Liver pathology in COVID-19 related death and leading role of autopsy in the pandemic

BACKGROUND Information on liver involvement in patients with coronavirus disease 2019 is currently fragmented.AIM To highlight the pathological changes found during the autopsy of severe acute respiratory syndrome coronavirus 2 positive patients.METHODS A systematic literature search on PubMed was carried out until June 21,2022.RESULTS A literature review reveals that pre-existing liver disease and elevation of liver enzyme in these patients are not common;liver enzyme elevations tend to be seen in those in critical conditions.Despite the poor expression of viral receptors in the liver,it seems that the virus is able to infect this organ and therefore cause liver damage.Unfortunately,to date,the search for the virus inside the liver is not frequent(16%of the cases)and only a small number show the presence of the virus.In most of the autopsy cases,macroscopic assessment is lacking,while microscopic evaluation of livers has revealed the frequent presence of congestion(42.7%)and steatosis(41.6%).Less frequent is the finding of hepatic inflammation or necrosis(19%)and portal inflammation(18%).The presence of microthrombi,frequently found in the lungs,is infrequent in the liver,with only 12%of cases presenting thrombotic formations within the vascular tree.CONCLUSION To date,the greatest problem in interpreting these modifications remains the association of the damage with the direct action of the virus,rather than with the inflammation or alterations induced by hypoxia and hypovolemia in patients undergoing oxygen therapy and decompensated patients.

The roles of macrophage migration inhibitory factor in retinal diseases

Macrophage migration inhibitory factor(MIF),a multifunctional cytokine,is secreted by various cells and participates in inflammatory reactions,including innate and adaptive immunity.There are some evidences that MIF is involved in many vitreoretinal diseases.For example,MIF can exacerbate many types of uveitis;measurements of MIF levels can be used to monitor the effectiveness of uveitis treatment.MIF also alleviates trauma-induced and glaucoma-induced optic nerve damage.Furthermore,MIF is critical for retinal/choroidal neovascularization,especially complex neovascularization.MIF exacerbates retinal degeneration;thus,anti-MIF therapy may help to mitigate retinal degeneration.MIF protects uveal melanoma from attacks by natural killer cells.The mechanism underlying the effects of MIF in these diseases has been demonstrated:it binds to cluster of differentiation 74,inhibits the c-Jun N-terminal kinase pathway,and triggers mitogen-activated protein kinases,extracellular signal-regulated kinase-1/2,and the phosphoinositide-3-kinase/Akt pathway.MIF also upregulates Toll-like receptor 4 and activates the nuclear factor kappa-B signaling pathway.This review focuses on the structure and function of MIF and its receptors,including the effects of MIF on uveal inflammation,retinal degeneration,optic neuropathy,retinal/choroidal neovascularization,and uveal melanoma.

Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease

Alzheimer's disease(AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low-and middle-income countries.

NLRP3/1-mediated pyroptosis:beneficial clues for the development of novel therapies for Alzheimer’s disease

The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.

Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer

BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Comparison of mismatch repair and immune checkpoint protein profile with histopathological parameters in pancreatic,periampullary/ampullary,and choledochal adenocarcinomas

BACKGROUND Pancreatic,periampullary/ampullary,and choledochal adenocarcinomas are aggressive malignancies with a poor prognosis.Immune checkpoint blockade is a promising treatment option for several tumor types.H long terminal repeatassociating 2(HHLA2),which is analogous to programmed death-ligand 1(PDL1),is a recently discovered member of the B7/cluster of differentiation 28 family and is expressed in many malignancies.AIM To analyze the expression of HHLA2 and its association with the pathologic biomarkers that predict sensitivity to immunotherapy.METHODS Ninety-two adenocarcinoma cases located in the pancreas,ampulla,and distal common bile duct were identified.This study assessed 106 pancreaticoduodenectomy and distal/total pancreatectomy samples that were delivered to Ankara City Hospital between 2019 and 2021.Immunohistochemistry was conducted to examine the expression of DNA mismatch repair(MMR),PD-L1,and HHLA2 proteins.RESULTS Patients with high HHLA2 expression had a higher mean age than those with low expression.Low HHLA2 expression was associated with high perineural invasion.HHLA2 expression was low in pathological stage T3(pT)3 cases and high in pathological stage T1,T2,and T4 cases.There was no correlation between HHLA2 expression and the expression of MMR proteins and PD-L1.CONCLUSION Evaluation of HHLA2 expression in microsatellite stable and PD-L1-negative tumors may be useful for predicting the response of individuals to immunotherapy and may serve as a novel therapeutic target for immunotherapy in advanced-stage disease.

