Acceptor Copolymerized Axially Chiral Conjugated Polymers with TADF Properties for Efficient Circularly Polarized Electroluminescence.

Chiral conjugated polymer has promoted the development of the efficient circularly polarized electroluminescence (CPEL) device, nevertheless, it remains a challenge to develop chiral polymers with high electroluminescence performance. Herein, by the acceptor copolymerization of axially chiral biphenyl emitting skeleton and benzophenone, a pair of axially chiral conjugated polymers namely R-PAC and S-PAC are synthesized. The target polymers exhibit obvious thermally activated delayed fluorescence (TADF) activities with high photoluminescence quantum yields of 81%. Moreover, the chiral polymers display significant circularly polarized luminescence features, with luminescence dissymmetry factor (|glum|) of nearly 3 × 10-3. By using the chiral polymers as emitters, the corresponding circularly polarized organic light-emitting diodes (CP-OLEDs) exhibit efficient CPEL signals with electroluminescence dissymmetry factor |gEL| of 3.4 × 10-3 and high maximum external quantum efficiency (EQEmax) of 17.8%. Notably, considering both EQEmax and |gEL| comprehensively, the device performance of R-PAC and S-PAC is the best among all the reported CP-OLEDs with chiral conjugated polymers as emitters. This work provides a facile approach to constructing chiral conjugated TADF polymers and discloses the potential of axially chiral conjugated luminescent skeletons in architecting high-performance CP-OLEDs.

Dietary E. coli promotes age-dependent chemotaxis decline in C. elegans.

An animal's ability to sense odors declines during aging, and its olfactory drive is tuned by internal states such as satiety. However, whether internal states modulate an age-dependent decline in odor sensation is unknown. To address this issue, we utilized the nematode Caenorhabditis elegans and compared their chemotaxis abilities toward attractive odorants when aged under different dietary conditions. Feeding with the standard laboratory diet, Escherichia coli attenuated the chemotaxis ability toward diacetyl, isoamyl alcohol, and benzaldehyde when aged. On the other hand, feeding with either the lactic acid bacteria Lactobacillus reuteri or food deprivation selectively maintained the chemotaxis ability toward diacetyl. Our results suggest that ingestion of E. coli causes age-dependent chemotaxis decline. The changes in the chemotaxis behavior are attributed to the different expressions of diacetyl receptor odr-10, and the chemotaxis behavior of aged animals under food deprivation is shown to be dependent on daf-16. Our study demonstrates the molecular mechanism of how diet shapes the trajectory of age-dependent decline in chemosensory behaviors.

A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer-associated death worldwide. The mitochondrial unfolded protein response (UPRmt) not only maintains mitochondrial integrity but also regulates cancer progression and drug resistance. However, no study has used the UPRmt to construct a prognostic signature for HCC. This work aimed to establish a novel signature for predicting patient prognosis, immune cell infiltration, immunotherapy, and chemotherapy response based on UPRmt-related genes (MRGs). Transcriptional profiles and clinical information were obtained from the TCGA and ICGC databases. Cox regression and LASSO regression analyses were applied to select prognostic genes and develop a risk model. The TIMER algorithm was used to investigate immunocytic infiltration in the high- and low-risk subgroups. Here, two distinct clusters were identified with different prognoses, immune cell infiltration statuses, drug sensitivities, and response to immunotherapy. A risk score consisting of seven MRGs (HSPD1, LONP1, SSBP1, MRPS5, YME1L1, HDAC1 and HDAC2) was developed to accurately and independently predict the prognosis of HCC patients. Additionally, the expression of core MRGs was confirmed by immunohistochemistry (IHC) staining, single-cell RNA sequencing, and spatial transcriptome analyses. Notably, the expression of prognostic MRGs was significantly correlated with sorafenib sensitivity in HCC and markedly downregulated in sorafenib-treated HepG2 and Huh7 cells. Furthermore, the knockdown of LONP1 decreased the proliferation, invasion, and migration of HepG2 cells, suggesting that upregulated LONP1 expression contributed to the malignant behaviors of HCC cells. To our knowledge, this is the first study to investigate the consensus clustering algorithm, prognostic potential, immune microenvironment infiltration and drug sensitivity based on the expression of MRGs in HCC. In summary, the UPRmt-related classification and prognostic signature could assist in determining the prognosis and personalized therapy of HCC patients from the perspectives of predictive, preventative and personalized medicine.

B,N-Embedded Hetero[9]helicene Toward Highly Efficient Circularly Polarized Electroluminescence.

The intrinsic helical π-conjugated skeleton makes helicenes highly promising for circularly polarized electroluminescence (CPEL). Generally, carbon helicenes undergo low external quantum efficiency (EQE), while the incorporation of a multi-resonance thermally activated delayed fluorescence (MR-TADF) BN structure has led to an improvement. However, the reported B,N-embedded helicenes all show low electroluminescence dissymmetry factors (gEL), typically around 1×10-3. Therefore, the development of B,N-embedded helicenes with both a high EQE and gEL value is crucial for achieving highly efficient CPEL. Herein, a facile approach to synthesize B,N-embedded hetero[9]helicenes, BN[9]H, is presented. BN[9]H shows a bright photoluminescence with a maximum at 578 nm with a high luminescence dissymmetry factor (|glum|) up to 5.8×10-3, attributed to its inherited MR-TADF property and intrinsic helical skeleton. Furthermore, circularly polarized OLED devices incorporating BN[9]H as an emitter show a maximum EQE of 35.5 %, a small full width at half-maximum of 48 nm, and, more importantly, a high |gEL| value of 6.2×10-3. The Q-factor (|EQE×gEL|) of CP-OLEDs is determined to be 2.2×10-3, which is the highest among helicene analogues. This work provides a new approach for the synthesis of higher helicenes and paves a new way for the construction of highly efficient CPEL materials.

Transcription factors-related molecular subtypes and risk prognostic model: exploring the immunogenicity landscape and potential drug targets in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, with a high mortality rate and poor prognosis. Mutated or dysregulated transcription factors (TFs) are significantly associated with carcinogenesis. The aim of this study was to develop a TF-related prognostic risk model to predict the prognosis and guide the treatment of HCC patients. METHODS: RNA sequencing data were obtained from the TCGA database. The ICGC and GEO databases were used as validation datasets. The consensus clustering algorithm was used to classify the molecular subtypes of TFs. Kaplan‒Meier survival analysis and receiver operating characteristic (ROC) analysis were applied to evaluate the prognostic value of the model. The immunogenic landscape differences of molecular subtypes were evaluated by the TIMER and xCell algorithms. Autodock analysis was used to predict possible binding sites of trametinib to TFs. RT‒PCR was used to verify the effect of trametinib on the expression of core TFs. RESULTS: According to the differential expression of TFs, HCC samples were divided into two clusters (C1 and C2). The survival time, signaling pathways, abundance of immune cell infiltration and responses to chemotherapy and immunotherapy were significantly different between C1 and C2. Nine TFs with potential prognostic value, including HMGB2, ESR1, HMGA1, MYBL2, TCF19, E2F1, FOXM1, CENPA and ZIC2, were identified by Cox regression analysis. HCC patients in the high-risk group had a poor prognosis compared with those in the low-risk group (p < 0.001). Moreover, the area under the ROC curve (AUC) values of the 1-year, 2-year and 3-year survival rates were 0.792, 0.71 and 0.695, respectively. The risk model was validated in the ICGC database. Notably, trametinib sensitivity was highly correlated with the expression of core TFs, and molecular docking predicted the possible binding sites of trametinib with these TFs. More importantly, the expression of core TFs was downregulated under trametinib treatment. CONCLUSIONS: A prognostic signature with 9 TFs performed well in predicting the survival rate and chemotherapy/immunotherapy effect of HCC patients. Trimetinib has potential application value in HCC by targeting TFs.

Intersphincteric resection following robotic-assisted versus laparoscopy-assisted total mesorectal excision for middle and low rectal cancer: a multicentre propensity score analysis of 1571 patients.

