Lysosomal acid lipase-deficiency(LAL-D)is a rare and systemic condition,secondary to lipase A gene mutations,responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues.It is a very ...Lysosomal acid lipase-deficiency(LAL-D)is a rare and systemic condition,secondary to lipase A gene mutations,responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues.It is a very heterogeneous disease in terms of the age of onset,severity,and the type of clinical and radiological manifestations.Dyslipidemia,hepatomegaly,and hepatosteatosis with increased levels of transaminases are the most common features.In association with liver dysfunction and evolution to cirrhosis,there is an increased risk of premature atherosclerosis and cardiovascular disorders,secondary to a generalized alteration of lipid profile and lipoprotein dysfunction associated with LAL-D.Therefore,we provide an update on the frequently under-recognized LAL-D,focusing on the late-onset form:Cholesteryl ester storage disease.展开更多
Nuclear receptors(NRs)function as crucial transcription factors in orchestrating essential functions within the realms of development,host defense,and homeostasis of body.NRs have garnered increased attention due to t...Nuclear receptors(NRs)function as crucial transcription factors in orchestrating essential functions within the realms of development,host defense,and homeostasis of body.NRs have garnered increased attention due to their potential as therapeutic targets,with drugs directed at NRs demonstrating significant efficacy in impeding chronic disease progression.Consequently,these pharmacological agents hold promise for the treatment and management of various diseases.Accumulating evidence emphasizes the regulatory role of exosome-derived microRNAs(miRNAs)in chronic inflammation,disease progression,and therapy resistance,primarily by modulating transcription factors,particularly NRs.By exploiting inflammatory pathways such as protein kinase B(Akt)/mammalian target of rapamycin(mTOR),nuclear factor kappa-B(NF-κB),signal transducer and activator of transcription 3(STAT3),and Wnt/β-catenin signaling,exosomes and NRs play a pivotal role in the panorama of development,physiology,and pathology.The internalization of exosomes modulates NRs and initiates diverse autocrine or paracrine signaling cascades,influencing various processes in recipient cells such as survival,proliferation,differentiation,metabolism,and cellular defense mechanisms.This comprehensive review meticulously examines the involvement of exosome-mediated NRs regulation in the pathogenesis of chronic ailments,including atherosclerosis,cancer,diabetes,liver diseases,and respiratory conditions.Additionally,it elucidates the molecular intricacies of exosome-mediated communication between host and recipient cells via NRs,leading to immunomodulation.Furthermore,it outlines the implications of exosome-modulated NR pathways in the prophylaxis of chronic inflammation,delineates current limitations,and provides insights into future perspectives.This review also presents existing evidence on the role of exosomes and their components in the emergence of therapeutic resistance.展开更多
The structure of intestinal tissue is complex.In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases.Recently,organoids have been successfully constructe...The structure of intestinal tissue is complex.In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases.Recently,organoids have been successfully constructed and they have come to play an important role in biomedical research.Organoids are miniaturized three-dimensional(3D)organs,derived from stem cells,which mimic the structure,cell types,and physiological functions of an organ,making them robust models for biomedical research.Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine,thereby providing a valuable platform for intestinal development and disease research.In this article,we review the latest progress in the construction and application of intestinal organoids.展开更多
Immunization has long played essential roles in preventing diseases.However,the desire for precision delivery of vaccines to boost a robust immune response remains largely unmet.Here,we describe the use of acupoint de...Immunization has long played essential roles in preventing diseases.However,the desire for precision delivery of vaccines to boost a robust immune response remains largely unmet.Here,we describe the use of acupoint delivery of nanovaccines(ADN)to elicit dual-niche immunological priming.ADN can simultaneously stimulate mast cell-assisted maturation of dendritic cells at the acupoint and enable direct delivery of nanovaccines into the draining lymph nodes.We demonstrate that ADN not only provokes antigen presentation by lymph node-resident CD8α^(+)dendritic cells,but also induces the accumulation of nanovaccines in B-cell zones,amplifying antigen-specific cytotoxic T lymphocyte responses and immunoglobulin G antibody expression in draining lymph nodes.ADN also generates systemic immune responses by causing immune memory and preventing T-cell anergy in the spleen.Further supported by evoking effective antitumor responses and high-level antiviral antibodies in mice,ADN provides a simple yet versatile platform for advanced nanovaccination.展开更多
OBJECTIVE To evalu ate the role of resting magnetocardiography in identifying seve re coronary artery stenosis in patients with suspected coronary artery disease.METHODS A total of 513 patients with angina symptoms we...OBJECTIVE To evalu ate the role of resting magnetocardiography in identifying seve re coronary artery stenosis in patients with suspected coronary artery disease.METHODS A total of 513 patients with angina symptoms were included and divided into two groups based on the extent of coronary artery disease determined by angiography:the non-severe coronary stenusis group(<70% stenosis) and the severe coronary stenosis group(≥70% stenosis).The diagnostic model was constructed using magnetic field map(MFM) parameters,either individually or in combination with clinical indicators.The performance of the models was evaluated using receiver operating characteristic curves,accuracy,sensitivity,specificity,positive predictive value(PPV) and ne gative predictive value(NPV).Calibration plots and decision curve analysis were performed to investigate the clinical utility and performance of the models,respectively.RESULTS In the severe coronary stenosis group,QR_MCTDd,S_MDp,and TT_(MA)C_(50) were significantly higher than those in the non-severe coronary stenosis group(10,46±10.66 vs,5.11±6.07,P <0.001;7.2±8.64 vs.4.68±6.95,P=0.003;0.32±57.29 vs.0.26±57.29,P <0.001).While,QR_MV_(amp),R_(MA),and T_(MA) in the severe coronary stenosis group were lower(0.23±0.16 vs.0.28±0.16,P<0.001;55.06±48.68 vs.59.24±53.01,P<0.001;51.67±39.32 vs. 60.45±51.33,P <0.001).Seven MFM parameters were integrated into the model,resulting in an area under the curve of 0.810(95% CI:0.765-0.855).The sensitivity,specificity,PPV,NPV,and accurecy were 71.7%,80.4%,93.3%,42.8 %,and 73.5%;respectevely.The combined model exhibited an area under the curve of 0.845(95% CI:0.798-0.892).The sensitivity,specificity,PPV,NPV,and accuracy were 84.3%,73.8%,92.6%,54.6%,and 82.1%;respectively.Calibration curves demonstrate d excellent agreement between the nomogram prediction and actual observation.The decision curve analysis showed that the c ombine d model provided greater net benefit compared to the magnetocardingraphy model.CONCLUSIONS The novel quantitative MFM parameters,whether used individually or in combination with clinical indicators,have been shown to effectively pre dict the risk of severe coronary stenosis in patients presenting with angina-like symptoms.Magnetocardiography,an emerging non-invasive diagnostic tool,warrants further exploration for its potential in diagnosing coronary heart disease.展开更多
We present a method using Zernike moments for quantifying rotational and reflectional symmetries in scanning transmission electron microscopy(STEM)images,aimed at improving structural analysis of materials at the atom...We present a method using Zernike moments for quantifying rotational and reflectional symmetries in scanning transmission electron microscopy(STEM)images,aimed at improving structural analysis of materials at the atomic scale.This technique is effective against common imaging noises and is potentially suited for low-dose imaging and identifying quantum defects.We showcase its utility in the unsupervised segmentation of polytypes in a twisted bilayer TaS_(2),enabling accurate differentiation of structural phases and monitoring transitions caused by electron beam effects.This approach enhances the analysis of structural variations in crystalline materials,marking a notable advancement in the characterization of structures in materials science.展开更多
Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border.However,the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts...Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border.However,the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown.Here,we show with GeneChip analysis that RUN and FYVE domain-containing protein 4(RUFY4)is strongly upregulated during osteoclastogenesis.Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo.Furthermore,deleting Rufy4 did not affect osteoclast differentiation,but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes,their trafficking to the membrane,and their secretion of cathepsin K into the extracellular space.Mechanistically,RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes.Consequently,Rufy4-deficient mice were highly protected from lipopolysaccharide-and ovariectomy-induced bone loss.Thus,RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.展开更多
Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis, but might also occur in absence of an overt liver disease. Several causes, either local or systemic, might play an imp...Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis, but might also occur in absence of an overt liver disease. Several causes, either local or systemic, might play an important role in PVT pathogenesis. Frequently, more than one risk factor could be identified; however, occasionally no single factor is discernable. Clinical examination, laboratory investigations, and imaging are helpful to provide a quick diagnosis, as prompt treatment might greatly affect a patient's outcome. In this review, we analyze the physiopathological mechanisms of PVT development, together with the hemodynamic and functional alterations related to this condition. Moreover, we describe the principal factors most frequently involved in PVT development and the recent knowledge concerning diagnostic and therapeutic procedures. Finally, we analyze the implications of PVT in the setting of liver transplantation and its possible influence on patients' future prognoses.展开更多
Hepatocellular carcinoma is one of the most frequent malignant tumors worldwide:Portal vein tumor thrombosis(PVTT)occurs in about 35%-50%of patients and represents a strong negative prognostic factor,due to the increa...Hepatocellular carcinoma is one of the most frequent malignant tumors worldwide:Portal vein tumor thrombosis(PVTT)occurs in about 35%-50%of patients and represents a strong negative prognostic factor,due to the increased risk of tumor spread into the bloodstream,leading to a high recurrence risk.For this reason,it is a contraindication to liver transplantation and in several prognostic scores sorafenib represents its standard of care,due to its antiangiogenetic action,although it can grant only a poor prolongation of life expectancy.Recent scientific evidences lead to consider PVTT as a complex anatomical and clinical condition,including a wide range of patients with different prognosis and new treatment possibilities according to the degree of portal system involvement,tumor biological aggressiveness,complications caused by portal hypertension,patient’s clinical features and tolerance to antineoplastic treatments.The median survival has been reported to range between 2.7 and 4 mo in absence of therapy,but it can vary from 5 mo to 5 years,thus depicting an extremely variable scenario.For this reason,it is extremely important to focus on the most adequate strategy to be applied to each group of PVTT patients.展开更多
Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).The most used treatments include transarterial chemoembolizati...Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).The most used treatments include transarterial chemoembolization and radiofrequency ablation.Surgical resection has also been successfully used as a bridging procedure,and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function.The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation,reducing HCC recurrence after transplantation,and improving post-transplant overall survival.To date,no data from prospective randomized studies are available;however,for HCC patients listed for LT within the Milan criteria,prolonging the waiting time over 6-12 mo is a risk factor for tumor spread.Bridging treatments are useful in containing tumor progression and decreasing dropout.Furthermore,the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT.Lastly,although a definitive conclusion can not be reached,the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival.Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT.Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging.展开更多
In recent years, a combination of intervention therapies has been widely applied in the treatment of hepatocellular carcinoma(HCC). One such combined strategy is based on the combination of the percutaneous approach, ...In recent years, a combination of intervention therapies has been widely applied in the treatment of hepatocellular carcinoma(HCC). One such combined strategy is based on the combination of the percutaneous approach, such as radiofrequency ablation(RFA), and the intra-arterial locoregional approach, such as trans-arterial chemoembolization(TACE). Several types of evidence have supported the feasibility and benefit of combined therapy, despite some studies reporting conflicting results and outcomes. The aim of this review was to explain the technical aspects of different combined treatments and to comprehensively analyze and compare the clinical efficacy and safety of this combined treatment option and monotherapy, either as TACE or RFA alone, in order to provide clinicians with an unbiased opinion and valuable information. Based on a literature review and our experience, combined treatment seems to be a safe and effective option in the treatment of patients with early/intermediate HCC when surgical resection is not feasible; furthermore, this approach provides better results than RFA and TACE alone for the treatment of large HCC, defined as those exceeding 3 cm in size. It can also expand the indication for RFA to previously contraindicated "complex cases", with increased risk of thermal ablation related complications due to tumor location, or to "complex patients" with high bleeding risk.展开更多
The high incidence of rectal cancer in both sexes makes it one of the most common tumors,with significant morbidity and mortality rates.To define the best treatment option and optimize patient outcome,several rectal c...The high incidence of rectal cancer in both sexes makes it one of the most common tumors,with significant morbidity and mortality rates.To define the best treatment option and optimize patient outcome,several rectal cancer biological variables must be evaluated.Currently,medical imaging plays a crucial role in the characterization of this disease,and it often requires a multimodal approach.Magnetic resonance imaging is the first-choice imaging modality for local staging and restaging and can be used to detect high-risk prognostic factors.Computed tomography is widely adopted for the detection of distant metastases.However,conventional imaging has recognized limitations,and many rectal cancer characteristics remain assessable only after surgery and histopathology evaluation.There is a growing interest in artificial intelligence applications in medicine,and imaging is by no means an exception.The introduction of radiomics,which allows the extraction of quantitative features that reflect tumor heterogeneity,allows the mining of data in medical images and paved the way for the identification of potential new imaging biomarkers.To manage such a huge amount of data,the use of machine learning algorithms has been proposed.Indeed,without prior explicit programming,they can be employed to build prediction models to support clinical decision making.In this review,current applications and future perspectives of artificial intelligence in medical imaging of rectal cancer are presented,with an imaging modality-based approach and a keen eye on unsolved issues.The results are promising,but the road ahead for translation in clinical practice is rather long.展开更多
Osteocytes, the most abundant bone cells, form an interconnected network in the lacunar-canalicular pore system （LCS） buried within the mineralized matrix, which allows osteocytes to obtain nutrients from the blood ...Osteocytes, the most abundant bone cells, form an interconnected network in the lacunar-canalicular pore system （LCS） buried within the mineralized matrix, which allows osteocytes to obtain nutrients from the blood supply, sense external mechanical signals, and communicate among themselves and with other cells on bone surfaces. In this study, we examined key features of the LCS network including the topological parameter and the detailed structure of individual connections and their variations in cortical and cancellous compa~ tments, at different ages, and in two disease conditions with altered mechanosensing （perlecan deficiency and diabetes）. LCS network showed both topological stability, in terms of conservation of connectivity among osteocyte lacunae （similar to the ＂nodes＂ in a computer network）, and considerable variability the pericellular annular fluid gap surrounding lacunae and canaliculi （similar to the ＂bandwidth＂ of individual links in a computer network）. Age, in the range of our study （15-32 weeks）, affected only the pericellular fluid annulus in cortical bone but not in cancellous bone. Diabetes impacted the spacing of the lacunae, while the perlecan deficiency had a profound influence on the pericellular fluid annulus. The LCS network features play important roles in osteocyte signaling and regulation of bone growth and adaptation.展开更多
The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified...The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified,culminating with the report that we renew 50% of our cardiomyocytes during our lifetime.The future of cardiac regenerative therapies is discussed,presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.展开更多
AIM: To meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose(18F-FDG) positron emission tomography(PET) and PET/computed tomography(PET/CT) in the evaluation of primary tumor in ...AIM: To meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose(18F-FDG) positron emission tomography(PET) and PET/computed tomography(PET/CT) in the evaluation of primary tumor in patients with gallbladder cancer(GBCa).METHODS: A comprehensive literature search of studies published through 30 th June 2014 regarding the role of 18F-FDG PET and PET/CT in the evaluation of primary gallbladder cancer(GBCa) was performed. All retrieved studies were reviewed. Pooled sensitivity and specificity of 18F-FDG PET or PET/CT in the evaluation of primary GBCa were calculated. The area under the summary receiving operator characteristics curve(AUC) was calculated to measure the accuracy of these methods. Sub-analyses considering the device used(PET vs PET/CT) were carried out.RESULTS: Twenty-one studies comprising 495 patients who underwent 18F-FDG PET or PET/CT for suspicious GBCa were selected for the systematic review. The meta-analysis of 13 selected studies provided the following results: sensitivity 87%(95%CI: 82%-92%),specificity 78%(95%CI: 68%-86%). The AUC was 0.88. Improvement of sensitivity and specificity was observed when PET/CT was used.CONCLUSION: 18F-FDG-PET and PET/CT demonstrated to be useful diagnostic imaging methods in the assessment of primary tumor in GBCa patients,nevertheless possible sources of false-negative and false-positive results should be kept in mind. PET/CT seems to have a better diagnostic accuracy than PET alone in this setting.展开更多
AIM:To assess the clinical diagnostic value of functional imaging,combining quantitative parameters of apparent diffusion coefficient(ADC) and standardized uptake value(SUV)max,before and after chemo-radiation therapy...AIM:To assess the clinical diagnostic value of functional imaging,combining quantitative parameters of apparent diffusion coefficient(ADC) and standardized uptake value(SUV)max,before and after chemo-radiation therapy,in prediction of tumor response of patients with rectal cancer,related to tumor regression grade at histology.METHODS:A total of 31 patients with biopsy proven diagnosis of rectal carcinoma were enrolled in our study.All patients underwent a whole body ^(18)FDG positron emission tomography(PET)/computed tomography(CT) scan and a pelvic magnetic resonance(MR)examination including diffusion weighted(DW) imaging for staging(PET1,RM1) and after completion(6.6 wk)of neoadjuvant treatment(PET2,RM2).Subsequently all patients underwent total mesorectal excision and the histological results were compared with imaging findings.The MR scanning,performed on 1.5 T magnet(Philips,Achieva),included T2-weighted multiplanar imaging and in addition DW images with b-value of 0 and 1000 mm^2/s.On PET/CT the SUVmax of the rectal lesion were calculated in PET1 and PET2.The percentage decrease of SUVmax(△SUV) and ADC(△ADC) values from baseline to presurgical scan were assessed and correlated with pathologic response classified as tumor regression grade(Mandard's criteria;TRG1 = complete regression,TRG5 = no regression).RESULTS:After completion of therapy,all the patients were submitted to surgery.According to the Mandard's criteria,22 tumors showed complete(TRG1) or subtotal regression(TRG2) and were classified as responders;9tumors were classified as non responders(TRG3,4 and5).Considering all patients the mean values of SUVmax in PET 1 was higher than the mean value of SUVmax in PET 2(P < 0.001),whereas the mean ADC values was lower in RM1 than RM2(P < 0.001),with a △SUV and △ADC respectively of 60.2%and 66.8%.The best predictors for TRG response were SUV2(threshold of4.4) and ADC2(1.29 × 10^(-3) mm^2/s) with high sensitivity and specificity.Combining in a single analysis both the obtained median value,the positive predictive value,in predicting the different group category response in related to TRG system,presented R^2 of 0.95.CONCLUSION:The functional imaging combining ADC and SUVmax in a single analysis permits to detect changes in cellular tissue structures useful for the assessment of tumour response after the neoadjuvant therapy in rectal cancer,increasing the sensitivity in correct depiction of treatment response than either method alone.展开更多
Magnetocardiography(MCG)measurement is important for investigating the cardiac biological activities.Traditionally,the extremely weak MCG signal was detected by using superconducting quantum interference devices(SQUID...Magnetocardiography(MCG)measurement is important for investigating the cardiac biological activities.Traditionally,the extremely weak MCG signal was detected by using superconducting quantum interference devices(SQUIDs).As a room-temperature magnetic-field sensor,optically pumped magnetometer(OPM)has shown to have comparable sensitivity to that of SQUIDs,which is very suitable for biomagnetic measurements.In this paper,a synthetic gradiometer was constructed by using two OPMs under spin-exchange relaxation-free(SERF)conditions within a moderate magnetically shielded room(MSR).The magnetic noise of the OPM was measured to less than 70 fT/Hz1/2.Under a baseline of 100 mm,noise cancellation of about 30 dB was achieved.MCG was successfully measured with a signal to noise ratio(SNR)of about 37 dB.The synthetic gradiometer technique was very effective to suppress the residual environmental fields,demonstrating the OPM gradiometer technique for highly cost-effective biomagnetic measurements.展开更多
文摘Lysosomal acid lipase-deficiency(LAL-D)is a rare and systemic condition,secondary to lipase A gene mutations,responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues.It is a very heterogeneous disease in terms of the age of onset,severity,and the type of clinical and radiological manifestations.Dyslipidemia,hepatomegaly,and hepatosteatosis with increased levels of transaminases are the most common features.In association with liver dysfunction and evolution to cirrhosis,there is an increased risk of premature atherosclerosis and cardiovascular disorders,secondary to a generalized alteration of lipid profile and lipoprotein dysfunction associated with LAL-D.Therefore,we provide an update on the frequently under-recognized LAL-D,focusing on the late-onset form:Cholesteryl ester storage disease.
基金supported by BT/556/NE/U-Excel/2016 grant awarded to ABKThe authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through Large Research Project under grant number RGP2/485/45.
文摘Nuclear receptors(NRs)function as crucial transcription factors in orchestrating essential functions within the realms of development,host defense,and homeostasis of body.NRs have garnered increased attention due to their potential as therapeutic targets,with drugs directed at NRs demonstrating significant efficacy in impeding chronic disease progression.Consequently,these pharmacological agents hold promise for the treatment and management of various diseases.Accumulating evidence emphasizes the regulatory role of exosome-derived microRNAs(miRNAs)in chronic inflammation,disease progression,and therapy resistance,primarily by modulating transcription factors,particularly NRs.By exploiting inflammatory pathways such as protein kinase B(Akt)/mammalian target of rapamycin(mTOR),nuclear factor kappa-B(NF-κB),signal transducer and activator of transcription 3(STAT3),and Wnt/β-catenin signaling,exosomes and NRs play a pivotal role in the panorama of development,physiology,and pathology.The internalization of exosomes modulates NRs and initiates diverse autocrine or paracrine signaling cascades,influencing various processes in recipient cells such as survival,proliferation,differentiation,metabolism,and cellular defense mechanisms.This comprehensive review meticulously examines the involvement of exosome-mediated NRs regulation in the pathogenesis of chronic ailments,including atherosclerosis,cancer,diabetes,liver diseases,and respiratory conditions.Additionally,it elucidates the molecular intricacies of exosome-mediated communication between host and recipient cells via NRs,leading to immunomodulation.Furthermore,it outlines the implications of exosome-modulated NR pathways in the prophylaxis of chronic inflammation,delineates current limitations,and provides insights into future perspectives.This review also presents existing evidence on the role of exosomes and their components in the emergence of therapeutic resistance.
基金funded by the National Natural Science Foundation of China(No.32300659)Shenzhen Science and Technology Innovation Commission Project(No.JCYJ20230807143302004)+6 种基金Zhangjiakou City Key R&D Plan Project(No.2421118D),Zhangjiakou City Key R&D Plan Project(No.2322088D)The Natural Science Project of Hebei North University(No.XJ2024034 and XJ2024035)Medical Science Research Subject Plan Project of Hebei Provincial Health Commission(No.20240782)Project of Administration of Traditional Chinese Medicine of Hebei Province(No.2025392)The 2025 Government-funded Training Project for Outstanding Clinical Medicine Talents(No.ZF2025264)Research Project of Medical Innovation for Chinese Youth(Project Leader:Jun Xue).g Project for Outstanding Clinical Medicine Talents(No.ZF2025264)Research Project of Medical Innovation for Chinese Youth(Project Leader:Jun Xue)。
文摘The structure of intestinal tissue is complex.In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases.Recently,organoids have been successfully constructed and they have come to play an important role in biomedical research.Organoids are miniaturized three-dimensional(3D)organs,derived from stem cells,which mimic the structure,cell types,and physiological functions of an organ,making them robust models for biomedical research.Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine,thereby providing a valuable platform for intestinal development and disease research.In this article,we review the latest progress in the construction and application of intestinal organoids.
基金supported by the National Key Research and Development Program of China(2021YFA0909400)the National Natural Science Foundation of China(22425505,32301099,and 21834007)+2 种基金the Shanghai Sailing Program(22YF1424200)the Interdisciplinary Program of Shanghai Jiao Tong University(YG2022QN032)the Xiangfu Lab Research Project(XF012022E0100).
文摘Immunization has long played essential roles in preventing diseases.However,the desire for precision delivery of vaccines to boost a robust immune response remains largely unmet.Here,we describe the use of acupoint delivery of nanovaccines(ADN)to elicit dual-niche immunological priming.ADN can simultaneously stimulate mast cell-assisted maturation of dendritic cells at the acupoint and enable direct delivery of nanovaccines into the draining lymph nodes.We demonstrate that ADN not only provokes antigen presentation by lymph node-resident CD8α^(+)dendritic cells,but also induces the accumulation of nanovaccines in B-cell zones,amplifying antigen-specific cytotoxic T lymphocyte responses and immunoglobulin G antibody expression in draining lymph nodes.ADN also generates systemic immune responses by causing immune memory and preventing T-cell anergy in the spleen.Further supported by evoking effective antitumor responses and high-level antiviral antibodies in mice,ADN provides a simple yet versatile platform for advanced nanovaccination.
基金supported by the National Key Research and Development Program (No.2022YFC2407001)。
文摘OBJECTIVE To evalu ate the role of resting magnetocardiography in identifying seve re coronary artery stenosis in patients with suspected coronary artery disease.METHODS A total of 513 patients with angina symptoms were included and divided into two groups based on the extent of coronary artery disease determined by angiography:the non-severe coronary stenusis group(<70% stenosis) and the severe coronary stenosis group(≥70% stenosis).The diagnostic model was constructed using magnetic field map(MFM) parameters,either individually or in combination with clinical indicators.The performance of the models was evaluated using receiver operating characteristic curves,accuracy,sensitivity,specificity,positive predictive value(PPV) and ne gative predictive value(NPV).Calibration plots and decision curve analysis were performed to investigate the clinical utility and performance of the models,respectively.RESULTS In the severe coronary stenosis group,QR_MCTDd,S_MDp,and TT_(MA)C_(50) were significantly higher than those in the non-severe coronary stenosis group(10,46±10.66 vs,5.11±6.07,P <0.001;7.2±8.64 vs.4.68±6.95,P=0.003;0.32±57.29 vs.0.26±57.29,P <0.001).While,QR_MV_(amp),R_(MA),and T_(MA) in the severe coronary stenosis group were lower(0.23±0.16 vs.0.28±0.16,P<0.001;55.06±48.68 vs.59.24±53.01,P<0.001;51.67±39.32 vs. 60.45±51.33,P <0.001).Seven MFM parameters were integrated into the model,resulting in an area under the curve of 0.810(95% CI:0.765-0.855).The sensitivity,specificity,PPV,NPV,and accurecy were 71.7%,80.4%,93.3%,42.8 %,and 73.5%;respectevely.The combined model exhibited an area under the curve of 0.845(95% CI:0.798-0.892).The sensitivity,specificity,PPV,NPV,and accuracy were 84.3%,73.8%,92.6%,54.6%,and 82.1%;respectively.Calibration curves demonstrate d excellent agreement between the nomogram prediction and actual observation.The decision curve analysis showed that the c ombine d model provided greater net benefit compared to the magnetocardingraphy model.CONCLUSIONS The novel quantitative MFM parameters,whether used individually or in combination with clinical indicators,have been shown to effectively pre dict the risk of severe coronary stenosis in patients presenting with angina-like symptoms.Magnetocardiography,an emerging non-invasive diagnostic tool,warrants further exploration for its potential in diagnosing coronary heart disease.
基金funding support from the National Research Foundation (Competitive Research Program grant number NRF-CRP16-2015-05)the National University of Singapore Early Career Research Award+1 种基金supported by the Eric and Wendy Schmidt AI in Science Postdoctoral Fellowshipa Schmidt Sciences program。
文摘We present a method using Zernike moments for quantifying rotational and reflectional symmetries in scanning transmission electron microscopy(STEM)images,aimed at improving structural analysis of materials at the atomic scale.This technique is effective against common imaging noises and is potentially suited for low-dose imaging and identifying quantum defects.We showcase its utility in the unsupervised segmentation of polytypes in a twisted bilayer TaS_(2),enabling accurate differentiation of structural phases and monitoring transitions caused by electron beam effects.This approach enhances the analysis of structural variations in crystalline materials,marking a notable advancement in the characterization of structures in materials science.
基金supported by grants from the National Research Foundation of Korea(RS-2023-00217798 and 2021R1A2C3003675 to S.Y.L.)by the Korea Basic Science Institute National Research Facilities&Equipment Center grant(2019R1A6C1010020).M.K.was supported in part by scholarship from Ewha Womans University.
文摘Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border.However,the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown.Here,we show with GeneChip analysis that RUN and FYVE domain-containing protein 4(RUFY4)is strongly upregulated during osteoclastogenesis.Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo.Furthermore,deleting Rufy4 did not affect osteoclast differentiation,but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes,their trafficking to the membrane,and their secretion of cathepsin K into the extracellular space.Mechanistically,RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes.Consequently,Rufy4-deficient mice were highly protected from lipopolysaccharide-and ovariectomy-induced bone loss.Thus,RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.
文摘Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis, but might also occur in absence of an overt liver disease. Several causes, either local or systemic, might play an important role in PVT pathogenesis. Frequently, more than one risk factor could be identified; however, occasionally no single factor is discernable. Clinical examination, laboratory investigations, and imaging are helpful to provide a quick diagnosis, as prompt treatment might greatly affect a patient's outcome. In this review, we analyze the physiopathological mechanisms of PVT development, together with the hemodynamic and functional alterations related to this condition. Moreover, we describe the principal factors most frequently involved in PVT development and the recent knowledge concerning diagnostic and therapeutic procedures. Finally, we analyze the implications of PVT in the setting of liver transplantation and its possible influence on patients' future prognoses.
文摘Hepatocellular carcinoma is one of the most frequent malignant tumors worldwide:Portal vein tumor thrombosis(PVTT)occurs in about 35%-50%of patients and represents a strong negative prognostic factor,due to the increased risk of tumor spread into the bloodstream,leading to a high recurrence risk.For this reason,it is a contraindication to liver transplantation and in several prognostic scores sorafenib represents its standard of care,due to its antiangiogenetic action,although it can grant only a poor prolongation of life expectancy.Recent scientific evidences lead to consider PVTT as a complex anatomical and clinical condition,including a wide range of patients with different prognosis and new treatment possibilities according to the degree of portal system involvement,tumor biological aggressiveness,complications caused by portal hypertension,patient’s clinical features and tolerance to antineoplastic treatments.The median survival has been reported to range between 2.7 and 4 mo in absence of therapy,but it can vary from 5 mo to 5 years,thus depicting an extremely variable scenario.For this reason,it is extremely important to focus on the most adequate strategy to be applied to each group of PVTT patients.
文摘Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).The most used treatments include transarterial chemoembolization and radiofrequency ablation.Surgical resection has also been successfully used as a bridging procedure,and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function.The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation,reducing HCC recurrence after transplantation,and improving post-transplant overall survival.To date,no data from prospective randomized studies are available;however,for HCC patients listed for LT within the Milan criteria,prolonging the waiting time over 6-12 mo is a risk factor for tumor spread.Bridging treatments are useful in containing tumor progression and decreasing dropout.Furthermore,the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT.Lastly,although a definitive conclusion can not be reached,the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival.Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT.Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging.
文摘In recent years, a combination of intervention therapies has been widely applied in the treatment of hepatocellular carcinoma(HCC). One such combined strategy is based on the combination of the percutaneous approach, such as radiofrequency ablation(RFA), and the intra-arterial locoregional approach, such as trans-arterial chemoembolization(TACE). Several types of evidence have supported the feasibility and benefit of combined therapy, despite some studies reporting conflicting results and outcomes. The aim of this review was to explain the technical aspects of different combined treatments and to comprehensively analyze and compare the clinical efficacy and safety of this combined treatment option and monotherapy, either as TACE or RFA alone, in order to provide clinicians with an unbiased opinion and valuable information. Based on a literature review and our experience, combined treatment seems to be a safe and effective option in the treatment of patients with early/intermediate HCC when surgical resection is not feasible; furthermore, this approach provides better results than RFA and TACE alone for the treatment of large HCC, defined as those exceeding 3 cm in size. It can also expand the indication for RFA to previously contraindicated "complex cases", with increased risk of thermal ablation related complications due to tumor location, or to "complex patients" with high bleeding risk.
文摘The high incidence of rectal cancer in both sexes makes it one of the most common tumors,with significant morbidity and mortality rates.To define the best treatment option and optimize patient outcome,several rectal cancer biological variables must be evaluated.Currently,medical imaging plays a crucial role in the characterization of this disease,and it often requires a multimodal approach.Magnetic resonance imaging is the first-choice imaging modality for local staging and restaging and can be used to detect high-risk prognostic factors.Computed tomography is widely adopted for the detection of distant metastases.However,conventional imaging has recognized limitations,and many rectal cancer characteristics remain assessable only after surgery and histopathology evaluation.There is a growing interest in artificial intelligence applications in medicine,and imaging is by no means an exception.The introduction of radiomics,which allows the extraction of quantitative features that reflect tumor heterogeneity,allows the mining of data in medical images and paved the way for the identification of potential new imaging biomarkers.To manage such a huge amount of data,the use of machine learning algorithms has been proposed.Indeed,without prior explicit programming,they can be employed to build prediction models to support clinical decision making.In this review,current applications and future perspectives of artificial intelligence in medical imaging of rectal cancer are presented,with an imaging modality-based approach and a keen eye on unsolved issues.The results are promising,but the road ahead for translation in clinical practice is rather long.
基金supported partially by funds from the NIH (RO1AR054385, P30GM103333)
文摘Osteocytes, the most abundant bone cells, form an interconnected network in the lacunar-canalicular pore system （LCS） buried within the mineralized matrix, which allows osteocytes to obtain nutrients from the blood supply, sense external mechanical signals, and communicate among themselves and with other cells on bone surfaces. In this study, we examined key features of the LCS network including the topological parameter and the detailed structure of individual connections and their variations in cortical and cancellous compa~ tments, at different ages, and in two disease conditions with altered mechanosensing （perlecan deficiency and diabetes）. LCS network showed both topological stability, in terms of conservation of connectivity among osteocyte lacunae （similar to the ＂nodes＂ in a computer network）, and considerable variability the pericellular annular fluid gap surrounding lacunae and canaliculi （similar to the ＂bandwidth＂ of individual links in a computer network）. Age, in the range of our study （15-32 weeks）, affected only the pericellular fluid annulus in cortical bone but not in cancellous bone. Diabetes impacted the spacing of the lacunae, while the perlecan deficiency had a profound influence on the pericellular fluid annulus. The LCS network features play important roles in osteocyte signaling and regulation of bone growth and adaptation.
文摘The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified,culminating with the report that we renew 50% of our cardiomyocytes during our lifetime.The future of cardiac regenerative therapies is discussed,presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.
文摘AIM: To meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose(18F-FDG) positron emission tomography(PET) and PET/computed tomography(PET/CT) in the evaluation of primary tumor in patients with gallbladder cancer(GBCa).METHODS: A comprehensive literature search of studies published through 30 th June 2014 regarding the role of 18F-FDG PET and PET/CT in the evaluation of primary gallbladder cancer(GBCa) was performed. All retrieved studies were reviewed. Pooled sensitivity and specificity of 18F-FDG PET or PET/CT in the evaluation of primary GBCa were calculated. The area under the summary receiving operator characteristics curve(AUC) was calculated to measure the accuracy of these methods. Sub-analyses considering the device used(PET vs PET/CT) were carried out.RESULTS: Twenty-one studies comprising 495 patients who underwent 18F-FDG PET or PET/CT for suspicious GBCa were selected for the systematic review. The meta-analysis of 13 selected studies provided the following results: sensitivity 87%(95%CI: 82%-92%),specificity 78%(95%CI: 68%-86%). The AUC was 0.88. Improvement of sensitivity and specificity was observed when PET/CT was used.CONCLUSION: 18F-FDG-PET and PET/CT demonstrated to be useful diagnostic imaging methods in the assessment of primary tumor in GBCa patients,nevertheless possible sources of false-negative and false-positive results should be kept in mind. PET/CT seems to have a better diagnostic accuracy than PET alone in this setting.
文摘AIM:To assess the clinical diagnostic value of functional imaging,combining quantitative parameters of apparent diffusion coefficient(ADC) and standardized uptake value(SUV)max,before and after chemo-radiation therapy,in prediction of tumor response of patients with rectal cancer,related to tumor regression grade at histology.METHODS:A total of 31 patients with biopsy proven diagnosis of rectal carcinoma were enrolled in our study.All patients underwent a whole body ^(18)FDG positron emission tomography(PET)/computed tomography(CT) scan and a pelvic magnetic resonance(MR)examination including diffusion weighted(DW) imaging for staging(PET1,RM1) and after completion(6.6 wk)of neoadjuvant treatment(PET2,RM2).Subsequently all patients underwent total mesorectal excision and the histological results were compared with imaging findings.The MR scanning,performed on 1.5 T magnet(Philips,Achieva),included T2-weighted multiplanar imaging and in addition DW images with b-value of 0 and 1000 mm^2/s.On PET/CT the SUVmax of the rectal lesion were calculated in PET1 and PET2.The percentage decrease of SUVmax(△SUV) and ADC(△ADC) values from baseline to presurgical scan were assessed and correlated with pathologic response classified as tumor regression grade(Mandard's criteria;TRG1 = complete regression,TRG5 = no regression).RESULTS:After completion of therapy,all the patients were submitted to surgery.According to the Mandard's criteria,22 tumors showed complete(TRG1) or subtotal regression(TRG2) and were classified as responders;9tumors were classified as non responders(TRG3,4 and5).Considering all patients the mean values of SUVmax in PET 1 was higher than the mean value of SUVmax in PET 2(P < 0.001),whereas the mean ADC values was lower in RM1 than RM2(P < 0.001),with a △SUV and △ADC respectively of 60.2%and 66.8%.The best predictors for TRG response were SUV2(threshold of4.4) and ADC2(1.29 × 10^(-3) mm^2/s) with high sensitivity and specificity.Combining in a single analysis both the obtained median value,the positive predictive value,in predicting the different group category response in related to TRG system,presented R^2 of 0.95.CONCLUSION:The functional imaging combining ADC and SUVmax in a single analysis permits to detect changes in cellular tissue structures useful for the assessment of tumour response after the neoadjuvant therapy in rectal cancer,increasing the sensitivity in correct depiction of treatment response than either method alone.
基金Project supported by the National Natural Science Foundation of China(Grant No.61701486)。
文摘Magnetocardiography(MCG)measurement is important for investigating the cardiac biological activities.Traditionally,the extremely weak MCG signal was detected by using superconducting quantum interference devices(SQUIDs).As a room-temperature magnetic-field sensor,optically pumped magnetometer(OPM)has shown to have comparable sensitivity to that of SQUIDs,which is very suitable for biomagnetic measurements.In this paper,a synthetic gradiometer was constructed by using two OPMs under spin-exchange relaxation-free(SERF)conditions within a moderate magnetically shielded room(MSR).The magnetic noise of the OPM was measured to less than 70 fT/Hz1/2.Under a baseline of 100 mm,noise cancellation of about 30 dB was achieved.MCG was successfully measured with a signal to noise ratio(SNR)of about 37 dB.The synthetic gradiometer technique was very effective to suppress the residual environmental fields,demonstrating the OPM gradiometer technique for highly cost-effective biomagnetic measurements.