Benign stricture of bilioenteric anastomosis after Whipple withsynthetic polypropylene suture

To the Editor:Biliary stricture formation at the bilioenteric anastomosis is an infrequent complication(2%-3%)after pancreaticoduodenectomy;the average presentation is within 13-14 months(range from 1 month to 9 years)after surgery[1,2].While the etiology is unknown,development of biliary stricture has shown to be more likely if a bile leak occurs in the postoperative period[3,4]and with younger patients[5].

Misdiagnosis of synovial sarcoma-cellular myofibroma with SRFRELA gene fusion:A case report

BACKGROUND Cellular myofibroma is a rare subtype of myofibroma that was first described in 2017.Its diagnosis is often challenging because of its relative rarity,lack of known genetic abnormalities,and expression of muscle markers that can be confused with sarcomas that have myogenic differentiation.Currently,scholars have limited knowledge of this disease,and published cases are few.Further accumulation of diagnostic and treatment experiences is required.CASE SUMMARY A 16-year-old girl experienced left upper limb swelling for 3 years.She sought medical attention at a local hospital 10 months ago,where magnetic resonance imaging revealed a 5-cm soft tissue mass.Needle biopsy performed at a local hospital resulted in the diagnosis of a spindle cell soft tissue sarcoma.The patient was referred to our hospital for limb salvage surgery with endoprosthetic replacement.She was initially diagnosed with a synovial sarcoma.Consequently,clinical management with chemotherapy was continued for the malignant sarcoma.Our pathology department also performed fluorescence in situ hybridization for result validation,which returned negative for SS18 gene breaks,indicating that it was not a synovial sarcoma.Next-generation sequencing was used to identify the SRF-RELA rearrangement.The final pathological diagnosis was a cellular/myofibroblastic neoplasm with an SRF-RELA gene fusion.The patient had initially received two courses of chemotherapy;however,chemotherapy was discontinued after the final diagnosis.CONCLUSION This case was misdiagnosed because of its rare occurrence,benign biological behavior,and pathological similarity to soft tissue sarcoma.

Success rate of current human-derived gastric cancer organoids establishment and influencing factors:A systematic review and meta-analysis

BACKGROUND Human-derived gastric cancer organoids(GCOs)are widely used in gastric cancer research;however,the culture success rate is generally low.AIM To explore the potential influencing factors,and the literature on successful culture rates of GCOs was reviewed using meta-analysis.METHODS PubMed,Web of Science,and EMBASE were searched for studies.Two trained researchers selected the studies and extracted data.STATA 17.0 software was used for meta-analysis of the incidence of each outcome event.The adjusted Methodological Index for Non-Randomized Studies scale was used to assess the quality of the included studies.Funnel plots and Egger’s test were used to detect publication bias.Subgroup analyses were conducted for sex,tissue source,histo-logical classification,and the pathological tumor-node-metastasis(pTNM)cancer staging system.RESULTS Eight studies with a pooled success rate of 66.6%were included.GCOs derived from women and men had success rates of 67%and 46.7%,respectively.GCOs from surgery or biopsy/endoscopic submucosal dissection showed success rates of 70.9%and 53.7%,respectively.GCOs of poorly-differentiated,moderately-differentiated and signet-ring cell cancer showed success rates of 64.6%,31%,and 32.7%,respectively.GCOs with pTNM stages I-II and III-IV showed success rates of 38.3%and 65.2%,respectively.Y-27632 and non-Y-27632 use showed success rates of 58.2%and 70%,respectively.GCOs generated with collagenase were more successful than those constructed with Liberase TH and TrypLE(72.1%vs 71%,respectively).EDTA digestion showed a 50%lower success rate than other methods(P=0.04).CONCLUSION GCO establishment rate is low and varies by sex,tissue source,histological type,and pTNM stage.Omitting Y-27632,and using Liberase TH,TrypLE,or collagenase yields greater success than EDTA.

