tbuckley/cabot-search huggingface dataset:
A novel pan-PI3K inhibitor KTC1101 synergizes with anti-PD-1 therapy by targeting tumor suppression and immune activation
Authors: Xin Peng, Xin Huang, Talal Ben Lulu, Wenqing Jia, Shaolu Zhang, Limor Cohen, Shengfan Huang, Jindian Fan, Xi Chen, Shanshan Liu, Yongzhe Wang, Kailin Wang, Sho Isoyama, Shingo Dan, Feng Wang, Zhe Zhang, Moshe Elkabets, Dexin Kong
Journal: Molecular Cancer (2024)

Abstract Background Phosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, restricted therapeutic indices, and cancer-acquired resistance. Hence, novel inhibitors that overcome some of these challenges are needed. Here, we describe the characterization of KTC1101, a novel pan-PI3K inhibitor that simultaneously targets tumor cell proliferation and the tumor microenvironment. Our studies demonstrate that KTC1101 significantly increases the anti-PD-1 efficacy in multiple pre-clinical mouse models. Methods KTC1101 was synthesized and characterized employing chemical synthesis, molecular modeling, Nuclear Magnetic Resonance (NMR), and mass spectrometry. Its target specificity was confirmed through the kinase assay, JFCR39 COMPARE analysis, and RNA-Seq analysis. Metabolic stability was verified via liver microsome and plasma assays, pharmacokinetics determined by LC–MS/MS, and safety profile established through acute toxicity assays to determine the LD50. The antiproliferative effects of KTC1101 were evaluated in a panel of cancer cell lines and further validated in diverse BALB/c nude mouse xenograft, NSG mouse xenograft and syngeneic mouse models. The KTC1101 treatment effect on the immune response was assessed through comprehensive RNA-Seq, flow cytometry, and immunohistochemistry, with molecular pathways investigated via Western blot, ELISA, and qRT-PCR. Results KTC1101 demonstrated strong inhibition of cancer cell growth in vitro and significantly impeded tumor progression in vivo. It effectively modulated the Tumor Microenvironment (TME), characterized by increased infiltration of CD8 + T cells and innate immune cells. An intermittent dosing regimen of KTC1101 enhanced these effects. Notably, KTC1101 synergized with anti-PD-1 therapy, significantly boosting antitumor immunity and extending survival in preclinical models. Conclusion KTC1101's dual mechanism of action—directly inhibiting tumor cell growth and dynamically enhancing the immune response— represents a significant advancement in cancer treatment strategies. These findings support incorporating KTC1101 into future oncologic regimens to improve the efficacy of immunotherapy combinations.
Reconsidering the link between past material culture and cognition in light of contemporary hunter-gatherer material use.
Authors: Duncan N. E. Stibbard-Hawkes
Journal: Behavioral and Brain Sciences (2024)

Many have interpreted symbolic material culture in the deep past as evidencing the origins sophisticated, modern cognition. Scholars from across the behavioural and cognitive sciences, including linguists, psychologists, philosophers, neuroscientists, primatologists, archaeologists and paleoanthropologists have used such artefacts to assess the capacities of extinct human species, and to set benchmarks, milestones or otherwise chart the course of human cognitive evolution. To better calibrate our expectations, the present paper instead explores the material culture of three contemporary African forager groups. Results show that, while these groups are unequivocally behaviourally modern, they would leave scant long-lasting evidence of symbolic behaviour. Artefact-sets are typically small, perhaps as consequence of residential mobility. When excluding traded materials, few artefacts have components with moderate-strong taphonomic signatures. Present analyses show that artefact function influences preservation probability, such that utilitarian tools for the processing of materials and the preparation of food are disproportionately likely to contain archaeologically traceable components. There are substantial differences in material-use between populations, which create important population-level variation preservation probability independent of cognitive differences. I discuss the factors - cultural, ecological and practical - that influence material choice. In so doing, I highlight the difficulties of using past material culture as an evolutionary or cognitive yardstick.
An Evaluation of the Efficacy and Safety of Timolol Maleate 0.5% Microdrops Administered with the Nanodropper
Authors: Jennifer S. Steger, Indira Durai, Annamalai Odayappan, Ramalakshmi Raman, Talla Sruthi, Allisa J. Song, George Puthuran, Rengaraj Venkatesh, Elizabeth Colantuoni, Alan L. Robin
Journal: Ophthalmology (2024)

To examine if 12.5 μl timolol maleate 0.5% microdrops dispensed with the Nanodropper Adaptor provide noninferior intraocular pressure (IOP) reduction compared with conventional 28 μl drops in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT).
Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer
Authors: Fangyan Gao, Yueyao Wu, Runtian Wang, Yuhui Yao, Yiqiu Liu, Lingling Fan, Jingtong Xu, Jian Zhang, Xin Han, Xiaoxiang Guan
Journal: Acta Pharmaceutica Sinica B (2024)

Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed to identify promising targeted agents that synergize with enzalutamide, a second-generation AR inhibitor, in TNBC. By using a strategy for screening drug combinations based on the Sensitivity Index (SI), we found that MK-8776, a selective checkpoint kinase1 (CHK1) inhibitor, showed favorable synergism with enzalutamide in AR-positive TNBC. The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776, respectively. Furthermore, a nanoparticle-based on hyaluronic acid (HA)-modified hollow-manganese dioxide (HMnO
Operationalizing the Women-Centred HIV Care Model for trans women and persons with transfeminine experience living with and affected by HIV: a qualitative study
Authors: Harshita Iyer, Angela Underhill, Yasmeen Persad, Ashley Lacombe-Duncan, V. Logan Kennedy, Kelendria Nation, Hannah Kia, Carmen H. Logie, Angela Kaida, Kinnon MacKinnon, Ian Armstrong, Celeste Bilbao-Joseph, Wangari Tharao, Mona Loutfy
Journal: International Journal of Transgender Health (2024)

Background The Women-Centered HIV Care (WCHC) Model and associated toolkits were created to address the health care barriers and disparities that women and gender diverse people living with HIV experience. Since trans women and transfeminine people experience disproportionately high rates of HIV acquisition (in comparison to their cisgender peers) amidst biologic, social, political, and historical factors that affect their general care experiences negatively, more research is needed.
Efficacy and safety of the Aria pulmonary endovascular device in pulmonary hypertension
Authors: Christian Gerges, Karl Vollmers, Nika Skoro‐Sajer, Varius Dannenberg, Valerie Hartig, Marc R. Pritzker, John Scandurra, E. Kenneth Weir, Irene M. Lang
Journal: European Journal of Heart Failure (2024)

ABSTRACT Aims A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (C PA ), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and haemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH‐LHD) and chronic lung disease (PH‐CLD). Methods and results Eight patients with PH‐LHD and 10 patients with PH‐CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas‐filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Haemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. No complications or investigational device‐related serious adverse events occurred. Device activation in PH‐LHD and PH‐CLD patients decreased pulmonary arterial pulse pressure by 5.6 ± 4.2 mmHg (−12%; p = 0.003) and 4.2 ± 2.2 mmHg (−11%; p &lt; 0.001), increased C PA by 0.4 ± 0.2 ml/mmHg (+23%; p = 0.004) and 0.4 ± 0.3 ml/mmHg (+25%; p = 0.001), and increased right ventricular‐to‐pulmonary vascular (RV‐PV) coupling by 0.24 ± 0.18 (+40%; p = 0.012) and 0.11 ± 0.07 (+21%; p = 0.001), respectively. Conclusions Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of C PA and RV‐PV coupling.
Scalable and Versatile Metal Ion Solidificated Alginate Hydrogel for Skin Wound Infection Therapy
Authors: Haomiao Zhang, Ye Lu, Lei Huang, Ping Liu, Jun Ni, Tianqi Yang, Yihong Li, Yu Zhong, Xinping He, Xinhui Xia, Jiancang Zhou
Journal: Advanced Healthcare Materials (2024)

Bacterial infections in wounds continue to be a major challenge in clinical settings worldwide and represent a significant threat to human health. This work proposes novel expandable and versatile methods for solidifying sodium alginate (SA) with metal ions (such as Fe
Diagnostic utility of gingival biopsy for pemphigus vulgaris and mucosa membrane pemphigoid: A 10-year cohort study
Authors: Junjiang Liu, Can Hu, Jing He, Jingtian Mu, Shimeng Wang, Qi Han, Jia Li, Mei Lin, Qinghong Gao, Fanglong Wu, Hongmei Zhou
Journal: Journal of the American Academy of Dermatology (2024)
Extracellular vesicles as carriers of mRNA: Opportunities and challenges in diagnosis and treatment
Authors: Robert D. Kirian, Darby Steinman, Christopher M. Jewell, Hannah C. Zierden
Journal: Theranostics (2024)

Extracellular vesicles (EVs) are produced by all cells in the body. These biological nanoparticles facilitate cellular communication through the transport of diverse cargoes, including small molecules, proteins, and nucleic acids. mRNA cargoes have gained particular interest given their role in the translation of functional proteins. As a biomarker platform, EVs can be found in nearly all biofluids-blood, mucus, urine, cerebrospinal fluid, and saliva-providing real-time insight into parent cell and tissue function. mRNAs carried by EVs are protected from degradation, resulting in improved detection compared to free mRNA, and recent work demonstrates promising results in using these mRNA cargoes as biomarkers for cancer, neurological diseases, infectious diseases, and gynecologic and obstetric outcomes. Furthermore, given the innate cargo carrying, targeting, and barrier crossing abilities of EVs, these structures have been proposed as therapeutic carriers of mRNA. Recent advances demonstrate methods for loading mRNAs into EVs for a range of disease indications. Here, we review recent studies using EVs and their mRNA cargoes as diagnostics and therapeutics. We discuss challenges associated with EVs in diagnostic and therapeutic applications and highlight opportunities for future development.
Dynamic pathological analysis reveals a protective role against skin fibrosis for TREM2-dependent macrophages
Authors: Yunsheng Liang, Yongfei Hu, Jun Zhang, Haosen Song, Xiaoqian Zhang, Yishan Chen, Yu Peng, Lihua Sun, Yuzhe Sun, Ruzeng Xue, Suyun Ji, Chuanwei Li, Zhili Rong, Bin Yang, Yingping Xu
Journal: Theranostics (2024)

Rationale: Systemic sclerosis (SSc) is a chronic and incurable autoimmune disease with high mortality rates, and skin fibrosis is one of distinguishing hallmarks in the pathogenesis.However, macrophage heterogeneity regulating skin fibrosis remain largely unknown.Methods: We established mouse disease model and performed single-cell RNA-sequencing (scRNA-seq) to resolve the dynamic and heterogenous characteristics of macrophages in skin fibrosis, and the role of TREM2-dependent macrophages in the pathological process was investigated using knockout mice and intraperitoneal transferring TREM2 + macrophages combining with functional assays.Results: We show that TREM2-expressing macrophages (TREM2 + MФs) accumulate in injured skin of mice treated by bleomycin (BLM) and human SSc, and their gene signatures and functional pathways are identified in the course of disease.Genetic ablation of Trem2 in mice globally accelerates and aggravates skin fibrosis, whereas transferring TREM2 hi macrophages improves and alleviates skin fibrosis.Amazingly, we found that disease-associated TREM2 + MФs in skin fibrosis exhibit overlapping signatures with fetal skin counterparts in mice and human to maintain skin homeostasis, but each has merits in skin remodeling and development respectively.Conclusion: This study identifies that TREM2 acts as a functional molecule and a major signaling by which macrophage subpopulations play a protective role against fibrosis, and disease-associated TREM2 + MФs in skin fibrosis might undergo a fetal-like reprogramming similar to fetal skin counterparts.
Tamoxifen Dose De-Escalation: An Effective Strategy for Reducing Adverse Effects?
Authors: Sanne M. Buijs, Stijn L. W. Koolen, Ron H. J. Mathijssen, Agnes Jager
Journal: Drugs (2024)

Tamoxifen, a cornerstone in the adjuvant treatment of estrogen receptor-positive breast cancer, significantly reduces breast cancer recurrence and breast cancer mortality; however, its standard adjuvant dose of 20 mg daily presents challenges due to a broad spectrum of adverse effects, contributing to high discontinuation rates. Dose reductions of tamoxifen might be an option to reduce treatment-related toxicity, but large randomized controlled trials investigating the tolerability and, more importantly, efficacy of low-dose tamoxifen in the adjuvant setting are lacking. We conducted an extensive literature search to explore evidence on the tolerability and clinical efficacy of reduced doses of tamoxifen. In this review, we discuss two important topics regarding low-dose tamoxifen: (1) the incidence of adverse effects and quality of life among women using low-dose tamoxifen; and (2) the clinical efficacy of low-dose tamoxifen examined in the preventive setting and evaluated through the measurement of several efficacy derivatives. Moreover, practical tools for tamoxifen dose reductions in the adjuvant setting are provided and further research to establish optimal dosing strategies for individual patients are discussed.
Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability
Authors: Alise K. Carlson, Moein Amin, Jeffrey A. Cohen
Journal: Drugs (2024)

Currently, there are four monoclonal antibodies (mAbs) that target the cluster of differentiation (CD) 20 receptor available to treat multiple sclerosis (MS): rituximab, ocrelizumab, ofatumumab, and ublituximab. B-cell depletion therapy has changed the therapeutic landscape of MS through robust efficacy on clinical manifestations and MRI lesion activity, and the currently available anti-CD20 mAb therapies for use in MS are a cornerstone of highly effective disease-modifying treatment. Ocrelizumab is currently the only therapy with regulatory approval for primary progressive MS. There are currently few data regarding the relative efficacy of these therapies, though several clinical trials are ongoing. Safety concerns applicable to this class of therapeutics relate primarily to immunogenicity and mechanism of action, and include infusion-related or injection-related reactions, development of hypogammaglobulinemia (leading to increased infection and malignancy risk), and decreased vaccine response. Exploration of alternative dose/dosing schedules might be an effective strategy for mitigating these risks. Future development of biosimilar medications might make these therapies more readily available. Although anti-CD20 mAb therapies have led to significant improvements in disease outcomes, CNS-penetrant therapies are still needed to more effectively address the compartmentalized inflammation thought to play an important role in disability progression.
Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk‐Enriched Rheumatoid Arthritis Patients
Authors: Christina Charles‐Schoeman, Roy Fleischmann, Eduardo Mysler, Maria Greenwald, Steven R. Ytterberg, Gary G. Koch, Deepak L. Bhatt, Cunshan Wang, Ted R. Mikuls, All‐shine Chen, Carol A. Connell, John C. Woolcott, Sujatha Menon, Yan Chen, Kristen Lee, Zoltán Szekanecz
Journal: Arthritis & Rheumatology (2024)

The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance.
The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women
Authors: Wenhui Yang, Tianpei Hong, Xu Chang, Meng Han, Hongwei Gao, Bailin Pan, Zhenmin Zhao, Ye Liu
Journal: International Journal of Transgender Health (2024)

Cyproterone acetate (CPA) and spironolactone (SPL) are different antiandrogens in gender-affirming hormone therapy (GAHT) for transgender women. Few studies have evaluated their efficacy and user satisfaction, especially among East Asians. This study aimed to evaluate these aspects in Chinese transgender women.
A Golgi Apparatus‐Targeted Photothermal Agent with Protein Anchoring for Enhanced Cancer Photothermal Therapy
Authors: Mingwan Shi, Zhongliang Fu, Wei Pan, Kaiye Wang, Xiaohan Liu, Na Li, Bo Tang
Journal: Advanced Healthcare Materials (2024)

The Golgi apparatus (GA) is central in shuttling proteins from the endoplasmic reticulum to different cellular areas. Therefore, targeting the GA to precisely destroy its proteins through local heat could induce apoptosis, offering a potential avenue for effective cancer therapy. Herein, a GA-targeted photothermal agent based on protein anchoring is introduced for enhanced photothermal therapy of tumor through the modification of near-infrared molecular dye with maleimide derivative and benzene sulfonamide. The photothermal agent can actively target the GA and covalently anchor to its sulfhydryl proteins, thereby increasing its retention within the GA. Under laser irradiation, the heat generated by the photothermal agent efficiently disrupts sulfhydryl proteins in situ, leading to GA dysfunction and ultimately inducing cell apoptosis. In vivo experiments demonstrate that the photothermal agent can precisely treat tumors and significantly reduce side effects.
Informing immunotherapy with multi-omics driven machine learning
Authors: Yawei Li, Xin Wu, Deyu Fang, Yuan Luo
Journal: npj Digital Medicine (2024)

Abstract Progress in sequencing technologies and clinical experiments has revolutionized immunotherapy on solid and hematologic malignancies. However, the benefits of immunotherapy are limited to specific patient subsets, posing challenges for broader application. To improve its effectiveness, identifying biomarkers that can predict patient response is crucial. Machine learning (ML) play a pivotal role in harnessing multi-omic cancer datasets and unlocking new insights into immunotherapy. This review provides an overview of cutting-edge ML models applied in omics data for immunotherapy analysis, including immunotherapy response prediction and immunotherapy-relevant tumor microenvironment identification. We elucidate how ML leverages diverse data types to identify significant biomarkers, enhance our understanding of immunotherapy mechanisms, and optimize decision-making process. Additionally, we discuss current limitations and challenges of ML in this rapidly evolving field. Finally, we outline future directions aimed at overcoming these barriers and improving the efficiency of ML in immunotherapy research.
<i>Notes from the Field:</i> Measles Outbreak — Cook County, Illinois, October–November 2023
Authors: Kelley Bemis, Mabel Frias, Sheila Giovanni, Tarek Shackour, Heather D. Reid, Jodi Morgan, Michael TeKippe, Demian Christiansen
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

On October 10, 2023, the Cook County Department of Public Health (CCDPH) in Illinois was notified by hospital A, a large pediatric facility, of a suspected measles case in a child aged 2 years (patient A) who had immigrated from Yemen on September 29 and who had no history of receipt of measles, mumps, and rubella (MMR) vaccine.The child visited hospital A's emergency department (ED) on October 5 with fever, cough, and coryza and, after receipt of negative COVID-19, influenza, and respiratory syncytial virus test results, received a diagnosis of an unspecified viral illness.On October 8, the child visited hospital B's ED with worsening respiratory symptoms and received a positive rhinovirus/enterovirus test result on a respiratory pathogen panel, after which the child was transferred to hospital A and admitted for respiratory distress related to bronchiolitis and underlying reactive airway disease.The next day, while hospitalized, the child developed a maculopapular rash.On October 10, the child's family reported contact with a person with clinically diagnosed measles before U.S. arrival.*Measles was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) testing on October 11; the child was discharged the same day.
Outbreak Linked to Morel Mushroom Exposure — Montana, 2023
Authors: Heather Demorest, Rachel Hinnenkamp, Maggie Cook-Shimanek, Alyssa N. Troeschel, Michael Yeh, Thao-Phuong Christy Hallett, David Kuai, Johnni Daniel, Andrea Winquist
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

During March-April 2023, a total of 51 persons reported mild to severe gastrointestinal illness after eating at restaurant A in Bozeman, Montana.The outbreak resulted in multiple severe outcomes, including three hospitalizations and two deaths.After an inspection and temporary restaurant closure, the Montana Department of Public Health and Human Services and Montana's Gallatin City-County Health Department collaborated with CDC to conduct a matched case-control study among restaurant patrons to help identify the source of the outbreak.Consumption of morel mushrooms, which are generally considered edible, was strongly associated with gastrointestinal illness.A dose-response relationship was identified, and consumption of raw morel mushrooms was more strongly associated with illness than was consumption of those that were at least partially cooked.In response to the outbreak, educational public messaging regarding morel mushroom preparation and safety was shared through multiple media sources.The investigation highlights the importance of prompt cross-agency communication and collaboration, the utility of epidemiologic studies in foodborne disease outbreak investigations, and the need for additional research about the impact of morel mushroom consumption on human health.Although the toxins in morel mushrooms that might cause illness are not fully understood, proper preparation procedures, including thorough cooking, might help to limit adverse health effects.