tbuckley/cabot-search huggingface dataset:
Phase 2 Trial of Topical Application of the Hedgehog Inhibitor Patidegib in Patients With Gorlin Syndrome
Authors: John T Lear, Catherine A Harwood, Zeeshaan Hasan, Jonathan Kentley, Jason Thomson, Andre Khoo, Alix Alderman, Mark DeSouza, Ervin H Epstein, Gerd G Kochendoerfer, Jean Y Tang
Journal: British Journal of Dermatology (2024)

Patients with Gorlin (basal cell nevus) syndrome (GS) have numerous phenotypic abnormalities due to over-activity of the hedgehog (HH) signaling pathway, most commonly due to a heritable mutation in the PTCH1 gene, which encodes a major inhibitor of this pathway. HH inhibitors (HHi) taken orally can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit:risk ratio, we have developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop treatment with oral HHis.
Nipple-Areolar complex sensory recovery based on incision placement after Nipple-Sparing mastectomy; a prospective Non-randomized controlled trial
Authors: Yoonwon Kook, Dooreh Kim, Soeun Park, Chihhao Chu, Ji Soo Jang, Seung Ho Baek, Soong June Bae, Sung Gwe Ahn, Joon Jeong
Journal: International Journal of Surgery (2024)

Introduction: Nipple-sparing mastectomy (NSM) aims to improve patient satisfaction by preserving the nipple-areola complex (NAC) while ensuring oncologic safety. Different surgical incisions, such as inframammary fold (IMF) and periareolar/radial incisions, are used in NSM; however, their impact on NAC sensory loss remains unclear. In this study, the authors aimed to assess NAC sensation after NSM and compare the results of different incisional approaches, specifically IMF versus periareolar/radial. Methods: In this prospective, single-center, nonrandomized controlled trial, 105 post-NSM patients were recruited from October 2019 to November 2021 and followed up at 24–48 months postsurgery. Of these, 97 (IMF: 65; periareolar/radial: 32) were analyzed for sensory assessment. NAC sensation was measured using the pin-prick test, with scores ranging from 0 (no sensation) to 2 (sharp sensation) across five NAC areas. Sensory loss was defined as a total score below 3. Results: The median total score on the pin-prick test for NAC sensation was significantly higher in the IMF incision group than in the periareolar/radial incision group (3.77±3.11 vs. 2.47±2.51; P =0.043). The rate of NAC sensory loss was significantly lower in the IMF group than in the periareolar/radial group (36.9% vs. 62.5%; P =0.017). Multivariable analysis revealed that the incisional approach (95% CI: 0.14–0.97; P =0.044) and radiotherapy (95% CI: 0.05–0.36; P &lt;0.01) were independent determinants of NAC sensory loss. Conclusion: Our study emphasized the importance of incision placement during NSM in preserving NAC sensation and may provide a valuable perspective for clinicians and patients considering this surgical approach.
Clinical evaluation of real-time artificial intelligence provision of expert representation in indocyanine green fluorescence angiography during colorectal resections
Authors: Ashokkumar Singaravelu, Philip D. Mc Entee, Niall P. Hardy, Mohammad F. Khan, Jurgen Mulsow, Conor Shields, Ronan A. Cahill
Journal: International Journal of Surgery (2024)

Singaravelu, Ashokkumar; Mc Entee, Philip D MB, BCh, BAO; Hardy, Niall P PhD; Khan, Mohammad Faraz MD; Mulsow, Jurgen MD; Shields, Conor MD; Cahill, Ronan A PhD Author Information
The role of fluorescent cholangiography to improve operative safety in different severity degrees of acute cholecystitis during emergency laparoscopic cholecystectomy: a prospective cohort study
Authors: Antonio Pesce, Nicolò Fabbri, Luca Bonazza, Carlo Feo
Journal: International Journal of Surgery (2024)

