Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling.

Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of ß-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.

Integrated analysis of single-cell and bulk transcriptomics develops a robust neuroendocrine cell-intrinsic signature to predict prostate cancer progression.

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Methods: Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Results: Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. Conclusion: The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.

Does decreased autophagy and dysregulation of LC3A in astrocytes play a role in major depressive disorder?

Astrocytic dysfunction contributes to the molecular pathogenesis of major depressive disorder (MDD). However, the astrocytic subtype that mainly contributes to MDD etiology and whether dysregulated autophagy in astrocytes is associated with MDD remain unknown. Using a single-nucleus RNA sequencing (snRNA-seq) atlas, three astrocyte subtypes were identified in MDD, while C2 State-1Q astrocytes showed aberrant changes in both cell proportion and most differentially expressed genes compared with other subtypes. Moreover, autophagy pathways were commonly inhibited in astrocytes in the prefrontal cortices (PFCs) of patients with MDD, especially in C2 State-1Q astrocytes. Furthermore, by integrating snRNA-seq and bulk transcriptomic data, we found significant reductions in LC3A expression levels in the PFC region of CUMS-induced depressed mice, as well as in postmortem PFC tissues and peripheral blood samples from patients with MDD. These results were further validated by qPCR using whole-blood samples from patients with MDD and healthy controls. Finally, LC3A expression in the whole blood of patients with MDD was negatively associated with the severity of depressive symptoms. Overall, our results underscore autophagy inhibition in PFC astrocytes as a common molecular characteristic in MDD and might reveal a novel potential diagnostic marker LC3A.

Microdissection of cancer-associated fibroblast infiltration subtypes unveils the secreted SERPINE2 contributing to immunosuppressive microenvironment and immuotherapeutic resistance in gastric cancer: A large-scale study integrating bulk and single-cell transcriptome profiling.

In the era of immunotherapy, the suboptimal response rate and the development of acquired resistance among the initial beneficiaries continue to present significant challenges across multiple malignancies, including gastric cancer (GC). Considering that the interactions of tumor stroma, especially the cancer-associated fibroblasts (CAFs), with immune and tumor cells, play indispensable roles in tumor progression, tumor microenvironment remodeling and therapeutic responsiveness, in-depth exploration on the roles of CAFs and pivotal mediators of their functions may provide novel clues to increase the effectiveness of current immunotherapeutic drugs and further achieve synergistic antitumor response. Herein, through the consensus clustering of canonical biomarkers, three GC subclasses with different abundance of CAFs were virtually microdissected in four integrated bulk cohorts encompassing 2148 GC patients from 11 independent datasets. An extensive immunogenomic analysis revealed that tumors with high CAFs infiltration were characterized with unfavorable outcomes, aggressive phenotypes, decreased tumor immunogenicity, high risk of immune evasion and thus immunotherapeutic resistance. By leveraging large-scale single-cell transcriptomic profiling, a series of CAF-secreted proteins were identified, among which the SERPINE2 was confirmed to be restrictively enriched in stromal fibroblasts of GC tissues and contribute to promoting a protumor milieu and fostering an immunosuppressive microenvironment via bioinformatics computations and tissue microarray analysis. Moreover, pan-cancer investigations generalized the immunological roles of SERPINE2, especially in pan-gastrointestinal malignancies, with multiple real-world immunotherapy cohorts further confirming its implications on predicting immunotherapeutic efficacy. In conclusion, these findings suggest that the CAF-derived SERPINE2 is a promising immune-oncology target with therapeutic implications to further synergize the immunotherapeutic combinations.

Integrated multiomics analyses unveil the implication of a costimulatory molecule score on tumor aggressiveness and immune evasion in breast cancer: A large-scale study through over 8,000 patients.

BACKGROUND: Although immunotherapy has revolutionised cancer management, reliable genomic biomarkers for identifying eligible patient subpopulations are lacking. Costimulatory molecules play a crucial role in mounting anti-tumour responses, and clinical trials targeting these novel biomarkers are underway. However, whether these molecules can determine tumour aggressiveness and the risk of tumour evasion in breast cancer (BC) remains largely unknown. METHODS: The whole-tissue transcriptomic data of 8236 patients with BC from 15 independent cohorts were extracted. An integrated scoring system named 'costimulatory molecule score' (CMS) was constructed and sufficient validated using least absolute shrinkage and selection operator regression (1000 iterations) and the random survival forest algorithm (1000 trees). The correlation among CMSs, cancer genotypes and clinicopathological characteristics was examined. Extensive multiomics and immunogenomic analyses were performed to investigate and verify the association among CMSs, enriched pathways, potential intrinsic and extrinsic immune escape mechanisms, immunotherapy response and therapeutic options. RESULTS: The predictive role of CMS model that relies on expression pattern of merely 5 costimulatory genes for prognosis is almost universally applicable to BC patients in a platform-independent manner. Through internal and external in silico validation, high CMS was characterized by favorable genotypes but decreased tumor immunogenicity, activation of stroma, immune-suppressive states and potential immunotherapeutic resistance. Similar results were observed in a real-world immunotherapy cohort and Pan-Cancer analysis. CONCLUSION: This comprehensive characterization indicates CMS model may be complemented for predicting tumor aggressiveness and immune evasion in BC patients, underlining the future clinical potential for further exploration of resistance mechanisms and optimization of immunotherapeutic strategies.

