tbuckley/cabot-search huggingface dataset:
Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer’s Disease and Associated Sleep Disorders
Authors: Matteo Carpi, Nicola Biagio Mercuri, Claudio Liguori
Journal: Drugs (2024)

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.
Catching the Silent Culprits: TERT Promoter Mutation Screening of Minimally Invasive Follicular and Oncocytic Thyroid Carcinoma in Clinical Practice
Authors: L Samuel Hellgren, Adam Stenman, Kenbugul Jatta, Vincenzo Condello, Catharina Larsson, Jan Zedenius, C Christofer Juhlin
Journal: Endocrine Pathology (2024)
Attribution of invasive group A streptococcal infections (iGAS) to predisposing viral infections, the Netherlands, 2010 to 2023
Authors: Brechje de Gier, Jan van de Kassteele, Liselotte van Asten, Annelot F Schoffelen, Mariette Hooiveld, Margreet JM te Wierik, Nina M van Sorge, Hester E de Melker
Journal: Eurosurveillance (2024)

Background After most COVID-19 pandemic control measures were lifted in 2022, many infectious diseases re-emerged. An increase in invasive group A streptococcal (iGAS) infections among adults and young children was reported by several countries. Viral infections including influenza and varicella, known risk factors for iGAS infection, also increased. Aim To estimate the proportion of GAS skin and soft tissue infections (SSTI) and pneumonia/sepsis in children (≤ 5 years) attributable to varicella, and the proportion of GAS pneumonia/sepsis in children and adults attributable to potentially predisposing respiratory viruses influenza A and B, RSV, hMPV and SARS-CoV-2 in the Netherlands. Methods We performed time series regression using weekly data on respiratory viruses, varicella and non-invasive GAS infections and GAS isolates cultured from blood, lower airways, skin, pus and wounds, from January 2010 to March 2023. Results In 2010–19, 50% (95% CI: 36–64) of GAS SSTI in children were attributable to varicella. Between January 2022 and March 2023, 34% (95% CI: 24–43) of GAS SSTI cases were attributable to varicella. Of iGAS pneumonia/sepsis between January 2022 and March 2023, 34% (95% CI: 20–49) and 25% (95% CI: 18–32) was attributable to respiratory virus infections in children and adults, respectively, with the largest contributor (17%) being influenza A. Conclusions Predisposing viral infections likely contributed to, but cannot fully explain, the observed iGAS increase among children and adults in 2022–23 in the Netherlands. Public health measures to control viral infections, such as vaccination against varicella or influenza, might reduce the iGAS disease burden.
Effectiveness of influenza vaccines in children aged 6 to 59 months: a test-negative case–control study at primary care and hospital level, Spain 2023/24
Authors: Gloria Pérez-Gimeno, Clara Mazagatos, Nicola Lorusso, Luca Basile, Isabel Martínez-Pino, Francisca Corpas Burgos, Noa Batalla Rebolla, Mercedes B Rumayor Zarzuelo, Blanca Andreu Ivorra, Jaume Giménez Duran, Daniel Castrillejo, Inés Guiu Cañete, Marta Huerta Huerta, Marta García Becerril, Violeta Ramos Marín, Inmaculada Casas, Francisco Pozo, Susana Monge
Journal: Eurosurveillance (2024)

During 2023/24, all children aged 6 to 59 months were targeted for seasonal influenza vaccination in Spain nationally. Using a test-negative case–control design with sentinel surveillance data, we estimated adjusted influenza vaccine effectiveness (IVE) against any influenza type to be 70% (95% confidence interval (CI): 51 to 81%) for primary care patients with acute respiratory illness (ARI) and 77% (95% CI: 21 to 93%) for hospitalised patients with severe ARI. In primary care, where most subtyped viruses (61%; 145/237) were A(H1N1), adjusted IVE was 77% (95% CI: 56 to 88%) against A(H1N1)pdm09.
Potentially zoonotic pathogens and parasites in opportunistically sourced urban brown rats (Rattus norvegicus) in and around Helsinki, Finland, 2018 to 2023
Authors: Tuomas Aivelo, Hussein Alburkat, Nina Suomalainen, Rebekka Kukowski, Petra Heikkinen, Antti Oksanen, Otso Huitu, Rauni Kivistö, Tarja Sironen
Journal: Eurosurveillance (2024)

