Promotion effect of TGF-β-Zfp423-ApoD pathway on lip sensory recovery after nerve sacrifice caused by nerve collateral compensation

Resection of oral and maxillofacial tumors is often accompanied by the inferior alveolar nerve neurectomy,resulting in abnormal sensation in lower lip.It is generally believed that spontaneous sensory recovery in this nerve injury is difficult.However,during our follow-up,patients with inferior alveolar nerve sacrifice showed different degrees of lower lip sensory recovery.In this study,a prospective cohort study was conducted to demonstrate this phenomenon and analyze the factors influencing sensory recovery.

Discrimination of Metastatic from Non-metastatic Mesorectal Lymph Nodes in Rectal Cancer Using Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Preoperative detection of lymph nodes（LNs） metastasis is always highly challenging for radiologists nowadays. The utility of quantitative dynamic contrast-enhanced magnetic resonance imaging（QDCE-MRI） in identifying LNs metastasis is not well understood. In the present study, 59 patients with histologically proven rectal carcinoma underwent preoperative QDCE-MRI. The short axis diameter ratio, long axis diameter ratio, short-to-long axis diameter ratio and QDEC-MRI parameters（Ktrans, Kep, fPV and Ve） values were compared between the non-metastatic（n=44） and metastatic（n=35） LNs groups based on pathological examination. Compared with the non-metastatic group, the metastatic group exhibited significantly higher short axis diameter（7.558±0.668 mm vs. 5.427±0.285 mm）, Ktrans（0.483±0.198 min-1 vs. 0.218±0.116 min^-1） and Ve（0.399±0.118 vs. 0.203±0.096） values（all P〈0.05）. The short-to-long axis diameter ratio, long axis diameter ratio, Kep and fPV values did not show significant differences between the two groups. In conclusion, our results showed that for LNs larger than 5 mm in rectal cancer, there are distinctive differences in the Ktrans and Ve values between the metastatic and non-metastatic LNs, suggesting that QDCE-MRI may be potentially helpful in identifying LNs status.

Identification of optimal contemporary antiemetic prophylaxis for doxorubicin-cyclophosphamide chemotherapy in Chinese cancer patients: post-hoc analysis of 3 prospective studies

Objective:Chemotherapy-induced nausea and vomiting(CINV)are common with doxorubicin-cyclophosphamide(AC)chemotherapy.Recommended antiemetic regimens incorporate neurokinin-1 receptor antagonist(NK1 RA),5-hydroxytryptamine type-3 receptor antagonist(5 HT3 RA),corticosteroid,and dopamine antagonists.This post-hoc analysis compared results of 3 prospective antiemetic studies conducted among Chinese breast cancer patients who received(neo)adjuvant AC,in order to identify optimal antiemetic prophylaxis.Methods:A total of 304 patients were included:Group 1,ondansetron/dexamethasone(D1);Group 2,aprepitant/ondansetron/dexamethasone(D1);Group 3,aprepitant/ondansetron/dexamethasone(D1–3);Group 4,aprepitant/ondansetron/dexamethasone(D1–3)/olanzapine;and Group 5,netupitant/palonosetron/dexamethasone(D1–3).Antiemetic efficacies of Groups 3,4,and 5 during cycle 1 of AC were individually compared with Group 1.In addition,emesis outcomes of patients in Groups 3 and 5,and those of Groups 2 and 3,were compared.Results:When comparing efficacies of a historical doublet(5 HT3 RA/dexamethasone)with triplet antiemetic regimens(NK1 RA/5 HT3 RA/dexamethasone)with/without olanzapine,complete response(CR)percentages and quality of life(QOL)in overall phase of cycle 1 AC were compared between Group 1 and the other groups:Group 1 vs.3,41.9%vs.38.3%(P=0.6849);Group 1 vs.4,41.9%vs.65.0%(P=0.0107);and Group 1 vs.5,41.9%vs.60.0%(P=0.0460).Groups 4 and 5 achieved a better QOL.When comparing netupitant-based(Group 3)with aprepitant-based(Group 5)triplet antiemetics,CR percentages were 38.3%vs.60.0%,respectively(P=0.0176);Group 5 achieved a better QOL.When comparing 1 day(Group 2)vs.3 day(Group 3)dexamethasone,CR percentages were 46.8%and 38.3%,respectively(P=0.3459);Group 3 had a worse QOL.Conclusions:Aprepitant-containing triplets were non-superior to doublet antiemetics.Netupitant-containing triplets and adding olanzapine to aprepitant-containing triplets were superior to doublets.Netupitant/palonosetron/dexamethasone was superior to aprepitant/ondansetron/dexamethasone.Protracted administration of dexamethasone provided limited additional benefit.

