Histone methyltransferases and demethylases:regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells

Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su（var）3-9, enhancer-of-zeste, trithorax （SET） domain-containing family and the Jumonji C （JmjC） domain-containing family represent the major histone lysine methyltransferases （KMTs） and histone lysine demethylases （KDMs）, respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.

CXCL12/SDF-1α Activates NF-κB and Promotes Oral Cancer Invasion through the Carma3/Bcl10/Malt1 Complex

Aim To determine how SDF-1α/CXCR4 activates nuclear factor-kappa B （NF-κB） and promotes oral squamous cell carcinoma （OSCC） invasion.Methodology A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-κB activation was evaluated by Western blot analysis and electrophoretic mobility shift （EMSA）. Results We show that the activation of NF-κB by CXCR4 occurs through the Carma3/Bcl10/Maltl （CBM） complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1α induced phosphorylation and degradation of IκBα, while TNFα induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1α mediated invasion of OSCC. Conclusion The CBM complex plays a critical role in CXCR4-induced NF-κB activation in OSCC. Targeting molecular components of the NF-κB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1α.

Diagnostic aids for detection of oral precancerous conditions

Oral cancer has a tendency to be detected at late stage which is detrimental to the patients because of its high mortality and morbidity rates. Early detection of oral cancer is therefore important to reduce the burden of this devastating disease. In this review article, the most common oral precancerous lesions are discussed and the importance of early diagnosis is emphasized. In addition, the most common non-invasive oral cancer devices that can aid the general practitioners in early diagnosis are also discussed.

AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs

AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFF1 and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFFI and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.

Thirty years of the human immunodeficiency virus epidemic and beyond

After more than 30 years of battling a global epidemic, the prospect of eliminating human immunodeficiency virus （HIV） as the most challenging infectious disease of the modern era is within our reach. Major scientific discoveries about the virus responsible for this immunodeficiency disease state, including its pathogenesis, transmission patterns and clinical course, have led to the development of potent antiretroviral drugs that offer great hopes in HIV treatment and prevention. Although these agents and many others still in development and testing are capable of effectively suppressing viral replication and survival, the medical management of HIV infection at the individual and the population levels remains challenging. Timely initiation of antiretroviral drugs, adherence to the appropriate therapeutic regimens, effective use of these agents in the pre and post-exposure prophylaxis contexts, treatment of comorbid conditions and addressin~ social and nsvcholo2ical factors involved in the care of individuals continue to be important considerations.

The clinical effectiveness of reflectance optical spectroscopy for the in vivo diagnosis of oral lesions

Optical spectroscopy devices are being developed and tested for the screening and diagnosis of oral precancer and cancer lesions. This study reports a device that uses white light for detection of suspicious lesions and green–amber light at 545 nm that detect tissue vascularity on patients with several suspicious oral lesions. The clinical grading of vascularity was compared to the histological grading of the biopsied lesions using specific biomarkers. Such a device, in the hands of dentists and other health professionals, could greatly increase the number of oral cancerous lesions detected in early phase. The purpose of this study is to correlate the clinical grading of tissue vascularity in several oral suspicious lesions using the IdentafiH system with the histological grading of the biopsied lesions using specific vascular markers. Twenty-one patients with various oral lesions were enrolled in the study. The lesions were visualized using IdentafiH device with white light illumination, followed by visualization of tissue autofluorescence and tissue reflectance. Tissue biopsied was obtained from the all lesions and both histopathological and immunohistochemical studies using a vascular endothelial biomarker（CD34） were performed on these tissue samples. The clinical vascular grading using the green–amber light at 545 nm and the expression pattern and intensity of staining for CD34 in the different biopsies varied depending on lesions, grading ranged from 1 to3. The increase in vascularity was observed in abnormal tissues when compared to normal mucosa, but this increase was not limited to carcinoma only as hyperkeratosis and other oral diseases, such as lichen planus, also showed increase in vascularity. Optical spectroscopy is a promising technology for the detection of oral mucosal abnormalities; however, further investigations with a larger population group is required to evaluate the usefulness of these devices in differentiating benign lesions from potentially malignant lesions.

KDM6B epigenetically regulates odontogenic differentiation of dental mesenchymal stem cells

Mesenchymal stem cells （MSCs） have been identified and isolated from dental tissues, including stem cells from apical papilla, which demonstrated the ability to differentiate into dentin-forming odontoblasts. The histone demethylase KDM6B （also known as JMJD3） was shown to play a key role in promoting osteogenic commitment by removing epigenetic marks H3K27me3 from the promoters of osteogenic genes. Whether KDM6B is involved in odontogenic differentiation of dental MSCs, however, is not known. Here, we explored the role of KDM6B in dental MSC fate determination into the odontogenic lineage. Using shRNA-expressing lentivirus, we performed KDM6B knockdown in dental MSCs and observed that KDM6B depletion leads to a significant reduction in alkaline phosphate （ALP） activity and in formation of mineralized nodules assessed by Alizarin Red staining. Additionally, mRNA expression of odontogenic marker gene SP7 （osterix, OSX）, as well as extracellular matrix genes BGLAP （osteoclacin, OCN） and SPP1 （osteopontin, OPN）, was suppressed by KDM6B depletion. When KDM6B was overexpressed in KDM6B-knockdown MSCs, odontogenic differentiation was restored, further confirming the facilitating role of KDM6B in odontogenic commitment. Mechanistically, KDM6B was recruited to bone morphogenic protein 2 （BMP2） promoters and the subsequent removal of silencing H3K27me3 marks led to the activation of this odontogenic master transcription gene. Taken together, our results demonstrated the critical role of a histone demethylase in the epigenetic regulation of odontogenic differentiation of dental MSCs. KDM6B may present as a potential therapeutic target in the regeneration of tooth structures and the repair of craniofacial defects.

Characterization of the osteogenic potential of mesenchymal stem cells from human periodontal ligament based on cell surface markers

Mesenchymal stem cell （MSC）-mediated therapy has been shown to be clinically effective in regenerating tissue defects. For improved regenerative therapy, it is critical to isolate homogenous populations of MSCs with high capacity to differentiate into appropriate tissues. The utilization of stem cell surface antigens provides a means to identify MSCs from various tissues. However, few surface markers that consistently isolate highly regenerative MSCs have been validated, making it challenging for routine clinical applications and making it all the more imperative to identify reliable surface markers. In this study, we used three surface marker combinations： CD51/CD140a, CD271, and STRO-1/CD146 for the isolation of homogenous populations of dental mesenchymal stem cells （DMSCs） from heterogeneous periodontal ligament cells （PDLCs）. Fluorescence-activated cell sorting analysis revealed that 24% of PDLCs were CD51＋/CD140a＋, 0.8% were CD271＋, and 2.4% were STRO-1＋/CD146＋. Sorted cell populations were further assessed for their multipotent properties by inducing osteogenic and chondrogenic differentiation. All three subsets of isolated DMSCs exhibited differentiation capacity into osteogenic and chondrogenic lineages but with varying degrees. CD271＋ DMSCs demonstrated the greatest osteogenic potential with strong induction of osteogenic markers such as DLX5, RUNX2, and BGLAP. Our study provides evidence that surface marker combinations used in this study are sufficient markers for the isolation of DMSCs from PDLCs. These results provide important insight into using specific surface markers for identifying homogenous populations of DMSCs for their improved utilization in regenerative medicine.

Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma(HNSCC),an aggressive malignancy,is characterized by high morbidity and low survival rates with limited therapeutic options outside of regional surgery,conventional cytotoxic chemotherapy,and irradiation.Increasing studies have supported the synergistic role of the tumor microenvironment(TME)in cancer advancement.The immune system,in particular,plays a key role in surveillance against the initiation,development,and progression of HNSCC.The understanding of how neoplastic cells evolve and evade the immune system whether through self-immunogenicity manipulation,or expression of immunosuppressive mediators,provides the foundation for the development of advanced therapies.Furthermore,the crosstalk between cancer cells and the host immune system have a detrimental effect on the TME promoting angiogenesis,proliferation,and metastasis.This review provides a recent insight into the role of the key inflammatory cells infiltrating the TME,with a focus on reviewing immunological principles related to HNSCC,as cancer immunosurveillance and immune escape,including a brief overview of current immunotherapeutic strategies and ongoing clinical trials.

Real-time-guided bone regeneration around standardized critical size calvarial defects using bone marrow-derived mesenchymal stem cells and collagen membrane with and without using tricalcium phosphate: an in vivo microcomputed tomographic and histologic e

The aim of the present real time in vivo micro-computed tomography （pCT） and histologic experiment was to assess the efficacy of guided bone regeneration （GBR） around standardized calvarial critical size defects （CSD） using bone marrow-derived mesenchymal stem cells （BMSCs）, and collagen membrane （CM） with and without tricalcium phosphate （TCP） graft material. In the calvaria of nine female Sprague-Dawley rats, full-thickness CSD （diameter 4.6 mm） were created under general anesthesia. Treatment-wise, rats were divided into three groups. In group 1, CSD was covered with a resorbable CM; in group 2, BMSCs were filled in CSD and covered with CM; and in group 3, TCP soaked in BMSCs was placed in CSD and covered with CM. All defects were closed using resorbable sutures. Bone volume and bone mineral density of newly formed bone （NFB） and remaining TCP particles and rate of new bone formation was determined at baseline, 2, 4, 6, and 10 weeks using in vivo pCT. At the lOth week, the rats were killed and calvarial segments were assessed histologically. The results showed that the hardness of NFB was similar to that of the native bone in groups I and 2 as compared to the NFB in group 3. Likewise, values for the modulus of elasticity were also significantly higher in group 3 compared to groups 1 and 2. This suggests that TCP when used in combination with BMSCs and without CM was unable to form bone of significant strength that could possibly provide mechanical ＂lock＂ between the natural bone and NFB. The use of BMSCs as adjuncts to conventional GBR initiated new bone formation as early as 2 weeks of treatment compared to when GBR is attempted without adiunct BMSC therapy.

Growth differentiation factor 6,a repressive target of EZH2,promotes the commitment of human embryonic stem cells to mesenchymal stem cells

Mesenchymal stem cells(MSCs)derived from human embryonic stem cells(hESCs)have significant potential for cell-mediated bone regeneration.Our recent study revealed that inhibiting the epigenetic regulator EZH2 plays a key role in promoting the mesodermal differentiation of hESCs.In this study,an epigenome-wide analysis of hESCs and MSCs revealed that growth differentiation factor 6(GDF6),which is involved in bone formation,was the most upregulated gene associated with MSCs compared to hESCs.Furthermore,we identified GDF6 as a repressive target of EZH2 and found that ectopic GDF6 selectively promoted hESC differentiation towards the mesodermal lineage and enriched the MSC population.Our results provide molecular insights governing the mesenchymal commitment of hESCs and identify an inducing factor that offers strong promise for the future of regenerative medicine.

PLEK2通过c-Myc介导的正反馈回路促进头颈鳞状细胞癌发生发展及干性形成

背景与目的头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)是全球高发的恶性肿瘤之一,具有预后不良、淋巴结转移率高以及早期复发的特点。然而,调控HNSCC发生发展的分子机制尚未明确。因此,揭示其潜在机制以寻找有治疗前景的新靶点具有重要意义。本研究主要探讨PLEK2(pleckstrin-2)在调控HNSCC发生发展中的作用。方法通过分析独立公共数据集以及内部队列,确定PLEK2在HNSCC表达情况及其临床意义。同时,使用体内外实验,包括细胞增殖、集落形成、Matrigel侵袭、肿瘤球形成、ALDEFLUOR检测、蛋白印迹分析,以及异种移植小鼠模型等方法,明确PLEK2在调控HNSCC细胞恶性生物学行为中的作用。另外,通过免疫共沉淀、环己酮霉素追踪分析、泛素化实验、染色质免疫沉淀–定量聚合酶链反应、荧光素酶报告基因实验和挽救实验等方法,阐明PLEK2在促进肿瘤发展中的潜在分子机制。结果在HNSCC组织中,PLEK2 mRNA和蛋白质表达水平较正常组织明显增加;PLEK2的过度表达与不良预后和治疗抗性显著关联。此外,PLEK2在维持HNSCC细胞的增殖、侵袭、上皮间质转换、癌症干细胞特征和肿瘤形成中发挥重要作用,并能改变癌细胞的代谢。在分子机制方面,PLEK2能与c-Myc结合,降低FBXW7(F-Box And WD Repeat Domain Containing 7)与c-Myc的相互作用,避免了c-Myc的泛素化和随后的蛋白酶体介导的降解。更进一步,PLEK2激活的c-Myc信号对于维持HNSCC细胞的恶性生物学行为至关重要。此外,c-Myc可结合到PLEK2启动子并促进其转录,形成了正反馈循环。结论我们揭示了PLEK2通过调控c-Myc促进HNSCC发生发展的分子机理,表明PLEK2可能成为HNSCC的潜在治疗靶点。

Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial–mesenchymal transition in mice

Growing evidence suggests close associations between periodontitis and atherosclerosis.To further understand the pathological relationships of these associations,we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/P.g.LPS) in Apolipoprotein E knock out mice and studied the atherogenesis process in these animals.The mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis,systemic inflammation,and atherosclerosis.Controls did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas,but mice receiving ligature or ligature/P.g.LPS showed severe periodontitis,systemic inflammation,and aortic plaque formation.The aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell markers.The severity of periodontitis was slightly higher in mice receiving ligature/P.g.LPS than ligature alone,and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/P.g.LPS.These observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe periodontitis.In vitro,P.g.LPS enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial cells.Moreover,secretory proteins,such as TNF-α,from macrophages induced endothelial–mesenchymal transitions of the endothelial cells.Taken together,systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via,in part,causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice.

From bulk, single-cell to spatial RNA sequencing

RNA sequencing(RNAseq)can reveal gene fusions,splicing variants,mutations/indels in addition to differential gene expression,thus providing a more complete genetic picture than DNA sequencing.This most widely used technology in genomics tool box has evolved from classic bulk RNA sequencing(RNAseq),popular single cell RNA sequencing(scRNAseq)to newly emerged spatial RNA sequencing(spRNAseq).Bulk RNAseq studies average global gene expression,scRNAseq investigates single cell RNA biology up to 20,000 individual cells simultaneously,while spRNAseq has ability to dissect RNA activities spatially,representing next generation of RNA sequencing.This article highlights these technologies,characteristic features and suitable applications in precision oncology.

Single CD271 marker isolates mesenchymal stem cells from human dental pulp

Mesenchymal stem cells （MSCs） are a promising tool in regenerative medicine due to their capacity to differentiate into multiple lineages. In addition to MSCs isolated from bone marrow （BMSCs）, adult MSCs are isolated from craniofacial tissues including dental pulp tissues （DPs） using various stem cell surface markers. However, there has been a lack of consensus on a set of surface makers that are reproducibly effective at isolating putative multipotent dental mesenchymal stem cel^s （~M^Cs）. II1 ~his stucly, we used clif^et（~nt combinations of surface markers （CD51/CD140a, CD271, and STRO-1/CD146） to isolate homogeneous populations of DMSCs from heterogeneous dental pulp cells （DPCs） obtained from DP and compared their capacity to undergo multilineage differentiation. Fluorescence-activated cell sorting revealed that 27.3% of DPCs were CD51＋/CD140a＋, 10.6% were CD271＋, and 0.3% were STRO-1＋/CD146＋. Under odontogenic conditions, all three subsets of isolated DMSCs exhibited differentiation capacity into odontogenic lineages. Among these isolated subsets of DMSCs, CD271＋ DMSCs demonstrated the greatest odontogenic potential. While all three combinations of surface markers in this study successfully isolated DMSCs from DPCs, the single CD271 marker presents the most effective stem cell surface marker for identification of DMSCs with high odontogenic potential. Isolated CD271＋ DMSCs could potentially be utilized for future clinical applications in dentistry and regenerative medicine.

