FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression.Aberrant glycosylation has been intricately linked with immune escape and tumor growth.SEMA7A is a highly glycosylated protein with five glycosylated sites.The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear.Here,we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma,and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides(Asn 105,157,258,330,and 602)via a direct protein‒protein interaction.A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane.Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8,whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition.Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8^(+)T cells along a trajectory toward an exhausted state,thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death.Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy.Finally,we also define RBM4,a splice regulator,as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing.These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair

While hypoxic signaling has been shown to play a role in many cellular processes,its role in metabolism-linked extracellular matrix(ECM)organization and downstream processes of cell fate after musculoskeletal injury remains to be determined.Heterotopicossification(HO)is a debilitating condition where abnormal bone formation occurs within extra-skeletal tissues.Hypoxia andhypoxia-inducible factor 1α(HIF-1α)activation have been shown to promote HO.However,the underlying molecular mechanisms bywhich the HIF-1αpathway in mesenchymal progenitor cells(MPCs)contributes to pathologic bone formation remain to beelucidated.Here,we used a proven mouse injury-induced HO model to investigate the role of HIF-1αon aberrant cell fate.Usingsingle-cell RNA sequencing(scRNA-seq)and spatial transcriptomics analyses of the HO site,we found that collagen ECM organizationis the most highly up-regulated biological process in MPCs.Zeugopod mesenchymal cell-specific deletion of Hif1α(Hoxa11-CreER^(T2);Hif1a^(fl/fl))significantly mitigated HO in vivo.ScRNA-seq analysis of these Hoxa11-CreER^(T2);Hif1a^(fl/fl)mice identified the PLOD2/LOXpathway for collagen cross-linking as downstream of the HIF-1αregulation of HO.Importantly,our scRNA-seq data and mechanisticstudies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1αdeletion.From a translational aspect,a pan-LOX inhibitor significantly decreased HO.A newly screened compound revealed that the inhibition of PLOD2 activity in MPCssignificantly decreased osteogenic differentiation and glycolytic metabolism.This suggests that the HIF-1α/PLOD2/LOX axis linked tometabolism regulates HO-forming MPC fate.These results suggest that the HIF-1α/PLOD2/LOX pathway represents a promisingstrategy to mitigate HO formation.

Aberrant activation of latent transforming growth factor-β initiates the onset of temporomandibular joint osteoarthritis

There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transforming growth factor-β(TGF-β)signalling in the cartilage and subchondral bone of the TMJ using a temporomandibular joint disorder(TMD) rat model, an ageing mouse model and a Camurati–Engelmann disease(CED) mouse model. In the three animal models, the subchondral bone phenotypes in the mandibular condyles were evaluated by μCT, and changes in TMJ condyles were examined by TRAP staining and immunohistochemical analysis of Osterix and p-Smad2/3. Condyle degradation was confirmed by Safranin O staining, the Mankin and OARSI scoring systems and type X collagen(Col X), p-Smad2/3 a and Osterix immunohistochemical analyses. We found apparent histological phenotypes of TMJ-OA in the TMD, ageing and CED animal models, with abnormal activation of TGF-βsignalling in the condylar cartilage and subchondral bone. Moreover, inhibition of TGF-β receptor I attenuated TMJ-OA progression in the TMD models. Therefore, aberrant activation of TGF-β signalling could be a key player in TMJ-OA development.

Accumulation of aberrant DNA methylation during colorectal cancer development

Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas.Among crucial roles of epigenetic alterations,gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms.Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes.Each epigenotype cooperates with specific genetic alterations,suggesting that they represent different molecular carcinogenic pathways.Precursor lesions of CRC,such as conventional and serrated adenomas,already show similar methylation accumulation to CRC,and can therefore be classified into those epigenotypes of CRC.In addition,specific DNA methylation already occurs in the normal colonic mucosa,which might be utilized for prediction of the personal CRC risk.DNA methylation is suggested to occur at an earlier stage than carcinoma formation,and may predict the molecular basis for future development of CRC.Here,we review DNA methylation and CRC classification,and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis,prediction of the prognosis and the response to therapy of CRC.

Azoxymethane-induced rat aberrant crypt foci:Relevance in studying chemoprevention of colon cancer

The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci （ACF） represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane （AOM）-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.