Background Brown rats ( Rattus norvegicus ) are synanthropic rodents with worldwide distribution, which are known to harbour many zoonotic pathogens and parasites. No systematic zoonotic surveys targeting multiple pathogens and parasites have previously been conducted in urban rats in Finland. Aim In Helsinki, Finland, we explored the presence and prevalence in brown rats of certain pathogens and parasites (including helminths, viruses and bacteria) across potentially zoonotic taxa. Methods We opportunistically received rat carcasses from pest management operators and citizens from 2018 to 2023. We searched for heart- or lungworms, performed rat diaphragm digestion to check for Trichinella and morphologically identified intestinal helminths. We assessed virus exposure by immunofluorescence assay or PCR, and detected bacteria by PCR ( Leptospira ) or culture ( Campylobacter ). Results Among the rats investigated for helminths, no heart- or lungworms or Trichinella species were detected and the most common finding was the cestode Hymenolepis nana (in 9.7% of individuals sampled, 28/288). For some of the surveyed virus taxa, several rats were seropositive (orthopoxviruses, 5.2%, 11/211; arenaviruses, 2.8%, 6/211; hantaviruses 5.2%, 11/211) or tested positive by PCR (rat hepatitis E virus, 1.8%, 4/216). Campylobacter jejuni (6.6%, 17/259) and Leptospira interrogans (1.2%, 2/163) bacteria were also present in the rat population examined. Conclusions Prevalences of potentially zoonotic pathogens and parasites in brown rats in Helsinki appeared low. This may explain low or non-existent diagnosis levels of rat-borne pathogen and parasite infections reported in people there. Nevertheless, further assessment of under-diagnosis, which cannot be excluded, would enhance understanding the risks of zoonoses.
Detection of airborne wild waterbird-derived DNA demonstrates potential for transmission of avian influenza virus via air inlets into poultry houses, the Netherlands, 2021 to 2022
Authors: Alex Bossers, Myrna MT de Rooij, Isabella van Schothorst, Francisca C Velkers, Lidwien AM Smit
Journal: Eurosurveillance (2024)

Background Outbreaks of highly pathogenic avian influenza (HPAI) on poultry farms and in wild birds worldwide persists despite intensified control measures. It causes unprecedented mortality in bird populations and is increasingly affecting mammalian species. Better understanding of HPAI introduction pathways into farms are needed for targeted disease prevention and control. The relevance of airborne transmission has been suggested but research involving air sampling is limited and unequivocal evidence on transmission routes is lacking. Aim We aimed to investigate whether HPAI virus from wild birds can enter poultry houses through air inlets by characterising host materials through eukaryote DNA sequencing. Methods We collected particulate matter samples in and around three HPAI-affected poultry farms which were cleared and decontaminated before sampling. Indoor measurements (n = 61) were taken directly in the airflow entering through air inlets, while outdoor air samples (n = 60) were collected around the poultry house. Positive controls were obtained from a bird rehabilitation shelter. We performed metabarcoding on environmental DNA by deep sequencing 18S rRNA gene amplicons. Results We detected waterbird DNA in air inside all three, and outside of two, poultry farms. Sequences annotated at species level included swans and tufted ducks. Waterbird DNA was present in all indoor and outdoor air samples from the bird shelter. Conclusion Airborne matter derived from contaminated wild birds can potentially introduce HPAI virus to poultry houses through air inlets. The eDNA metabarcoding could assess breaches in biosecurity for HPAI virus and other pathogens potentially transmitted through air via detection of their hosts.
LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer
Authors: Christopher A. Ladaika, Ahmed H. Ghobashi, William C. Boulton, Samuel A. Miller, Heather M. O'Hagan
Journal: Cancer Research (2024)

Abstract Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics uncovered epigenetic alterations that accompany EEC differentiation, identified STAT3 as a regulator of EEC specification, and discovered a rare cancer-specific cell type with enteric neuron-like characteristics. Furthermore, LSD1 and CoREST2 mediated STAT3 demethylation and enhanced STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.
An injectable self-lubricating supramolecular polymer hydrogel loaded with platelet lysate to boost osteoarthritis treatment
Authors: Peng Zhang, Jianhai Yang, Zhuoya Wang, Hongying Wang, Mingyang An, Maihemuti Yakufu, Wenliang Wang, Yujie Liu, Wenguang Liu, Chunbao Li
Journal: Journal of Controlled Release (2024)