The functional implication of ATF6α in castration-resistant prostate cancer cells.

Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration-resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin-A7 treatment. In addition, combined analyses of human CRPC bulk RNA-seq and single-cell RNA-seq (scRNA-seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14-gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.

Inhibiting the IRE1α Axis of the Unfolded Protein Response Enhances the Antitumor Effect of AZD1775 in TP53 Mutant Ovarian Cancer.

Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA-like ER kinase (PERK) and inositol-required enzyme 1α (IRE1α) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF-κB mediated senescence-associated secretory phenotype. Upon AZD1775 treatment, activated PERK promotes apoptotic signaling via C/EBP-homologous protein (CHOP), while IRE1α-induced splicing of XBP1 (XBP1s) maintains cell survival by repressing apoptosis. This leads to an encouraging synergistic antitumor effect of combining AZD1775 and an IRE1α inhibitor MKC8866 in multiple cell lines and preclinical models of ovarian cancers. Taken together, the data reveal an important dual role of the UPR signaling network in mtTP53 ovarian cancer models in response to AZD1775 and suggest that inhibition of the IRE1α-XBP1s pathway may enhance the efficacy of AZD1775 in the clinics.

Effect of evolocumab on the progression of intraplaque neovascularization of the carotid based on contrast-enhanced ultrasonography (EPIC study): A prospective single-arm, open-label study.

Background and Purpose: The aim of this study was to explore the effect of half a year of evolocumab plus moderate-intensity statin treatment on carotid intraplaque neovascularization (IPN) and blood lipid levels. Methods: A total of 31 patients with 33 carotid plaques who received evolocumab plus statin treatment were included. Blood lipid levels, B-mode ultrasound and contrast-enhanced ultrasonography (CEUS) at baseline and after half a year of evolocumab plus statin therapy were collected. The area under the curve (AUC) reflected the total amount of acoustic developer entering the plaque or lumen within the 180 s measurement period. The enhanced intensity reflected the peak blood flow intensity during the monitoring period, and the contrast agent area reflected the area of vessels in the plaques. Results: Except for high-density lipoprotein cholesterol (HDL-c), all other lipid indices decreased. Compared with baseline, low-density lipoprotein cholesterol (LDL-c) decreased by approximately 57% (p < 0.001); total cholesterol (TC) decreased by approximately 34% (p < 0.001); small dense low-density lipoprotein (sd-LDL) decreased by approximately 52% (p < 0.001); and HDL-c increased by approximately 20% (p < 0.001). B-mode ultrasonography showed that the length and thickness of the plaque and the hypoechoic area ratio were reduced (p < 0.05). The plaque area, calcified area ratio, and lumen cross-sectional area changed little (p > 0.05). CEUS revealed that the area under the curve of plaque/lumen [AUC (P/L)] decreased from 0.27 ± 0.13 to 0.19 ± 0.11 (p < 0.001). The enhanced intensity ratio of plaque/lumen [intensity ratio (P/L)] decreased from 0.37 ± 0.16 to 0.31 ± 0.14 (p = 0.009). The contrast agent area in plaque/area of plaque decreased from 19.20 ± 13.23 to 12.66 ± 9.59 (p = 0.003). The neovascularization score decreased from 2.64 ± 0.54 to 2.06 ± 0.86 (p < 0.001). Subgroup analysis based on statin duration (<6 months and ≥6 months) showed that there was no significant difference in the AUC (P/L) or intensity ratio (P/L) at baseline or after half a year of evolocumab treatment. Conclusion: This study found that evolocumab combined with moderate-intensity statins significantly improved the blood lipid profile and reduced carotid IPN. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier: NCT04423406.

Hypertension May Reduce the Infection Risk but Increase the Severity of COVID-19: Based on the Current Data in China.