Epithelioid malignant peripheral nerve sheath tumor of the bladder and concomitant urothelial carcinoma: A case report

BACKGROUND Epithelioid malignant peripheral nerve sheath tumor(EMPNST)of the bladder is a rare entity with devastating features.These tumors are thought to originate from malignant transformation of pre-existing schwannomas of pelvic autonomic nerve plexuses,and unlike the conventional malignant peripheral nerve sheath tumor(MPNST),are not associated with neurofibromatosis.The tumor has dis-tinctive morphological,immunohistochemical and molecular features.Addi-tionally,it tends to be more aggressive and have a higher mortality.This is the first case that presents with a synchronous urothelial carcinoma of the bladder and the epithelioid variant of MPNST in the literature.It’s also the second re-ported case of EMPNST originating from the bladder wall.CASE SUMMARY In this case report,we present the detailed clinical course of a 71-year-old patient with EMPNST of the bladder alongside a literature review.CONCLUSION During the management of EMPNST cases,offering aggressive treatment moda-lities to the patient,such as radical cystectomy,is appropriate for the best chance to contain the disease,regardless of the tumor stage and the extent of local disease at initial diagnosis.

Prognostic significance and relationship of SMAD3 phosphoisoforms and VEGFR-1 in gastric cancer:A clinicopathological study

BACKGROUND The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis.SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer.AIM To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer.METHODS This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years(median age 65)between July 2006 and April 2007.Patients were followed up until death or the study ended(median follow-up duration of 28.5 mo).The samples were used to generate tissue microarrays(TMAs)for immunohistochemical(IHC)staining.The expressions of TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 in gastric cancer(GC)tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients.Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015.The relationship between TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient.The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test.A survival curve was generated using the Kaplan-Meier survival analysis.RESULTS TGFβ-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent noncancerous tissue.The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site[pSMAD3C(S423/425):51.0%and pSMAD3L(S204):31.6%].High expression of pSMAD-3L(S204)was significantly correlated with larger tumors(P=0.038)and later N stages(P=0.035).Additionally,high expression of VEGFR-1 was closely correlated with tumor size(P=0.015)and pathological grading(P=0.013).High expression of both pSMAD3L(S204)and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival(OS).Multivariate analysis indicated that high expression of pSMAD3L(S204)and VEGFR-1 were independent risk factors for prognosis in GC patients.VEGFR-1 protein expression was correlated with TGF-β1(r=0.220,P=0.029),pSMAD3C(S423/425)(r=0.302,P=0.002),and pSMAD3L(S204)(r=0.201,P=0.047),respectively.Simultaneous overexpression of pSMAD3L(S204)and VEGFR-1 was associated with poor OS in gastric cancer patients.CONCLUSION Co-upregulation of pSMAD3L(S204)and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis,and pSMAD3L(204)may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.

Value of multiple models of diffusion-weighted imaging to predict hepatic lymph node metastases in colorectal liver metastases patients