The RhoA nuclear localization changes in replicative senescence:New evidence from in vitro human mesenchymal stem cells studies

All non-immortalized mesenchymal stem cells have a limited proliferative potential,that is,replicative senescence(RS)is an integral characteristic of the life of all mesenchymal stem cells(MSCs).It is known that one of the important signs of RS is a decrease of cell motility,and that violations of migration processes contribute to the deterioration of tissue regeneration.Therefore,the characterization of the properties of the cell line associated with RS is a prerequisite for the effective use of MSCs in restorative medicine.One of the key proteins regulating cell motility is the small GTPase RhoA.The main purpose of this work was to study the nuclear-cytoplasmic redistribution of the RhoA protein during RS in MSC lines recently obtained and characterized in our laboratory.The study found that a comparative analysis of the intracellular localization of RhoA in three cell lines(MSCWJ-1,FetMSC,DF2)showed a decrease in the nuclear localization of RhoA during RS.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib

BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.

Platelet RNA enables accurate detection of ovarian cancer:an intercontinental,biomarker identification study

Platelets are reprogrammed by cancer via a process called education,which favors cancer development.The transcriptional profile of tumor-educated platelets(TEPs)is skewed and therefore practicable for cancer detection.This intercontinental,hospital-based,diagnostic study included 761 treatment-naive inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers(China,n=3;Netherlands,n=5;Poland,n=1)between September 2016 and May 2019.The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese(VC1 and VC2)and the European(VC3)validation cohorts collectively and independently.Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets.The AUCs for TEPs in the combined validation cohort,VC1,VC2,and VC3 were 0.918(95%CI 0.889-0.948),0.923(0.855-0.990),0.918(0.872-0.963),and 0.887(0.813-0.960),respectively.Combination of TEPs and CA125 demonstrated an AUC of 0.922(0.889-0.955)in the combined validation cohort;0.955(0.912-0.997)in VC1;0.939(0.901-0.977)in VC2;0.917(0.824-1.000)in VC3.For subgroup analysis,TEPs exhibited an AUC of o.858,0.859,and 0.920 to detect early-stage,borderline,non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis.TEPs had robustness,compatibility,and universality for preop.erative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities,heterogeneous histoiogical subtypes,and early-stage ovarian cancer.However,these observations warrant prospective validations in a larger population beforeclinicalutilities.

Cellular zinc metabolism and zinc signaling:from biological functions to diseases and therapeutic targets

Zinc metabolism at the cellular level is critical for many biological processes in the body.A key observation is the disruption of cellular homeostasis,often coinciding with disease progression.As an essential factor in maintaining cellular equilibrium,cellular zinc has been increasingly spotlighted in the context of disease development.Extensive research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells,despite its low tissue concentration.This has led to a growing body of literature investigating zinc’s cellular metabolism,particularly the functions of zinc transporters and storage mechanisms during cancer progression.Zinc transportation is under the control of two major transporter families:SLC30(ZnT)for the excretion of zinc and SLC39(ZIP)for the zinc intake.Additionally,the storage of this essential element is predominantly mediated by metallothioneins(MTs).This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression,with a special focus on cancer.We also compile a summary of clinical trials involving zinc ions.Given the main localization of zinc transporters at the cell membrane,the potential for targeted therapies,including small molecules and monoclonal antibodies,offers promising avenues for future exploration.

