tbuckley/cabot-search huggingface dataset:
Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001
Authors: Derek Croote, Joyce J.W. Wong, Paige Creeks, Venu Aruva, Jeffrey J. Landers, Matthew Kwok, Zainab Jama, Robert G. Hamilton, Alexandra F. Santos, Jessica J. O’Konek, Roger Ferrini, G. Roger Thomas, Henry B. Lowman
Journal: Journal of Allergy and Clinical Immunology (2024)

BackgroundExisting therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions.ObjectiveGuided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies.MethodsWe applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs.ResultsWe determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model.ConclusionsWe developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.
Application of hemostatic forceps to treat post-sphincterotomy bleeding near the pancreatic duct opening
Authors: Jay A. Bapaye, Reid D. Wasserman, Klaus Mönkemüller, Vivek Kesar, Varun Kesar
Journal: Endoscopy (2024)

A 36-year-old man underwent endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy, which resulted in the extraction of several large stones. A 10-mm × 4-cm fully covered metal stent was placed in the bile duct and a 5-Fr × 4-cm flapless straight plastic stent in the pancreatic duct. The patient returned to the emergency department 2 days later complaining of dizziness, melanic stool, and a syncopal event. His hemoglobin showed a downward trend of 16 to 8.3g/dL. The patient underwent esophagogastroduodenoscopy, which showed active oozing with an adherent clot at the sphincterotomy site at the inferior aspect of the major papilla ([Fig. 1]). The biliary stent was removed for better visualization, the clot was suctioned, and epinephrine (1:10 000) was injected around the site. Next, a hemostatic forceps (coagrasper) was utilized to inspect and expose the area ([Fig. 2]). Blood was seen to be issuing near the pancreatic duct as well as a visible vessel at the apex of the papilla ([Video 1]). Because of the tight space and the risk of clipping the pancreatic duct, the coagrasper was used to achieve hemostasis. Before applying coagulation, the ampulla was submerged under water to decrease the risk of thermal burn to the thin duodenal wall ([Fig. 3]). A 10-mm × 4-cm biliary stent was deployed, and a 5-Fr × 4-cm stent was placed in the pancreatic duct to prevent post-procedure pancreatitis.
Endoscopic ultrasound-guided detection and internal drainage of a pancreato-cutaneous fistula after acute pancreatitis
Authors: Ahmad Kattan, Olivier Monneuse, Alice Burgevin, Rosario DʼAlmeida, Gwladys Pointet, Jérôme Rivory, Mathieu Pioche
Journal: Endoscopy (2024)

Pancreatocutaneous fistulas are an uncommon complication of acute pancreatitis [1] [2]. Endoscopic management of these fistulas is not straightforward [3]. One approach involves catheterizing the fistula through the skin using a percutaneous drain; however, catheterization of the disconnected pancreatic duct is nearly impossible. Alternatively, pigtail drains can be placed in the peripancreatic collection, if present, but this cavity is often virtual and tends to empty through the cutaneous fistula [4] [5].
Technical tips for antegrade endopancreatic radiofrequency ablation for severe pancreatojejunal stricture
Authors: Takeshi Ogura, Kimi Bessho, Nobuhiro Hattori, Jun Matsuno, Hiroki Nishikawa
Journal: Endoscopy (2024)

Pancreatojejunal stricture (PJS) is one of the late adverse events after pancreatoduodenectomy, and can lead to pancreatitis or endocrine pancreatic insufficiency as complications [1]. PJS is usually treated under enteroscopic guidance [2], although, because of the relatively low technical success rate and prolonged procedure time, an endoscopic ultrasound (EUS)-guided transluminal approach has recently been developed for pancreatic disease [3]. However, in cases of severe PJS, guidewire passage through the PJS into the intestine under the EUS-guided approach might be challenging, since the PJS site cannot be directly visualized. To overcome this issue, a technique involving antegrade transluminal pancreatoscope insertion has been developed. However, despite successful guidewire passage, PJS dilation might still be challenging because the pushing force might be lower in the EUS-guided approach than the enteroscopic approach. Although electrocautery dilation is a useful technique [4], recurrence of PJS is possible since the burning effect is small. On the other hand, endobiliary radiofrequency ablation (RFA) can sufficiently burn fibrotic tissue [5]. We herein describe a novel technique for PJS treatment using RFA with a pancreatoscope.
Endoscopic ischemic polypectomy using a large endoclip for Peutz–Jeghers polyps
Authors: Takashi Taida, Yuki Ohta, Keiko Saito, Kenichiro Okimoto, Tomoaki Matsumura, Jun Kato, Naoya Kato
Journal: Endoscopy (2024)