Implications of the presence of an aberrant right hepatic artery in patients undergoing pancreaticoduodenectomy

AIM:To analyze the differences in outcomes and the clinical impact following pancreatoduodenectomy(PD)in patients with and without aberrant right hepatic artery(aRHA).METHODS:All patients undergoing PD between January 2008 and December 2012 were divided into two groups,one with aRHA and the other without.These groups were compared to identify differences in the intraoperative variables,the oncological clearance and the postoperative morbidity,mortality and hospital stay.RESULTS:A total of 225 patients underwent PD,of which 43(19.1%)patients were found to have eitheraccessory or replaced right hepatic arteries(aRHA group).The aRHA was preserved in 79%of the patients.There was no significant difference in the intraoperative blood loss but operative time was prolonged,reflecting the complexity of the procedure[420±44(240-540)min vs 480±45(300-600)min,P<0.05)].There were no differences in the incidence of postoperative complications(pancreatic leak,pancreatic fistula,delayed gastric emptying and mortality)and hospital stay.Oncological clearance in the form of positive resection margins[13(7.1%)vs 3(6.9%)]and lymph node yield were also similar in the two groups.CONCLUSION:An aRHA is found in approximately one fifth of patients undergoing PD.Preservation is technically possible in most patients and can increase the operative complexity but does not negatively affect the safety or oncological outcomes of the procedure.

Management of aberrant bile duct during laparoscopic cholecystectomy

Objective: To investigate the incidence of aberrant bile duct and its management during laparoscopic cholecystectomy (LC). Methods: In 10 000 patients undergoing laparoscopic cholecystectomy from 1992 to July 2001, 3 had the involvement of the right accessory hepatic duct. In patient 1, the aberrant duct drained into the cystic duct was confirmed by open operation. In patient 2, the aberrant duct, which drained to the common bile duct (CBD), was injured and treated with suture and ligature under laparoscopy. In patient 3, the ab- errant duct, which also drained to the CBD, was confirmed and preserved. Results: All patients recovered well except patient 1 who had a transient elevation of ALT. No bile leak- age or other complication occurred. Conclusions: Only variation near the confluence and the entrance of the cystic duct into the bile duct is discovered during laparoscopic cholecystectomy. Right accessory hepatic duct is common and should be preserved during the operation. The accidentally injured small accessory hepatic duct can be treated with ligature without severe disturbance to liver func- tion.

Aberrant crypt focus and fragile histidine triad protein in sporadic colorectal carcinoma

AIM:To characterize aberrant crypt focus (ACF) in adjoining mucosa in sporadic colorectal carcinoma and to evaluate fragile histidine triad (Fhit) protein and Ki67. METHODS:ACF was identified grossly and classified histologically in 75 resected specimens. ACF was typed into hyperplastic ACF (HACF) and dysplastic ACF (DACF). Sections of ACF, carcinoma and normal colonic mucosa as control were studied for Fhit and Ki67 expressions by immunohistochemistry and were grouped according to staining intensity and the number of positive stained cells observed in different histological groups. Comparison was done between the different groups by Pearson's χ 2 test and γ test for the ordinal data. P value < 0.05 was considered as significant.RESULTS:Age range was 40 to 86 years in males (mean = 43.36) and 45 to 70 years in females (mean = 56). HACF was identified in all cases studied in the non-tumorous colonic mucosa; ACF was observed as non-contiguous scattered foci, which supports the hypothesis of acquisition of single focus monoclonality by colonic epithelial cells in tumor generation. Twenty-four (32%) had DACF and were observed as closure to carcinoma foci. Intensity of Fhit expression:(1) HACF 40% exhibited strong intensity, similar to normal, moderate in 36% and weak in 24%; (2) DACF strong in 25%, moderate in 37.5% and weak in 37.5%; and (3) carcinoma negative in 16%, strong in 43% and moderate and weak in 28.5% each. Significant difference was observed in intensity of the Fhit protein expressions by HACF and DACF (P < 0.05). Tumor in older patients showed a stronger Fhit intensity compared to younger patients (P = 0.036). Vegetarian diet intake and nonsmokers showed stronger Fhit intensities. Advanced stage tumor, non-vegetarian diet and younger age was associated with loss of Fhit protein. Ki67 positivity was an extended crypt pattern in HACF and DACF showed extension up to the neck region of the crypts and surface epithelium. Carcinomas showed a marked increase in Ki67 expression (P < 0.05). Fhit protein had an inverse association with Ki67 expression. CONCLUSION:Weaker Fhit intensity was associated with smoking, non-vegetarian diet intake and increasing Ki67 expression. Loss of Fhit protein expression is possibly influenced by environmental factors like smoking and non-vegetarian diet intake.

Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma

The functional interdependence of nerves and blood vessels is a well-established concept during tissue morphogenesis, yet the role of neurovascular coupling in proper and aberrant tissue repair is an emerging field of interest. Here, we sought to define the regulatory relationship of peripheral nerves on vasculature in a severe extremity trauma model in mice, which results in aberrant cell fate and heterotopic ossification(HO). First, a high spatial degree of neurovascular congruency was observed to exist within extremity injury associated heterotopic ossification. Vascular and perivascular cells demonstrate characteristic responses to injury,as assessed by single cell RNA sequencing. This vascular response to injury was blunted in neurectomized mice, including a decrease in endothelial proliferation and type H vessel formation, and a downregulation of key transcriptional networks associated with angiogenesis. Independent mechanisms to chemically or genetically inhibit axonal ingrowth led to similar deficits in HO site angiogenesis, a reduction in type H vessels, and heterotopic bone formation. Finally, a combination of single cell transcriptomic approaches within the dorsal root ganglia identified key neural-derived angiogenic paracrine factors that may mediate neuron-to-vascular signaling in HO. These data provide further understanding of nerve-to-vessel crosstalk in traumatized soft tissues, which may reflect a key determinant of mesenchymal progenitor cell fate after injury.

Inhibition of aberrant Hif1αactivation delays intervertebral disc degeneration in adult mice

The intervertebral disc(IVD) is the largest avascular tissue. Hypoxia-inducible factors(HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease(DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate(EP) and annulus fibrosus(AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol(2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

Total endovascular repair of aberrant right subclavian artery using caster branched stent-graft

A 57-year-old man has 20-year history of hypertension presented with intermittent chronic pain in the chest area and shoulder blades over the last three months.Computed tomographic angiography(CTA)on admission revealed a chronic type B aortic dissection(TBAD)with an aberrant right subclavian artery(ARSA)crossed behind the trachea and bovine aortic arch(Figure IB).

Bilateral common carotid artery common trunk with aberrant right subclavian artery combined with right subclavian steal syndrome: A case report

BACKGROUND We report a rare case of numbness in the right hand,finally diagnosed as bilateral common carotid artery common trunk with aberrant right subclavian artery combined with right subclavian steal syndrome and explain the cause of these diseases.CASE SUMMARY The patient was a 65-year-old woman.She complained of dizziness,numbness and weakness of the right hand for 6 mo.She was diagnosed with bilateral common carotid artery common trunk with aberrant right subclavian artery combined with right subclavian steal syndrome by ultrasound,enhanced computed tomography,computed tomography angiography and other examinations.Considering the surgical risks,the patient refused the aberrant right subclavian artery stent implantation and was discharged.We hypothesize that these two kinds of deformity and right subclavian steal syndrome may not occur by accident and result from multiple malformations.CONCLUSION Bilateral common carotid artery common trunk with aberrant right subclavian artery combined with right subclavian steal syndrome is rare.This case reminds interventional radiologists of the possibility of these abnormalities before surgery.

Aberrant pyramidal tract in a patient with corona radiata infarct A diffusion tensor tractography study

The aberrant pyramidal tract refers to the collateral pathway of the pyramidal tract through the medial lemniscus in the brainstem. A 63-year-old male patient presented with severe paralysis of the left extremities due to a right corona radiata infarct. He was able to extend the affected fingers against resistance at 2 months after stroke onset. At 6 months after stroke onset, he was able to perform some fine motor activities, as well as to walk with a nearly normal gait. Functional MRI, which was performed at 6 months after onset, showed that the contralateral primary sensorimotor cortex was activated during affected （left） hand movements. Diffusion tensor tractography results showed that at 2 weeks after stroke onset, pyramidal tracts of the affected hemisphere originated from the primary motor cortex and descended along the known pathway of the pyramidal tract with an aberrant pyramidal tract, which was bypassed through the medial lemniscus from the midbrain to the lower pons. However, the pyramidal tract from midbrain to pons in the affected hemisphere could not be depicted by diffusion tensor tractography at 6 months after stroke onset; instead, only the aberrant pyramidal tract existed for the course of the disappeared pyramidal tract. Results from this study indicate that the main motor functions of the affected extremities appeared to be controlled via the aberrant pyramidal tract with degeneration of the pyramidal tract in the brainstem of the affected hemisphere.

Motor recovery via aberrant pyramidal tract in a patient with a cerebral peduncle infarct

The presence of the aberrant pyramidal tract has been demonstrated by several studies; however, little is known about its role in motor recovery in stroke patients. In the present study, we reported a 69-year-old right-handed female patient with an infarct in the mid to lateral portion of the left cerebra peduncle, who showed an aberrant pyramidal tract by diffusion tensor tractography. The patient presented with severe weakness of the right extremities at stroke onset. The patient showed progressive motor recovery as much as being able to extend the affected extremities against some resistance at 6 months after onset. At 20 months after stroke onset, motor function of the left extremities had recovered to a nearly normal state. Diffusion tensor tractography results showed that the PT was disrupted at the lower midbrain of the affected （left） hemisphere at 3 weeks after stroke onset and this disruption was not changed at 20 months. An aberrant pyramidal tract in the left hemisphere was also observed, which originated from the primary motor cortex and descended through the corona radiata, posterior limb of the internal capsule, thalamus, the medial lemniscus pathway from the midbrain to the pons, and then entered into the pyramidal tract area at the pontomedullary junction. Transcranial magnetic stimulation did not elicit motor evoked potential from the affected hand muscle at 3 weeks, but it elicited motor evoked potential with mildly delayed latency and low amplitude in the affected hand muscle at 20 months. The main motor functions of the affected extremities in this patient appeared to be recovered via this aberrant pyramidal tract.

Motor recovery via aberrant pyramidal tract in a patient with traumatic brain injury A diffusion tensor tractography study

The aberrant pyramidal tract is the collateral pathway of the pyramidal tract through the medial lemniscus in the brainstem. A 21-year-old man presented with right hemiparesis due to a traumatic intracerebral hemorrhage in the left corona radiata. His motor function recovered almost to the normal state at 10 months after onset. Through diffusion tensor tractography, the pyramidal tract in the affected （left） hemisphere showed discontinuation at the pontine level at 13 months after onset. An aberrant pyramidal tract was observed, which originated from the primary motor cortex and the supplementary motor area and descended through the corona radiata, then through the posterior limb of the internal capsule and the medial lemniscus pathway from the midbrain to the pons, finally entered into the pyramidal tract area at the pontomedullary junction, it suggests that the motor functions of the right extremities in this patient had recovered by this aberrant pyramidal tract.

Aberrant DNA Methylation in Human Cancers

DNA methylation, one of the best-characterized epigenetic modifications, plays essential roles in diseases, including human cancers. In recent years, our understanding on DNA methylation with human cancers has made significant progress, which was facilitated by stunning development in the analysis of the human methylome of multiple cancer types. In this review, recent developments in the characterization of aberrant DNA methylation involved in human cancers development were discussed with special emphasis on the mechanisms of aberrant DNA methylation in human cancers. We also summarize the recent treatment strategy for human cancers with de-methylation drugs.

Prenatal Exposure to Perfluorooctane Sulfonate impairs Placental Angiogenesis and Induces Aberrant Expression of LncRNA Xist

Perfluorooctane sulfonate （PFOS） is a class of stable organic compounds with wide industrial,commercial, and consumer applications, such as in textiles, paper, pesticides, and shampoos;. It is readily absorbed, but poorly eliminated, with the elimination half-life of approximately 5 years;.Hence, there have been concerns regarding its potential damage to human health. Some studies

Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.

Aberrant methylation and downregulation of sall3 in human hepatocellular carcinoma

AIM: To investigated whether sall3 transcription was regulated by promoter CpG island hypermethylation in hepatocellular carcinoma (HCC). METHODS: The cell lines Huh7, HepG2, SK-HEP1, SM-MC7721, Bel7402, QGY7703 and a cohort of 38 HCC tissue specimens and corresponding nontumorous tissues were subjected to analysis for sall3 promoter CpG island methylation and mRNA transcription. sall3 promoter CpG island methylation levels were determined using the MassARRAY platform and mRNA transcription levels of the gene were detected by quantitative realtime polymerase chain reaction.RESULTS: The levels of sall3 mRNA were decreased by more than twofold in 33 of 38 tumor tissues compared to adjacent noncancerous tissues. Among these 33 tumor tissues with lower levels of sall3 mRNA, 24 showed higher levels of methylation. Based on these results, we hypothesized that the decrease in sall3 mRNA transcription level was likely due to promoter CpG island hypermethylation. Changes in sall3 mRNA transcription and promoter CpG island methylation were determined in the above six cell lines after treatment with 0, 0.1, 0.5 and 2.5 mmol 5-aza-2-deoxycytidine, a demethylating agent. Promoter CpG island methylation levels de- creased in a dose-dependent manner in all six cell lines, while the mRNA transcription level increased dose-dependently in Huh7, HepG2, SK-HEP1 and SMMC7721 cells and irregularly in Bel7402 and QGY7703 cells. CONCLUSION: These results indicated that promoter CpG island hypermethylation contributes to the downregulation of sall3 mRNA transcription in HCC.

Link between dysregulated hypoxia signaling and aberrant methylation in clear cell renal cell carcinoma？

Dysregulated pseudo-hypoxia （through its effects on cell survival, angiogenesis, metabolism, invasion） and epigenetic dysregulation [through widespread suppression of tumor suppressor genes involved in cell cycle, apoptosis, adhesion, immune evasion, etc. （1）] are considered to be the two central driving pathogenic features in the progression of clear cell Renal Cell Carcinoma （ccRCC） （2,3）.