Catheter and Non-Catheter-Related Venous Thromboembolism in Cancer Patients: Survival, Anticoagulation Efficacy, and Safety.

PURPOSE: To investigate the differences in survival after venous thromboembolism (VTE) and anticoagulation efficacy and safety between catheter (CRVTE) and non-catheter-related VTE (NCRVTE) in cancer patients. METHODS: A retrospective research was conducted, and consecutive cancer (digestive, respiratory, genitourinary, blood and lymphatic, and the other cancers) patients with VTE were enrolled. The anticoagulation therapies included low-molecular-weight heparin (LMWH), warfarin, new type of direct oral anticoagulants (NDOACs), LMWH combined with warfarin, and LMWH combined with NDOACs. Data were collected from the electronic medical record database of our hospital and were analyzed accordingly by Kruskal-Wallis H Test, Chi-square test, Fisher's exact test, Logistic regressions, Kaplan-Meier analysis, and Cox regressions. RESULTS: 263 patients were included, median age in years (interquartile range) was 64(56-71) and 60.5% were male. VTE recurrence rate was 16.7% in CRVTE group which was significantly lower than 34.8% in NCRVTE group (P = .032). Heart diseases were independently associated with VTE recurrence (P = .025). Kaplan-Meier survival estimates at 1, 2, and 3 years for CRVTE group were 62.5%, 60.0%, and 47.5%, respectively, compared with 47.9% (P = .130), 38.7% (P = .028), and 30.1% (P = .046), respectively, for NCRVTE group. Cox regression showed surgery (P = .003), anticoagulation therapy types (P = .009), VTE types (P = .006) and cancer types (P = .039) were independent prognostic factors for 3-year survival after VTE. Nonmajor and major bleeding were not significantly different (P = .417). Anticoagulation therapy types were independently associated with the bleeding events (P = .030). CONCLUSIONS: Cancer patients with CRVTE potentially have a better anticoagulation efficacy and survival compared to NCRVTE, and the anticoagulation safety seems no significant difference.

Glycosylated gelatin prepared based on electron beam irradiation and its physicochemical properties.

The influence of electron beam irradiation (EBI) treatment on the modification of gelatin-galactose glycosylation was thoroughly examined. The results of the degree of grafting and browning revealed that EBI triggered the glycosylation reaction of gelatin. The degree of glycosylation exhibited a gradual increase with the rising irradiation dose, reaching a maximum of 25 kGy. Moreover, the irradiation process opened up gelatin's internal structure, exposing its hydrophobic groups. This exposure led to an enhancement in sample surface hydrophobicity. The fluorescence intensity at the maximum emission wavelength of the fluorescence spectra decreased; Fourier infrared spectroscopy demonstrated a new absorption peak at 1074 cm-1 for the glycosylation product. These findings substantiate that gelatin formed a new product through covalent bonding with galactose. Glycosylation boosted the emulsification stability of gelatin from 1.92 min to 10.42 min and improved its emulsification and rheological properties. These outcomes affirm that EBI can effectively induce the glycosylation reaction of gelatin, thereby enhancing its functional properties. In addition, EBI has the potential to supplant the conventional heating glycosylation method. This study lays a solid theoretical foundation for the future application of glycosylation and gelatin.

Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.

Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.