Hamartomatous polyps seen in Peutz–Jeghers syndrome are called Peutz–Jeghers polyps (PJPs), and PJPs 15 mm or larger in size may cause intestinal intussusception that requires surgical treatment. The usefulness of balloon-assisted enteroscopy has been reported for PJPs in the small intestine [1]. Although endoscopic resection was the conventional treatment for PJP, endoscopic ischemic polypectomy (EIP), namely the strangulation of the polyps using endoclips without resection, is now preferred for PJPs because of the need to treat many PJPs at one endoscopic session [2]. For polyps with large stalks, conventional clips may not provide sufficient ischemia even with repeated clipping, resulting in the need for snare ischemia [3]. However, the snare technique takes a longer time and is challenging to perform because of the difficulty in obtaining adequate endoscopic images of large polyps and the limited maneuverability of the endoscope [2]. Moreover, if ligation with a snare fails, the snare cannot be reopened and must be discarded, representing a treatment failure. Recently, the SureClip (Micro-Tech) has been developed as a novel endoclip that rotates smoothly and can be reopened after grasping tissue. Although its usefulness in endoscopic treatment has been reported [4] [5], the utility of this device in EIP for PJPs is unclear. The SureClip has available a longer clip width (16 mm) than conventional clips and allows reopening and repositioning, making it easier to achieve strong clamping of the polyps. We report on EIP for PJPs, using the longer clip ([Video 1]).
Cholangioscopy-guided laser ablation for intraductal papillary neoplasm of bile duct
Authors: Yuhuan Wu, Weigang Gu, Ka Shing Cheung, Jianfeng Yang, Xiaofeng Zhang, Hangbin Jin
Journal: Endoscopy (2024)

A 65-year-old man with a history of metastatic bladder cancer was admitted with jaundice. Blood tests revealed a cholestatic pattern of liver function, hyperbilirubinemia, and deranged clotting profile. Computed tomography and magnetic resonance cholangiopancreatography showed cirrhosis and dilated extrahepatic and intrahepatic biliary systems without hyperdense stones ([Fig. 1]). Endoscopic retrograde cholangiopancreatography revealed a fish-mouth deformity of the papillary opening ([Fig. 2]), dilated intrahepatic ducts, and poor contrast filling of the common bile duct ([Fig. 3]). Repeated balloon trawling (18 mm) yielded a copious amount of jelly-like mucus. Cholangioscopy (SpyGlass; Boston Scientific, Natick, Massachusetts, United States) revealed multiple foci of papillary growth in the upper common bile duct, common hepatic duct, and proximal left biliary duct ([Fig. 4]). The biopsy samples revealed papillary proliferation with a gastric subtype and low-grade dysplasia. A diagnosis of intraductal papillary neoplasm of the bile duct (IPNB) was made. Repeat cholangioscopy was performed by introducing an end-on irradiation fiber connected to a laser system (Leonardo 1470 nm/980 nm dual-wavelength laser; CeramOptec GmbH/Biolitec AG, Bonn, Germany) ([Fig. 5]). Ablation of the papillary growth was performed until a whitish discoloration and necrosis appeared ([Video 1]). The patient did not experience any discomfort or adverse events after the procedure and was discharged 9 days later.
Transcolonic endoscopic appendectomy via snare-through-line resection for stump appendicitis
Authors: Yun Wang, Ming-Yan Cai, Sheng-Li Lin, Mo-Fan Li, Ping-Hong Zhou
Journal: Endoscopy (2024)

A 16-year-old girl was admitted due to recurrent abdominal pain 10 months after laparoscopic appendectomy. Physical examination showed tenderness at the McBurney point. Computed tomography revealed a distended appendiceal stump with peristump inflammation and dense suture material at the ligated end. After comprehensive preoperative assessment, transcolonic endoscopic appendectomy was chosen.
Endoscopic submucosal dissection of early gastric cancer using a novel image-enhanced endoscopy: amber-red color imaging
Authors: Kohei Funasaka, Noriyuki Horiguchi, Hyuga Yamada, Keishi Koyama, Teiiji Kuzuya, Ryoji Miyahara, Yoshiki Hirooka
Journal: Endoscopy (2024)

Hemostasis during endoscopic submucosal dissection (ESD) is essential to ensuring success with few complications [1] [2]. FUJIFILM has recently developed a novel image-enhanced technology for ESD, called amber-red color imaging (ACI). ACI improves the visualization of blood flow in bleeding situations by using amber and orange colors while keeping the submucosal layer blue. We report two cases of gastric ESD using continuous ACI ([Video 1]).
Two-stage cap-assisted endoscopic mucosal resection and papillectomy for duodenal papillary tumors with lateral growth
Authors: Nobuhiko Fukuba, Masaki Onoe, Yasuhide Kodama, Satoshi Kotani, Koutarou Shibagaki, Norihisa Ishimura, Shunji Ishihara
Journal: Endoscopy (2024)