Globally, osteoarthritis (OA) is the most prevalent joint disease and is characterized by infiltration of M1 macrophages in the synovium, anabolic-catabolic imbalance of the extracellular matrix (ECM), increased articular shear force and overproduction of reactive oxygen species (ROS). Disease-modifying OA drugs are not yet available, and treatments for OA focus solely on reducing pain and inflammation and have limited therapeutic effect. Herein, we developed an injectable self-lubricating poly(N-acryloyl alaninamide) (PNAAA) hydrogel loaded with platelet lysate (PL) (termed "PNAAA@PL") for treating OA. Tribological and drug release tests revealed suitable lubrication properties and sustained release of bioactive factors in PNAAA@PL. In vitro experiments showed that PNAAA@PL alleviated interleukin-1β (IL-1β)-induced anabolic-catabolic imbalance of chondrocytes and repolarized pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype via intracellular ROS scavenging. Additionally, the PNAAA@PL hydrogel enhanced the migratory capacity and chemotaxis ability of stem cells, which are essential for chondrogenesis. In vivo, the functionalized PNAAA@PL hydrogel acted like synovial fluid following intra-articular injection into a rat OA model with anterior cruciate ligament transection, ultimately attenuating cartilage degeneration and synovitis. According to molecular mechanism studies, PNAAA@PL repairs cartilage in the OA model by inhibiting the NF-ĸB pathway. Overall, this self-lubricating PNAAA@PL hydrogel offers a comprehensive strategy for preventing OA progression by engineering a biophysiochemical microenvironment to generate high-quality hyaline cartilage.
Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer
Authors: Chao Zheng, Linyang Jiang, Xiang Gong, Wen Zhang, Rong Pu, Yuan Zhang, Mengmeng Zhao, Chen Jiang, Hao Wang, Pengcheng Zhang, Yaping Li
Journal: Journal of Controlled Release (2024)
Glofitamab in Relapsed/Refractory Mantle Cell Lymphoma: Results From a Phase I/II Study
Authors: Tycel Jovelle Phillips, Carmelo Carlo-Stella, Franck Morschhauser, Emmanuel Bachy, Michael Crump, Marek Trněný, Nancy L. Bartlett, Jan Zaucha, Tomasz Wrobel, Fritz Offner, Kathryn Humphrey, James Relf, Audrey Filézac de L'Etang, David J. Carlile, Ben Byrne, Naseer Qayum, Linda Lundberg, Michael Dickinson
Journal: Journal of Clinical Oncology (2024)

PURPOSE Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have a poor prognosis. The phase I/II NP30179 study (ClinicalTrials.gov identifier: NCT03075696 ) evaluated glofitamab monotherapy in patients with R/R B-cell lymphomas, with obinutuzumab pretreatment (Gpt) to mitigate the risk of cytokine release syndrome (CRS) with glofitamab. We present data for patients with R/R MCL. METHODS Eligible patients with R/R MCL (at least one previous therapy) received Gpt (1,000 or 2,000 mg) 7 days before the first glofitamab dose (single dose or split over 2 days if required). Glofitamab step-up dosing was administered once a day on days 8 (2.5 mg) and 15 (10 mg) of cycle 1, with a target dose of 16 or 30 mg once every 3 weeks from cycle 2 day 1 onward, for 12 cycles. Efficacy end points included investigator-assessed complete response (CR) rate, overall response rate (ORR), and duration of CR. RESULTS Of 61 enrolled patients, 60 were evaluable for safety and efficacy. Patients had received a median of two previous therapies (range, 1-5). CR rate and ORR were 78.3% (95% CI, 65.8 to 87.9) and 85.0% (95% CI, 73.4 to 92.9), respectively. In patients who had received previous treatment with a Bruton tyrosine kinase inhibitor (n = 31), CR rate was 71.0% (95% CI, 52.0 to 85.8) and ORR was 74.2% (95% CI, 55.4 to 88.1). CRS after glofitamab administration occurred in 70.0% of patients, with a lower incidence in the 2,000 mg (63.6% [grade ≥2, 22.7%]) versus 1,000 mg (87.5%; grade ≥2, 62.5%) Gpt cohort. Four adverse events led to glofitamab withdrawal (all infections). CONCLUSION Fixed-duration glofitamab induced high CR rates in heavily pretreated patients with R/R MCL; the safety profile was manageable with appropriate support.
Multi-modal artificial intelligence enhanced systematic colorectal cancer pathology evaluation.
Authors: Po-Jen Lin, Tsung-Lu Michael Lee, Cheng-Hsiu Tsai, Xuan Gong, Mu-Hung Tsai, Hsi-Huei Liu, Amy H Huang, Irene Tai-Lin Lee, Ronan Wenhan Hsieh, Jeffrey A. Meyerhardt, Kun-Hsing Yu
Journal: Journal of Clinical Oncology (2024)