BACKGROUND About 10%-31% of colorectal liver metastases(CRLM)patients would concomitantly show hepatic lymph node metastases(LNM),which was considered as sign of poor biological behavior and a relative contraindication for liver resection.Up to now,there’s still lack of reliable preoperative methods to assess the status of hepatic lymph nodes in patients with CRLM,except for pathology examination of lymph node after resection.AIM To compare the ability of mono-exponential,bi-exponential,and stretchedexponential diffusion-weighted imaging(DWI)models in distinguishing between benign and malignant hepatic lymph nodes in patients with CRLM who received neoadjuvant chemotherapy prior to surgery.METHODS In this retrospective study,97 CRLM patients with pathologically confirmed hepatic lymph node status underwent magnetic resonance imaging,including DWI with ten b values before and after chemotherapy.Various parameters,such as the apparent diffusion coefficient from the mono-exponential model,and the true diffusion coefficient,the pseudo-diffusion coefficient,and the perfusion fraction derived from the intravoxel incoherent motion model,along with distributed diffusion coefficient(DDC)andαfrom the stretched-exponential model(SEM),were measured.The parameters before and after chemotherapy were compared between positive and negative hepatic lymph node groups.A nomogram was constructed to predict the hepatic lymph node status.The reliability and agreement of the measurements were assessed using the coefficient of variation and intraclass correlation coefficient.RESULTS Multivariate analysis revealed that the pre-treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes.A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients,with an area under the curve of 0.873.Furthermore,parameters from SEM showed substantial repeatability.CONCLUSION The developed nomogram,incorporating the pre-treatment DDC and the short axis of the largest lymph node,can be used to predict the presence of hepatic LNM in CRLM patients undergoing chemotherapy before surgery.This nomogram was proven to be more valuable,exhibiting superior diagnostic performance compared to quantitative parameters derived from multiple b values of DWI.The nomogram can serve as a preoperative assessment tool for determining the status of hepatic lymph nodes and aiding in the decision-making process for surgical treatment in CRLM patients.

Clinical pathological characteristics of“crawling-type”gastric adenocarcinoma cancer:A case report

BACKGROUND Gastric cancer(GC)is a significant health problem worldwide,and early detection and accurate diagnosis are crucial for improving patient outcomes.Crawling-type gastric adenocarcinoma is a rare subtype of GC that has unique histopathological and clinical characteristics,and its diagnosis and management can be challenging.This pathological type of GC is also rare.CASE SUMMARY Here,we report the case of a patient who underwent ordinary endoscopy,na-rrow-band imaging,and endoscopic ultrasonography intending to determine the extent of tumor invasion and upper abdominal enhanced computed tomography and whether there was tumor metastasis.Then,endoscopic submucosal dissection was performed.After pathological and immunohistochemical examination,the pathological diagnosis was crawling-type gastric adenocarcinoma.This is a very rare and special pathological type of tumor.This case highlights the importance of using advanced endoscopic techniques and pathological examination in diagnosing and managing gastric crawling-type adenocarcinoma.Moreover,the findings underscore the need for continued research and clinical experience in this rare subtype of GC to improve patient outcomes.CONCLUSION The“crawling-type”GC is a rare and specific tumor pathology.It is difficult to identify and diagnose gliomas via endoscopy.The tumor is ill-defined,with a flat appearance and indistinct borders due to the lack of contrast against the background mucosa.Pathology revealed that the tumor cells were hand-like,so the patient has diagnosed with“crawling-type”gastric adenocarcinoma.

Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

Primary anaplastic lymphoma kinase-positive large B-cell lymphoma of the left bulbar conjunctiva: A case report

BACKGROUND Anaplastic lymphoma kinase(ALK)-positive large B-cell lymphoma(LBCL)is an aggressive and rare variant of diffuse LBCL.Herein,we report an uncommon case of stage IE extranodal ALK-positive LBCL initially originating in the bulbar con-junctiva.CASE SUMMARY A 63-year-old woman presented with a mass in the left bulbar conjunctiva that had persisted for six months,accompanied by swelling and pain that had per-sisted for 3 d.Eye examination revealed an 8 mm slightly elevated pink mass in the lower conjunctival sac of the left eye.Microscopically,the tumor was com-posed of large immunoblastic and plasmablastic large lymphoid cells with scattered anaplastic or multinucleated large cells.Immunophenotypically,the neoplastic cells were positive for ALK,CD10,CD138,Kappa,MUM1,BOB.1,OCT-2,CD4,CD45,EMA,CD79a,CD38,and AE1/AE3,and negative for CD20,PAX5,Lambda,BCL6,CD30 and all other T-cell antigens.The results of gene rearrangement tests showed monoclonal IGH/IGK/IGL and TCRD rearran-gements.Fluorescence in situ hybridization studies did not reveal any BCL2,BCL6 or MYC rearrangements.Furthermore,Epstein-Barr virus was not detected by in situ hybridization in the lesions.Based on the histopathological and imaging examinations,the neoplasm was classified as stage IE ALK-positive LBCL.No further treatments were administered.At the 6,15,and 21 mo postoperative follow-up visits,the patient was in good condition,without obvious discomfort.This case represents the first example of primary extranodal ALK-positive LBCL presenting as a bulbar conjunctival mass,which is extremely rare and shares morphological and immunohistochemical features with a variety of other neo-plasms that can result in misdiagnosis.CONCLUSION Awareness of the condition presented in this case report is necessary for early and accurate diagnosis and appropriate treatment.

Primary unifocal penile follicular center non-Hodgkin lymphoma:Report of a rare case and review of the literature

Dear Editor,We present a rare case of a primary penile follicular center non-Hodgkin lymphoma and a review of the available literature on this condition.A BCL2 gene transposition which was identified with fluorescent in situ hybridization(FISH)molecular analysis is a unique manifestation not previously reported to the best of our knowledge.A 67-year-old man presented with a 3-month history of a small nodule on the left side of the corona of glans penis.The patient had no significant medical or family history.The patient underwent excision and biopsy of the penile lesion with a 0.5 cm macroscopic margin under local anesthesia and sedation.He was discharged on the day of surgery,and there were no postoperative complications or adverse events.The informed consent was obtained from thepatient.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Elimination of methicillin‑resistant Staphylococcus aureus biofilms on titanium implants via photothermally‑triggered nitric oxide and immunotherapy for enhanced osseointegration

Background:Treatment of methicillin-resistant Staphylococcus aureus(MRSA)biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium(Ti)implants.There is a need to explore more effective approaches for the treatment of MRSA biofilm infections.Methods:Herein,an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles(PDA),nitric oxide(NO)release donor sodium nitroprusside(SNP)and osteogenic growth peptide(OGP)onto Ti implants,denoted as Ti-PDA@SNP-OGP.The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy,X-ray photoelectron spectroscope,water contact angle,photothermal property and NO release behavior.The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2′,7′-dichlorofluorescein diacetate probe,1-N-phenylnaphthylamine assay,adenosine triphosphate intensity,O-nitrophenyl-β-D-galactopyranoside hydrolysis activity,bicinchoninic acid leakage.Fluorescence staining,assays for alkaline phosphatase activity,collagen secretion and extracellular matrix mineralization,quantitative real‑time reverse transcription‑polymerase chain reaction,and enzyme-linked immunosorbent assay(ELISA)were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells(MSCs),RAW264.7 cells and their co-culture system.Giemsa staining,ELISA,micro-CT,hematoxylin and eosin,Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms,inhibition of inflammatory response,and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo.Results:Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light(NIR)irradiation,and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species(ROS)-mediated oxidative stress,destroying bacterial membrane integrity and causing leakage of intracellular components(P<0.01).In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs,but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype(P<0.05 or P<0.01).The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways(P<0.01).In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model(P<0.01).Conclusions:Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Roles and application of exosomes in the development,diagnosis and treatment of gastric cancer

As important messengers of intercellular communication,exosomes can regulate local and distant cellular communication by transporting specific exosomal con-tents and can also promote or suppress the development and progression of gas-tric cancer(GC)by regulating the growth and proliferation of tumor cells,the tumor-related immune response and tumor angiogenesis.Exosomes transport bioactive molecules including DNA,proteins,and RNA(coding and noncoding)from donor cells to recipient cells,causing reprogramming of the target cells.In this review,we will describe how exosomes regulate the cellular immune respon-se,tumor angiogenesis,proliferation and metastasis of GC cells,and the role and mechanism of exosome-based therapy in human cancer.We will also discuss the potential application value of exosomes as biomarkers in the diagnosis and treat-ment of GC and their relationship with drug resistance.

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.