Striatal functional alterations link to distinct symptomatology across mood states in bipolar disorder.

BACKGROUND: As a central hub in cognitive and emotional brain circuits, the striatum is considered likely to be integrally involved in the psychopathology of bipolar disorder (BD). However, it remains unclear how alterations in striatal function contribute to distinct symptomatology of BD during different mood states. METHODS: Behavioral assessment (i.e., emotional symptoms and cognitive performance) and neuroimaging data were collected from 125 participants comprising 31 (hypo)manic, 31 depressive and 31 euthymic patients with BD, and 32 healthy controls. We compared the functional connectivity (FC) of striatal subregions across BD mood states with healthy controls and then used a multivariate data-driven approach to explore dimensional associations between striatal connectivity and behavioral performance. Finally, we compared the FC and behavioral composite scores, which reflect the individual weighted representation of the associations, among different mood states. RESULTS: Patients in all mood states exhibited increased FC between the bilateral ventral rostral putamen (VRP) and ventrolateral thalamus. Bipolar (hypo)mania uniquely exhibited increased VRP connectivity and superior ventral striatum connectivity. One latent component was identified, whereby increased FCs of striatal subregions were associated with distinct psychopathological symptomatology (more manic symptoms, elevated positive mood, less depressive symptoms and worse cognitive performance). Bipolar (hypo)manic patients had the highest FC and behavioral composite scores while bipolar depressive patients had the lowest. CONCLUSIONS: Our data demonstrated both trait features of BD and state features specific to bipolar (hypo) mania. The findings underscored the fundamental role of the striatum in the pathophysiological processes underlying specific symptomatology across all mood states.

Ecological risk assessment of commonly used antibiotics in aquatic ecosystems along the coast of China.

The consistent input of antibiotics into aquatic environments may pose risks to various creatures and ecosystems. However, risk assessment of pharmaceuticals and personal care products (PPCPs) in aquatic environments is frequently limited by the lack of toxicity data. To investigate the risk of commonly used antibiotics to various aquatic creatures, we focused on the distribution patterns and temporal dynamics of antibiotics in the coastal estuary area of China and performed a comprehensive ecological risk assessment for four antibiotics: erythromycin (ERY), tetracycline (TCN), norfloxacin (NOR) and sulfamethoxazole (SMX). An interspecies correlation estimation (ICE)-species sensitivity distribution (SSD) combined model was applied to predict the toxicity data of untested aquatic species, and an accurate ecological risk assessment procedure was developed to evaluate the risk level of PPCPs. The results of risk quotient assessments and probabilistic risk assessments (PRAs) suggested that four objective antibiotics in the Chinese coastal estuary area were at a low risk level. These antibiotics posed a high risk in antibiotic-related global hot spots, with probabilistic risk values for ERY, NOR, SMX, and TCN of 81.33 %, 27.08 %, 21.13 %, and 15.44 %, respectively. We applied an extrapolation method to overcome the lack of toxicity data in ecological risk assessment, enhanced the ecological reality of water quality criteria derivation and reduced the uncertainty of risk assessment for antibiotics.

25(OH)D level and vascular lesion scores in kidney histopathology as risk-stratification tool for predicting renal progression in people with type 2 diabetes.

AIM: To evaluate the potential of the combined individual vascular histopathological lesion and serum 25-hydroxy vitamin D [25(OH)D] level as predictors of outcomes in patients with diabetes and chronic kidney disease. METHODS: A total of 190 patients with type 2 diabetes and kidney disease stages 1-4 were retrospectively included. Kaplan-Meier analysis and the log-rank test were performed to assess renal survival differences. And the time-dependent receiver operating characteristic analyses were used to characterize the predictive accuracy. Hazard ratios for vascular lesion scores and 25(OH)D levels with renal outcomes were estimated using Cox proportional hazards regression models with follow-up time. RESULTS: Over a median follow-up of 23.78 (12.61, 37.14) months, 71 patients (37.4 %) experienced the renal outcomes. Enrolled patients with more severe vascular lesions had worse kidney function, heavier proteinuria, lower serum 25(OH)D levels, and higher prevalence of composite kidney outcomes. Baseline serum 25(OH)D was a significant independent risk factor for vascular lesion scores. The effect of serum 25(OH)D level on kidney prognosis was more pronounced in males and those with more exacerbated vascular lesions (score 2). The severity of vascular lesions and serum 25(OH)D levels were associated with unfavorable kidney outcomes. Accordingly, further time-dependent receiver operating characteristic curves confirmed that combined 25(OH)D level and vascular lesion score had a stable and reliable performance in renal outcomes prediction at short and long-term follow-up times. CONCLUSIONS: 25(OH)D level and vascular lesion scores in kidney histopathology could serve as a useful risk-stratification tool for predicting renal progression in patients with type 2 diabetes.

Direct conversion of cardiac fibroblasts into endothelial-like cells using Sox17 and Erg.

Endothelial cells are a heterogeneous population with various organ-specific and conserved functions that are critical to organ development, function, and regeneration. Here we report a Sox17-Erg direct reprogramming approach that uses cardiac fibroblasts to create differentiated endothelial cells that demonstrate endothelial-like molecular and physiological functions in vitro and in vivo. Injection of these induced endothelial cells into myocardial infarct sites after injury results in improved vascular perfusion of the scar region. Furthermore, we use genomic analyses to illustrate that Sox17-Erg reprogramming instructs cardiac fibroblasts toward an arterial-like identity. This results in a more efficient direct conversion of fibroblasts into endothelial-like cells when compared to traditional Etv2-based reprogramming. Overall, this Sox17-Erg direct reprogramming strategy offers a robust tool to generate endothelial cells both in vitro and in vivo, and has the potential to be used in repairing injured tissue.

Rutaecarpine Alleviates Early Brain Injury-Induced Inflammatory Response Following Subarachnoid Hemorrhage via SIRT6/NF-[Formula: see text]B Pathway.

Subarachnoid hemorrhage (SAH), a specific subtype of cerebrovascular accident, is characterized by the extravasation of blood into the interstice between the brain and its enveloping delicate tissues. This pathophysiological phenomenon can precipitate an early brain injury (EBI), which is characterized by inflammation and neuronal death. Rutaecarpine (Rut), a flavonoid compound discovered in various plants, has been shown to have protective effects against SAH-induced cerebral insult in rodent models. In our study, we used a rodent SAH model to evaluate the effect of Rut on EBI and investigated the effect of Rut on the inflammatory response and its regulation of SIRT6 expression in vitro. We found that Rut exerts a protective effect on EBI in SAH rats, which is partly due to its ability to inhibit the inflammatory response. Notably, Rut up-regulated Sirtuin 6 (SIRT6) expression, leading to an increase in H3K9 deacetylation and inhibition of nuclear factor-kappa B (NF-[Formula: see text]B) transcriptional activation, thereby mediating the inflammatory response. In addition, further data showed that SIRT6 was proven to mediate the regulation of Rut on the microglial inflammatory response. These findings highlight the importance of SIRT6 in the regulation of inflammation and suggest a potential mechanism for the protective effect of Rut on EBI. In summary, Rut may have the potential to prevent and treat SAH-induced brain injury by interacting with SIRT6. Our findings may provide a new therapeutic strategy for the treatment of SAH-induced EBI.

Hypoxic adipose stem cell-derived exosomes carrying high-abundant USP22 facilitate cutaneous wound healing through stabilizing HIF-1α and upregulating lncRNA H19.

Hypoxic preconditioning has been recognized as a promotive factor for accelerating cutaneous wound healing. Our previous study uncovered that exosomal lncRNA H19, derived from adipose-derived stem cells (ADSCs), plays a crucial role in orchestrating cutaneous wound healing. Herein, we aimed to explore whether there is a connection between hypoxia and ADSC-derived exosomes (ADSCs-exos) in cutaneous wound healing. Exosomes extracted from ADSCs under normoxic and hypoxic conditions were identified using transmission electron microscope (TEM) and particle size analysis. The effects of ADSCs-exos on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by CCK-8, EdU, wound healing, and tube formation assays. Expression patterns of H19, HIF-1α, and USP22 were measured. Co-immunoprecipitation, chromatin immunoprecipitation, ubiquitination, and luciferase reporter assays were conducted to confirm the USP22/HIF-1α/H19 axis, which was further validated in a mice model of skin wound. Exosomes extracted from hypoxia-treated ADSCs (termed as H-ADSCs-exos) significantly increased cell proliferation, migration, and angiogenesis in H2O2-exposed HUVECs, and promoted cutaneous wound healing in vivo. Moreover, H-ADSCs and H-ADSCs-exos, which exhibited higher levels of H19, were found to be transcriptionally activated by HIF-1α. Mechanically, H-ADSCs carrying USP22 accounted for deubiquitinating and stabilizing HIF-1α. Additionally, H-ADSCs-exos improved cell proliferation, migration, and angiogenesis in H2O2-triggered HUVECs by activating USP22/HIF-1α axis and promoting H19 expression, which may provide a new clue for the clinical treatment of cutaneous wound healing.

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Computed tomography-based radiomics diagnostic approach for differential diagnosis between early- and late-stage pancreatic ductal adenocarcinoma.

BACKGROUND: One of the primary reasons for the dismal survival rates in pancreatic ductal adenocarcinoma (PDAC) is that most patients are usually diagnosed at late stages. There is an urgent unmet clinical need to identify and develop diagnostic methods that could precisely detect PDAC at its earliest stages. AIM: To evaluate the potential value of radiomics analysis in the differentiation of early-stage PDAC from late-stage PDAC. METHODS: A total of 71 patients with pathologically proved PDAC based on surgical resection who underwent contrast-enhanced computed tomography (CT) within 30 d prior to surgery were included in the study. Tumor staging was performed in accordance with the 8th edition of the American Joint Committee on Cancer staging system. Radiomics features were extracted from the region of interest (ROI) for each patient using Analysis Kit software. The most important and predictive radiomics features were selected using Mann-Whitney U test, univariate logistic regression analysis, and minimum redundancy maximum relevance (MRMR) method. Random forest (RF) method was used to construct the radiomics model, and 10-times leave group out cross-validation (LGOCV) method was used to validate the robustness and reproducibility of the model. RESULTS: A total of 792 radiomics features (396 from late arterial phase and 396 from portal venous phase) were extracted from the ROI for each patient using Analysis Kit software. Nine most important and predictive features were selected using Mann-Whitney U test, univariate logistic regression analysis, and MRMR method. RF method was used to construct the radiomics model with the nine most predictive radiomics features, which showed a high discriminative ability with 97.7% accuracy, 97.6% sensitivity, 97.8% specificity, 98.4% positive predictive value, and 96.8% negative predictive value. The radiomics model was proved to be robust and reproducible using 10-times LGOCV method with an average area under the curve of 0.75 by the average performance of the 10 newly built models. CONCLUSION: The radiomics model based on CT could serve as a promising non-invasive method in differential diagnosis between early and late stage PDAC.

Differentiating the human heart: A focus on atrioventricular canal cardiomyocytes.

Bioengineering of a functional human heart continues to face many challenges, including the production of distinct cardiac cell types. Now, in Cell Stem Cell, Ye et al.1 develop AVC-like cardiomyocytes through timing- and concentration-specific activation of canonical Wnt signaling.

Stauntonia chinensis injection relieves neuropathic pain by increasing the expression of PSD-95 and reducing the proliferation of phagocytic microglia.

Neuroinflammation induced by engulfment of synapses by phagocytic microglia plays a crucial role in neuropathic pain. Stauntonia chinensis is extracted from Stauntonia chinensis DC, which has been used as a traditional Chinese medicine to control trigeminal neuralgia or sciatica. However, the specific anti-neuralgia mechanism of Stauntonia chinensis is unknown. In this study, the analgesic effect of Stauntonia chinensis injection (SCI) in mice with neuropathic pain and the possible mechanisms are explored. We find that a local injection of 0.1 mL Stauntonia chinensis for 14 days can considerably relieve mechanical hyperalgesia and thermal hyperalgesia in mice with sciatic chronic constriction injury (CCI). Immunofluorescence staining shows that SCI reduces neuroinflammation in the spinal cord of CCI mice. RNA sequencing reveals that the expression of postsynaptic density protein 95 (PSD-95), a postsynaptic scaffold protein, is downregulated in the spinal cord of CCI mice, but upregulated after SCI administration. Immunofluorescence experiments also demonstrate that SCI administration reverses microglia proliferation and PSD-95 downregulation in CCI mice. These data suggest that SCI relieves neuropathic pain by increasing the expression of PSD-95 and reducing the proliferation of phagocytic microglia.

Development and Evaluation of Messages for Reducing Overscreening of Breast Cancer in Older Women.

BACKGROUND: Many older women are screened for breast cancer beyond guideline-recommended thresholds. One contributor is pro-screening messaging from health care professionals, media, and family/friends. In this project, we developed and evaluated messages for reducing overscreening in older women. METHODS: We surveyed women ages 65+ who were members of a nationally representative online panel. We constructed 8 messages describing reasons to consider stopping mammograms, including guideline recommendations, false positives, overdiagnosis, and diminishing benefits from screening due to competing risks. Messages varied in their format; some presented statistical evidence, and some described short anecdotes. Each participant was randomized to read 4 of 8 messages. We also randomized participants to one of 3 message sources (clinician, family member, and news story). We assessed whether the message would make participants "want to find out more information" and "think carefully" about mammograms. RESULTS: Participants (N=790) had a mean age of 73.5 years; 25.8% were non-White. Across all messages, 73.0% of the time, participants agreed that the messages would make them seek more information (range among different messages=64.2%-78.2%); 46.5% of the time participants agreed that the messages would make them think carefully about getting mammograms (range =36.7%-50.7%). Top-rated messages mentioned false-positive anecdotes and overdiagnosis evidence. Ratings were similar for messages from clinicians and news sources, but lower from the family member source. CONCLUSIONS: Overall, participants positively evaluated messages designed to reduce breast cancer overscreening regarding perceived effects on information seeking and deliberation. Combining the top-rated messages into messaging interventions may be a novel approach to reduce overscreening.

An Intelligent Early Warning System for Harmful Algal Blooms: Harnessing the Power of Big Data and Deep Learning.

Harmful algal blooms (HABs) pose a significant ecological threat and economic detriment to freshwater environments. In order to develop an intelligent early warning system for HABs, big data and deep learning models were harnessed in this study. Data collection was achieved utilizing the vertical aquatic monitoring system (VAMS). Subsequently, the analysis and stratification of the vertical aquatic layer were conducted employing the "DeepDPM-Spectral Clustering" method. This approach drastically reduced the number of predictive models and enhanced the adaptability of the system. The Bloomformer-2 model was developed to conduct both single-step and multistep predictions of Chl-a, integrating the " Alert Level Framework" issued by the World Health Organization to accomplish early warning for HABs. The case study conducted in Taihu Lake revealed that during the winter of 2018, the water column could be partitioned into four clusters (Groups W1-W4), while in the summer of 2019, the water column could be partitioned into five clusters (Groups S1-S5). Moreover, in a subsequent predictive task, Bloomformer-2 exhibited superiority in performance across all clusters for both the winter of 2018 and the summer of 2019 (MAE: 0.175-0.394, MSE: 0.042-0.305, and MAPE: 0.228-2.279 for single-step prediction; MAE: 0.184-0.505, MSE: 0.101-0.378, and MAPE: 0.243-4.011 for multistep prediction). The prediction for the 3 days indicated that Group W1 was in a Level I alert state at all times. Conversely, Group S1 was mainly under an Level I alert, with seven specific time points escalating to a Level II alert. Furthermore, the end-to-end architecture of this system, coupled with the automation of its various processes, minimized human intervention, endowing it with intelligent characteristics. This research highlights the transformative potential of integrating big data and artificial intelligence in environmental management and emphasizes the importance of model interpretability in machine learning applications.

Complications and psychological impact of pressure ulcers on patients and caregivers.

Pressure ulcers are persistent skin lesions that have substantial detrimental effects on the physical well-being of patients. Moreover, their psychological ramifications for both patients and their caregivers are becoming more widely acknowledged. This research was conducted to examine the psychological ramifications of pressure ulcers and ascertain efficacious approaches to mitigate these effects and improve overall well-being. A cross-sectional study was conducted from March 2022 to December 2023 across tertiary care centres located in Beijing. The cohort consisted of 431 participants, which included primary caregivers and patients who were diagnosed with pressure ulcers. The data were gathered through the utilization of structured questionnaires and semi-structured interviews. These methods encompassed demographic details, clinical characteristics and validated scales that assessed psychological parameters, including quality of life, anxiety, stress and depression. The research exposed substantial psychological toll on both individuals receiving care and those providing care, with caregivers enduring diminished quality of life and elevated levels of anxiety, depression and stress (p < 0.05). A significant positive correlation was identified between the degree of psychological distress and severity of pressure ulcers (p < 0.05). Both location of the ulcer and duration of care were substantial contributors to the psychological burden (p < 0.05). In spite of the apparent necessity, a significant proportion of the participants refrained from obtaining psychological counselling. The results underscored the significant psychological ramifications of pressure ulcers for both individuals receiving care and the caregivers. As a result, comprehensive care strategies that incorporate psychological assistance into the prescribed treatment plan are imperative. This research highlighted the criticality of implementing all-encompassing, interdisciplinary approaches to tackle the complex issues presented by pressure ulcers in an effort to enhance the general welfare of those influences.

Pharmacist-led telehealth deprescribing for people living with dementia and polypharmacy in primary care: A pilot study.

BACKGROUND: People living with dementia (PLWD) have complex medication regimens, exposing them to increased risk of harm. Pragmatic deprescribing strategies that align with patient-care partner goals are needed. METHODS: A pilot study of a pharmacist-led intervention to optimize medications with patient-care partner priorities, ran May 2021-2022 at two health systems. PLWD with ≥7 medications in primary care and a care partner were enrolled. After an introductory mailing, dyads were randomized to a pharmacist telehealth intervention immediately (intervention) or delayed by 3 months (control). Feasibility outcomes were enrollment, intervention completion, pharmacist time, and primary care provider (PCP) acceptance of recommendations. To refine pragmatic data collection protocols, we assessed the Medication Regimen Complexity Index (MRCI; primary efficacy outcome) and the Family Caregiver Medication Administration Hassles Scale (FCMAHS). RESULTS: 69 dyads enrolled; 27 of 34 (79%) randomized to intervention and 28 of 35 (80%) randomized to control completed the intervention. Most visits (93%) took more than 20 min and required multiple follow-up interactions (62%). PCPs responded to 82% of the pharmacists' first messages and agreed with 98% of recommendations. At 3 months, 22 (81%) patients in the intervention and 14 (50%) in the control had ≥1 medication discontinued; 21 (78%) and 12 (43%), respectively, had ≥1 new medication added. The mean number of medications decreased by 0.6 (3.4) in the intervention and 0.2 (1.7) in the control, reflecting a non-clinically meaningful 1.0 (±12.4) point reduction in the MRCI among intervention patients and a 1.2 (±12.9) point increase among control. FCMAHS scores decreased by 3.3 (±18.8) points in the intervention and 2.5 (±14.4) points in the control. CONCLUSION: Though complex, pharmacist-led telehealth deprescribing is feasible and may reduce medication burden in PLWD. To align with patient-care partner goals, pharmacists recommended deprescribing and prescribing. If scalable, such interventions may optimize goal-concordant care for PLWD.

Transcriptome Analysis of Compensatory Growth and Meat Quality Alteration after Varied Restricted Feeding Conditions in Beef Cattle.

Compensatory growth (CG) is a physiological response that accelerates growth following a period of nutrient limitation, with the potential to improve growth efficiency and meat quality in cattle. However, the underlying molecular mechanisms remain poorly understood. In this study, 60 Huaxi cattle were divided into one ad libitum feeding (ALF) group and two restricted feeding groups (75% restricted, RF75; 50% restricted, RF50) undergoing a short-term restriction period followed by evaluation of CG. Detailed comparisons of growth performance during the experimental period, as well as carcass and meat quality traits, were conducted, complemented by a comprehensive transcriptome analysis of the longissimus dorsi muscle using differential expression analysis, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and weighted correlation network analysis (WGCNA). The results showed that irrespective of the restriction degree, the restricted animals exhibited CG, achieving final body weights comparable to the ALF group. Compensating animals showed differences in meat quality traits, such as pH, cooking loss, and fat content, compared to the ALF group. Transcriptomic analysis revealed 57 genes and 31 pathways differentially regulated during CG, covering immune response, acid-lipid metabolism, and protein synthesis. Notably, complement-coagulation-fibrinolytic system synergy was identified as potentially responsible for meat quality optimization in RF75. This study provides novel and valuable genetic insights into the regulatory mechanisms of CG in beef cattle.

POU2F2-mediated upregulation of lncRNA PTPRG-AS1 inhibits ferroptosis in breast cancer via miR-376c-3p/SLC7A11 axis.

Background: Triple-negative breast cancer (TNBC) is a subtype of BC with high rates of mortality. The mechanism of PTPRG-AS1 in ferroptosis of TNBC was investigated. Methods: Chromatin immunoprecipitation and dual-luciferase reporter assays were used to measure intermolecular relationships. MTT and colony formation assays detected cell viability and proliferation. Kits detected Fe2+ and reactive oxygen species levels. The role of PTPRG-AS1 in tumor growth was analyzed in vivo. Results: PTPRG-AS1 was increased in TNBC tissues and cells. PTPRG-AS1 silencing increased the reduction of glutathione and GPX4, increased Fe2+ and reactive oxygen species in erastin-treated cells and inhibited proliferation. POU2F2 transcriptionally upregulated PTPRG-AS1. PTPRG-AS1 targeted miR-376c-3p to upregulate SLC7A11. PTPRG-AS1 knockdown suppressed tumor growth in vivo. Conclusion: POU2F2 transcriptionally activates PTPRG-AS1 to modulate ferroptosis and proliferation by miR-376c-3p/SLC7A11, promoting TNBC.

Triple-negative breast cancer (TNBC) is a kind of breast cancer with high recurrence and low survival rates. Activation of the ferroptosis pathway can inhibit BC proliferation and distant metastasis. Therefore, identifying effective biomarkers and molecular mechanisms of ferroptosis in TNBC is important for its earlier detection and therapy. PTPRG-AS1 is a new type of lncRNA discovered in recent years that is increased in various diseases and is related to prognosis. In the present study, the authors found that POU2F2 promoted PTPRG-AS1 transcription. PTPRG-AS1 knockdown activated ferroptosis in TNBC and inhibited proliferation. Mechanistically, PTPRG-AS1 targeted miR-376c-3p to upregulate SLC7A11, thereby inhibiting ferroptosis and promoting TNBC development. These results indicate that PTPRG-AS1 is a possible therapeutic target in TNBC.

Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer.

The clinical implications of extrachromosomal DNA (ecDNA) in cancer therapy remain largely elusive. Here, we present a comprehensive analysis of ecDNA amplification spectra and their association with clinical and molecular features in multiple cohorts comprising over 13,000 pan-cancer patients. Using our developed computational framework, GCAP, and validating it with multifaceted approaches, we reveal a consistent pan-cancer pattern of mutual exclusivity between ecDNA amplification and microsatellite instability (MSI). In addition, we establish the role of ecDNA amplification as a risk factor and refine genomic subtypes in a cohort from 1015 colorectal cancer patients. Importantly, our investigation incorporates data from four clinical trials focused on anti-PD-1 immunotherapy, demonstrating the pivotal role of ecDNA amplification as a biomarker for guiding checkpoint blockade immunotherapy in gastrointestinal cancer. This finding represents clinical evidence linking ecDNA amplification to the effectiveness of immunotherapeutic interventions. Overall, our study provides a proof-of-concept of identifying ecDNA amplification from cancer whole-exome sequencing (WES) data, highlighting the potential of ecDNA amplification as a valuable biomarker for facilitating personalized cancer treatment.

Progesterone receptor potentiates macropinocytosis through CDC42 in pancreatic ductal adenocarcinoma.

Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a promising therapeutic avenue in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment. To meet their ascendant energy demands, cancer cells can internalize extracellular proteins via macropinocytosis. However, the roles of endocrine receptors in macropinocytosis are not clear. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, is highly expressed in PDAC tissues obtained from both patients and transgenic LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in a marked attenuation of macropinocytosis in PDAC cells and subcutaneous tumor models, indicating the involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR upregulated CDC42, a critical regulator in macropinocytosis, through PGR-mediated transcriptional activation. These data deepen the understanding of how the endocrine system influences tumor progression via a non-classical pathway and provide a novel therapeutic option for patients with PDAC.