3532 Background: Multi-modal artificial intelligence (AI) approaches have substantial promise for capturing the relationships between pathology images, text descriptions, and patients’ clinical characteristics. Previous attempts showed that multi-modal AI methods classified colorectal cancer (CRC) types with an accuracy of 90%. However, it is unclear if this new AI framework can reliably predict histologic grade and the extent of primary tumor at scale (T stage). To address this research gap, here we developed a multi-modal AI system for detailed CRC pathology analyses, with a focus on histologic factors related to patient prognoses. Methods: We obtained whole-slide pathology images, pathology reports, and detailed clinical information from 441 colorectal adenocarcinoma patients who participated in The Cancer Genome Atlas. These patients were divided into training or testing sets using a 75/25 split. We extracted histology types (invasive adenocarcinoma with or without mucinous features), histology grades (well, moderate, or poorly differentiated), and the extent of the primary tumor (pT2, pT3, or pT4) from the pathology reports in the training subset. We employed the CLIP (Contrastive Language-Image Pre-Training) prefix captioning model as a backbone and developed an AI model for predicting these pathology profiles using whole-slide pathology images. We evaluated the performance (sensitivity, specificity, accuracy, precision, and F1 score) of our model by comparing the model-based prediction in the testing set and the ground-truth information from the pathology reports. Results: Our model successfully predicted histology types with an accuracy of 0.89 and an F1 score of 0.93 (sensitivity = 0.92, specificity = 0.76, and precision = 0.94). In addition, our approach further predicted histology grades with an accuracy of 0.79 and an F1 score of 0.87 (sensitivity = 0.96, specificity = 0.31, and precision = 0.80). Furthermore, our model achieved an accuracy of 0.69 and an F1 score of 0.80 (sensitivity = 0.78, specificity = 0.38, and precision = 0.83) in predicting T stages. Conclusions: Our study suggests that multi-modal AI has the potential to assist with the histopathology diagnosis of CRC tissues. Our approaches performed well in identifying CRC types and could provide second opinions on CRC diagnosis. However, the performance of our model varies across prediction tasks. Extensive external validation using larger and more diverse pathology datasets is crucial to moving our novel AI approaches closer to clinical applications. Category Sensitivity Specificity Accuracy Precision F1 score Histology types 0.92 0.76 0.89 0.94 0.93 Histology grades 0.96 0.31 0.79 0.80 0.87 T stages 0.78 0.38 0.69 0.83 0.80
Heterogeneity of immune status in patient-derived malignant pleural effusion and ascites: Relationship to the ex-vivo efficacy of a HER2-targeted tri-specific antibody and a novel cytokine fusion protein.
Authors: Liming Liu, Zhen Han, Yang Fan, Qi Pan, Ping Kang, Zhijian Sun
Journal: Journal of Clinical Oncology (2024)

e13000 Background: Malignant pleural effusion (MPE) and malignant ascites (MA) are common complications of malignant tumors, often indicating that the malignant tumors have reached an advanced stage, leading to a shorter survival. Historical studies have shown that the effusion or asities are deficient in innate immunity and/or adaptive immunity. It would be a high therapeutic value if the immune status (deficiency or exhaustion) in this tumor microenvironment can be corrected using innate and adaptive immune targeting molecules. Here we have studied the immune status of one MPE sample from an advanced Her2 positive breast cancer patient and one MA sample from an advanced ovarian cancer patient; and used a novel tri-specific molecule targeting Her2, macrophage and NK cell (IAMA-004) and a novel Fc-cytokine fusion protein (IAMA-005) to treat the cells from MPE or MA samples to determine the efficacy in the killings of tumor cells and the modulation of IFN-γ and Granzyme B levels. Methods: A pleural effusion sample from a 61-year-old female patient suffering from breast cancer lung metastasis and an ascitic fluid sample from a 58-year-old female patient with poorly differentiated advanced ovarian cancer were collected. The cells were immunophenotyped and treated with IAMA-004, IAMA-005, anti-PD1 or control. The killing of Her2 positive or EpCAM positive tumor cells and the levels of IFN-γ and Granzyme B were measured. Results: MPE immune status: NK cells, 6.47%; Macrophages, 2.11% (M1, 0.06%; M2, 0.33%); CD3 + T cells, 5.47%; CD4 + T cells, 2.93%; CD8 + T cells, 1.66%; Treg, not detectable. IAMA-004 and IAMA-005 enhanced the killing of Her2 positive tumor cells by ~30% and ~40% respectively; Herceptin plus TTI-622 was not able to enhance the tumor cell killing. In combination with nivolumab, IAMA-004 was able to enhance the Granzyme B and IFN-γ secretion significantly without enhancing the tumor cell killing. Ascites immune status: NK cells, 0.5%; macrophage, 10.74% (M1, 0.31%; M2 0.05%); CD3 + T cells, 5.98%; CD4 + T cells, 4.36%; CD8 + T cells, 0.97%; Treg, not detectable. While anti-PD1 antibody was not able to kill the tumor cells over the background, IAMA-004, IAMA-005 or Herceptin plus TTI-622 was able to enhance the tumor cell killing over the background more than 2.5-fold. Addition of anti-PD1 to IAMA-004 or IAMA-005 did not further increase the efficacy. The immune status of MPE being NK competent while MA being macrophage competent seems to determine the efficacy of the respective therapeutic molecules. Conclusions: Immune status from MPE or MA are heterogenous in both adaptive and innate immunity. Using combinations of innate immune targeting therapeutics and adaptive immune check point inhibitors may be able to correct the specific deficiency with precision and effectively treat these diseases.
Incorporating ALBI Grade with Geriatric Nutritional Risk Index Enhances Hepatocellular Carcinoma Risk Stratification
Authors: Heechul Nam, Pil Soo Sung, Sung Won Lee, Do Seon Song, Jung Hyun Kwon, Jeong Won Jang, Chang Wook Kim, Si Hyun Bae
Journal: Liver Cancer (2024)

Introduction: Despite its prognostic impact, nutritional status has not yet been integrated into the assessment of hepatocellular carcinoma (HCC). This study investigated the association between geriatric nutritional risk index (GNRI) and overall survival (OS) in patients with HCC using a nationwide registry. Methods: Data from the Korea Central Cancer Registry between 2008 and 2019 were analyzed. We explored the integration of the GNRI with the albumin-bilirubin (ALBI) grade for prognostic stratification. Restricted cubic spline regression was used to assess the association between GNRI and survival, stratified by ALBI grade. Results: Among the 16,416 treatment-naïve HCC patients, the ALBI grades were distributed as follows: grade 1, 7,409; grade 2, 7,445; and grade 3, 1,562. Patients were categorized according to Barcelona Clinic Liver Cancer (BCLC) stages: 5,132 stage 0/A, 2,608 stage B, 5,289 stage C, and 968 stage D. The median OS for all patients was 3.1 years (95% CI: 3.0–3.2) and significantly differed with the inclusion of ALBI grade and GNRI (p &lt; 0.001). The effect of combining ALBI grade and GNRI was further evaluated for each BCLC stage. This risk stratification showed a significant correlation with OS for each BCLC stage (all p &lt; 0.001), except for stage D (p = 0.082). Multivariate analysis revealed that a combination of favorable ALBI grade and high GNRI score was independently associated with decreased mortality risk. Conclusion: The GNRI was significantly correlated with OS across ALBI grades and BCLC stages. Integrating the GNRI into the ALBI grade may enhance risk stratification for patients with HCC.
Isoniazid resistance pattern among pulmonary tuberculosis patients in Bangladesh: an exploratory study
Authors: S M Mazidur Rahman, Pushpita Samina, Tanjina Rahman, Ahammad Shafiq Sikder Adel, Rumana Nasrin, Mohammad Khaja Mafij Uddin, Md Jahid Hasan, Shahriar Ahmed, Paul Daru, Pronab Kumar Modak, Md Abdul Hamid Salim, Sardar Munim Ibna Mohsin, Sayera Banu
Journal: Clinical Microbiology and Infection (2024)