The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins(BMPs). The epigenetic regulation of estrogen-mediated osteogenesis,however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B(KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs.Mechanistically, upon estrogen stimulation, estrogen receptor-α(ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen’s pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop

Background:Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis,high lymph node metastasis and early recurrence.However,the molecular events regulating HNSCC tumorigenesis remain poorly understood.Therefore,uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC.In this study,we aimed to explore the role of pleckstrin-2(PLEK2)in regulating HNSCC tumorigenesis.Methods:The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort.In vitro and in vivo experiments,including cell proliferation,colony formation,Matrigel invasion,tumor sphere formation,ALDEFLUOR,Western blotting assays and xenograft mouse models,were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells.The underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation,cycloheximide chase analysis,ubiquitination assays,chromatin immunoprecipitation-quantitative polymerase chain reaction,luciferase reporter assays and rescue experiments.Results:The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues,and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance.Additionally,PLEK2 was important for maintaining the proliferation,invasion,epithelial-mesenchymal transition,cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells.Mechanistically,PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7(FBXW7)with c-Myc,thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of c-Myc.Moreover,the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells.c-Myc also directly bounded to the PLEK2 promoter and activated its transcription,forming a positive feedback loop.Conclusions:Collectively,these findings uncover a previously unknown molecular basis of PLEK2-enhanced c-Myc signaling in HNSCC,suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.

Neutrophil-sourced TNF in cancer:deciphering an intricate orchestrator of immunosuppressive communication in the tumor microenvironment

In a recent Cancer Discovery publication,Bianchi et al.unveil a crucial mechanism driving therapeutic resistance in pancreatic ductal adenocarcinoma(PDAC),orchestrated by cell-autonomous Cxcl1 and TNF from polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs).This insight provides fresh perspectives for surmounting such resistance in PDAC.1 PDAC represents a highly aggressive malignancy exhibiting substantial therapeutic resistance,attributable to factors such as intractable genomic aberrations,immunosuppression mediated by myeloid cells,and pro-inflammatory activation of cancerassociated fibroblasts.

In inflammatory bowel disease and extraintestinal manifestations:What role does microbiome play?

Inflammatory bowel disease(IBD)is a systemic disorder affecting intestinal tract and other organs outside the gut,known as extraintestinal manifestations(EIMs).These EIMs are complex and diverse,and early treatment may reduce teratogenic rates and improve quality of life.However,our understanding of EIMs in IBD is currently limited by a lack of mechanistic insight.Fortunately,advances in our understanding of intestinal microecology are allowing us to uncover the underlying mechanisms of EIMs.The gut microbiota can drive aberrant immune activation and intestinal inflammation.Intriguingly,chronic inflammation can also shape the microbiome in reverse and aggravate dysbiosis.Recent research has revealed that microbiome-derived signal molecules play a crucial role in catalyzing enterocolitis and altering mucosal barrier function.Furthermore,gut microbiota-associated antigens can translocate from the intestine to extraintestinal sites,leading to systemic inflammatory responses.The microbiome is showing its potential in treating IBD and EIMs,and microbial engineering approaches,such as probiotic engineering and engineered fecal microbiota transplantation,are exhibiting great promise for IBD therapeutics.