Gas6/Axl signaling promotes hematoma resolution and motivates protective microglial responses after intracerebral hemorrhage in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) stands out as the most fatal subtype of stroke, currently devoid of effective therapy. Recent research underscores the significance of Axl and its ligand growth arrest-specific 6 (Gas6) in normal brain function and a spectrum of neurological disorders, including ICH. This study is designed to delve into the role of Gas6/Axl signaling in facilitating hematoma clearance and neuroinflammation resolution following ICH. METHODS: Adult male C57BL/6 mice were randomly assigned to sham and ICH groups. ICH was induced by intrastriatal injection of autologous arterial blood. Recombinant mouse Gas6 (rmGas6) was administered intracerebroventricularly 30 min after ICH. Virus-induced knockdown of Axl or R428 (a selective inhibitor of Axl) treatment was administrated before ICH induction to investigate the protective mechanisms. Molecular changes were assessed using western blot, enzyme-linked immunosorbent assay and immunohistochemistry. Coronal brain slices, brain water content and neurobehavioral tests were employed to evaluate histological and neurofunctional outcomes, respectively. Primary glia cultures and erythrophagocytosis assays were applied for mechanistic studies. RESULTS: The expression of Axl increased at 12 h after ICH, peaking on day 3. Gas6 expression did not remarkably changed until day 3 post-ICH. Early administration of rmGas6 following ICH significantly reduced hematoma volume, mitigated brain edema, and restored neurological function. Both Axl-knockdown and Axl inhibitor treatment abolished the neuroprotection of exogenous Gas6 in ICH. In vitro studies demonstrated that microglia exhibited higher capacity for phagocytosing eryptotic erythrocytes compared to normal erythrocytes, a process reversed by blocking the externalized phosphatidylserine on eryptotic erythrocytes. The erythrophagocytosis by microglia was Axl-mediated and Gas6-dependent. Augmentation of Gas6/Axl signaling attenuated neuroinflammation and drove microglia towards pro-resolving phenotype. CONCLUSIONS: This study demonstrated the beneficial effects of recombinant Gas6 on hematoma resolution, alleviation of neuroinflammation, and neurofunctional recovery in an animal model of ICH. These effects were primarily mediated by the phagocytotic role of Axl expressed on microglia.

Maintenance infusion rate of oxytocin after initial 1-IU bolus for elective Cesarean delivery: a dose-finding study.

PURPOSE: The purpose of our study was to determine the minimum effective dose of oxytocin maintenance infusion required to maintain adequate uterine tone in 90% of patients (ED90) after administration of the initial bolus at elective Cesarean delivery (CD) under spinal anesthesia. METHODS: We conducted a prospective, double-blind dose-finding study with biased coin up-down design. Immediately after delivery, a 1-IU oxytocin bolus was administered, followed by a maintenance infusion. The obstetrician assessed the uterine tone by palpation as satisfactory or unsatisfactory. In case of unsatisfactory response, the dose for the next patient was increased by 2 IU·hr-1. For satisfactory response, the dose for the next patient was either decreased by 2 IU·hr-1 with a probability of 1/9, or remained unchanged. The primary outcome was a satisfactory uterine tone from five minutes after delivery until discharge from postanesthesia care unit. The secondary outcomes were blood loss, need for additional uterotonics, and side effects. RESULTS: We analyzed data for 40 patients. The ED90 of oxytocin maintenance infusion was 4.5 IU·hr-1 (95% confidence interval, 3.3 to 5.5) based on the isotonic regression estimator. The median [interquartile range] blood loss was 861 [553-1,181] mL; 18% received additional uterotonics, and 38% developed hypotension post delivery. CONCLUSION: Based on the results of this dose-finding study, we recommend a maintenance infusion rate of 4.5 IU·hr-1 following an oxytocin bolus of 1 IU for adequate uterine tone in pregnant patients undergoing elective CDs. This infusion rate is four-fold lower than that required without an initial bolus. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04946006 ); first submitted 25 June 2021.

