Diagnostic Performance of Carotid Ring Sign on CT-Angiography in Internal Carotid True Occlusion.

BACKGROUND: To differentiate between pseudo occlusion (PO) and true occlusion (TO) of internal carotid artery (ICA) is important in thrombectomy treatment planning for patients with acute ischemic stroke. Although delayed contrast filling has been differentiated carotid PO from TO, its application has been limited by the implementations of multiphasic computed tomography angiography. In this study, we hypothesized that carotid ring sign, which is readily acquired from single-phasic CTA, can sufficiently differentiate carotid TO from PO. METHODS: One thousand four hundred and twenty patients with anterior circulation stroke receiving endovascular therapy were consecutively recruited through a hospital- and web-based registry. Two hundred patients with nonvisualization of the proximal ICA were included in the analysis after a retrospective screening. Diagnosis of PO or TO of the cervical segment of ICA was made based on digital subtraction angiography. Diagnostic performances of carotid ring sign on arterial-phasic CTA and delayed contrast filling on multiphasic computed tomography angiography were evaluated and compared. RESULTS: One-hundred twelve patients had ICA PO and 88 had TO. Carotid ring sign was more common in patients with TO (70.5% versus 6.3%; P<0.001), whereas delayed contrast filling was more common in PO (94.9% versus 7.7%; P<0.001). The sensitivity and specificity of carotid ring sign in diagnosing carotid TO were 0.70 and 0.94, respectively, whereas sensitivity and specificity of delayed contrast filling was 0.95 and 0.92 in judging carotid PO. CONCLUSIONS: Carotid ring sign is a potent imaging marker in diagnosing ICA TO. Carotid ring sign could be complementary to delayed contrast filling sign in differentiating TO from PO, in particular in centers with only single-phasic CTA.

Raloxifene-driven benzothiophene derivatives: Discovery, structural refinement, and biological evaluation as potent PPARγ modulators based on drug repurposing.

By virtue of the drug repurposing strategy, the anti-osteoporosis drug raloxifene was identified as a novel PPARγ ligand through structure-based virtual high throughput screening (SB-VHTS) of FDA-approved drugs and TR-FRET competitive binding assay. Subsequent structural refinement of raloxifene led to the synthesis of a benzothiophene derivative, YGL-12. This compound exhibited potent PPARγ modulation with partial agonism, uniquely promoting adiponectin expression and inhibiting PPARγ Ser273 phosphorylation by CDK5 without inducing the expression of adipongenesis associated genes, including PPARγ, aP2, CD36, FASN and C/EBPα. This specific activity profile resulted in effective hypoglycemic properties, avoiding major TZD-related adverse effects like weight gain and hepatomegaly, which were demonstrated in db/db mice. Molecular docking studies showed that YGL-12 established additional hydrogen bonds with Ile281 and enhanced hydrogen-bond interaction with Ser289 as well as PPARγ Ser273 phosphorylation-related residues Ser342 and Glu343. These findings suggested YGL-12 as a promising T2DM therapeutic candidate, thereby providing a molecular framework for the development of novel PPARγ modulators with an enhanced therapeutic index.

Circular RNA MAP2K2-modified immunosuppressive dendritic cells for preventing alloimmune rejection in organ transplantation.

Long-term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long-term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to prevent immune rejection. We hypothesized that knockdown of circMAP2K2 induces immunosuppressive DCs and that treatment with circMAP2K2 silenced-DCs can prevent alloimmune rejection. DCs were cultured and transfected with siRNA for circMAP2K2. circMAP2K2 levels were measured by qRT-PCR. DC's maturation and immune function were assessed by flow cytometry and mixed lymphocyte reactions. The function of circMAP2K2 was illustrated by a series of RIP and IP. The therapeutics of engineered DCs was tested in a mouse heart transplantation model. We found that circMAP2K2 was highly expressed in mature DCs. Knockdown of circMAP2K2 reduced expression of MHCII, CD40 and CD80, attenuated the ability of DCs to activate allogeneic naïve T cells, and enhanced CD4+CD25+FOXP3+ regulatory T cells (Treg). circMAP2K2-induced immunosuppressive DCs by interacting with SENP3. Treatment with circMAP2K2-knockdown DCs attenuated alloimmune rejection and prolonged allograft survival in a murine heart transplantation model. The immune suppression induced in vivo was donor-antigen specific. In conclusion, knockdown of circMAP2K2 can induce immunosuppressive DCs which are able to inhibit overactive immune response, highlighting a new promising therapeutic approach for immune disorder diseases.

Safety and Effectiveness of High-dose Liposomal Amphotericin B: A Systematic Review and Meta-analysis.

Background: Although the level of medical care has been improved in recent years, the probability of patients contracting pathogens has increased greatly, with a rising incidence of invasive fungal infections. Deep-seated fungi have become common pathogens of nosocomial infections. Objective: This study aims to systematically assess the effectiveness, mortality, survival rate, and adverse reactions (ARs) of high-dose (HD) liposomal amphotericin B (L-AMB) for human diseases. Methods: Ten articles (1661 patients) of randomized controlled trials (RCTs; whether randomized, single-blind, or double-blind) from January 1, 1960, to December 31, 2020, of HD-L-AMB treatment of diseases were retrieved from the PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases. The primary outcome measure was the overall therapeutic effect, and the secondary outcome measures were mortality, ≥10-week survival, and ARs. Data were meta-analyzed using RevMan 5.3. Results: Ten RCTs involving 1661 patients were included. HD-L-AMB did not show a significant therapeutic advantage in anti-infection treatment. In addition, HD-L-AMB treatment of invasive Aspergillus infection led to high mortality and low survival (≥10 weeks, OR = 0.57, 95%CI 0.34-0.94, P = .03). According to subgroup analysis, the incidence of ARs and the incidence of renal dysfunction associated with invasive fungal infection treatment were higher with HD-L-AMB than with regular-dose L-AMB. Conclusion: HD-L-AMB had no obvious advantage for the treatment of diseases and was accompanied by increased mortality, reduced long-term survival, and increased ARs (including renal insufficiency). Therefore, the use of HD-L-AMB to control infections is recommended with caution only when the preferred treatment is contraindicated.

Neuroprotective mechanism of salvianolic acid B against cerebral ischemia-reperfusion injury in mice through downregulation of TLR4, p-p38MAPK, p-JNK, NF-κB, and IL-1ß.

OBJECTIVE: Tissue injury and inflammation are two potential outcomes of cerebral ischemia-reperfusion (I/R) injury. Salvianolic acid B (Sal B), isolated from the roots of Salvia miltiorrhiza, is one of the major water-soluble compounds with a wide range of pharmacological effects including antioxidant, anti-inflammatory, antiproliferative, and neuroprotective effects. In the present study, we explored the neuroprotective effects and potential mechanisms of Sal B after I/R injury. METHODS: We induced cerebral ischemia in male CD-1 mice through transient (60 min) middle cerebral artery occlusion (tMCAO), and then injected Sal B (30 mg/kg) intraperitoneally. Neurological deficits, infarct volumes, and brain edema were assessed at 24 and 72 h after tMCAO. We detected the expression of Toll-like receptor 4 (TLR4), phosphorylated-p38 mitogen-activated protein kinase (P-p38 MAPK), phosphorylated c-Jun amino (N)-terminal kinases (p-JNK), nuclear factor-κB (NF-κB), and interleukin-1ß (IL-1ß) in the brain tissue. RESULTS: Compared with the tMCAO group, Sal B significantly improved neurological deficits, reduced infarct size, attenuated cerebral edema, and downregulated the expression of pro-inflammatory mediators TLR4, p-p38MAPK, p-JNK, nuclear NF-κB, and IL-1ß in brain tissue after I/R injury. CONCLUSION: We found that Sal B protects brain tissues from I/R injury by activating its anti-inflammatory properties.

PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies.

Colorectal cancer (CRC) is the second most common cause of cancer mortality, with mismatch repair proficient (pMMR) and/or microsatellite stable (MSS) CRC making up more than 80% of metastatic CRC. Programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) immune checkpoint inhibitors (ICIs) are approved as monotherapy in many cancers including a subset of advanced or metastatic colorectal cancer (CRC) with deficiency in mismatch repair (dMMR) and/or high microsatellite instability (MSI-H). However, proficient mismatch repair and microsatellite stable (pMMR/MSS) cold CRCs have not shown clinical response to ICIs alone. To potentiate the anti-tumor response of PD-L1/PD-1 inhibitors in patients with MSS cold cancer, combination strategies currently being investigated include dual ICI, and PD-L1/PD-1 inhibitors in combination with chemotherapy, radiotherapy, vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors, mitogen-activated protein kinase (MEK) inhibitors, and signal transducer and activation of transcription 3 (STAT3) inhibitors. This paper will review the mechanisms of PD-1/PD-L1 ICI resistance in pMMR/MSS CRC and potential combination strategies to overcome this resistance, summarize the published clinical experience with different combination therapies, and make recommendations for future avenues of research.

