tbuckley/cabot-search huggingface dataset:
CoNIC Challenge: Pushing the frontiers of nuclear detection, segmentation, classification and counting
Authors: Simon Graham, Quoc Dang Vu, Mostafa Jahanifar, Martin Weigert, Uwe Schmidt, Wenhua Zhang, Jun Zhang, Sen Yang, Jinxi Xiang, Xiyue Wang, Josef Lorenz Rumberger, Elias Baumann, Peter Hirsch, Lihao Liu, Chenyang Hong, Angelica I. Aviles-Rivero, Ayushi Jain, Heeyoung Ahn, Yiyu Hong, Hussam Azzuni, Min Xu, Mohammad Yaqub, Marie-Claire Blache, Benoît Piégu, Bertrand Vernay, Tim Scherr, Moritz Böhland, Katharina Löffler, Jiachen Li, Weiqin Ying, Chixin Wang, David Snead, Shan E. Ahmed Raza, Fayyaz Minhas, Nasir M. Rajpoot
Journal: Medical Image Analysis (2023)

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery.
Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity
Authors: Xiaojin Luan, Ting Lei, Jie Fang, Xue Liu, Huijia Fu, Yiran Li, Wei Chu, Peng Jiang, Chao Tong, Hongbo Qi, Yong Fu
Journal: Molecular Therapy (2023)

Macrophages play a crucial role in shaping the immune state within the tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs toward an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and a high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications. Macrophages play a crucial role in shaping the immune state within the tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs toward an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and a high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications.
Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing
Authors: Wen-Bin Zhao, Ying Shen, Guo-Xin Cai, Yi-Ming Li, Wen-Hui Liu, Jing-Cheng Wu, Ying-Chun Xu, Shu-Qing Chen, Zhan Zhou
Journal: Molecular Therapy (2023)
Hepatitis B core-related antigen dynamics and risk of subsequent clinical relapses after nucleos(t)ide analog cessation
Authors: Ying-Nan Tsai, Jia-Ling Wu, Cheng-Hao Tseng, Tzu-Haw Chen, Yi-Ling Wu, Chieh-Chang Chen, Yu-Jen Fang, Tzeng-Huey Yang, Mindie H. Nguyen, Jaw-Town Lin, Yao-Chun Hsu
Journal: Clinical and Molecular Hepatology (2023)

Background/Aims: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR).Methods: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase &gt; two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR.Results: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5–40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7–67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1–62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12–2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg &lt;1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21–0.81).Conclusions: Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.
Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis B
Authors: Terry Cheuk-Fung Yip, Jimmy Che-To Lai, Tsz-Fai Yam, Yee-Kit Tse, Vicki Wing-Ki Hui, Mandy Sze-Man Lai, Henry Lik-Yuen Chan, Vincent Wai-Sun Wong, Grace Lai-Hung Wong
Journal: Journal of Hepatology (2023)
Lax oversight of semaglutide advertising could harm patients, warn critics
Authors: Hristio Boytchev
Journal: BMJ (2023)

Lax oversight of semaglutide advertising could harm patients, warn critics Hristio BoytchevUK organisations responsible for protecting the public from advertisements of prescription-only drugs are putting patients at risk from the harms of weight loss drugs by not enforcing the law, critics have told The BMJ.
Endoscopic esophageal cicatricotomy assisted by submucosal injection for the treatment of esophageal stenosis after endoscopic submucosal dissection
Authors: Wen Ji, Senrong Luo, Shijun Wang, Huan He, Weiqing Chen
Journal: Endoscopy (2023)

Esophageal stenosis is a common complication after endoscopic submucosal dissection (ESD) for early esophageal cancer [1] [2]. Post-ESD esophageal stenosis is considered to be related to scar tissue proliferation and fibrosis during the healing process [3]. Symptom relief can be achieved through dilation and radial incision in 83% [4]. However, these invasive strategies do not allow visual control of the operation, and it is difficult to control complications such as bleeding or perforation caused by these treatments.
Tip-in underwater endoscopic mucosal resection for a residual lower rectal lesion extending to the dentate line
Authors: Taishi Okumura, Kenichiro Imai, Kinichi Hotta, Sayo Ito, Yoshihiro Kishida, Kazunori Takada, Hiroyuki Ono
Journal: Endoscopy (2023)

Endoscopic resection of lower rectal lesions close to the dentate line remains challenging because the narrow lumen in proximity to the anal sphincter results in poor visualization of the lesion [1]. Furthermore, submucosal scarring after previously attempted endoscopic removal significantly reduces the efficacy of submucosal injection. Underwater endoscopic mucosal resection (UEMR) can be effective for poorly visualized polyps, such as orifice- or diverticular-related polyps, or for scarred residual polyps [2] [3] [4]. Nevertheless, suboptimal visualization of the proximal margins in the deflated lumen hampers effective snaring. The tip-in maneuver ensures proximal margin visualization, achieving improved en bloc resection [5]. Here, we present a case of successful en bloc resection of a residual anorectal adenoma using tip-in UEMR ([Fig. 1]).
Misidentification of a duodenal neuroendocrine tumor as an adenoma, with subsequent attempted resection by cold snare polypectomy
Authors: Hirotaka Oura, Akihiro Miyakawa, Tadao Nakazawa
Journal: Endoscopy (2023)