The effect of the magnetic fields from three different configurations of the MRIgRT systems on the dose deposition from lateral opposing photon beams in a laryngeal geometry–A Monte Carlo study

Objective:To investigate the impact of different magnetic field strengths and orientations on the dose deposition from lateral opposing photon beams irradiating a laryngeal geometry,with particular attention focused on the dose homogeneity of the area around the air cavity inside the larynx.Methods:Geant4 simulation toolkit was used to perform Monte Carlo simulations on a phantom resembling the larynx.The energy spectrum of a 6 MV photon beam from a Varian Clinac iX machine was used to provide the source of radiation.Three configurations of the Magnetic Resonance Image-Guided Radiation Therapy(MRIgRT)system were simulated:the Fixed Cylindrical(FC)geometry,the Longitudinal Rotating Biplanar(LRBP)geometry,and the Transverse Rotating Biplanar(TRBP)geometry.Uniform magnetic fields of different field strengths were applied.The relative dose maps and the homogeneity index(HI)were obtained for evaluations.Results:The LRBP geometry together with a magnetic field strength of 0.5 T produced the most homogeneous dose distribution with a HI of 0.139 for the region of interest around the air cavity,compared with a HI of 0.180 when the magnetic field was absent.For TRBP geometry,the dose distribution shifted towards the cranial direction,leading to a region of hot spots at the superior edge and a region of cold spots at the inferior edge of the irradiated volume.The HI around the air cavity was therefore worse.In addition,strong electron streaming effect(ESE)was observed.For the FC geometry,hot and cold spots were formed around the air cavity which increased the HI.Conclusions:Out of the three configurations of the MRIgRT systems,the LRBP geometry produced the most clinically beneficial dose distribution in which it provided a higher dose to the treatment area and a boost in dose to the tissue immediately adjacent to the air cavity.

Signaling pathways in cancer metabolism:mechanisms and therapeutic targets

A wide spectrum of metabolites(mainly,the three major nutrients and their derivatives)can be sensed by specific sensors,then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics,which is called metabolite sensing.Life body regulates metabolism,immunity,and inflammation by metabolite sensing,coordinating the pathophysiology of the host to achieve balance with the external environment.Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell,including cell proliferation,migration,invasion,angiogenesis,etc.Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer,thus forming a vicious circle.At the same time,exogenous metabolites can also affect the biological behavior of tumors.Here,we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives,as well as their abnormalities in the development of various cancers,and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.

The Hong Kong consensus statements on unresectable hepatocellular carcinoma:narrative review and update for 2021

Background and Objective:Hong Kong,like many parts of Asia,faces a high burden of hepatocellular carcinoma(HCC)caused by high endemic rates of hepatitis B virus infection.Hong Kong clinicians have developed a high level of expertise in HCC treatment across surgical,transarterial,ablative,radiotherapeutic and systemic modalities.This publication summarizes the latest evidence-based recommendations on how these modalities should be used.Methods:In two meetings held in 2020,a multidisciplinary panel of surgeons,oncologists and interventional radiologists performed a narrative review of evidence on the management of HCC,with an emphasis on treatment of HCC not amenable to surgical resection.Close attention was paid to new evidence published since the previous version of these statements in 2018.Key Content and Findings:The expert panel has formulated 60 consensus statements to guide the staging and treatment of unresectable HCC.Since the previous version of these statements,considerable additions have been made to the recommendations on use of targeted therapies and immunotherapies because of the large volume of new evidence.Conclusions:Our consensus statements offer guidance on how to select HCC patients for surgical or non-surgical treatment and for choosing among non-surgical modalities for patients who are not candidates for resection.In particular,there is a need for more evidence to aid physicians in the selection of second-line systemic therapies,as currently most data are limited to patients with disease progression on first-line sorafenib.

Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factors drive metastatic spread is incompletely understood.Here,we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase(CCRK)signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment.Using an inducible liverspecific transgenic model,we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer(CRC)metastasis to the liver,which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells(PMNMDSCs)and lacking natural killer T(NKT)cells.Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7%(metastatic tumor weights)in the melanoma and CRC models,respectively.Mechanistically,CCRK activated nuclear factor-kappa B(NF-κB)signaling to increase the PMN-MDSC trafficking chemokine C-X-C motif ligand 1(CXCL1),which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice.Accordingly,CRC liver metastasis patients exhibited hyperaaivation of hepatic CCRK/NF-κB/CXCL1 signaling,which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors.In summary,this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance.Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.