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Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib

Purpose. Guillain-Barré syndrome (GBS) in pregnancy is very rare, and there is no detailed description of rehabilitation in the literature. We report a case of GBS involving a pregnant, 34-year-old woman. Case Description. She was diagnosed with Hughes grade 5 GBS during the 20th week of gestation (GW). Almost all basic motions showed total dependence. The motor functional independence measure (motor FIM) score was 31. We developed a training programme that considered the pregnancy-associated increase in her weight. Results. At the 34th GW, her transfer activity became independent and she began gait training. At the 37th GW, she delivered a healthy baby spontaneously. She nursed her baby independently using a sling. After the motor FIM improved to 84, the mother and infant were discharged together 5 weeks after delivery and home-visit rehabilitation was performed while using a baby-sitter. One month after discharge, she became able to walk alone over a short distance. Finally, her endurance improved, facilitating her return to office work 15 months after discharge. Conclusion. We are following the patient, providing training in the movements needed for child care and suggesting environmental improvements for the mother and infant. As a result, her recovery from disability has been promoted. [ABSTRACT FROM AUTHOR]

Abstract Purpose It is still technically difficult to collect high purity cancer cells from tumor tissues, which contain noncancerous cells. We hypothesized that xenograft models of NOG mice expressing enhanced green fluorescent protein (eGFP), referred to as NOG-EGFP mice, may be useful for obtaining such high purity cancer cells for detailed molecular and cellular analyses. Methods Pancreato-biliary cancer cell lines were implanted subcutaneously to compare the tumorigenicity between NOG-EGFP mice and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. To obtain high purity cancer cells, the subcutaneous tumors were harvested from the mice and enzymatically dissociated into single-cell suspensions. Then, the cells were sorted by fluorescence-activated cell sorting (FACS) for separation of the host cells and the cancer cells. Thereafter, the contamination rate of host cells in collected cancer cells was quantified by using FACS analysis. The viability of cancer cells after FACS sorting was evaluated by cell culture and subsequent subcutaneous reimplantation in NOG-EGFP mice. Results The tumorigenicity of NOG-EGFP mice was significantly better than that of NOD/SCID mice in all of the analyzed cell lines (p Conclusions This method provides a novel cancer sampling system for molecular and cellular analysis with high accuracy and should contribute to the development of personalized medicine.

Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We report vitrimer-like elastomers that exhibit significantly fast stress relaxation using carboxy exchange via the conjugate substitution reaction of α-(acyloxymethyl) acrylate skeletons. This network design is inspired by a small-molecule model that shows the carboxy exchange reaction even at ambient temperature in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). The acrylate and acrylic acid copolymers are cross-linked using bis[α-(bromomethyl)acrylates] and doped with 10 wt% DABCO, exhibiting processability to obtain a transparent film by hot pressing. The high-speed bond exchange in the network, validated by stress-relaxation tests, allows quick molding with household iron. In addition, the material is applied as an adhesion sheet for plastic and metal substrates. Because dynamic cross-linking with the proposed bond exchange mechanism can be implemented for any polymer bearing carboxyl pendants, our approach can be applied to versatile backbones, which must thus be meaningful in the practical sense., (© 2024. The Author(s).)

Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis., (© 2024. The Author(s).)

A 62-year-old male with a history of stent graft replacement for an infectious aortic aneurysm, followed by multiple interventions for postoperative complications, was admitted with melena and anemia. Enhanced computed tomography (eCT) demonstrated fluffing and hyperdensities surrounding the graft, despite no evidence of an aortoenteric fistula (AEF). Emergency esophagogastroduodenoscopy (EGD) showed a massive bleeding in the reconstructed tract and the protruding lesion of postoperative granulation tissue with clots at the end of the blind pouch. Thereafter, hemorrhage temporarily reoccurred several times; however, the source could not be identified using eCT or EGD. Finally, on the third attempt, we performed gel immersion endoscopy (GIE) with manual injection of VISCOCLEAR Ⓡ , and it showed purulent blood flowing from one side of the protruding lesion in the pouch. Based on the eCT findings showing exudation of the contrast agent from the graft into the pouch, we made a diagnosis of an AEF. However, radical surgery was not performed because of the patient's poor general condition. During conservative management, he died of uncontrolled bleeding from the AEF on the 5th day of hospitalization. This is the first case in which the GIE might provide tips to identify herald bleeding from a lethal AEF., (© 2024. Japanese Society of Gastroenterology.)