BACKGROUND: Robotic-assisted total mesorectal excision (RaTME) may be associated with reduced conversion to an open approach and a higher rate of complete total mesorectal excision (TME); however, studies on its advantages in intersphincteric resection (ISR) are inadequate. MATERIALS AND METHODS: This retrospective multicenter cohort study enroled consecutive patients who underwent RaTME and laparoscopy-assisted total mesorectal excision (LaTME) at four medical centres between January 2020 and March 2023. Propensity score matching (PSM), inverse probability of treatment weight (IPTW), and multivariate logistic regression analyses were performed. The primary outcome was the ISR rate. Secondary outcomes were coloanal anastomosis (CAA), conversion to open surgery, conversion to transanal TME, abdominoperineal resection, postoperative morbidity and mortality within 30 days, and pathological outcomes. RESULTS: Among the 1571 patients, 1211 and 450 underwent LaTME and RaTME, respectively, with corresponding ISR incidences of 5.3% and 8.4% ( P =0.024). After PSM and IPTW, RaTME remained associated with higher ISR rates (4.5% versus 9.4%, P =0.022 after PSM; 4.9% versus 9.2, P =0.005 after IPTW). This association remained in multivariate analysis after adjusting for other confounding factors. RaTME was further associated with a higher CAA rate, longer operating time, and higher hospitalization expenses. CONCLUSIONS: RaTME may facilitate ISR in middle and low rectal cancers, showing an independent association with a higher ISR incidence, with pathological outcomes and complications comparable to those of LaTME. However, it may also require a longer operating time and incur higher hospitalization expenses.

Apoptosis-related prognostic biomarkers and potential targets for acute kidney injury based on machine learning algorithm and in vivo experiments.

Acute kidney injury (AKI) is a common critical illness in hospitalized patients, characterized by a rapid decline in kidney function over a short period, which can seriously endanger the patient's life. Currently, there is a lack of precise and universal AKI diagnostic biomarkers in clinical practice. In this study, weighted gene coexpression network analysis (WGCNA), differential expression analysis, univariate and multivariate logistic regression analyses, receiver operating characteristic (ROC) curves, and immune cell infiltration were performed to identify apoptosis-related biomarkers that can be used for AKI diagnosis. Three core apoptosis-related genes (ARGs), CBFB, EGF and COL1A1, were identified as AKI biomarkers. More importantly, an apoptosis-related signature containing three hub ARGs was validated as a diagnostic model. The hub genes exhibited good correlations with glomerular filtration rate (GFR) and serum creatinine (SCr) in the Nephroseq kidney disease database. Additionally, CIBERSORT immune infiltration analysis indicated that these core ARGs may affect immune cell recruitment and infiltration in AKI patients. Subsequently, we investigated the alteration of the expression levels of three core ARGs in AKI samples using single-cell RNA sequencing analysis and analyzed the cell types that mainly expressed these ARGs. More importantly, the expression of core ARGs was validated in folic acid- and cisplatin-induced AKI mouse models. In summary, our study identified three diagnostic biomarkers for AKI, explored the roles of ARGs in AKI progression and provided new ideas for the clinical diagnosis and treatment of AKI.

Long-term outcomes and cost-effectiveness evaluation of robot-assisted stereotactic hematoma drainage for spontaneous intracerebral hemorrhage.

