pTaG2 low‐grade, 32.0% of 178 pTaG2 high‐grade, and 43.0% of 93 pTaG3 tumours (p 0.25). Conclusion CEA increases markedly with grade progression in pTa tumours, and expression occurs in a significant fraction of pT2–4 urothelial bladder carcinomas. The high rate of CEA positivity in pT2–4 carcinomas offers the opportunity of using CEA serum measurement for monitoring the clinical course of these cancers. Moreover, CEA positive urothelial carcinomas are candidates for a treatment by targeted anti‐CEA drugs.

ABSTRACT Backround Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing. Methods To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). Results AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%–100%), urothelial carcinoma (74.6%–100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%–99.6%), and pancreaticobiliary cancers (65.2%–98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%–77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP (p

Introduction: Articular cartilage injuries of the knee are a complex and challenging clinical pathology. Objectives: The purpose of this study was to establish consensus statements via a Delphi process on the management of failed knee cartilage surgery. Methods: A consensus process on knee cartilage injuries utilizing a modified Delphi technique was conducted. Seventy-nine surgeons across 17 countries participated in these consensus statements. Eleven questions were generated on the management of failed knee cartilage surgery, with 3 rounds of questionnaires and final voting occurring. Consensus was defined as achieving 80% to 89% agreement, whereas strong consensus was defined as 90% to 99% agreement, and unanimous consensus was defined as 100% agreement with a proposed statement. Results: Of the 11 total questions and consensus statements on the management of failed knee cartilage surgery developed from 3 rounds of voting, 0 achieved unanimous consensus, 10 achieved strong consensus, and 1 achieved consensus. Conclusions: The statements that achieved strong consensus related to revision cartilage indications, contraindications, lesion size, prior procedures, unipolar/bipolar lesions, and salvage procedures. The statement that did not achieve strong consensus was related to the management of a failed osteochondral autograft/allograft.