Inducing mismatch repair deficiency sensitizes immune-cold neuroblastoma to anti-CTLA4 and generates broad anti-tumor immune memory.

Immune checkpoint blockade can induce potent and durable responses in patients with highly immunogenic mismatch repair-deficient tumors; however, these drugs are ineffective against immune-cold neuroblastoma tumors. To establish a role for a T cell-based therapy against neuroblastoma, we show that T cell and memory T cell-dependent gene expression are associated with improved survival in high-risk neuroblastoma patients. To stimulate anti-tumor immunity and reproduce this immune phenotype in neuroblastoma tumors, we used CRISPR-Cas9 to knockout MLH1-a crucial molecule in the DNA mismatch repair pathway-to induce mismatch repair deficiency in a poorly immunogenic murine neuroblastoma model. Induced mismatch repair deficiency increased the expression of proinflammatory genes and stimulated T cell infiltration into neuroblastoma tumors. In contrast to adult cancers with induced mismatch repair deficiency, neuroblastoma tumors remained unresponsive to anti-PD1 treatment. However, anti-CTLA4 therapy was highly effective against these tumors. Anti-CTLA4 therapy promoted immune memory and T cell epitope spreading in cured animals. Mechanistically, the effect of anti-CTLA4 therapy against neuroblastoma tumors with induced mismatch repair deficiency is CD4+ T cell dependent, as depletion of these cells abolished the effect. Therefore, a therapeutic strategy involving mismatch repair deficiency-based T cell infiltration of neuroblastoma tumors combined with anti-CTLA4 can serve as a novel T cell-based treatment strategy for neuroblastoma.

Predictors of futile recanalization in basilar artery occlusion patients undergoing endovascular treatment: a post hoc analysis of the ATTENTION trial.

Background: Few studies have focused on factors associated with futile recanalization in patients with an acute basilar artery occlusion (BAO) that was treated with modern endovascular therapy (EVT). The aim of this study was to explore the factors associated with futile recanalization in patients with an acute BAO presented within 12 h. Methods: This is a post-hoc analysis of the ATTENTION trial (The Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion, ClinicalTrials.gov, number NCT04751708). Demographics, clinical characteristics, acute stroke workflow interval times, and imaging characteristics were compared between the futile recanalization and favorable recanalization groups. The favorable outcome was defined as a modified Rankin scale (mRS) score of 0-3 at 90 days, successful reperfusion was defined as thrombolysis in cerebral infarction (TICI) 2b and 3 on the final angiogram, and futile recanalization was defined as failure to achieve a favorable outcome despite successful reperfusion. A multivariate analysis was performed to identify the predictors of futile recanalization. Results: In total, 185 patients were included in the final analysis: 89 (48.1%) patients had futile recanalization and 96 (51.9%) patients had favorable recanalization. In the multivariable logistic regression analysis, older age (OR 1.04, 95% CI 1.01 to 1.08, p = 0.01) and diabetes mellitus (OR 3.35, 95% CI 1.40 to 8.01, p = 0.007) were independent predictors of futile recanalization. Conclusion: Futile recanalization occurred in nearly half of patients with acute BAO following endovascular treatment. Old age and diabetes mellitus were identified as independent predictors of futile recanalization after endovascular therapy for acute BAO.

Application of Balloon AngioplaSty with the dIstal protection of Stent Retriever (BASIS) technique for acute intracranial artery atherosclerosis-related occlusion.

Background: Endovascular therapy (EVT) is complex in the context of intracranial atherosclerosis (ICAS)-related large vessel occlusion (LVO) and the re-occlusion rates are high due to residual stenosis, the procedure time is long and the optimal EVT technique is unclear. The Balloon AngioplaSty with the dIstal protection of Stent Retriever (BASIS) technique is a novel thrombectomy technique that allows emergent balloon angioplasty to be performed via the wire of the retrieval stent. Our study presents our initial experience with the BASIS technique in ICAS-related LVO and assesses its feasibility. Method: In patients with ICAS-related LVO treated with BASIS, clinical and angiographic data were retrospectively analyzed. Angiographic data included first-pass reperfusion (PFR), the rate of residual stenosis, distal emboli, and re-occlusion post-procedure. The Extended Thrombolysis in Cerebral Infarction (eTICI) scale was used to assess reperfusion extent, and an eTICI score ≥2b was defined as successful perfusion. Clinical outcome was evaluated at 3 months (modified Rankin score [mRS]), and an mRS ≤ 2 was defined as a good clinical outcome. Results: A total of seven patients with ICAS-related LVO were included, and the median age of the patients was 76 years. All patients achieved eTICI 3 reperfusion and FPR. The residual stenosis rate ranged from 5 to 10%. None of the patients had re-occlusion post-procedure. The median puncture-to-reperfusion time was 51 min. None of the patients had a symptomatic cerebral hemorrhage, re-occlusion, distal embolism, and dissection. Good clinical outcomes were observed in four patients (4/7, 57.1%), and 1 patient (1/7, 14.3%) died. Conclusion: The BASIS technique is feasible and safe for treating acute ICAS-related LVO.

Hydrogen sulfide: A new therapeutic target in vascular diseases.

Hydrogen sulfide (H2S) is one of most important gas transmitters. H2S modulates many physiological and pathological processes such as inflammation, oxidative stress and cell apoptosis that play a critical role in vascular function. Recently, solid evidence show that H2S is closely associated to various vascular diseases. However, specific function of H2S remains unclear. Therefore, in this review we systemically summarized the role of H2S in vascular diseases, including hypertension, atherosclerosis, inflammation and angiogenesis. In addition, this review also outlined a novel therapeutic perspective comprising crosstalk between H2S and smooth muscle cell function. Therefore, this review may provide new insight inH2S application clinically.

Endovascular Treatment of ICAS Patients: Targeting Reperfusion Rather than Residual Stenosis.

BACKGROUND AND PURPOSE: Previous studies showed that acute reocclusion after endovascular therapy is related to residual stenosis. However, we observed that reperfusion status but not residual stenosis severity is related to acute reocclusion. This study aimed to assess which factor mention above is more likely to be associated with artery reocclusion after endovascular treatment. METHODS: This study included 86 acute ischemic stroke patients who had middle cerebral artery (MCA) atherosclerotic occlusions and received endovascular treatment within 24 h of a stroke. The primary outcomes included intraprocedural reocclusion assessed during endovascular treatment and delayed reocclusion assessed through follow-up angiography. RESULTS: Of the 86 patients, the intraprocedural reocclusion rate was 7.0% (6/86) and the delayed reocclusion rate was 2.3% (2/86). Regarding intraprocedural occlusion, for patients with severe residual stenosis, patients with successful thrombectomy reperfusion showed a significantly lower rate than unsuccessful thrombectomy reperfusion (0/30 vs. 6/31, p = 0.003); on the other hand, for patients with successful thrombectomy reperfusion, patients with severe residual stenosis showed no difference from those with mild to moderate residual stenosis in terms of intraprocedural occlusion (0/30 vs. 0/25, p = 1.00). In addition, after endovascular treatment, all patients achieved successful reperfusion. There was no significant difference in the delayed reocclusion rate between patients with severe residual stenosis and those with mild to moderate residual stenosis (2/25 vs. 0/61, p = 0.085). CONCLUSION: Reperfusion status rather than residual stenosis severity is associated with artery reocclusion after endovascular treatment. Once successful reperfusion was achieved, the reocclusion occurrence was fairly low in MCA atherosclerosis stroke patients, even with severe residual stenosis.

Different phenotypes of neurological diseases, including alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism, caused by de novo ATP1A3 mutation in a family.

BACKGROUND: The spectrum of neurological diseases related to ATP1A3 gene mutations is highly heterogeneous and exhibits different phenotypes. Phenotype overlaps, including alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy, and rapid-onset dystonia-parkinsonism (RDP), can also occur at extremely low incidences. Currently, over 90 types of pathogenic mutations have been identified in ATP1A3. PATIENTS AND METHODS: The family of a 2-year-11-month-old proband with AHC was recruited for this clinical investigation. The proband was screened for candidate mutation gene sites using next-generation sequencing and target-region capture technology. Sanger sequencing was used to identify carriers among family members. RESULTS: The mother of the proband with AHC was diagnosed with dystonia (later diagnosed as RDP). The biochemical and immune indices of the proband and the mother were not abnormal. Moreover, brain imaging of the proband revealed no significant abnormalities. However, the electroencephalogram of the mother was mildly abnormal, with no spike wave discharge. Brain MRI revealed slight cerebellar atrophy. Electromyography revealed neurogenic damage, with a decrease in the conduction velocity of the left ulnar and radial nerves. Based on the sequencing data, both the proband and her mother carried c.823G > C p. (Ala275Pro) heterozygotes; other family members were not identified as carriers. With a PolyPhen-2 score of 0.997 and SIFT score of 0.001, this mutation can be considered damaging. CONCLUSION: Family genotype-phenotype correlation analysis revealed that the phenotype and gene mutation were co-segregated, suggesting that it may be a pathogenic mutation.

Association of baseline core volume and early midline shift in acute stroke patients with a large ischaemic core.

Background: Midline shift (MLS) is troublesome problem that may occur in patients with a large infarct core (LIC) and may be related to the baseline infarct core volume. The purpose of this study was to explore the relationship between baseline infarct core volume and early MLS presence. Materials and methods: Patients with acute intracranial large artery occlusion and a pretreatment relative cerebral blood flow (rCBF) <30% volume ≥50 ml on CT perfusion (CTP) were included, clinical outcomes following endovascular treatment (EVT) were retrospectively analyzed. The primary endpoint was MLS within 48 h (early MLS presence). The association between baseline ICV and early MLS presence was evaluated with multivariable regression. Results: Ultimately, 95 patients were included, and 29.5% (28/95) of the patients had early MLS. The number of patients with a baseline rCBF < 15% volume (median [interquartile range], 46 [32-60] vs. 29 [19-40]; P < 0.001) was significantly larger in the early severe MLS presence group. A baseline rCBF < 15% volume showed significantly better predictive accuracy for early MLS presence than an rCBF < 30% volume (area under the curve, 0.74 vs. 0.64, P = 0.0023). In addition, an rCBF < 15% volume ≥40 ml (odds ratio, 4.34 [95% CI, 1.571-11.996]) was associated with early MLS presence after adjustment for sex, age, baseline National Institutes of Health Stroke Scale score, onset-to-recanalization time. Conclusion: In patients with an acute LIC following EVT, a pretreatment infarct core volume > 40 ml based on an rCBF < 15% showed good predictive value for early MLS occurrence.

Decreased TMEM40 expression is associated with malignant behavior of cutaneous squamous cell carcinoma and inhibits tumor progression.

Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer in humans worldwide. The identification and characterization of cancer-associated transmembrane proteins are important for understanding the molecular biology of CSCC. The aim of the present study was to evaluate the expression pattern of transmembrane protein 40 (TMEM40) in CSCC and its clinical significance. The underlying mechanisms were also examined. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analysis were used to determine the relative expression of TMEM40 in CSCC cell lines and clinical tissue samples. The effect of TMEM40 gene silencing on cell proliferation was also evaluated using Cell Counting Kit-8 assays. Wound healing assays, flow cytometry and Transwell assays were used to explore the migration, cell cycle distribution/apoptosis and invasion of CSCC cells following TMEM40 silencing, respectively. In the present study, increased TMEM40 expression was observed in CSCC tissue samples, compared with normal skin, and TMEM40 expression was associated with large tumor size in patients with CSCC. In vitro functional assays indicated that TMEM40 was involved in the regulation of A431 and SCL1 cell growth through its effects on the cell cycle and apoptosis. Silencing TMEM40 in A431 and SCL1 cells resulted in cell cycle arrest at the G0/G1 phase and promoted apoptosis. In addition, migration and invasion were significantly inhibited following silencing of TMEM40 expression in CSCC cells. Taken together, the results of the present study indicated that reduced TMEM40 expression could inhibit CSCC development and that TMEM40 may represent a therapeutic target in CSCC.

Anti-Fibrotic Effects of Low Toxic Microcystin-RR on Bleomycin-Induced Pulmonary Fibrosis: A Comparison with Microcystin-LR.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disease characterized with radiographically evident pulmonary infiltrates and extracellular matrix deposition with limited treatment options. We previously described that microcystin-LR (MC-LR) reduces transforming growth factor (TGF)-ß1/Smad signaling and ameliorates pulmonary fibrosis in bleomycin (BLM)-induced rat models. In the present study, we further demonstrate that microcystin-RR (MC-RR), an MC congener with lower toxicity than MC-LR, exerted an anti-fibrotic effect on BLM-induced pulmonary fibrosis rodent models and compared it with MC-LR. Our data show that MC-RR treatment attenuated BLM-associated pulmonary inflammation and collagen deposition in both therapeutic and preventive models. MC-RR reduced the expression of fibrotic markers, including vimentin, α-smooth muscle actin, collagen 1α1, and fibronectin, in rat pulmonary tissues. Furthermore, the core features of BLM-induced pulmonary fibrotic lesions were better alleviated by MC-RR than by MC-LR. MC-RR treatment substantially decreased the number of pulmonary M2 macrophages. In vitro, MC-RR attenuated the epithelial-mesenchymal transition and fibroblast-myofibroblast transition triggered by M2 macrophages. Therefore, we highlight MC-RR as a promising molecule for developing therapeutic and prophylactic strategies against IPF, a refractory lung disease.

Preventing alloimmune rejection using circular RNA FSCN1-silenced dendritic cells in heart transplantation.

BACKGROUND: While heart transplantation is used as a standard treatment for heart failure, transplant rejection continues to pose a challenge. Recent evidence has shown that circular RNA (circRNA) is a new type of gene regulator in cell development. Our aim was to demonstrate that treatment with tolerogenic dendritic cells (Tol-DCs) generated by circular RNA FSCN1 (circFSCN1) silencing could prevent alloimmune rejection and prolong heart graft survival in heart transplantation. METHODS: Bone marrow-derived DCs were transfected with circFSCN1 siRNA in vitro. The circFSCN1 level was measured by qRT-PCR. DC maturation was determined by flow cytometry. Mixed lymphocyte reactions (MLRs) were conducted to assess the function of DCs to activate T cells and to generate regulatory T cells (Tregs). In situ RNA hybridization and fluorescent microscopy were performed to detect the distribution of circFSCN1 in DCs. A heterotopic allogeneic murine heart transplantation was conducted where recipients were pre-treated with donor derived circFSCN1-silenced Tol-DCs. Heartbeat was monitored to assess immune rejection. RESULTS: Exonic circFSCN1 was highly expressed in the cytoplasm of mature DCs. Knockdown of circFSCN1 using siRNA arrested DCs at an immature state, impaired DC's ability to activate T cells and enhanced Treg generation. Treatment with circFSCN1-silenced Tol-DCs prevented alloimmune rejection, prolonged allograft survival, reduced fibrosis, and induced Tregs in vivo. CONCLUSIONS: Knockdown of circFSCN1 induces Tol-DCs and treatment with these Tol-DCs prevents alloimmune rejection and prolongs allograft survival. This is a promising therapeutic target to combat transplant rejection in heart transplantation and increases our understanding of circRNA in the immune system.

Circular RNA in colorectal cancer.

Circular RNA (circRNA) is a highly abundant type of single-stranded non-coding RNA. Novel research has discovered many roles of circRNA in colorectal cancer (CRC) including proliferation, metastasis and apoptosis. Furthermore, circRNAs also play a role in the development of drug resistance and have unique associations with tumour size, staging and overall survival in CRC that lend circRNAs the potential to serve as diagnostic and prognostic biomarkers. Among cancers worldwide, CRC ranks second in mortality and third in incidence. In order to have a better understanding of the influence of circRNA on CRC development and progression, this review summarizes the role of specific circRNAs in CRC and evaluates their potential value as therapeutic targets and biomarkers for CRC. We aim to provide insight in the development of therapy and clinical decision-making.

FAM83H-AS1 is a noncoding oncogenic driver and therapeutic target of lung adenocarcinoma.

BACKGROUND: Little is known about noncoding oncogenes of lung adenocarcinoma (LUAD), and these potential drivers might provide novel therapeutic targets. METHODS: Since abnormally overexpression of oncogenic drivers is induced by genomic variation, we here utilized genomic, transcriptomic, and clinical prognosis data of The Cancer Genome Atlas (TCGA) LUAD datasets to discover novel drivers from long noncoding RNAs. We further used zebrafish models to validate the biological function of candidates in vivo. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends assay. RNA pull-down, RNA immunoprecipitation, quantitative mass spectrometry, and RNA sequencing assays were conducted to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) method and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1. RESULTS: The results suggest that FAM83H-AS1 is a potential oncogenic driver due to chromosome 8q24 amplification. Upregulation of FAM83H-AS1 results in poor prognosis of LUAD patients in both Jiangsu Cancer Hospital (JSCH) and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds HNRNPK to enhance the translation of antiapoptotic oncogenes RAB8B and RAB14. Experiments using CRISPRi-mediated xenografts and PDTX models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo. CONCLUSIONS: Our work demonstrates that FAM83H-AS1 is a noncoding oncogenic driver that inhibits LUAD apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis, which highlights the importance and potential roles that FAM83H-AS1 may serve as a novel therapeutic target for LUAD.