Background: To investigate the long-term follow-up and economic estimation outcomes of hematoma drainage for spontaneous intracerebral hemorrhage (SICH) with the assistance of neurosurgical navigation and positioning planning system (referred to as robot). Methods: Data were retrospectively obtained from consecutive patients with SICH who were admitted to our single-center between March 2019 and March 2022. Different minimally invasive surgery (MIS) procedures were performed according to the inclusion/exclusion criteria. The different groups were sampled and matched using the propensity score method, with age, sex, history of stroke, hypertension, bleeding volume and site of bleeding as matching variables, and matched with inverse probability weighting using R statistical analysis software. From the time of discharge up until 1 year after the surgery, records were gathered on clinical results and medical expenditures. An analysis was conducted to compare the costs and health outcomes of both robot-assisted stereotactic hematoma drainage and neuro-endoscopic surgery, considering both short-term and long-term effects. Health outputs were measured using modified Rankin scale (mRS) and quality adjusted life years (QALYs). Results: Of the 142 patients, there were 77 patients in the robotic surgery group and 65 patients in the neuro-endoscopic surgery group. Propensity score sampling was matched, resulting in a balanced and comparable group of 37 patients in each, with the robotic surgery group [mean age (57.29 ± 12.74) years, 27 males (72.97%), hematoma volume (44.54 ± 10.49 ml), 22 deep location (59.46%)] and the neuro-endoscopic surgery group [mean age (57.27 ± 11.12) years, 27 males (72.97%), hematoma volume (44.70 ± 10.86 ml), 23 deep location (62.16%)]. At both three-month and one-year postoperative follow-up, the proportion of mRS scores ≤3 was higher in the robotic surgery group (45.95%,70.27%) than in the neuro-endoscopic surgery group (35.14%, 62.16%), but there was no statistically significant difference (P = 0.344, 0.461). One year after surgery, the robotic group demonstrated cost savings of ¥36,862.14 per individual and a gain of 0.062 QALYs compared to the neuro-endoscopic group. Conclusion: Our calculations based on a model for SICH suggest that robotic-assisted stereotactic drainage offers health economic benefits due to its lower cost and higher effectiveness. However, to confirm these findings, more data from multicenter, prospective randomized controlled trials with larger sample sizes are needed.

Real Aperture Radar Super-Resolution Imaging for Sea Surface Monitoring Based on a Hybrid Model.

In recent years, super-resolution imaging techniques have been intensely introduced to enhance the azimuth resolution of real aperture scanning radar (RASR). However, there is a paucity of research on the subject of sea surface imaging with small incident angles for complex scenarios. This research endeavors to explore super-resolution imaging for sea surface monitoring, with a specific emphasis on grounded or shipborne platforms. To tackle the inescapable interference of sea clutter, it was segregated from the imaging objects and was modeled alongside I/Q channel noise within the maximum likelihood framework, thus mitigating clutter's impact. Simultaneously, for characterizing the non-stationary regions of the monitoring scene, we harnessed the Markov random field (MRF) model for its two-dimensional (2D) spatial representational capacity, augmented by a quadratic term to bolster outlier resilience. Subsequently, the maximum a posteriori (MAP) criterion was employed to unite the ML function with the statistical model regarding imaging scene. This hybrid model forms the core of our super-resolution methodology. Finally, a fast iterative threshold shrinkage method was applied to solve this objective function, yielding stable estimates of the monitored scene. Through the validation of simulation and real data experiments, the superiority of the proposed approach in recovering the monitoring scenes and clutter suppression has been verified.

Vitamin E stabilizes iron and mitochondrial metabolism in pulmonary fibrosis.

Introduction: Pulmonary fibrosis (PF) is a fatal chronic lung disease that causes structural damage and decreased lung function and has a poor prognosis. Currently, there is no medicine that can truly cure PF. Vitamin E (VE) is a group of natural antioxidants with anticancer and antimutagenic properties. There have been a few reports about the attenuation of PF by VE in experimental animals, but the molecular mechanisms are not fully understood. Methods: Bleomycin-induced PF (BLM-PF) mouse model, and cultured mouse primary lung fibroblasts and MLE 12 cells were utilized. Pathological examination of lung sections, immunoblotting, immunofluorescent staining, and real-time PCR were conducted in this study. Results: We confirmed that VE significantly delayed the progression of BLM-PF and increased the survival rates of experimental mice with PF. VE suppressed the pathological activation and fibrotic differentiation of lung fibroblasts and epithelial-mesenchymal transition and alleviated the inflammatory response in BLM-induced fibrotic lungs and pulmonary epithelial cells in vitro. Importantly, VE reduced BLM-induced ferritin expression in fibrotic lungs, whereas VE did not exhibit iron chelation properties in fibroblasts or epithelial cells in vitro. Furthermore, VE protected against mitochondrial dysmorphology and normalized mitochondrial protein expression in BLM-PF lungs. Consistently, VE suppressed apoptosis in BLM-PF lungs and pulmonary epithelial cells in vitro. Discussion: Collectively, VE markedly inhibited BLM-induced PF through a complex mechanism, including improving iron metabolism and mitochondrial structure and function, mitigating inflammation, and decreasing the fibrotic functions of fibroblasts and epithelial cells. Therefore, VE presents a highly potential therapeutic against PF due to its multiple protective effects with few side effects.

Detection of Cytoplasmic and Nuclear Circular RNA via RT-qPCR.

Circular RNA (circRNA) is an intriguing class of non-coding RNA that exists as a continuous closed loop. With the improvements in high throughput sequencing, biochemical analysis, and bioinformatic algorithms, studies on circRNA expression became abundant in recent years. However, functional studies of circRNA are still limited. Subcellular localization of circRNA may provide some clues in elucidating its biological functions by performing subcellular fractionation assay. Notably, circRNAs that are predominantly found in the cytoplasm are more likely to be involved in post-transcriptional gene regulation, e.g., acting as micoRNA sponge, whereas nuclear-retained circRNAs are predicted to play a role in transcriptional regulation. Subcellular fractionation could help researchers to narrow down and prioritize downstream experiments. The majority of the currently available protocols describe the steps for subcellular fractionation followed by western blot analysis for protein molecules. Here, we present a protocol for the subcellular fractionation of cells to detect circRNA via RT-qPCR with divergent primers. Moreover, detailed steps for the generation of specific circRNAs-enriched cDNA included in this protocol will enhance the amplification and detection of low-abundance circRNAs. This will be useful for researchers studying low-abundance circRNAs. Key features This protocol builds upon the method developed by Gagnon et al. (2014) and extends its application to circRNA study. Protocol for amplification of low levels of circRNA expression. Analysis takes into consideration the ratio of cytoplasmic RNA concentration to nuclear RNA concentration.

Two-Fold Interpenetrated Binuclear Nickel Metal-Organic Framework as a Heterogeneous Catalyst for N-Heterocycle Synthesis.

A binuclear Ni(II)-based metal-organic framework {[Ni2(btb)1.333(H2O)3.578(py)1.422]·(DMF)(H2O)3.25}n (Nibtb) was solvothermally synthesized (H3btb = 1,3,5-tri(4-carboxylphenyl)benzene, py = pyridine, DMF = N,N-dimethylformamide). Nibtb shows a rare 2-fold interpenetrating (3,4)-connected 3D network with a point symbol of (83)4(86)3 based on binuclear Ni(II) clusters. Nibtb as a heterogeneous catalyst combines the high stability of MOFs and excellent catalytic activity of nickel, which exhibits excellent catalytic activity for the synthesis of benzimidazoles and pyrazoles under mild conditions. Moreover, the catalyst can be easily separated and reused for seven successive cycles and maintains high catalytic activity.

Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases.

Kidney diseases remain one of the leading causes of human death and have placed a heavy burden on the medical system. Regulated cell death contributes to the pathology of a plethora of renal diseases. Recently, with in-depth studies into kidney diseases and cell death, a new iron-dependent cell death modality, known as ferroptosis, has been identified and has attracted considerable attention among researchers in the pathogenesis of kidney diseases and therapeutics to treat them. The majority of studies suggest that ferroptosis plays an important role in the pathologies of multiple kidney diseases, such as acute kidney injury (AKI), chronic kidney disease, and renal cell carcinoma. In this review, we summarize recently identified regulatory molecular mechanisms of ferroptosis, discuss ferroptosis pathways and mechanisms of action in various kidney diseases, and describe the protective effect of ferroptosis inhibitors against kidney diseases, especially AKI. By summarizing the prominent roles of ferroptosis in different kidney diseases and the progress made in studying ferroptosis, we provide new directions and strategies for future research on kidney diseases. In summary, ferroptotic factors are potential targets for therapeutic intervention to alleviate different kidney diseases, and targeting them may lead to new treatments for patients with kidney diseases.

Staurantherafloribunda, a new species of Gesneriaceae from Yunnan, China.

Staurantherafloribunda F.Su, C.Y.Hao & K.Tan, a new species of Gesneriaceae from Yunnan, China, is described and illustrated here. It is morphologically similar to S.grandifolia Benth. in the shape of corolla, stigma, leaves and the number of stamens. However, it can be readily distinguished from the compared species by its dense cymes, leaf indumentum, lack of a corolla spur, calyx colour and stamen shape. The description of the new species, photographs, detailed descriptions, notes on etymology, distribution and habitat, as well as comparisons with morphologically similar species, are provided.

How to predict the outcome of primary brainstem hemorrhage: Six-year results of a single-center retrospective analysis.

Primary brainstem hemorrhage (PBH) is one of the most fatal intracranial hemorrhages, evaluating the prognosis in the early stage is vital for appropriate therapeutic planning. Our study aimed to identify risk factors for 30-day mortality and 90-day functional recovery of PBH. Data from 63 patients with PBH admitted to Beijing Chaoyang Hospital between 2016 and 2022 were retrieved for this study. We grouped the patients according to 30-day survival or 90-day functional recovery. Independent risk factors of 30-day mortality and 90-day functional recovery were identified by univariate and multivariate logistic regression analyses. 31 patients (49.2%) died within 30 days and 22 patients (34.9%) achieved better functional recovery. By multivariate analysis, Glasgow coma scale <9 on admission and tachycardia were significantly associated with 30-day mortality, while the hematoma volume >5 mL was an independent risk factor for 90-day functional recovery. Initial level of consciousness, tachycardia, massive hematoma were risk factors for prognosis, which must be seriously evaluated for therapeutic planning.

A new species of Hiptage (Malpighiaceae) from northwest Yunnan (China) based on molecular and morphological data.

Hiptagestenopterum K.Tan & M.X.Ren, a new species of Hiptage collected from a deep valley close to the Nujiang Gorge, northwest of Yunnan Province, China, is described and illustrated based on molecular and morphological data. The new species was found isolated in an entrenched valley of the Laowo River, a tributary of the Nujiang River, at the northern edge of the distribution range of the genus. H.stenopterum shares some morphological similarities with the narrowly endemic H.incurvatum and H.lushuiensis. However, H.stenopterum is easily distinguished by its oblanceolate lateral wing of winged mericarp, 10 to 12 calyx glands, and branchlets densely rusty tomentose. The new species status is also supported by molecular phylogenetic analyses based on nuclear ribosome internal transcribed spacer (nrITS), which showed distinct systematic boundaries from the most morphologically similar species, H.incurvatum and their morphological relatives, H.lushuiensis.

Pan-cancer analyses reveal GTSE1 as a biomarker for the immunosuppressive tumor microenvironment.

G2 and S phase-expressed-1 (GTSE1) has been reported to be associated with poor prognosis in many cancer types. However, the knowledge of GTSE1 across 33 cancer types remains scarce, and the mechanisms by which GTSE1 promotes cancer development remain incompletely understood. R language and TIMER2.0 were used to analyze the clinical relevance of GTSE1 across > 10,000 subjects representing 33 cancer types based on the cancer genome atlas databases. The expression of GTSE1 was upregulated in almost all cancer types and hyperactivity of GTSE1 is likely to induce DNA repair response and positively correlates with the tumor mutational burden and microsatellite instability which are both promising predictive biomarkers for immunotherapy. GTSE1 was upregulated in TP53 mutation patients. Additionally, GTSE1 also positively correlates with tumor purity and tumor infiltration of immune-suppressive myeloid-derived suppressor cells. Consistently, high expression of GTSE1 is associated with poor patient survival in many cancer types. Conclusion: Our study provides new insights into the diagnostic and prognostic role of GTSE1 in cancers and suggests therapeutic approaches for GTSE1-overexpressing cancers by targeting DNA repair response, and the tumor immune microenvironment.

A new lithophilous species of Gesneriaceae, Petrocodonrubrostriatus, from the karst area of South Yunnan, China.

A new lithophytic species of Gesneriaceae, Petrocodonrubrostriatus K.Tan, X.Q.Song & M.X.Ren, sp. nov. from Lvchun County, South Yunnan, China, is described and illustrated here. It closest resembles P.mollifolius (W.T.Wang) A.Weber & Mich.Möller, but the new species is differentiated from it by red to brownish-red stripes in the yellow corolla throat and 4.5 mm long bract lobes, a ca. 10 mm long style, and staminodes inserted at 2.5-3 mm from the corolla base. The species is preliminarily assessed as 'Critically Endangered' (CR) according to IUCN criteria, since currently only one single locality is known with a few subpopulations on a fragmented limestone cliff, with fewer than 300 individuals.

Clinical evidence for a role of E2F1-induced replication stress in modulating tumor mutational burden and immune microenvironment.

DNA replication stress (RS) is frequently induced by oncogene activation and is believed to promote tumorigenesis. However, clinical evidence for the role of oncogene-induced RS in tumorigenesis remains scarce, and the mechanisms by which RS promotes cancer development remain incompletely understood. By performing a series of bioinformatic analyses on the oncogene E2F1, other RS-inducing factors, and replication fork processing factors in TCGA cancer database using previously established tools, we show that hyperactivity of E2F1 likely promotes the expression of several of these factors in virtually all types of cancer to induce RS and cytosolic self-DNA production. In addition, the expression of these factors positively correlates with that of ATR and Chk1 that govern the cellular response to RS, the tumor mutational load, and tumor infiltration of immune-suppressive CD4+Th2 cells and myeloid-derived suppressor cells (MDSCs). Consistently, high expression of these factors is associated with poor patient survival. Our study provides new insights into the role of E2F1-induced RS in tumorigenesis and suggests therapeutic approaches for E2F1-overexpressing cancers by targeting genomic instability, cytosolic self-DNA and the tumor immune microenvironment.

Immunogenic landscape and risk score prediction based on unfolded protein response (UPR)-related molecular subtypes in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common type of cancer and causes a significant number of cancer-related deaths worldwide. The molecular mechanisms underlying the development of HCC are complex, and the heterogeneity of HCC has led to a lack of effective prognostic indicators and drug targets for clinical treatment of HCC. Previous studies have indicated that the unfolded protein response (UPR), a fundamental pathway for maintaining endoplasmic reticulum homeostasis, is involved in the formation of malignant characteristics such as tumor cell invasiveness and treatment resistance. The aims of our study are to identify new prognostic indicators and provide drug treatment targets for HCC in clinical treatment based on UPR-related genes (URGs). Methods: Gene expression profiles and clinical information were downloaded from the TCGA, ICGC and GEO databases. Consensus cluster analysis was performed to classify the molecular subtypes of URGs in HCC patients. Univariate Cox regression and machine learning LASSO algorithm were used to establish a risk prognosis model. Kaplan-Meier and ROC analyses were used to evaluate the clinical prognosis of URGs. TIMER and XCell algorithms were applied to analyze the relationships between URGs and immune cell infiltration. Real time-PCR was performed to analyze the effect of sorafenib on the expression levels of four URGs. Results: Most URGs were upregulated in HCC samples. According to the expression pattern of URGs, HCC patients were divided into two independent clusters. Cluster 1 had a higher expression level, worse prognosis, and higher expression of immunosuppressive factors than cluster 2. Patients in cluster 1 were more prone to immune escape during immunotherapy, and were more sensitive to chemotherapeutic drugs. Four key UPR genes (ATF4, GOSR2, PDIA6 and SRPRB) were established in the prognostic model and HCC patients with high risk score had a worse clinical prognosis. Additionally, patients with high expression of four URGs are more sensitive to sorafenib. Moreover, ATF4 was upregulated, while GOSR2, PDIA6 and SRPRB were downregulated in sorafenib-treated HCC cells. Conclusion: The UPR-related prognostic signature containing four URGs exhibits high potential application value and performs well in the evaluation of effects of chemotherapy/immunotherapy and clinical prognosis.