A woman in her 70s underwent esophagogastroduodenoscopy screening, which indicated a 5-mm erythematous elevated lesion on the anterior side of the duodenal bulb ([Fig. 1]). The biopsy pathology findings indicated an adenoma, and the patient was referred to our hospital for treatment. The lesion showed minor irregularity on narrow-band imaging (NBI) ([Fig. 2] , [Fig. 3]). However, combined with the result of the biopsy, we diagnosed it as a low-grade adenoma. We attempted to resect it by cold snare polypectomy, but resistance during snaring made resection impossible. In addition, white mucus flowed from the tumor during snaring ([Fig. 4] ; [Video 1]). The tumor was successfully resected en bloc by endoscopic mucosal resection. Pathology findings showed a G1 neuroendocrine tumor (NET; World Health Organization classification) with negative margins ([Fig. 5] a). There was scattered submucosal retention of mucin in Brunner's gland adjacent to the NET ([Fig. 5] b,c), which was thought to have drained out under pressure during snaring. The retention of the mucin may have occurred due to obstruction by the NET or inflammation, because reactive lymphoid follicles were also seen near the NET.
A new approach in monitoring blood tests in anti-tumour necrosis factor-α therapies in psoriasis
Authors: Andrea Conti, Matteo Paolinelli
Journal: British Journal of Dermatology (2023)

Journal Article Corrected proof A new approach in monitoring blood tests in anti-tumour necrosis factor-α therapies in psoriasis Get access Andrea Conti, Andrea Conti Conceptualization, Writing - original draft, Writing - review & editing Dermatology Unit, Department of Surgery, Infermi Hospital Rimini, AUSL Romagna, Rimini, Italy Correspondence: Andrea Conti. Email: andrea.conti@auslromagna.it https://orcid.org/0000-0003-4848-3817 Search for other works by this author on: Oxford Academic Google Scholar Matteo Paolinelli Matteo Paolinelli Conceptualization, Writing - original draft, Writing - review & editing Dermatology Unit, Department of Surgery, Infermi Hospital Rimini, AUSL Romagna, Rimini, Italy Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad490, https://doi.org/10.1093/bjd/ljad490 Published: 13 December 2023 Article history Received: 27 November 2023 Accepted: 30 November 2023 Published: 13 December 2023 Corrected and typeset: 23 January 2024
Successful removal of a migrated plastic stent using a new endoscopic sheath
Authors: Manabu Yamada, Takeshi Okamoto, Naoki Sasahira
Journal: Endoscopy (2023)

Migration of plastic stents after endoscopic biliary stenting (EBS) occurs in 5%–10% of patients [1]. We report successful removal of a migrated plastic stent using EndoSheather (Piolax, Inc., Kanagawa, Japan), a new endoscopic sheath designed to facilitate targeted biopsies of the biliary tree [2].
Long-term oncological outcomes of transanal versus laparoscopic total mesorectal excision for mid-low rectal cancer: a retrospective analysis of 2502 patients
Authors: Ze Li, Huashan Liu, Shuangling Luo, Yujie Hou, Yebohao Zhou, Xiaobin Zheng, Xingwei Zhang, Liang Huang, Ziwei Zeng, Liang Kang
Journal: International Journal of Surgery (2023)

Transanal total mesorectal resection (taTME) has recently emerged as a promising surgical approach for the treatment of mid-low rectal cancer. However, there is limited evidence on the long-term survival outcomes associated with taTME. This retrospective study aimed to compare the overall survival (OS), disease-free survival (DFS), and cancer-specific survival of taTME and laparoscopic TME (laTME) in patients with mid-low rectal cancer.
Procedures in cosmetic dermatology: Soft tissue augmentation, fifth edition
Authors: Alanoud Alhadyani
Journal: Journal of the American Academy of Dermatology (2023)

The fifth edition of Procedures in Cosmetic Dermatology: Soft Tissue Augmentation is a comprehensive guide for health care providers who want to incorporate minimally invasive cosmetic procedures into their practice. The authors review different fillers, all relevant anatomies of each region of the face, and highlight injection sites and exterior landmarks to help practitioners perform procedures more effectively and minimize complication risk. In addition, the book emphasizes the importance of understanding the aesthetic desires of each subject and how to target volume mobilization carefully.
Update on microbiota-derived therapies for recurrent Clostridioides difficile infections
Authors: Nicolas Benech, Frédéric Barbut, Fidelma Fitzpatrick, Marcela Krutova, Kerrie Davies, Celine Druart, Magali Cordaillat-Simmons, John Heritage, Benoît Guery, Ed Kuijper
Journal: Clinical Microbiology and Infection (2023)
Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse
Authors: Yu Ouyang, Yimei Hong, Cong Mai, Hangzhen Yang, Zicong Wu, Xiaoyan Gao, Weiyue Zeng, Xiaohui Deng, Baojuan Liu, Yuelin Zhang, Qingling Fu, Xiaojia Huang, Juli Liu, Xin Li
Journal: Bioactive Materials (2023)

Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.
Corrigendum to “Virological and clinical rebounds of COVID-19 soon after nirmatrelvir/ritonavir discontinuation” [Clin Microbiol Infect 28 (12) (2022 Dec) 1657–1658]
Authors: Guido Antonelli, Daniele Focosi, Ombretta Turriziani, Marco Tuccori, Rossella Brandi, Silvia Fillo, Camilla Ajassa, Florigio Lista, Claudio M. Mastroianni
Journal: Clinical Microbiology and Infection (2023)

The authors regret that in the third paragraph towards the end of the paper, the text reads "Bocau et al. in France" which should instead have been "Boucau et al. in USA". The authors would like to apologise for any inconvenience caused. Virological and clinical rebounds of COVID-19 soon after nirmatrelvir/ritonavir discontinuationClinical Microbiology and InfectionVol. 28Issue 12PreviewWe read with interest the recent commentary by Girardin et al. on the pharmacokinetic interactions with nirmatrelvir/ritonavir published online in Clinical and Microbiological Infections on 28 March 2022 [1]. Oral small-chemical antivirals have been recently authorized around the world and come with the promise of simplifying the management and reducing hospitalization of COVID-19 outpatients at risk of disease progression. Nirmatrelvir tablets co-packaged with ritonavir tablets (Paxlovid, Pfizer, New York, NY, USA) (300/100 mg dose twice daily for 5 days) was granted a conditional marketing authorization by the European Medicines Agency (EMA) on 29 January 2022 on the basis of a phase 2/3 randomised controlled trial (RCT) in 2246 unvaccinated outpatients (mostly during the wave driven by the Delta variant of concern—July-December 2021) in which treatment at a median of 3 days since onset of symptoms led to an 88.9% reduction in the relative risk of hospitalization (-5.81%) [2]. Full-Text PDF
Similarities and differences in peripheral itch and pain pathways in atopic dermatitis
Authors: Gil Yosipovitch, Brian Kim, Thomas Luger, Ethan Lerner, Martin Metz, Roni Adiri, Juliana M. Canosa, Amy Cha, Sonja Ständer
Journal: Journal of Allergy and Clinical Immunology (2023)

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in atopic dermatitis. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system including common mediators (such as serotonin [5-HT], endothelin-1 [ET-1], interleukin-33 [IL-33], and thymic stromal lymphopoietin [TSLP]), receptors (such as members of the G protein-coupled receptor [GCPR] family and toll-like receptors [TLRs]), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C–C [CCL2, CCL5] and C–X–C motif ligands [CXCL]) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of mu-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in atopic dermatitis.
Super-resolution imaging for in situ monitoring sub-cellular micro-dynamics of small molecule drug
Authors: Huimin Chen, Guiqian Fang, Youxiao Ren, Weiwei Zou, Kang Ying, Zhiwei Yang, Qixin Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Small molecule drugs play a pivotal role in the arsenal of anticancer pharmacological agents. Nonetheless, their small size poses a challenge when directly visualizing their localization, distribution, mechanism of action (MOA), and target engagement at the subcellular level in real time. We propose a strategy for developing triple-functioning drug beacons that seamlessly integrate therapeutically relevant bioactivity, precise subcellular localization, and direct visualization capabilities within a single molecular entity. As a proof of concept, we have meticulously designed and constructed a boronic acid fluorescence drug beacon using coumarin–hemicyanine (CHB). Our CHB design includes three pivotal features: a boronic acid moiety that binds both adenosine triphosphate (ATP) and adenosine diphosphate (ADP), thus depleting their levels and disrupting the energy supply within mitochondria; a positively charged component that targets the drug beacon to mitochondria; and a sizeable conjugated luminophore that emits fluorescence, facilitating the application of structured illumination microscopy (SIM). Our study indicates the exceptional responsiveness of our proof-of-concept drug beacon to ADP and ATP, its efficacy in inhibiting tumor growth, and its ability to facilitate the tracking of ADP and ATP distribution around the mitochondrial cristae. Furthermore, our investigation reveals that the micro-dynamics of CHB induce mitochondrial dysfunction by causing damage to the mitochondrial cristae and mitochondrial DNA. Altogether, our findings highlight the potential of SIM in conjunction with visual drug design as a potent tool for monitoring the in situ MOA of small molecule anticancer compounds. This approach represents a crucial advancement in addressing a current challenge within the field of small molecule drug discovery and validation.
Menin Inhibitors Trigger Leukemia Remissions
Journal: Cancer Discovery (2023)

Abstract Menin inhibitors have proven effective in patients with acute leukemias. A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations.