TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury.

Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22-weeks in TLY012-rescued survivors versus un-rescued surviving irradiated-mice.

Synergistic combination therapy with ONC201 or ONC206, and enzalutamide or darolutamide in preclinical studies of castration-resistant prostate cancer.

Androgen receptor (AR) signaling is a target in prostate cancer therapy and can be treated with non-steroidal anti-androgens (NSAA) including enzalutamide, and apalutamide for patients with advanced disease. Metastatic castration-resistant prostate cancer (mCPRC) develop resistance becomes refractory to therapy limiting patient overall survival. Darolutamide is a novel next-generation androgen receptor-signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC).

Development and Validation of the Communities Geriatric Mild Cognitive Impairment Risk Calculator (CGMCI-Risk).

: The aim was to develop and validate the Communities Geriatric Mild Cognitive Impairment Risk Calculator (CGMCI-Risk), aiding community healthcare workers in the early identification of individuals at high risk of mild cognitive impairment (MCI). : Based on nationally representative community survey data, backward stepwise regression was employed to screen the variables, and logistic regression was utilized to construct the CGMCI-Risk. Internal validation was conducted using bootstrap resampling, while external validation was performed using temporal validation.

Targeting apoptotic pathways for cancer therapy.

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology.

Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer.

Incidence and spontaneous clearance of gonorrhea and chlamydia infections among men who have sex with men: a prospective cohort study in Zhuhai, China.

Background: Men who have sex with men (MSM) face significant risks of (CT) and/or (NG) infection. Nevertheless, only limited studies have looked into the site-specific infection and clearance of CT/NG. In order to prevent transmission, it is essential to understand the underlying factors that drive infection and spontaneous clearance.

An evolutionary game analysis of algorithmic indirect copyright infringement from the perspective of collusion between UGC platforms and direct infringers.

User-generated content (UGC) is developing rapidly as an emerging platform form, however, the problem of indirect copyright infringement by algorithms is becoming more and more prominent, and infringement governance has become a key act in the development of UGC platforms. When infringement occurs, recommendation algorithms expand the scope and results of infringement, while platforms choose to conspire with direct infringers for their own interests, making it difficult for infringed persons to defend their rights. In order to analyse the influence of different factors in the platform ecosystem on the subject's behavioural strategies, a "platform-infringer" evolutionary game model is constructed, and numerical simulation is used to verify the correctness of the stable results.

ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma.

Gastric adenocarcinoma typically presents with advanced stage when inoperable. Chemotherapy options include non-targeted and toxic agents, leading to poor 5-year patient survival outcomes. Small molecule ONC201/TIC10 (TRAIL-Inducing Compound #10) induces cancer cell death via ClpP-dependent activation of the integrated stress response (ISR) and up-regulation of the TRAIL pathway.

Novel combination of imipridones and histone deacetylase inhibitors demonstrate cytotoxic effect through integrated stress response in pediatric solid tumors.

There is a demonstrated need for new chemotherapy options in pediatric oncology, as pediatric solid tumors continue to plateau at 60% with event-free survival. Imipridones, a novel class of small molecules, represent a potential new therapeutic option, with promising pre-clinical data and emerging clinical trial data in adult malignancies. ONC201, ONC206, and ONC212 are imipridones showing pro-apoptotic anti-cancer response.

Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer.

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types.

Pan-integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling.

Colorectal cancer is the third leading cause of cancer-related death and the third most common cause of cancer. As the five-year survival with advanced metastatic colorectal cancer (mCRC) is 14%, new treatment strategies are needed. Immune checkpoint blockade, which takes advantage of an individual's immune system to fight cancer, has an impact in the clinic; however, for CRC, it is only effective and approved for treating mismatch repair (MMR)-deficient cancer.

Broad spectrum integrin inhibitor GLPG-0187 bypasses immune evasion in colorectal cancer by TGF-β signaling mediated downregulation of PD-L1.

Integrin receptors have long posed as a potentially attractive target for disrupting cancer hallmarks. Promising preliminary findings with integrin inhibition as an adjuvant to chemotherapy have not translated to clinical success. However, the effect of integrin inhibition on tumor-immune cell interactions remains largely unexplored.

GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that has been implicated in numerous oncogenic processes. GSK-3 inhibitor elraglusib (9-ING-41) has shown promising preclinical and clinical antitumor activity across multiple tumor types. Despite promising early-phase clinical trial results, there have been limited efforts to characterize the potential immunomodulatory properties of elraglusib.

Influence of Antenna Element Position Deviation on Radiation Performance of Helical Antenna Array.

The electrical performance of the feed array is degraded because of the position deviation of the array elements caused by manufacturing and processing, which cannot meet the high performance feeding requirements of large feed arrays. In this paper, a radiation field model of the helical antenna array considering the position deviation of array elements is proposed to investigate the influence law of position deviation on the electrical performance of the feed array. With the established model, the rectangular planar array and the circular array of the helical antenna with a radiating cup are discussed and the relationship between electrical performance index and position deviation is established by numerical analysis and curve fitting method.

Vitexin inhibits pain and itch behavior via modulating TRPV4 activity in mice.

Itching and pain are distinct unpleasant sensations. The transient receptor potential cation channel subfamily V member 4 (TRPV4) pathway is regarded as a shared pathway that mediates pain and itching. Vitexin (Mujingsu, MJS), a C-glycosylflavonoid, is an effective analgesic.

Activation of the Epac/Rap1 signaling pathway alleviates blood-brain barrier disruption and brain damage following cerebral ischemia/reperfusion injury.

Blood brain barrier (BBB) destruction plays a key role in ischemia stroke, including promoting BBB leakage and brain edema, and leads to unfavorable patient prognosis. Epac/Rap1 signaling pathway is important in mediating endothelial cell barrier function. This study will investigate the regulatory role of Epac/Rap1 signaling pathway in BBB disruption after cerebral ischemia/reperfusion (CI/R) injury.

GSK-3 inhibitor elraglusib enhances tumor-infiltrating immune cell activation in tumor biopsies and synergizes with anti-PD-L1 in a murine model of colorectal cancer.

Unlabelled: Inhibition of GSK-3 using small-molecule elraglusib has shown promising preclinical antitumor activity. Using in vitro systems, we found that elraglusib promotes immune cell-mediated tumor cell killing, enhances tumor cell pyroptosis, decreases tumor cell NF-κB-regulated survival protein expression, and increases immune cell effector molecule secretion. Using in vivo systems, we observed synergy between elraglusib and anti-PD-L1 in an immunocompetent murine model of colorectal cancer.

Synergistic activity of ABT-263 and ONC201/TIC10 against solid tumor cell lines is associated with suppression of anti-apoptotic Mcl-1, BAG3, pAkt, and upregulation of pro-apoptotic Noxa and Bax cleavage during apoptosis.

A major underlying cause of the resistance of solid tumor cells to cancer therapy is the evasion of cell death following anti-cancer drug treatment. We explored the combination of TRAIL-inducing compound ONC201/TIC10 and Bcl-xL/Bcl-2 inhibitor ABT-263 to target the extrinsic and intrinsic apoptotic pathways, respectively, in solid tumor cell lines (N = 13) derived from different tissues (colon, prostate, lung, breast, ovary, bladder). We found an IC50 range of 0.

The successful treatment of Microsporidiosis with nitazoxanide in a patient with B-ALL: A Case Report.

Introduction: () Microsporidia can cause opportunistic infections in immunocompromised patients and is also an emerging disease in these individuals. Its clinical manifestations are chronic diarrhea and severe wasting syndrome, these can be extremely debilitating and carry a significant risk of death for immunocompromised patients. Often, microsporidia cannot be confirmed immediately by routine examination and culture.

Therapeutic targeting of TRAIL death receptors.

The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) along with its potent and selective antitumor effects initiated a decades-long search for therapeutic strategies to target the TRAIL pathway. First-generation approaches were focused on the development of TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and TRAIL receptor-targeted agonistic antibodies. While such TRAIL pathway-targeted therapies showed promise in preclinical data and clinical trials have been conducted, none have advanced to FDA approval.

Clinical characteristics and prognosis of 16 relapsed/refractory B-cell malignancy patients with CAR T-cell-related hyperferritinaemia.

With the success of chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (r/r) B-cell malignancies, severe complications after CAR T-cell infusion have emerged as nonnegligible prognosis-related factors. However, the prognosis of patients with CAR T-cell-related hyperferritinaemia (HFA) is unclear. We report the efficacy and safety of CAR T-cell therapy in 16 r/r B-cell malignancy patients with CAR T-cell-related HFA.

Attention impairment in patients with cervical dystonia: An attention network test study.

Objective: The purpose of this study was to investigate attentional network functional characteristics in patients with cervical dystonia (CD).

Methods: A total of 29 patients with CD and 26 healthy controls (HCs) were recruited. All subjects participated in the study and underwent the Attention Network Test (ANT), which evaluated the efficiencies of three independent attention networks (alerting, orienting, and executive control), as well as reaction time (RT) and accuracy.

Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma.

GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response.

STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models.

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties.