Construction and validation of somatic mutation-derived long noncoding RNAs signatures of genomic instability to predict prognosis of hepatocellular carcinoma

BACKGROUND Long non-coding RNAs(LncRNAs)have been found to be a potential prognostic factor for cancers,including hepatocellular carcinoma(HCC).Some LncRNAs have been confirmed as potential indicators to quantify genomic instability(GI).Nevertheless,GI-LncRNAs remain largely unexplored.This study established a GI-derived LncRNA signature(GILncSig)that can predict the prognosis of HCC patients.AIM To establish a GILncSig that can predict the prognosis of HCC patients.METHODS Identification of GI-LncRNAs was conducted by combining LncRNA expression and somatic mutation profiles.The GI-LncRNAs were then analyzed for functional enrichment.The GILncSig was established in the training set by Cox regression analysis,and its predictive ability was verified in the testing set and TCGA set.In addition,we explored the effects of the GILncSig and TP53 on prognosis.RESULTS A total of 88 GI-LncRNAs were found,and functional enrichment analysis showed that their functions were mainly involved in small molecule metabolism and GI.The GILncSig was constructed by 5 LncRNAs(miR210HG,AC016735.1,AC116351.1,AC010643.1,LUCAT1).In the training set,the prognosis of high-risk patients was significantly worse than that of low-risk patients,and similar results were verified in the testing set and TCGA set.Multivariate Cox regression analysis and stratified analysis confirmed that the GILncSig could be used as an independent prognostic factor.Receiver operating characteristic curve analysis of the GILncSig showed that the area under the curve(0.773)was higher than the two LncRNA signatures published recently.Furthermore,the GILncSig may have a better predictive performance than TP53 mutation status alone.CONCLUSION We established a GILncSig that can predict the prognosis of HCC patients,which will help to guide prognostic evaluation and treatment decisions.

Failure evaluation and control factor analysis of slope block instability along traffic corridor in Southeastern Tibet

The instability of slope blocks occurred frequently along traffic corridor in Southeastern Tibet(TCST),which was primarily controlled by the rock mass structures.A rapid method evaluating the control effects of rock mass structures was proposed through field statistics of the slopes and rock mass structures along TCST,which combined the stereographic projection method,modified M-JCS model,and limit equilibrium theory.The instabilities of slope blocks along TCST were then evaluated rapidly,and the different control factors of instability were analyzed.Results showed that the probabilities of toppling(5.31%),planar(16.15%),and wedge(35.37%)failure of slope blocks along TCST increased sequentially.These instability modes were respectively controlled by the anti-dip joint,the joint parallel to slope surface with a dip angle smaller than the slope angle(singlejoint),and two groups of joints inclined out of the slope(double-joints).Regarding the control effects on slope block instability,the stabilization ability of doublejoints(72.7%),anti-dip joint(67.4%),and single-joint(57.6%)decreased sequentially,resulting in different probabilities of slope block instability.Additionally,nearby regional faults significantly influenced the joints,leading to spatial heterogeneity and segmental clustering in the stabilization ability provided by joints to the slope blocks.Consequently,the stability of slope blocks gradually weakened as they approached the fault zones.This paper can provide guidance and assistance for investigating the development characteristics of rock mass structures and the stability of slope blocks.

Parametric instability in the pure-quartic nonlinear Schrödinger equation

We study the nonlinear stage of modulation instability(MI)in the non-intergrable pure-quartic nonlinear Schrödinger equation where the fourth-order dispersion is modulated periodically.Using the three-mode truncation,we reveal the complex recurrence of parametric resonance(PR)breathers,where each recurrence is associated with two oscillation periods(PR period and internal oscillation period).The nonlinear stage of parametric instability admits the maximum energy exchange between the spectrum sidebands and central mode occurring outside the MI gain band.

Growth mechanism and characteristics of electron drift instability in Hall thruster with different propellant types

The existence of a significant electron drift instability(EDI) in the Hall thruster is considered as one of the possible causes of the abnormal increase in axial electron mobility near the outlet of the channel. In recent years, extensive simulation research on the characteristics of EDI has been conducted, but the excitation mechanism and growth mechanism of EDI in linear stage and nonlinear stage remain unclear. In this work, a one-dimensional PIC model in the azimuthal direction of the thruster near-exit region is established to gain further insights into the mechanism of the EDI in detail, and the effects of different types of propellants on EDI characteristics are discussed. The changes in axial electron transport caused by EDI under different types of propellants and electromagnetic field strengths are also examined. The results indicate that EDI undergoes a short linear growth phase before transitioning to the nonlinear phase and finally reaching saturation through the ion Landau damping. The EDI drives a significant ion heating in the azimuthal direction through electron–ion friction before entering the quasi-steady state, which increases the axial mobility of the electrons. Using lighter atomic weight propellant can effectively suppress the oscillation amplitude of EDI, but it will increase the linear growth rate, frequency, and phase velocity of EDI. Compared with the classical mobility, the axial electron mobility under the EDI increases by three orders of magnitude, which is consistent with experimental phenomena. The change of propellant type is insufficient to significantly change the axial electron mobility. It is also found that the collisions between electrons and neutral gasescan significantly affect the axial electron mobility under the influence of EDI, and lead the strength of the electric field to increase and the strength of the magnetic field to decrease, thereby both effectively suppressing the axial transport of electrons.

Effect of external magnetic field on the instability of THz plasma waves in nanoscale graphene field-effect transistors

The instability of plasma waves in the channel of field-effect transistors will cause the electromagnetic waves with THz frequency.Based on a self-consistent quantum hydrodynamic model,the instability of THz plasmas waves in the channel of graphene field-effect transistors has been investigated with external magnetic field and quantum effects.We analyzed the influence of weak magnetic fields,quantum effects,device size,and temperature on the instability of plasma waves under asymmetric boundary conditions numerically.The results show that the magnetic fields,quantum effects,and the thickness of the dielectric layer between the gate and the channel can increase the radiation frequency.Additionally,we observed that increase in temperature leads to a decrease in both oscillation frequency and instability increment.The numerical results and accompanying images obtained from our simulations provide support for the above conclusions.

Contrasts of bimodal tropical instability waves(TIWs)-induced wind stress perturbations in the Pacific Ocean among observations,ocean models,and coupled climate models

The coupling between wind stress perturbations and sea surface temperature(SST)perturbations induced by tropical instability waves(TIWs)in the Pacific Ocean has been revealed previously and proven crucial to both the atmosphere and ocean.However,an overlooked fact by previous studies is that the loosely defined“TIWs”actually consist of two modes,including the Yanai wave-based TIW on the equator(hereafter eTIW)and the Rossby wave-based TIW off the equator(hereafter vTIW).Hence,the individual feedbacks of the wind stress to the bimodal TIWs remain unexplored.In this study,individual coupling relationships are established for both eTIW and v TIW,including the relationship between the TIW-induced SST perturbations and two components of wind stress perturbations,and the relationship between the TIW-induced wind stress perturbation divergence(curl)and the downwind(crosswind)TIW-induced SST gradients.Results show that,due to different distributions of eTIW and vTIW,the coupling strength induced by the eTIW is stronger on the equator,and that by the vTIW is stronger off the equator.The results of any of eTIW and vTIW are higher than those of the loosely defined TIWs.We further investigated how well the coupling relationships remained in several widely recognized oceanic general circulation models and fully coupled climate models.However,the coupling relationships cannot be well represented in most numerical models.Finally,we confirmed that higher resolution usually corresponds to more accurate simulation.Therefore,the coupling models established in this study are complementary to previous research and can be used to refine the oceanic and coupled climate models.

Wave nature of Rosensweig instability

The explicit analytical solution of Rosensweig instability spikes'shapes obtained by Navier-Stokes(NS)equation in diverse magnetic field H vertical to the flat free surface of ferrofluids are systematically studied experimentally and theoretically.After carefully analyzing and solving the NS equation in elliptic form,the force balanced surface equations of spikes in Rosensweig instability are expressed as cosine wave in perturbated magnetic field and hyperbolic tangent in large magnetic field,whose results both reveal the wave-like nature of Rosensweig instability.The results of hyperbolic tangent form are perfectly fitted to the experimental results in this paper,which indicates that the analytical solution is basically correct.Using the forementioned theoretical results,the total energy of the spike distribution pattern is calculated.By analyzing the energy components under different magnetic field intensities H,the hexagon-square transition of Rosensweig instability is systematically discussed and explained in an explicit way.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors

Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Transverse mode-coupling instability with longitudinal impedance

Transverse mode-coupling instability(TMCI)is a dangerous transverse single-bunch instability that can lead to severe par-ticle loss.The mechanism of TMCI can be explained by the coupling of transverse coherent oscillation modes owing to the transverse short-range wakefield(i.e.,the transverse broadband impedance).Recent studies on future circular colliders,e.g.,FCC-ee,showed that the threshold of TMCI decreased significantly when both longitudinal and transverse impedances were included.We performed computations for the circular electron-positron collider(CEPC)and observed a similar phenom-enon.Systematic studies on the influence of longitudinal impedance on the TMCI threshold were conducted.We concluded that the imaginary part of the longitudinal impedance,which caused a reduction in the incoherent synchrotron tune,was the primary reason for the reduction in the TMCI threshold.Additionally,the real part of the longitudinal impedance assists in increasing the TMCI threshold.

Urgent need for prognostic markers for hepatocellular carcinoma in the light of genomic instability and non-coding RNA signatures

In this editorial,we comment on an original article by Duan et al.Despite ad-vancements in the diagnosis and treatment of hepatocellular carcinoma(HCC),the identification of suitable prognostic factors remains challenging.In their paper,Duan et al identified long non-coding RNAs(LncRNAs)to quantify ge-nomic instability(GI)by combining LncRNA expression and somatic mutation profiles.They confirmed that the GI-derived LncRNA signature(GI-LncSig)could be an independent prognostic factor with the area under the curve of 0.773.Fur-thermore,the authors stated that GI-LncSig may have a better predictive perfor-mance than TP53 mutation status alone.However,studies exploring genetic markers for predicting the prognosis of HCC are crucial for identifying thera-peutic targets and enhancing diagnostic and treatment strategies to mitigate the global burden of liver cancer.

Clinical application value of long non-coding RNAs signatures of genomic instability in predicting prognosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)presents challenges due to its high recurrence and metastasis rates and poor prognosis.While current clinical diagnostic and prognostic indicators exist,their accuracy remains imperfect due to their biol-ogical complexity.Therefore,there is a quest to identify improved biomarkers for HCC diagnosis and prognosis.By combining long non-coding RNA(lncRNA)expression and somatic mutations,Duan et al identified five representative lncRNAs from 88 lncRNAs related to genomic instability(GI),forming a GI-derived lncRNA signature(LncSig).This signature outperforms previously re-ported LncSig and TP53 mutations in predicting HCC prognosis.In this editorial,we comprehensively evaluate the clinical application value of such prognostic evaluation model based on sequencing technology in terms of cost,time,and practicability.Additionally,we provide an overview of various prognostic models for HCC,aiding in a comprehensive understanding of research progress in pro-gnostic evaluation methods.

Homogeneity-Breaking Instability of Periodic Solutions of Gierer-Meindardt Model

The homogeneity-breaking instability of the periodic solutions triggered by Hopf bifurcations of a diffusive Gierer-Meinhart system is studied in this paper.Sufficient conditions on the diffusion coefficients and the cross diffusion coefficients were derived to guarantee the occurrence of the aforementioned homogeneity-breaking instability.

Advancing prognostic understanding in hepatocellular carcinoma through the integration of genomic instability and lncRNA signatures: GILncSig model

The recently published study by Duan et al introduces a promising method that combines genomic instability and long non-coding RNAs to improve the prognostic evaluation of hepatocellular carcinoma(HCC),a deadly cancer associated with considerable morbidity and mortality.This editorial aims to analyze the methodology,key findings,and broader implications of the study within the fields of gastroenterology and oncological surgery,highlighting the shift towards precision medicine in the management of HCC.

Comparative effectiveness of immunotherapy and chemotherapy in patients with metastatic colorectal cancer stratified by microsatellite instability status

BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemotherapy for patients with low MSI(MSI-L),and microsatellite stable(MSS)metastatic colorectal cancer remains unclear.AIM To investigate immunotherapy vs chemotherapy for treatment of MSI-L/MSS metastatic colorectal cancer,and to evaluate the success of immunotherapy against chemotherapy in managing MSI-H metastatic colorectal cancer during a follow-up of 50 months.METHODS We conducted a retrospective cohort study using the National Cancer Database(NCDB)to evaluate the overall survival(OS)of patients with metastatic colorectal cancer treated with immunotherapy or chemotherapy.The study population was stratified by MSI status(MSI-H,MSI-L,and MSS).Multivariable Cox proportional hazard models were used to assess the association between treatment modality and OS,adjusting for potential confounders.RESULTS A total of 21951 patients with metastatic colorectal cancer were included in the analysis,of which 2358 were MSI-H,and 19593 were MSI-L/MSS.In the MSI-H cohort,immunotherapy treatment(n=142)was associated with a significantly improved median OS compared to chemotherapy(n=860).After adjusting for potential confounders,immunotherapy treatment remained significantly associated with better OS in the MSI-H cohort[adjusted hazard ratio(aHR):0.57,95%confidence interval(95%CI):0.43-0.77,P<0.001].In the MSS cohort,no significant difference in median OS was observed between immunotherapy treatment and chemotherapy(aHR:0.94,95%CI:0.69-1.29,P=0.715).CONCLUSION In this population-based study using the NCDB,immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer,but not in those with MSI-L/MSS metastatic colorectal cancer.Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer.

A Study of Radiation-Induced Telomere Instability Using Multiplex Ligation-Dependent Probe Amplification (MLPA)

The integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation was analyzed by Multiplex Ligation-Dependent Probe Amplification (MLPA). The TK6 cell line has the native p53 tumor-suppressor gene, whereas WTK1 cells contain a p53 mutation. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. The impact of irradiation on these two cell lines was investigated using probes that target specific regions on chromosomes associated with subtelomeric regions. Results indicate that WTK1 and TK6 are impacted differently after irradiation, and that each cell line presents its own unique MLPA profile. The most notable differences are the appearance of a number of probes in the post-irradiated MLPA profile that are not present in the controls, and two unique probe signals only seen in WTK1 cells. These results build on our previous studies that indicate how different human cell lines can be affected by radiation in significantly different ways depending on the presence or absence of wild type p53.

Chronic Ankle Instability: Therapeutic Exercise and Data Analysis

Background and Objectives: Ankle injuries are the most common type of injury in healthy active individuals. If not treated properly, recurrent sprains can lead to a condition of chronic ankle instability (CAI). The present paper examines some subjects with a previous history of acute inversion ankle sprain who have developed a subsequent condition of instability, grouping them according to inclusion criteria and analyzing them through four field tests considered objective by the scientific literature: SEBT test, BEES test, TIBT test, SHT test. The data obtained were stored in order to compare them following a re-education protocol aimed at improving proprioception, balance, walking and strengthening the extrinsic and intrinsic muscles of the foot. per year. The subjects were then divided into two categories: subjects with CAI > 1 year and subjects with CAI ≤ 1 year. A protocol lasting 6 weeks was administered to both groups, trying to work on improving balance in single stance, improving static and dynamic stability, strengthening the gluteus medius and maximus (pelvis stabilizers) and strengthening of the intrinsic muscles of the foot. At the end of the protocol the subjects were all re-evaluated with the same field tests used previously and the data obtained were compared both with the pre-protocol data and with the data measured by the control subjects.

Tendoscopic Surgery for Peroneal Tendons Instability: A Literature Review

Introduction: There has been a surge in the use of tendoscopic surgery for treating peroneal tendons instability. The novelty of this approach demanded a literature review of its indications, limitations, and clinical outcomes. Aim: a literature review of the clinical studies reporting on tendoscopic peroneal tendon stabilisation surgery along with its outcomes and complications. Methods: We carried out a comprehensive review of the literature up until September 2022 with an extensive search of the MEDLINE, Embase and Cochrane library databases. Results: Initial search resulted in 66 articles. Four duplicate articles were removed. Further 30 articles were excluded after title and abstract screening. Eight studies satisfied the inclusion criteria and were included in this review. Articles were analysed for outcomes and complications. Conclusion: The tendoscopic technique for peroneal tendon instability is an effective and safe surgical technique with very low failure rate. Levels of Evidence: Level IV.

Theoretical analysis of the elastic Kelvin-Helmholtz instability in explosive weldings

By considering the joint effects of the Kelvin-Helmholtz(KH) and Rayleigh-Taylor(RT) instabilities, this paper presents an interpretation of the wavy patterns that occur in explosive welding. It is assumed that the elasticity of the material at the interface effectively determines the wavelength, because explosive welding is basically a solid-state welding process. To this end, an analytical model of elastic hydrodynamic instabilities is proposed, and the most unstable mode is selected in the solid phase. Similar approaches have been widely used to study the interfacial behavior of solid metals in high-energy-density physics. By comparing the experimental and theoretical results, it is concluded that thermal softening,which significantly reduces the shear modulus, is necessary and sufficient for successful welding. The thermal softening is verified by theoretical analysis of the increase in temperature due to the impacting and sliding of the flyer and base plates, and some experimental observations are qualitatively validated.In summary, the combined effect of the KH and RT instabilities in solids determines the wavy morphology, and our theoretical results are in good qualitative agreement with experimental and numerical observations.

The Effect of External Magnetic Field on Electron Scale Kelvin–Helmholtz Instability

We use particle-in-cell,fully electromagnetic,plasma kinetic simulation to study the effect of external magnetic field on electron scale Kelvin–Helmholtz instability(ESKHI).The results are applicable to collisionless plasmas when,e.g.,solar wind interacts with planetary magnetospheres or a magnetic field is generated in AGN jets.We find that as in the case of magnetohydrodynamic(MHD)KHI,in the kinetic regime,the presence of an external magnetic field reduces the growth rate of the instability.In the MHD case,there is a known threshold magnetic field for KHI stabilization,while for ESKHI this is to be analytically determined.Without a kinetic analytical expression,we use several numerical simulation runs to establish an empirical dependence of ESKHI growth rate,Γ(B_(0))ω_(pe),on the strength of the applied external magnetic field.We find the best fit is hyperbolic,Γ(B_(0))ω_(pe)=Γ_(0)ω_(pe)/(A+BB_(0)),where Γ_(0) is the ESKHI growth rate without an external magnetic field and B_(0)=B_(0)/B_(MHD)is the ratio of external and two-fluid MHD stability threshold magnetic field,derived here.An analytical theory to back up this growth rate dependence on the external magnetic field is needed.The results suggest that in astrophysical settings where a strong magnetic field pre-exists,the generation of an additional magnetic field by the ESKHI is suppressed,which implies that nature provides a“safety valve”—natural protection not to“over-generate”magnetic field by the ESKHI mechanism.Remarkably,we find that our two-fluid MHD threshold magnetic field is the same(up to a factor √γ_(0))as the DC saturation magnetic field,previously predicted by fully kinetic theory.