Background: Currently, there is limited scientific evidence regarding the effectiveness of fluorescent cholangiography in emergency cholecystectomy for acute cholecystitis. The primary aim of this study was to assess the efficacy of near-infrared fluorescent cholangiography (NIRF-C) in different severity degrees of acute cholecystitis. Materials and methods: Inclusion criteria were patients with a clinical and radiological (abdominal ultrasound and/or computed tomography) diagnosis of acute cholecystitis based on the revised 2018 Tokyo guidelines who underwent laparoscopic cholecystectomy within 24–72 h from the onset of symptoms and patients with ASA score of 0–3. NIRF-C was performed at three-time points during laparoscopic cholecystectomy: (i) following exposure of Calot’s triangle, prior to any dissection; (ii) after partial dissection of Calot’s triangle; and (iii) after complete dissection of Calot’s triangle. The intraoperative severity degree of acute cholecystitis was assessed according to the American Association of Surgery for Trauma (AAST) classification. Results: NIRF-C was successfully performed in all 81 consecutive patients who underwent emergency laparoscopic cholecystectomy. The cystic duct was identified by NIRF-C in 46 (56.8%) and 77 (95.1%) of the 81 patients before and after Calot’s dissection, respectively. The common hepatic duct and common bile duct were successfully identified in 11 (13.6%) and 32 patients (39.5%) before Calot’s dissection, respectively, and in 45 (55.6%) and 76 patients (93.8%) after complete Calot’s dissection, respectively. When comparing the visualization rate of biliary structures before and after Calot dissection in different severity degrees of cholecystitis, the authors found a statistically significant difference in nongangrenous (AAST I) versus gangrenous and complicated forms (AAST II–V) for all biliary structures, both before and after Calot’s dissection. Conclusions: The study indicates that the use of fluorescence cholangiography during emergency laparoscopic cholecystectomy for acute cholecystitis may represent a valuable and useful tool for intraoperative visualization of the extrahepatic biliary tract.
Intraoperative liquid biopsy as a tool for detecting R1 resection during pancreatoduodenectomy in patients with pancreatic carcinoma. the CETUPANC trial (part II)
Authors: Javier Padillo-Ruiz, Carlos Garcia, Gonzalo Suarez, Gerardo Blanco, Luis Muñoz-Bellvis, Iago Justo, Maria I. García-Domingo, Fabio Ausania, Elena Muñoz-Forner, Alejandro Serrablo, Elena Martin, Luis Díez, Carmen Cepeda, Luis Marin, Jose Alamo, Carmen Bernal, Sheila Pereira, Francisco Calero, Imán Laga, Sandra Paterna, Esteban Cugat, Constantino Fondevila, Diego López-Guerra, Inmaculada Gallego-Jiménez, Juan José Borrero-Martín, Miguel Ángel Gomez-Bravo, Jose Tinoco, Luis Sabater
Journal: International Journal of Surgery (2024)

Introduction: A positive surgical margin (R1 resection) is a relevant risk factor for local recurrence in patients with pancreatic ductal adenocarcinoma of the pancreas (PDAC). An intraoperative liquid biopsy (ILB) based on tumor cell mobilization could help to detect R1 resection intraoperatively. Objective: To evaluate the potential role of the intraoperative circulating tumor cells (CTCs) and cluster mobilization on the R0/R1 detection. Methods: Sixty-three patients with resectable PDAC of the head of the pancreas were prospective enrolled under the CETUPANC trial. Open pancreaticoduodenectomy (PD) was done in all patients. Intraoperative CTCs and clusters were determined during PD. Results: The overall rate of R1 resection was 34.9% (22/63 patients). Multivariate analysis showed that factors associated with R1 resection (AUC=0.920) were the presence of undifferentiated G3 tumor ( P =0.017), microscopic vascular invasion ( P =0.016), and the intraoperative increase of both free CTCs and clusters in portal vein determination from the beginning to the end of the surgery ( P =0.002 and P =0.005, respectively). A specific logistic regression model, including delta end to baseline CTCs and cluster mobilization to achieve a combined cut-off to detect R1 detection was calculated (AUC=0.799). The obtained R1-index based on ILB had 84% of sensitivity and 68% of specificity to detect R1 resection. Conclusions: The ILB based on the intraoperative mobilization of CTCs and clusters from the beginning to the end of the PD was a predictive factor to detect R1 resection in patients with PDAC.
Using Time in Tight Glucose Range as a Health-Promoting Strategy in Preschoolers With Type 1 Diabetes
Authors: Frida Sundberg, Carmel E. Smart, John Samuelsson, Karin Åkesson, Lars Krogvold
Journal: Diabetes Care (2024)

Children who develop diabetes in their first years of life risk being exposed to many decades of hyperglycemia, hence having a high risk of early complications and premature death. An additional age-dependent risk is that dysglycemia, especially hyperglycemia, negatively affects the developing brain. In evaluating the outcome of insulin treatment at an individual and group level, cutoff thresholds for glucose values are needed. Time in tight range (TITR) was defined as a measurement of time spent in a state of normoglycemia. The International Society of Pediatric and Adolescent Diabetes recommended that for preschoolers with type 1 diabetes (T1D), either &amp;gt;70% of time with glucose in range 70–180 mg/dL (3.9–10 mmol/L) or &amp;gt;50% of time in a tighter range 70–140 mg/dL (TITR) can be used as continuous glucose monitoring targets. In Sweden, over the past two decades, pediatric diabetes teams set glycemic targets to 70–140 mg/dL (3.9–7.8 mmol/L). Swedish registry data show that &amp;gt;50% of children &amp;lt;7 years old have &amp;gt;50% TITR. The purpose of this review is to share and discuss international knowledge and experiences of working with TITR as a health-promoting strategy in preschoolers with T1D on a structural and individual level. We conclude that as insulin treatment improves, a reasonable goal is to strive for as much time in a state of normoglycemia as possible, and this can easily be explained to families of children with diabetes. For children with access to an experienced health care team and diabetes technologies a currently realistic target can be at least half of the time in normoglycemic range, i.e., TITR &amp;gt;50%.
Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity
Authors: Zhaoying Zhang, Caiyue Ren, Rong Xiao, Shuaiya Ma, Huimin Liu, Yutong Dou, Yuchen Fan, Shuo Wang, Peng Zhan, Chengjiang Gao, Xuetian Yue, Chunyang Li, Lifen Gao, Xiaohong Liang, Zhuanchang Wu, Chunhong Ma
Journal: Science Immunology (2024)