Endoscopic papillectomy is indicated for the treatment of duodenal papillary adenoma [1] [2]. However, en bloc resection using a snare may be challenging in cases with lateral extension of tumor. For lesions that are difficult to remove en bloc with papillectomy alone, resection of two parts of the lesion with staggered timing is effective, without requiring submucosal dissection [3]. A man in his fifties was referred to our hospital following a medical examination. Duodenoscopy revealed a flat lesion arising from the papilla and extending toward the anus ([Fig. 1]). A diagnosis of ampullary adenoma was made. The use of a snare was considered to increase the risk of residual peripheral lesions. Consequently, a strategy was devised to remove the lesion in two parts: the anal side and the ampullary side. First, we excised the anal side of the lesion using cap-assisted endoscopic mucosal resection [4]. Then, we inserted an endoscope (GIF-Q260J; Olympus, Tokyo, Japan) with a disposable hood (D-206-05; Olympus) ([Video 1]). Following administration of physiological saline under the lesion, a 25-mm snare was set in the claw of the hood, and the anal side of the lesion was suctioned, grasped with the snare, and excised using the ENDO CUT Q mode (VAIO2; Erbe, Tübingen, Germany). Prior to resection, several trial suctions were performed to test the grip accuracy. After 8 weeks, the ulcer had scarred, and endoscopic papillectomy was performed for the residual tumor ([Fig. 2]). Using a TJF-Q290V endoscope (Olympus, Tokyo, Japan) in the ENDO CUT Q mode, the residual tumor was excised by applying a snare from the oral side to the anal side. The treatment was completed by placing plastic stents in the bile and pancreatic ducts and applying clip sutures. The histopathological diagnosis was well-differentiated adenocarcinoma localized to the mucosa. Reconstruction of the lesion removed using cap-assisted endoscopic mucosal resection and endoscopic papillectomy revealed no residual tumor ([Fig. 3]). No adverse events of the procedures were observed. At 1 year, endoscopy revealed no tumor recurrence.
New drug-delivery balloon catheter for easy and fast injection of triamcinolone after esophageal endoscopic submucosal dissection
Authors: Takashi Hirose, Hiroyuki Shibata, Kazuhiro Furukawa, Takeshi Yamamura, Takuya Ishikawa, Masanao Nakamura, Hiroki Kawashima
Journal: Endoscopy (2024)

Esophageal endoscopic submucosal dissection (ESD) is a very common and useful endoscopic treatment for superficial esophageal cancer [1]. The most common delayed adverse event of esophageal ESD for extensive lesions is stenosis [2]. Local injection of triamcinolone is the most common form of stenosis prevention [3], and the method using a needle is a rather complicated and time-consuming procedure. A new drug-delivery balloon catheter is a device with multiple micro holes on its surface that eject fluid from the balloon when the balloon pressure rises.
Combination of PARP Inhibitors and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer
Authors: Louise Kostos, Ben Tran, Arun A. Azad
Journal: Drugs (2024)

Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing for homologous recombination repair pathway alterations is recommended for all patients with advanced prostate cancer given that a mutation is present in up to 25% of cases. Poly(ADP-ribose) polymerase (PARPis) are now approved for use in patients with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor pathway inhibitor (ARPI) and harbour a germline or somatic homologous recombination repair mutation. Preclinical data support a synergistic effect with an ARPI and PARPi, and various ARPI-PARPi combinations have therefore been explored in phase III clinical trials. Despite heterogeneous findings, a clear hierarchy of benefit is evident, with patients harbouring a BRCA mutation deriving the greatest magnitude of benefit, followed by any homologous recombination repair mutation. The benefit in homologous recombination repair-proficient cohort is less clear, and questions remain about whether ARPI-PARPi combination therapy should be offered to patients without a homologous recombination repair mutation. With ARPIs now considered standard-of-care for metastatic hormone-sensitive prostate cancer, ARPI-PARPi combination therapy is currently being explored earlier in the treatment paradigm. The purpose of this review is to discuss the rationale behind ARPI-PARPi combination therapy, summarise the results of key clinical trials, and discuss clinical considerations and future perspectives.
Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response
Authors: Elizabeth Theusch, Flora Y. Ting, Yuanyuan Qin, Kristen Stevens, Devesh Naidoo, Sarah M. King, Neil V. Yang, Joseph Orr, Brenda Y. Han, Jason G. Cyster, Yii-Der I. Chen, Jerome I. Rotter, Ronald M. Krauss, Marisa W. Medina
Journal: Genome Medicine (2024)

Abstract Background Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. Methods To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified ( ZNF335 ), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335 ). Results The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 ( ZNF335 aka NIF-1 , rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 ( CNOT3 , rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model ( p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335 R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (−43 ± 18% and −23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335 R1092W allele(s) exhibited a significantly blunted LDL statin response. Conclusions Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
Association of social determinants, lifestyle, and metabolic factors with mortality in Chinese adults: A nationwide 10-year prospective cohort study
Authors: Jieli Lu, Mian Li, Jiang He, Yu Xu, Ruizhi Zheng, Jie Zheng, Guijun Qin, Yingfen Qin, Yuhong Chen, Xulei Tang, Zhen Ye, Min Xu, Tiange Wang, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Zhiyun Zhao, Qin Wan, Gang Chen, Zhengnan Gao, Guixia Wang, Feixia Shen, Xuejiang Gu, Zuojie Luo, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Hong Qiao, Yinfei Zhang, Tianshu Zeng, Chunyan Hu, Qiuyu Cao, Xiaojing Jia, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Hongyan Qi, Xueyan Wu, Di Zhang, Meng Dai, Donghui Li, Shenghan Lai, Lulu Chen, Jiajun Zhao, Yiming Mu, Weiguo Hu, Guang Ning, Ruying Hu, Yufang Bi, Weiqing Wang
Journal: Cell Reports Medicine (2024)
When I use a word . . . . Fictional drugs and wish fulfilment in Anthony Burgess, Philip K Dick, and Larry Niven
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

I define fictional drugs as non-existent medicines, intended for human use, invented for the purposes of some forms of fiction, usually novels, but also plays or films, including TV dramas. In several cases the inventions could be interpreted as representing some form of wish fulfilment on the author's part. Examples include: Moloko plus in <i>A Clockwork Orange</i> (1962) by Anthony Burgess; Can-D and Chew-Z in <i>The Three Stigmata of Palmer Eldritch</i> (1965) and Ubik in the novel of that name (1969), both by Philip K Dick; and boosterspice in <i>Ringworld</i> (1970) and other novels by Larry Niven. But be careful what you wish for—there may be adverse effects.
Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation
Authors: Tobias Grass, Zeynep Dokuzluoglu, Felix Buchner, Ines Rosignol, Joshua Thomas, Antonio Caldarelli, Anna Dalinskaya, Jutta Becker, Fabian Rost, Michele Marass, Brunhilde Wirth, Marc Beyer, Lorenzo Bonaguro, Natalia Rodriguez-Muela
Journal: Cell Reports Medicine (2024)

Whether neurodevelopmental defects underlie postnatal neuronal death in neurodegeneration is an intriguing hypothesis only recently explored. Here, we focus on spinal muscular atrophy (SMA), a neuromuscular disorder caused by reduced survival of motor neuron (SMN) protein levels leading to spinal motor neuron (MN) loss and muscle wasting. Using the first isogenic patient-derived induced pluripotent stem cell (iPSC) model and a spinal cord organoid (SCO) system, we show that SMA SCOs exhibit abnormal morphological development, reduced expression of early neural progenitor markers, and accelerated expression of MN progenitor and MN markers. Longitudinal single-cell RNA sequencing reveals marked defects in neural stem cell specification and fewer MNs, favoring mesodermal progenitors and muscle cells, a bias also seen in early SMA mouse embryos. Surprisingly, SMN2-to-SMN1 conversion does not fully reverse these developmental abnormalities. These suggest that early neurodevelopmental defects may underlie later MN degeneration, indicating that postnatal SMN-increasing interventions might not completely amend SMA pathology in all patients.
Estimation of ventilatory thresholds during exercise using respiratory wearable sensors
Authors: Felipe Contreras-Briceño, Jorge Cancino, Maximiliano Espinosa-Ramírez, Gonzalo Fernández, Vader Johnson, Daniel E. Hurtado
Journal: npj Digital Medicine (2024)

Ventilatory thresholds (VTs) are key physiological parameters used to evaluate physical performance and determine aerobic and anaerobic transitions during exercise. Current assessment of these parameters requires ergospirometry, limiting evaluation to laboratory or clinical settings. In this work, we introduce a wearable respiratory system that continuously tracks breathing during exercise and estimates VTs during ramp tests. We validate the respiratory rate and VTs predictions in 17 healthy adults using ergospirometry analysis. In addition, we use the wearable system to evaluate VTs in 107 recreational athletes during ramp tests outside the laboratory and show that the mean population values agree with physiological variables traditionally used to exercise prescription. We envision that respiratory wearables can be useful in determining aerobic and anaerobic parameters with promising applications in health telemonitoring and human performance.
Covid-19 inquiry: We must not ignore the long term health impacts of covid
Authors: Ondine Sherwood
Journal: BMJ (2024)

Module 1 of the UK covid-19 inquiry reported on 18 July 2024.The report is rightly critical and does not hold back from emphasising the devastating truth.Far from the UK being one of the most prepared countries for a pandemic-as was erroneously thought-"the processes, planning, and policy of the civil contingency structures across the UK failed the citizens of all four nations," said Heather Hallett, chair of the inquiry.