Increasing evidence has shown an unusual relationship between hypertension and COVID-19, which may not be as simple as previously thought. The purpose of our study was to determine the association of hypertension with the onset and development of COVID-19. A meta-analysis was performed to summarize the prevalence of hypertension in COVID-19 patients, as well as the usage of ACEIs/ARBs. Metaregression analyses were used to evaluate the association of hypertension with disease severity and mortality. PubMed and Google Scholar were searched for relevant studies. A total of 42 studies including 14138 patients were enrolled in the study. The proportion of hypertension in COVID-19 patients in China was 17.7% according to the enrolled studies, while it was 6.0% in a study containing 72314 confirmed cases, which are both much lower than in the general population. All of the data from the 11 provinces in China showed the same tendency. The proportions of hypertension were higher in severe/ICU patients and nonsurvivors than in nonsevere/ICU patients and survivors. The metaregression analyses suggested that both disease severity and risk of death were associated with the incidence of hypertension. A total of 27.6% of COVID-19 patients with hypertension received ACEI/ARB therapy. The proportion of deaths in COVID-19 patients with hypertension treated with ACEIs/ARBs was significantly lower than that in nonuse patients treated with ACEIs/ARBs. In conclusion, hypertension may reduce the infection risk of COVID-19 but increase the risk of developing worse clinical outcomes. The use of ACEIs/ARBs may benefit COVID-19 patients with hypertension.

Characterization of Molecular Subtypes in Head and Neck Squamous Cell Carcinoma With Distinct Prognosis and Treatment Responsiveness.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies with complex phenotypic, etiological, biological, and clinical heterogeneities. Previous studies have proposed different clinically relevant subtypes of HNSCC, but little is known about its corresponding prognosis or suitable treatment strategy. Here, we identified 101 core genes from three prognostic pathways, including mTORC1 signaling, unfold protein response, and UV response UP, in 124 pairs of tumor and matched normal tissues of HNSCC. Moreover, we identified three robust subtypes associated with distinct molecular characteristics and clinical outcomes using consensus clustering based on the gene expression profiles of 944 HNSCC patients from four independent datasets. We then integrated the genomic information of The Cancer Genome Atlas (TCGA) HNSCC cohort to comprehensively evaluate the molecular features of different subtypes and screen for potentially effective therapeutic agents. Cluster 1 had more arrested oncogenic signaling, the highest immune cell infiltration, the highest immunotherapy and chemotherapeutic responsiveness, and the best prognosis. By contrast, Cluster 3 showed more activated oncogenic signaling, the lowest immune cell infiltration, the lowest immunotherapy and chemotherapy responsiveness, and the worst prognosis. Our findings corroborate the molecular diversity of HNSCC tumors and provide a novel classification strategy that may guide for prognosis and treatment allocation.

Maternal Benzophenone Exposure Impairs Hippocampus Development and Cognitive Function in Mouse Offspring.

Benzophenones are widely supplemented in personal care products, but little is known about its neurodevelopmental toxicity. The previous epidemiological study discovered a negative correlation between maternal exposure to a benzophenone metabolite 4-hydroxybenzophenone (4HBP) and child's neurodevelopment, yet the causal relationship and detailed mechanism remain to be defined. Here, it is reported that prenatal, but not postnatal, exposure to environmentally relevant level of 4HBP impairs hippocampus development and causes cognitive dysfunction in offspring mice. Transcriptomic analyses reveal that 4HBP induces the endoplasmic reticulum stress-induced apoptotic signaling and inflammatory response in hippocampal neural stem cells. Mechanistically, 4HBP exposure activates protein kinase R-like ER kinase (PERK) signaling, which induces CHOP, inhibits IκB translation, and transactivates p65, thereby promoting inflammation and apoptosis on multiple levels. Importantly, genetic or pharmacological inhibition of PERK pathway significantly attenuates 4HBP-induced NFκB signaling and neurodevelopmental abnormalities in mice and in a human brain organoid model. The study uncovers the neurodevelopmental toxicity of BP and cautions its exposure during pregnancy.

Tak1 in the astrocytes of mediobasal hypothalamus regulates anxiety-like behavior in mice.

Anxiety disorder is characterized by excessive fear, anxiety, and avoidance of perceived threats in internal to oneself or the environment, however, the underlying mechanisms are less well understood. Here, we show that transforming growth factor-ß-activated kinase 1 (Tak1) expressed in the astrocytes of mediobasal hypothalamus (MBH) plays a crucial role in anxiety-like behavior in mice. Our data demonstrate that deficiency of Tak1 in astrocytes increased anxiety level, but did not impact locomotor activity in mice. Astrocytic activation of Tak1 in the MBH mitigated the anxiety-like behavior, whereas suppression of Tak1 in MBH astrocytes promoted the anxiety-like behavior in mice. Collectively, these data suggest that Tak1 expressed in the MBH astrocytes could modulate the anxiety-like behavior in mice.

Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders.

The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.

Reversal of prolonged obesity-associated cerebrovascular dysfunction by inhibiting microglial Tak1.

Prolonged obesity is associated with cerebrovascular dysfunction; however, the underlying mechanisms remain largely unclear. In the present study, using a prolonged obesity mouse model that suffers from basilar artery (BA) abnormalities, we find that microglial transforming growth factor ß-activated kinase 1 (Tak1) is over-activated in the brainstem. Both pharmacological inhibition primarily in the brainstem and genetic microglia-selective deletion of Tak1 ameliorated BA vascular dysfunction. Conversely, microglia-specific activation of Tak1 in the brainstem was sufficient to cause an impairment in BA function in chow-fed mice. Mechanistically, Tak1 activation leads to increased interleukin-18 (IL-18) production, whereas blockade of IL-18 receptor in the brain helped protect against cerebrovascular dysfunction despite prolonged obesity. Microglia-selective deletion of Tak1 also protects against ischemic stroke in prolonged obesity. Taken together, these findings provide evidence that microglial Tak1 in the brain, and particularly the brainstem, contributes to the pathogenesis of obesity-associated cerebrovascular dysfunction.

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.

BACKGROUND: Studies have reminded that cardiovascular metabolic comorbidities made patients more susceptible to suffer 2019 novel corona virus (2019-nCoV) disease (COVID-19), and exacerbated the infection. The aim of this analysis is to determine the association of cardiovascular metabolic diseases with the development of COVID-19. METHODS: A meta-analysis of eligible studies that summarized the prevalence of cardiovascular metabolic diseases in COVID-19 and compared the incidences of the comorbidities in ICU/severe and non-ICU/severe patients was performed. Embase and PubMed were searched for relevant studies. RESULTS: A total of six studies with 1527 patients were included in this analysis. The proportions of hypertension, cardia-cerebrovascular disease and diabetes in patients with COVID-19 were 17.1%, 16.4% and 9.7%, respectively. The incidences of hypertension, cardia-cerebrovascular diseases and diabetes were about twofolds, threefolds and twofolds, respectively, higher in ICU/severe cases than in their non-ICU/severe counterparts. At least 8.0% patients with COVID-19 suffered the acute cardiac injury. The incidence of acute cardiac injury was about 13 folds higher in ICU/severe patients compared with the non-ICU/severe patients. CONCLUSION: Patients with previous cardiovascular metabolic diseases may face a greater risk of developing into the severe condition and the comorbidities can also greatly affect the prognosis of the COVID-19. On the other hand, COVID-19 can, in turn, aggravate the damage to the heart.

Auditory Impairment in Young Type 1 Diabetics.

BACKGROUND AND AIMS: More attention has recently been focused on auditory impairment of young type 1 diabetics. This study aimed to evaluate auditory function of young type 1 diabetics and the correlation between clinical indexes and hearing impairment. METHODS: We evaluated the auditory function of 50 type 1 diabetics and 50 healthy subjects. Clinical indexes were measured along with analyzing their relation of auditory function. RESULTS: Type 1 diabetic patients demonstrated a deficit with elevated thresholds at right ear and left ear when compared to healthy controls (p <0.01). The elevated auditory threshold was significantly related with HDL-cholesterol, diabetes duration, and systemic blood pressure (p <0.05). Moreover, latencies of right ear (wave III, V and interwave I-V) and left ear (wave III, V and interwave I-III, I-V) in diabetic group significantly increased compared to those in control subjects (p <0.01). Auditory brainstem response was significantly related with GHbA1C and microalbuminuria (p <0.01). Furthermore, distortion product evoked otoacoustic emissions (DPOAE) of diabetes group were statistically significant in right ears at 4.0, 6.0 kHz and in left ears at 4.0, 6.0, 8.0 kHz (p <0.01) compared with those of controls. Diabetic patients demonstrated lower amplitude responses of the right ear than the left ear at 8.0 kHz. Only triglyceride was positively correlated to the hearing impairment defined by DPOAE (p <0.01). There was no significance of transient evoked otoacoustic emissions (TEOAE) between groups. TEOAE was associated with age and GHbA1C (p <0.01). CONCLUSIONS: Type 1 diabetics exerted higher auditory threshold, slower auditory conduction time and cochlear impairment. HDL-cholesterol, diabetes duration, systemic blood pressure, microalbuminuria, GHbA1C, triglyceride, and age may affect the auditory function of type 1 diabetics.