RéSUMé: OBJECTIF: L'objectif de notre étude était de déterminer la dose minimale efficace de perfusion d'entretien d'ocytocine nécessaire pour maintenir un tonus utérin adéquat chez 90 % des personnes parturientes (DE90) après l'administration du bolus initial lors d'une césarienne programmée sous rachianesthésie. MéTHODE: Nous avons réalisé une étude prospective et en double aveugle de détermination de la dose avec une méthodologie de conception biaisée type « up-and down ¼. Immédiatement après l'accouchement, un bolus d'ocytocine de 1 UI a été administré, suivi d'une perfusion d'entretien. L'obstétricien·ne a évalué le tonus utérin par palpation comme satisfaisant ou insatisfaisant. En cas de réponse insatisfaisante, la dose pour la personne suivante a été augmentée de 2 UI·h−1. Lors d'une réponse satisfaisante, la dose pour la personne suivante a été diminuée de 2 UI·h−1 avec une probabilité de 1/9, ou est restée inchangée. Le critère d'évaluation principal était un tonus utérin satisfaisant de cinq minutes après l'accouchement jusqu'à la sortie de la salle de réveil. Les critères d'évaluation secondaires étaient la perte de sang, la nécessité d'utérotoniques supplémentaires et les effets secondaires. RéSULTATS: Nous avons analysé les données de 40 patient·es. La DE90 de perfusion d'entretien d'ocytocine était de 4,5 UI·h−1 (intervalle de confiance à 95 %, 3,3 à 5,5) basé sur l'estimateur de régression isotonique. La perte de sang médiane [écart interquartile] était de 861 [553-1 181] mL; 18 % ont reçu des utérotoniques supplémentaires et 38 % ont développé une hypotension après l'accouchement. CONCLUSION: D'après les résultats de cette étude de détermination de la dose, nous recommandons un débit de perfusion d'entretien de 4,5 UI·h−1 après un bolus d'ocytocine de 1 UI pour un tonus utérin adéquat chez les personnes parturientes bénéficiant d'une césarienne programmée. Ce débit de perfusion est quatre fois inférieur à celui requis sans bolus initial. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT04946006 ); première soumission le 25 juin 2021.

First-Principles Study on Bi2Te2S Monolayer for Adsorption Performance and Sensing Capability.

In this study, a comprehensive investigation into the gas sensing capabilities of the two-dimensional (2D) Bi2Te2S was conducted using first-principles calculations based on density functional theory. A wide array of gas molecules, including CH4, Cl2, CO, CO2, H2, H2O, H2S, N2, NH3, NO, NO2, O2, and SO2, was encompassed in this work. Through the strategic placement of these gas molecules at different locations on the Bi2Te2S monolayer and taking into account a range of configurations, the adsorption process was thoroughly investigated, with a particular emphasis on the structures that are most thermodynamically stable. It was revealed that Cl2, O2, NO, and NO2 molecules exhibit a pronounced affinity for the Bi2Te2S monolayer. Notably, it was found that the Cl2@Bi2Te2S, O2@Bi2Te2S, and NO2@Bi2Te2S systems' gas adsorption capabilities are greatly enhanced by the introduction of an external electric field. Moreover, the addition of horizontal biaxial strain significantly impacts the gas adsorption properties of the O2@Bi2Te2S system, underscoring the tunability of the Bi2Te2S monolayer's sensing capabilities. In light of these theoretical results, the Bi2Te2S monolayer is proposed to have great potential as an extremely sensitive and selective gas sensing material, especially for identifying Cl2, O2, NO, and NO2. This study clarifies the intrinsic gas sensing capabilities of the Bi2Te2S monolayer, while highlighting how its performance can be tailored in response to external stimuli, setting the stage for the advancement of more sophisticated gas sensing devices.

The role of stereotactic body radiotherapy in oligoprogressive malignant disease (RADIANT): oncologic outcomes from a phase 2 non-randomized controlled trial.

BACKGROUND: In oligoprogressive (OP) cancer there are a limited numbers of metastatic areas progressing on a background of stable or responding widespread cancer. While the standard-of-care for OP is changing systemic therapy (ST), stereotactic body radiotherapy (SBRT) is being explored as an alternative local therapy targeting the sites of progression. MATERIALS/METHODS: XXX (NCTXXX) was a single-centre phase-2 study of patients with metastatic genitourinary (GU), breast and gastrointestinal (GI) cancers, receiving ST for >3 months, with radiographic OP disease in <5 sites. Patients received SBRT to all OP disease in 1-5 fractions, and were maintained on ST. The primary endpoint was the cumulative incidence of change in ST estimated using Aalen-Johansen method. Secondary endpoints included progression-free survival (PFS) and overall survival (OS) estimated using Kaplan-Meier method, toxicity, and health-related quality-of-life (HRQOL). Comparisons between diagnosis groups were done using log-rank test. A two-sided p-value of <0.05 was considered as statistical significance. RESULTS: Seventy patients were analyzed, with median age 69 years; 32 patients (46%) were female; median number of lines of prior ST was 3. Primary sites were GU (n=32; 46%), breast (n=23; 33%) and GI (n=15; 21%). Median follow-up was 12.3 months (IQR 8.2-21.6). At 1-year, change in ST occurred in 47% (95% CI 36-61%) (GU 45%, breast 41%, GI 60%, p=0.23). PFS at 1-year was 32% (95% CI 23-45%), and median PFS was 4.7 months (95% CI 3.8-8.1) (GU 4.8, breast 6.5, GI 3.2), which significantly differed by disease type (p=0.006). OS was 75% at 1-year (95% CI 65-87%), which significantly differed between cancer type (GU 86%, breast 96%, GI 22%, p<0.001). Cumulative incidence of late grade >2 toxicity was 1.2%, with 1 patient experiencing late grade 3 toxicity, and no grade 4-5 acute or late toxicities. HRQOL declined from mean (standard deviation) of 66.9 (20.2) at baseline to 60.5 (22.2) at 6 months, which did not meet the threshold for a minimal clinically important difference. CONCLUSIONS: SBRT for OP metastases delayed change in ST in approximately half of patients, warranting investigation in randomized trials.

Improvement on gel properties of chicken myofibrillar protein with electron beam irradiation: Based on protein structure, gel quality, water state.

This study aimed to investigate the effects of electron beam (E-beam) irradiation at different doses (0-15 kGy) on the solubility, rheological properties, emulsification characteristics, and moisture distribution of chicken myofibrillar proteins (MPs). Irradiation treatment notably increased the solubility, surface hydrophobicity, emulsification properties, and apparent viscosity of MPs, based on conformational changes caused by irradiation-induced oxidative denaturation of proteins. However, high doses of irradiation (15 kGy) induced in excessive cross-linking and aggregation of proteins, reducing the solubility, emulsification properties, and shear stress. Degradation of myosin heavy and light chains in irradiated MPs increased the content of ß-turns and random coils. Additionally, the initial relaxation times of T21 and T22 in irradiated protein gels were reduced, and the peak value of P21 was increased, which improved the water-capturing ability of protein gels. Altogether, these results findings suggest that electron beam irradiation can be applied as a potential technique for modifying muscle proteins.

Role perceptions and experiences of adult children in remote glucose management for older parents with type 2 diabetes mellitus: a qualitative study.

BACKGROUND: With the advent of the smart phone era, managing blood glucose at home through apps will become more common for older individuals with diabetes. Adult children play important roles in glucose management of older parents. Few studies have explored how adult children really feel about engaging in the glucose management of their older parents with type 2 diabetes mellitus (T2DM) through mobile apps. This study provides insights into the role perceptions and experiences of adult children of older parents with T2DM participating in glucose management through mobile apps. METHODS: In this qualitative study, 16 adult children of older parents with T2DM, who had used mobile apps to manage blood glucose for 6 months, were recruited through purposive sampling. Semi-structured, in-depth, face-to-face interviews to explore their role perceptions and experiences in remotely managing their older parents' blood glucose were conducted. The Consolidated Criteria for Reporting Qualitative Research (COREQ) were followed to ensure rigor in the study. The data collected were analyzed by applying Colaizzi's seven-step qualitative analysis method. RESULTS: Six themes and eight sub-themes were identified in this study. Adult children's perceived roles in glucose management of older parents with T2DM through mobile apps could be categorized into four themes: health decision-maker, remote supervisor, health educator and emotional supporter. The experiences of participation could be categorized into two themes: facilitators to participation and barriers to participation. CONCLUSION: Some barriers existed for adult children of older parents with T2DM participating in glucose management through mobile apps; however, the findings of this study were generally positive. It was beneficial and feasible for adult children to co-manage the blood glucose of older parents. Co-managing blood glucose levels in older parents with T2DM can enhance both adherence rates and confidence in managing blood glucose effectively.

What influences the implementation of clinical guidelines related to enteral nutrition in the intensive care unit: A mixed-methods systematic review.

AIMS: To systematically evaluate and analyse literature concerning the factors influencing the implementation of clinical practice guidelines related to enteral nutrition in the adult intensive care unit. BACKGROUND: Guidelines serve as crucial tools for guiding clinical practice. However, a significant gap persists between current clinical practice and guidelines pertaining to enteral nutrition. It is essential to identify the reasons behind this disparity to foster clinical transformation. METHODS: A mixed-methods systematic review. DATA SOURCES: A systematic search was conducted across PubMed, Embase, Medline, Cochrane, PsycINFO and CNKI databases to identify impediments and facilitators to the implementation of ICU clinical practice guidelines related to enteral nutrition. The types of studies included quantitative, qualitative and mixed-methods studies. The search spanned from January 2003 to January 2024 and was updated in May 2024. The quality assessment of the included literature was conducted using the Mixed-Methods Study Evaluation Tool (MMAT). Data analysis was performed using a data-based convergent integration approach. The protocol for this study was prospectively registered (PROSPERO2023, CRD42023483287). RESULTS: Twenty papers were finally included, and 65 findings were extracted, integrating a total of three categories, Category 1: healthcare provider factors, including three sub-themes: knowledge of guideline-related knowledge and awareness of guideline application; social/professional roles and identity domains; beliefs, attitudes and self-efficacy; collaboration, Category 2: practice environments, including two sub-themes: environmental factors and resource areas; systems and behavioural norms, Category 3: patient values and nutritional support preferences including two sub-themes: patient disease status and value orientation. CONCLUSION: Healthcare professionals should analyse obstacles and facilitators to guideline implementation from multiple perspectives, strengthen healthcare collaboration, improve education and training systems, correct misperceptions and increase awareness of evidence-based practice.

Effect of electron beam irradiation on glycosylation reaction and structural characterization of whey isolate protein.

BACKGROUND: Whey protein isolate (WPI) is a high-quality animal protein resource. The modification of WPI through physical, chemical and biological methods can substantially improve the functional properties of proteins. This study investigated the effect of electron beam irradiation (EBI) on the modification of WPI-xylose glycosylation. RESULTS: The degree of grafting and browning revealed that EBI promoted WPI glycosylation. The maximum emission wavelength of intrinsic fluorescence was red-shifted and the fluorescence intensity was reduced, suggesting that irradiation induced the unfolding of the WPI structure, thereby promoting glycosylation. Fourier-transformed infrared spectroscopy revealed that the covalent binding of the conjugates occurred on the introduction of the hydrophilic groups, resulting in decreased surface hydrophobicity. When compared with conventional wet-heat glycosylation, irradiation-assisted glycosylation improved the emulsifying activity of WPI from 179.76 ± 0.83 to 277.83 ± 1.44 m2 g-1, and the emulsifying and rheological properties improved. CONCLUSION: These results confirmed that EBI can increase the degree of WPI glycosylation and improve the functional properties of proteins, thereby laying a theoretical foundation for the further application of WPI. © 2024 Society of Chemical Industry.

A T2-weighted MRI-based radiomic signature for disease-free survival in locally advanced cervical cancer following chemoradiation: An international, multicentre study.

INTRODUCTION: To develop and validate a T2-weighted magnetic resonance imaging (MRI)-based radiomic signature associated with disease-free survival (DFS) in locally advanced cervical cancer. MATERIALS AND METHODS: The study comprised a training dataset of 132 patients (93 Norwegian; 39 The Cancer Imaging Archive (TCIA) and an independent validation Canadian dataset of 199 patients with FIGO stage IB-IVA cervical cancer treated with chemoradiation. Radiomic features were extracted using PyRadiomics. A radiomic signature was developed based on a multivariable radiomic prognostic model for DFS built using the training dataset, with minimal redundancy maximum relevancy feature selection method. Univariate and multivariable Cox regression analyses were then conducted to examine the association of the derived radiomic signature with DFS. RESULTS: A radiomic signature was prognostic for DFS in the training cohort (Norwegian hazard ratio [HR] 5.54, p = 0.002; TCIA HR 3.59, p = 0.04). The radiomic signature remained independently associated with DFS (HR 3.70, p = 0.004) when adjusted for stage and tumor volume. The radiomic signature was also prognostic for DFS in the validation cohort, both on univariate analysis (HR 2.22, p = 0.003), and multivariable analysis adjusted for stage and tumor volume (HR 1.84, p = 0.04). The 4-year DFS rates of patients with radiomic signature score > 0 vs ≤ 0 were 48.2 % vs 87.9 %, and 56.4 % vs 80.8 % for training and validation cohorts respectively. CONCLUSION: An MRI-based radiomic signature can be used as a prognostic biomarker for DFS in patients with locally advanced cervical cancer undergoing chemoradiation.

Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Probe capsid structure stability and dynamics of adeno-associated virus as an important viral vector for gene therapy by hydrogen-deuterium exchange-mass spectrometry.

Adeno-associated virus (AAV), a widely used gene therapy vector, is a small, nonenveloped virus that contains a single-stranded DNA genome with a maximum length of 4.7 kb. Despite extensive biophysical and structural characterization, many aspects of AAV functions remain elusive. This knowledge gap is primarily due to a lack of structurally resolved dynamic information and the absence of structural coverage of functionally critical segments on the AAV capsid. Here, we developed a protocol to study AAV structural dynamics by hydrogen-deuterium exchange mass spectrometry (HDX-MS), a powerful method for monitoring protein structure stability and dynamics in solution. We performed HDX-MS measurements on AAVs without or with different DNA payloads of different sizes, and obtained detailed dynamic information on the entire AAV sequence including the two functionally important segments not previously structurally characterized. The unique N terminus of the capsid protein VP1 (VP1u) was found to adopt a highly dynamic and unstable conformation with low HDX protection across the entire region, whereas the presence of a DNA payload increased its protection. The VP1 and VP2 shared region (VP1/2) showed no measurable protection, with or without DNA. Differential HDX between empty and full capsid samples allowed us to identify potential new DNA-capsid interaction sites located primarily around the five-fold channel, which differ from the three-fold pocket binding site previously identified. Our HDX-MS method for characterizing AAV structural dynamics opens a new way for future efforts to understand AAV structure-function relationships and engineer next-generation AAV vectors with improved gene delivery properties.

HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment.

Bifunctional conjugates targeting PD-L1/PARP7 were designed, synthesized, and evaluated for the first time. Compounds B3 and C6 showed potent activity against PD-1/PD-L1 interaction (IC50 = 0.426 and 0.342 µM, respectively) and PARP7 (IC50 = 2.50 and 7.05 nM, respectively). They also displayed excellent binding affinity with hPD-L1, approximately 100-200-fold better than that of hPD-1. Both compounds restored T-cell function, leading to the increase of IFN-γ secretion. In the coculture assay, B3 and C6 enhanced the killing activity of MDA-MB-231 cells by Jurkat T cells in a concentration-dependent manner. Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential anticancer therapy.

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.