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys
A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma
Authors: Olivier Demaria, Guillaume Habif, Marie Vetizou, Laurent Gauthier, Romain Remark, Laura Chiossone, Constance Vagne, Lucas Rebuffet, Rachel Courtois, Caroline Denis, François Le Floch, Marianna Muller, Mathilde Girard-Madoux, Séverine Augier, Julie Lopez, Barbara Carrette, Aurélie Maguer, Jean-Baptiste Vallier, Gwendoline Grondin, William Baron, Justine Galluso, Nadia Yessaad, Marilyn Giordano, Léa Simon, Fabien Chanuc, Audrey Blanchard Alvarez, Ivan Perrot, Cécile Bonnafous, Agnès Represa, Benjamin Rossi, Ariane Morel, Yannis Morel, Carine Paturel, Eric Vivier
Journal: Science Immunology (2024)

NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell–activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.
Interoceptive Awareness Is Associated With Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes
Authors: Austin M. Matus, Barbara Riegel, Michael R. Rickels
Journal: Diabetes Care (2024)

OBJECTIVE To assess the association between impaired awareness of hypoglycemia (IAH) and interoceptive awareness in type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 154 adults with type 1 diabetes completed IAH surveys and the Multidimensional Assessment of Interoceptive Awareness, Version 2 (MAIA-2). Logistic regression was performed for assessment of associations between IAH and MAIA-2, accounting for covariates. RESULTS Significant relationships were observed between IAH and two MAIA-2 scales. Each 1-point increase on the Not-Worrying subscale was associated with 87% increased odds of IAH (odds ratio 1.87, CI 1.01–3.46) and on the Attention Regulation subscale was associated with 72% decreased odds of IAH (0.28, 0.12–0.66). Compared with scoring &amp;gt;90th percentile for Attention Regulation, scoring &amp;lt;10th percentile and scoring in the 10th–90th percentiles were associated with 71-fold (71.26, 3.42–1482.10) and 12-fold (12.73, 1.19–135.57) increased odds of IAH, respectively. CONCLUSIONS Less worry about and reduced ability to sustain and control attention to body sensations were associated with significantly increased odds of IAH.
Proportion of Gleason Score ≥8 Prostate Cancer on Biopsy and Tumor Aggressiveness in Matched Cohorts of East Asian and Non-East Asian Men
Authors: Liang Dong, Katherine Lajkosz, Rafael Sanchez-Salas, Cynthia Kuk, Wei Xu, Raj Vikesh Tiwari, Caio Pasquali Dias dos Santos, Hongyang Qian, Jiayi Wang, Baijun Dong, Jiahua Pan, Yinjie Zhu, Qiang Liu, Amy Chan, Jethro C.C. Kwong, Dixon T.S. Woon, Michael Nesbitt, Annette Erlich, Girish S. Kulkarni, Nathan Perlis, Robert J. Hamilton, Laurence Klotz, Christopher J.D. Wallis, David-Dan Nguyen, Petr Macek, Kae Jack Tay, Honghong Huang, Ants Toi, Antonio Finelli, Neil E. Fleshner, Christopher W.S. Cheng, Xavier Cathelineau, Theodorus H. van der Kwast, Wei Xue, Alexandre R. Zlotta
Journal: Journal of the National Comprehensive Cancer Network (2024)

Historically, Asia had a lower prostate cancer (PCa) incidence and mortality compared with Western countries, but the gap is narrowing. Paradoxically, Asians have been reported to present with more advanced disease though more favorable outcomes. Despite PCa becoming an emerging health priority in East Asia, our knowledge remains limited. We compared the prevalence of high-grade PCa on biopsy and disease progression after radical prostatectomy (RP) in East Asian men from Asia and non-East Asian men from Western countries.
Outcomes of patients with acute myeloid leukemia and bone marrow fibrosis
Authors: Samuel Urrutia, Hagop M. Kantarjian, Farhad Ravandi-Kashani, Carlos Bueso-Ramos, Rashmi Kanagal-Shamanna, Elias Jabbour, Guillermo Montalban-Bravo, Nicholas J. Short, Naval Daver, Gautam Borthakur, Courtney D. Dinardo, Tapan M. Kadia, Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Guillermo Garcia-Manero, Koji Sasaki
Journal: Journal of Hematology & Oncology (2024)

Abstract The outcomes of patients with acute myeloid leukemia (AML) and bone marrow fibrosis (MF) are not well defined. The study objectives were to evaluate the degrees of MF in AML, and corresponding response rates and outcomes. We performed a retrospective review of 2302 patients with AML. We annotated the clinical and molecular characteristics, response to therapy, and survival outcomes of patients with bone marrow fibrosis. Overall, 492 patients (21.4%) had a reported microscopic evaluation of MF: 344 (69.9%) had MF grade 0–1 and 148 (30.1%) had MF grade 2–3. Patients with MF 2–3 had a higher proportion of complex cytogenetics (39.2% vs. 24.7%, p = 0.002) JAK2 mutations (25.7% vs. 18%, p = 0.07) and lower proportion of IDH2 (16.9% vs. 25.9%, p = 0.03) and CEBPA (15.5% vs. 27.6%, p = 0.006) mutations. 64% were treated with low-intensity chemotherapy (LIT) and 36.1% with intensive chemotherapy (IT). The complete remission (CR)/CR with incomplete count recovery (CRi) rates were 63.5% with IC versus 37.9% with LIT ( p = 0.007). In patients aged 60 or older 4-week mortality was 12.5% with IC vs. 9.3% with LIT ( p = 0.8). The median overall survival (OS) was 14.2 with MF 0–1 versus 7.5 months with MF 2–3 ( p &lt; 0.005). In patients aged 60 or older with MF 2–3 median OS was 6.5 months with IT versus 7.0 months with LIT ( p = 0.19). In a multivariate analysis, grade 2–3 MF (HR 2.0, 95%CI 1.59–2.51) was the strongest prognostic factor for survival. In summary, grade 2–3 MF in AML is associated with worse outcomes.
The Platform Trial In COVID-19 priming and BOOsting (PICOBOO): the immunogenicity, reactogenicity, and safety of licensed COVID-19 vaccinations administered as a second booster in BNT162b2 primed individuals aged 18-&lt;50 and 50-&lt;70 years old.
Authors: C McLeod, M Dymock, K L Flanagan, M Plebanski, H S Marshall, M J Estcourt, U Wadia, M C Tjiam, C C Blyth, K Subbarao, F L Mordant, S Nicholson, N Cain, R Brizuela, S N Faust, R B Thornton, Z Ellis, A Mckenzie, J A Marsh, T L Snelling, P C Richmond
Journal: Journal of Infection (2024)

PICOBOO is a randomised, adaptive trial evaluating the immunogenicity, reactogenicity, and safety of COVID-19 booster strategies. Here, we present data for second boosters among individuals aged 18-<50 and 50-<70 years old primed with BNT162b2 until Day (D) 84.
Reply to: Peak Corticosteroid Dose for Immune-Related Adverse Events and Survival: Not the Whole Story
Authors: Rik J. Verheijden, Jolien S. de Groot, Babs O. Fabriek, Miki N. Hew, Anne M. May, Karijn P.M. Suijkerbuijk
Journal: Journal of Clinical Oncology (2024)
Tumor heterogeneity and cooperating cancer hallmarks driven by divergent EMT programs
Authors: Phoebe Carter, Yibin Kang
Journal: Cancer Research (2024)

Abstract Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms underlying these processes vary depending on the biological context. Furthermore, how different EMT states cooperate to create a heterogeneous tumor population and promote different pro-malignant features remains largely undefined. In a recent study published in Nature Cancer, Youssef and colleagues described how two disparate EMT programs, active in either organ fibrosis or embryonic development, are utilized within different cells within the same murine mammary tumor model. This work provides mechanistic insight into the development of intratumoral heterogeneity, providing evidence for the cooperation between the two EMT trajectories.
Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling
Authors: Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M. Kaech
Journal: Cancer Research (2024)

Abstract Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.
Haematogenous seeding in mycosis fungoides and Sézary syndrome: Current evidence and clinical implications
Authors: Robert Gniadecki, Emmanuella Guenova, Christiane Querfeld, Jan P Nicolay, Julia Scarisbrick, Lubomir Sokol
Journal: British Journal of Dermatology (2024)

Abstract Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterised by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T-cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T-cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T-cells which colonise the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression – ‘consecutive haematogenous seeding’ captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardising our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes.