Chikungunya virus(CHIKV) is an arbovirus transmitted by Aedes mosquitos in tropical and subtropical regions across the world. After decades of sporadic outbreaks, it re-emerged in Africa,Asia, India Ocean and America ...Chikungunya virus(CHIKV) is an arbovirus transmitted by Aedes mosquitos in tropical and subtropical regions across the world. After decades of sporadic outbreaks, it re-emerged in Africa,Asia, India Ocean and America suddenly, causing major regional epidemics recently and becoming a notable global health problem. Infection by CHIKV results in a spectrum of clinical diseases including an acute self-limiting febrile illness in most individuals, a chronic phase of recurrent join pain in a proportion of patients, and long-term arthralgia for months to years for the unfortunate few. No specific anti-viral drugs or licensed vaccines for CHIKV are available so far. A better understanding of virus-host interactions is essential for the development of therapeutics and vaccines. To this end, we reviewed the existing knowledge on CHIKV's epidemiology, clinical presentation, molecular virology, diagnostic approaches, host immune response, vaccine development, and available animal models. Such a comprehensive overview, we believe, will shed lights on the promises and challenges in CHIKV vaccine development.展开更多
Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we gener...Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we generated a novel mouse model with a conditional C451A mutation in Esr1,which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα(C451A^(f/f)).First,we used Runx2-Cre mice to generate Runx2-C451A^(f/f)mice with conditional inactivation of mERαsignaling in Runx2-expressing osteoblast lineage cells.No significant changes were observed in body weight,weights of estrogen-responsive organs,or serum concentrations of estradiol between female Runx2-C451A^(f/f)and homozygous C451A^(f/f)littermate controls.High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia,femur,and vertebra L5 of Runx2-C451A^(f/f)mice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in Runx2-C451A^(f/f)female mice compared to controls.Additionally,primary osteoblast cultures from mice lacking mERαsignaling showed impaired differentiation compared to controls.展开更多
Hand, foot and mouth disease(HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71(EVA71) and coxsackievirus A16(CVA1...Hand, foot and mouth disease(HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71(EVA71) and coxsackievirus A16(CVA16). Since its first large outbreak in 2008, the dominant HFMD pathogens are constantly changing. In 2013 and 2015, CVA6 exceeded both EVA71 and CVA16 to become the leading cause of HFMD in some provinces. However, there still lacks a comprehensive overview on the molecular epidemiology and evolution of HFMD-related enteroviruses at the national level. In this study, we performed systematic epidemiological analyses of HFMD-related enteroviruses using the data of 64 published papers that met the inclusion criteria, and conducted phylogenetic analyses based on 12,080 partial VP1 sequences identified in China before 31 st June 2018. We found that EVA71 prevalence has decreased sharply but other enteroviruses have increased rapidly from 2008 to 2016 and that one subtype of each enterovirus is represented during the epidemic. In addition, four genotypes EVA71_C4, CVA16_B1, CVA6_D and CVA10_C are the most predominant enterovirus strains and collectively they cause over 90% of all HFMD cases in China according to the phylogenetic trees using representative partial VP1 sequences. These four major enterovirus genotypes have different geographical distributions, and they may cocirculate with other genotypes and serotypes. These results suggest that more molecular epidemiological studies should be performed on several enteroviruses simultaneously, and such information should have implications for virological surveillance, disease management, vaccine development and policy-making on the prevention and control of HFMD.展开更多
In recent years,further understanding of the interaction between the immune system and tumor growth has led to the development of several immunotherapies.These immunotherapies include cancer vaccines and immune checkp...In recent years,further understanding of the interaction between the immune system and tumor growth has led to the development of several immunotherapies.These immunotherapies include cancer vaccines and immune checkpoint inhibitors that have been tested in various solid tumors,including those traditionally considered non-immunogenic,such as non-small cell展开更多
Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40%of colorectal cancer patients.The hallmarks of systemic inflammation include an increased production of proinflammatory cytok...Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40%of colorectal cancer patients.The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation.While the low-level systemic inflammation is often clinically silent,its consequences are many and may ultimately lead to chronic cancer-associated wasting,cachexia.In this review,we discuss the pathogenesis of cancer-related systemic inflammation,explore the role of systemic inflammation in promoting cancer growth,escaping antitumor defense,and shifting metabolic pathways,and how these changes are related to less favorable outcome.展开更多
In resectable colorectal liver metastasis(CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine fo...In resectable colorectal liver metastasis(CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases(both resectable and non-resectable) and the shift in indication from "what is taken out"(e.g., how much liver has to be resected) to "what is left behind"(that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.展开更多
To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically ...To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed. RESULTSNormal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours. CONCLUSIONTumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.展开更多
Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the im...Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.展开更多
A cross-sectional online survey was conducted.A high proportion of the Chinese breast cancer(BC)physician respondents(n=77)would prescribe extended adjuvant endocrine therapy(AET)with aromatase inhibitors(AI)beyond 5 ...A cross-sectional online survey was conducted.A high proportion of the Chinese breast cancer(BC)physician respondents(n=77)would prescribe extended adjuvant endocrine therapy(AET)with aromatase inhibitors(AI)beyond 5 years for postmenopausal females with BC,especially those with higher risk.Respondents with≥15 years of clinical experience were more likely to prescribe a longer duration of AET for low-risk patients.Half of the respondents considered intermittent letrozole as an acceptable option.Most respondents would prescribe adjuvant chemotherapy to genomic high-intermediate risk[Oncotype DX recurrence score(RS)21-25]females aged≤50 years regardless of the clinical risk classification.展开更多
Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early di...Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early diagnosis of multiple system atrophy is of utmost impo rtance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients.The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging marke rs supporting diagnosis of multiple system atrophy.Nonetheless,especially in the early disease stage,it can be challenging to differentiate multiple system atrophy from mimic disorders,in particular Parkinson’s disease.Electromyography of the external anal sphincter represents a useful neurophysiological tool for diffe rential diagnosis since it can provide indirect evidence of Onuf’s nucleus degeneration,which is a pathological hallmark of multiple system atrophy.However,the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controve rsial reports in the literature.In this review,after a brief ove rview of the electrophysiological methodology,we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography.We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electro myography.Finally,we repo rted recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.展开更多
An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas.The evaluation and management of pancreatic cystic neopl...An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas.The evaluation and management of pancreatic cystic neoplasms is a controversial topic and with existing guidelines based on a lack of strong evidence there is discordance between centres and guidelines with regard to when to offer surgery and when to favour surveillance.The frequency,duration and modality of surveillance is also controversial as this is resource-consuming and must be balanced against the perceived benefits and risks involved.While there is consensus that the risk of malignancy should be balanced against the lifeexpectancy and comorbidities,the indications for surgery and surveillance strategies vary among the guidelines.Thus,the tug of war between surveillance or resection continues.Here we discuss the recommendations from guidelines with further accumulating data and emerging reports on intraductal papillary mucinous neoplasm in the literature.展开更多
Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonf...Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.展开更多
Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific mol...Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.展开更多
BACKGROUND Diabetes mellitus(DM)is one of the largest global health emergencies of the 21st century.In recent years,its connection with environmental pollutants,such as bisphenol A(BPA),has been demonstrated;consequen...BACKGROUND Diabetes mellitus(DM)is one of the largest global health emergencies of the 21st century.In recent years,its connection with environmental pollutants,such as bisphenol A(BPA),has been demonstrated;consequently,new structurally similar molecules are used to replace BPA in the plastics industry(BPS,BPF and BPAF).AIM To carry out a systematic review to allow coherent evaluation of the state of the art.Subsequently,a meta-analysis was performed to unify the existing quantitative data.METHODS Firstly,a systematic review was carried out,using the terms“(bisphenol)AND(Diabetes OR Hyperglycemia)”,to maximize the number of results.Subsequently,three authors analyzed the set of articles.Finally,a meta-analysis was performed for each BP,using RevMan software.In addition,funnel plots were developed to study publication bias.RESULTS The systematic analysis of the literature revealed 13 recent articles(2017–2023)related to the study paradigm.The qualitative analysis showed interesting data linking diabetes to the three most widely used substitute BPs in the industry:BPS,BPF and BPAF.Finally,the meta-analysis determined a positive relationship with BPS,BPF and BPAF,which was only statistically significant with BPS.CONCLUSION There is a need to apply the precautionary principle,regulating the use of new BPs.Therefore,replacing BPA with BPS,BPF or BPAF is unlikely to protect the population from potential health risks,such as DM.展开更多
Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-sm...Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer(NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor(EGFR), and anaplastic lymphoma kinase(ALK)] and a vast number of "hills"(representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.展开更多
Dear Editor,Head and neck squamous cell carcinoma(HNSCC)is the sixth most common cancer worldwide,with a constantly growing incidence.HNSCC comprises a group of heterogeneous tumors that originate from the upper diges...Dear Editor,Head and neck squamous cell carcinoma(HNSCC)is the sixth most common cancer worldwide,with a constantly growing incidence.HNSCC comprises a group of heterogeneous tumors that originate from the upper digestive region.Tobacco,alcohol abuse,and human papillomaviruses(HPV)infection are the major etiologic agents for HNSCC.Local relapse and metastasis are major causes of mortality,accounting for 50%of cases.展开更多
Objective To determine whether topical applications of thiosulfinate-enriched Allium sativum extract(TASE)can accelerate acute cutaneous wound healing(WH)in a murine model.Methods Keratinocyte viability and in vitro w...Objective To determine whether topical applications of thiosulfinate-enriched Allium sativum extract(TASE)can accelerate acute cutaneous wound healing(WH)in a murine model.Methods Keratinocyte viability and in vitro wound closure were assessed in keratinocyte cultures.Effects of topical TASE(0.5μg/mL of allicin in 97%ethanol)on acute cutaneous WH were determined in a murine model of acute cutaneous wound.Twelve mice were alternately assigned to the vehicle-and TASE-treated groups(n=6 per group).Expression levels of mRNA for keratinocyte differentiation marker-related proteins(filaggrin,loricrin and involucrin)and lipid synthetic enzymes(elongation of very long chain fatty acids protein 4(ELOVL4),fatty acid synthase(FA2H),3-hydroxy-3-methyl-glutaryl-coenzyme A reductase(HMGCoA),and serine palmitoyltransferase(SPT))were assessed using real-time quantitative polymerase chain reaction on day 3 and 8 after wounding,while transepidermal water loss(TEWL)rates were measured in wounded areas.Results TASE accelerated WH both in vivo(40%vs.22%reduction in wound area,P<0.01)and in vitro(90%vs.65%reduction in wound area,P<0.01).Moreover,topical applications of TASE upregulated the expression levels of epidermal mRNA for ELOVL4,HMGCoA,SPT,filaggrin,loricrin and involucrin(P<0.05 vs.vehicle-treated controls)on day 3 after wounding.Likewise,TASE significantly lowered TEWL rates in comparison with vehicle alone on day 8(33.06±2.09 g/(m^2·h)vs.24.60±2.04 g/(m^2·h),P<0.01).Conclusions Topical applications of TASE stimulated keratinocyte proliferation and formation of epidermal permeability barrier function,leading to acceleration of acute cutaneous WH.Topical products containing TASE could be used to manage acute cutaneous WH.展开更多
Pancreatic cancer remains a disease with an overall grim prognosis,even in the limited number of patients who are amenable for resection attempted at cure.Indeed,pancreatic cancer demonstrate a predisposition for inva...Pancreatic cancer remains a disease with an overall grim prognosis,even in the limited number of patients who are amenable for resection attempted at cure.Indeed,pancreatic cancer demonstrate a predisposition for invasive growth and distant metastasis-even in the very early stages of the disease.Alas,while surgical resection is the strongest factor for long-term survival,early recurrence after surgery is associated with a poor prognosis(1).In light of this knowledge and,despite the lack of good level I data,it seems that patients and practitioners have been voting with their feet regarding systemic therapy;an increasing number of institutions are giving systemic treatment before surgery with the hopes of better disease control and avoiding futile surgery.However,the contemporary practice is based on an“radiant autonomy”-as it would seem,that pretty much any regimen and combination of drugs and modalities will be offered in current practice,with the lack of randomized studies for most options but often with an institutional signature to preference and delivery.展开更多
As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environm...As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57^(+)CD4^(+)T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell RNA-seq analysis of matched CD57^(+)CD4^(+)T cells from blood and tonsil samples.Circulating CD57^(+)CD4^(+)T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8^(+)effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a preexhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57^(+)CD4^(+)T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4^(+)T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.展开更多
Hepatocellular carcinoma(HCC)stands as a primary malignant liver tumor characterized by chronic inflammation and complex alterations within the tumor microenvironment(TME).Lymphocyte activation gene 3(LAG-3),also know...Hepatocellular carcinoma(HCC)stands as a primary malignant liver tumor characterized by chronic inflammation and complex alterations within the tumor microenvironment(TME).Lymphocyte activation gene 3(LAG-3),also known as CD223,has gained prominence as a potential next-generation immune checkpoint,maintaining continuous expression in response to persistent antigen exposure within the TME,warranting our attention.In patients with HCC,LAG-3 expression on T cells,regulatory T cells(Tregs),and natural killer(NK)cells contributes to immune evasion,while high expression of LAG-3 leads to increased angiogenesis and poor prognosis.By interacting with major histocompatibility complex class II molecules,LAG-3 promotes T cell exhaustion and suppresses antitumor responses,often in collaboration with other immune checkpoints like programmed cell death protein 1(PD-1),while on Tregs and NK cells,LAG-3 modulates their suppressive functions,indirectly facilitating tumor immune escape.LAG-3 expression may offer prognostic insights,correlating with disease progression and outcomes in HCC patients,while various preclinical studies highlight the potential of LAG-3-targeted therapies in reinvigorating immune responses against HCC,with a few combination approaches targeting LAG-3 alongside other checkpoints demonstrating synergistic effects in restoring T cell function.Therefore,harnessing LAG-3 as a therapeutic target holds promise for enhancing antitumor immunity and potentially improving HCC treatment outcomes.Our narrative review aims to delve into the full spectrum of LAG-3 signaling in HCC,with the goal of a better understanding of the pathophysiological and immunological basis of its use to arrest HCC growth and development.展开更多
基金supported in part by the National Key Program Project Grant from MOST #2016YFC1201000
文摘Chikungunya virus(CHIKV) is an arbovirus transmitted by Aedes mosquitos in tropical and subtropical regions across the world. After decades of sporadic outbreaks, it re-emerged in Africa,Asia, India Ocean and America suddenly, causing major regional epidemics recently and becoming a notable global health problem. Infection by CHIKV results in a spectrum of clinical diseases including an acute self-limiting febrile illness in most individuals, a chronic phase of recurrent join pain in a proportion of patients, and long-term arthralgia for months to years for the unfortunate few. No specific anti-viral drugs or licensed vaccines for CHIKV are available so far. A better understanding of virus-host interactions is essential for the development of therapeutics and vaccines. To this end, we reviewed the existing knowledge on CHIKV's epidemiology, clinical presentation, molecular virology, diagnostic approaches, host immune response, vaccine development, and available animal models. Such a comprehensive overview, we believe, will shed lights on the promises and challenges in CHIKV vaccine development.
基金supported by the Swedish Research Council(2017-01286,2020-01840)the Swedish state under the agreement between the Swedish government and the county councils(ALF-agreement)(ALFGBG721581)+2 种基金the Gustaf V 80-years fund(FAI-2018-0466)the IngaBritt and Arne Lundberg Foundation(LU2017-0076)the Novo Nordisk Foundation(26844).
文摘Membrane-initiated estrogen receptorα(mERα)signaling has been shown to affect bone mass in murine models.However,it remains unknown which cell types mediate the mERα-dependent effects on bone.In this study,we generated a novel mouse model with a conditional C451A mutation in Esr1,which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα(C451A^(f/f)).First,we used Runx2-Cre mice to generate Runx2-C451A^(f/f)mice with conditional inactivation of mERαsignaling in Runx2-expressing osteoblast lineage cells.No significant changes were observed in body weight,weights of estrogen-responsive organs,or serum concentrations of estradiol between female Runx2-C451A^(f/f)and homozygous C451A^(f/f)littermate controls.High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia,femur,and vertebra L5 of Runx2-C451A^(f/f)mice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in Runx2-C451A^(f/f)female mice compared to controls.Additionally,primary osteoblast cultures from mice lacking mERαsignaling showed impaired differentiation compared to controls.
基金supported by the TOTAL foundation,and the Grants from the National Science and Technology Major Project of China(2017ZX10103009-002)the "One Belt One Road" Project(153831KYSB20170043)of the Chinese Academy of Sciencesthe133 Project of Institut Pasteur of Shanghai,CAS.
文摘Hand, foot and mouth disease(HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71(EVA71) and coxsackievirus A16(CVA16). Since its first large outbreak in 2008, the dominant HFMD pathogens are constantly changing. In 2013 and 2015, CVA6 exceeded both EVA71 and CVA16 to become the leading cause of HFMD in some provinces. However, there still lacks a comprehensive overview on the molecular epidemiology and evolution of HFMD-related enteroviruses at the national level. In this study, we performed systematic epidemiological analyses of HFMD-related enteroviruses using the data of 64 published papers that met the inclusion criteria, and conducted phylogenetic analyses based on 12,080 partial VP1 sequences identified in China before 31 st June 2018. We found that EVA71 prevalence has decreased sharply but other enteroviruses have increased rapidly from 2008 to 2016 and that one subtype of each enterovirus is represented during the epidemic. In addition, four genotypes EVA71_C4, CVA16_B1, CVA6_D and CVA10_C are the most predominant enterovirus strains and collectively they cause over 90% of all HFMD cases in China according to the phylogenetic trees using representative partial VP1 sequences. These four major enterovirus genotypes have different geographical distributions, and they may cocirculate with other genotypes and serotypes. These results suggest that more molecular epidemiological studies should be performed on several enteroviruses simultaneously, and such information should have implications for virological surveillance, disease management, vaccine development and policy-making on the prevention and control of HFMD.
文摘In recent years,further understanding of the interaction between the immune system and tumor growth has led to the development of several immunotherapies.These immunotherapies include cancer vaccines and immune checkpoint inhibitors that have been tested in various solid tumors,including those traditionally considered non-immunogenic,such as non-small cell
文摘Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40%of colorectal cancer patients.The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation.While the low-level systemic inflammation is often clinically silent,its consequences are many and may ultimately lead to chronic cancer-associated wasting,cachexia.In this review,we discuss the pathogenesis of cancer-related systemic inflammation,explore the role of systemic inflammation in promoting cancer growth,escaping antitumor defense,and shifting metabolic pathways,and how these changes are related to less favorable outcome.
文摘In resectable colorectal liver metastasis(CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases(both resectable and non-resectable) and the shift in indication from "what is taken out"(e.g., how much liver has to be resected) to "what is left behind"(that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.
基金Supported by a grant from the Mary and Georg C Ehrnrooth Foundation,Finland
文摘To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed. RESULTSNormal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours. CONCLUSIONTumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.
文摘Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.
文摘A cross-sectional online survey was conducted.A high proportion of the Chinese breast cancer(BC)physician respondents(n=77)would prescribe extended adjuvant endocrine therapy(AET)with aromatase inhibitors(AI)beyond 5 years for postmenopausal females with BC,especially those with higher risk.Respondents with≥15 years of clinical experience were more likely to prescribe a longer duration of AET for low-risk patients.Half of the respondents considered intermittent letrozole as an acceptable option.Most respondents would prescribe adjuvant chemotherapy to genomic high-intermediate risk[Oncotype DX recurrence score(RS)21-25]females aged≤50 years regardless of the clinical risk classification.
基金supported by the Italian Ministry of Health (’Ricerca Corrente’2020-2021)(to MT)。
文摘Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early diagnosis of multiple system atrophy is of utmost impo rtance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients.The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging marke rs supporting diagnosis of multiple system atrophy.Nonetheless,especially in the early disease stage,it can be challenging to differentiate multiple system atrophy from mimic disorders,in particular Parkinson’s disease.Electromyography of the external anal sphincter represents a useful neurophysiological tool for diffe rential diagnosis since it can provide indirect evidence of Onuf’s nucleus degeneration,which is a pathological hallmark of multiple system atrophy.However,the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controve rsial reports in the literature.In this review,after a brief ove rview of the electrophysiological methodology,we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography.We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electro myography.Finally,we repo rted recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.
文摘An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas.The evaluation and management of pancreatic cystic neoplasms is a controversial topic and with existing guidelines based on a lack of strong evidence there is discordance between centres and guidelines with regard to when to offer surgery and when to favour surveillance.The frequency,duration and modality of surveillance is also controversial as this is resource-consuming and must be balanced against the perceived benefits and risks involved.While there is consensus that the risk of malignancy should be balanced against the lifeexpectancy and comorbidities,the indications for surgery and surveillance strategies vary among the guidelines.Thus,the tug of war between surveillance or resection continues.Here we discuss the recommendations from guidelines with further accumulating data and emerging reports on intraductal papillary mucinous neoplasm in the literature.
文摘Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.
文摘Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.
基金the“Margarita Salas”postdoctoral fellowship from the Universidad de Alcaláand FPI fellowships from the Universidad de Alcalá.
文摘BACKGROUND Diabetes mellitus(DM)is one of the largest global health emergencies of the 21st century.In recent years,its connection with environmental pollutants,such as bisphenol A(BPA),has been demonstrated;consequently,new structurally similar molecules are used to replace BPA in the plastics industry(BPS,BPF and BPAF).AIM To carry out a systematic review to allow coherent evaluation of the state of the art.Subsequently,a meta-analysis was performed to unify the existing quantitative data.METHODS Firstly,a systematic review was carried out,using the terms“(bisphenol)AND(Diabetes OR Hyperglycemia)”,to maximize the number of results.Subsequently,three authors analyzed the set of articles.Finally,a meta-analysis was performed for each BP,using RevMan software.In addition,funnel plots were developed to study publication bias.RESULTS The systematic analysis of the literature revealed 13 recent articles(2017–2023)related to the study paradigm.The qualitative analysis showed interesting data linking diabetes to the three most widely used substitute BPs in the industry:BPS,BPF and BPAF.Finally,the meta-analysis determined a positive relationship with BPS,BPF and BPAF,which was only statistically significant with BPS.CONCLUSION There is a need to apply the precautionary principle,regulating the use of new BPs.Therefore,replacing BPA with BPS,BPF or BPAF is unlikely to protect the population from potential health risks,such as DM.
文摘Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer(NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor(EGFR), and anaplastic lymphoma kinase(ALK)] and a vast number of "hills"(representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.
基金supported Ministry of Health PNRR(funding issued according to“Missione 6/componente 2/Investimento:2.1-Rafforzamento e potenziamento della ricerca biomedica del SSN”,funding by NextGenerationEU/H53C22001150001 to BG)PNRR-POC-2022-12376580:“Analyses of HPV and host body fluid biomarkers as non-invasive strategy for detection of head and neck cancer relapse”.
文摘Dear Editor,Head and neck squamous cell carcinoma(HNSCC)is the sixth most common cancer worldwide,with a constantly growing incidence.HNSCC comprises a group of heterogeneous tumors that originate from the upper digestive region.Tobacco,alcohol abuse,and human papillomaviruses(HPV)infection are the major etiologic agents for HNSCC.Local relapse and metastasis are major causes of mortality,accounting for 50%of cases.
基金Supported by the European Commission/FSE Funds to EMG-M,the European Regional Development Fund(JRM-R and JMP-O,Castilla-La Mancha FEDER 2014-20 PO)the Government of Castilla-La Mancha(MAC-M,Ref.II-2016-06)+1 种基金and the National Institute of Arthritis,Musculoskeletal and Skin Diseases of the National Institutes of Health(PEM&MQM,AR061106)with additi onal resources provided by The Vetera ns Affairs Medical Center,San Fran cisco,CA,USA。
文摘Objective To determine whether topical applications of thiosulfinate-enriched Allium sativum extract(TASE)can accelerate acute cutaneous wound healing(WH)in a murine model.Methods Keratinocyte viability and in vitro wound closure were assessed in keratinocyte cultures.Effects of topical TASE(0.5μg/mL of allicin in 97%ethanol)on acute cutaneous WH were determined in a murine model of acute cutaneous wound.Twelve mice were alternately assigned to the vehicle-and TASE-treated groups(n=6 per group).Expression levels of mRNA for keratinocyte differentiation marker-related proteins(filaggrin,loricrin and involucrin)and lipid synthetic enzymes(elongation of very long chain fatty acids protein 4(ELOVL4),fatty acid synthase(FA2H),3-hydroxy-3-methyl-glutaryl-coenzyme A reductase(HMGCoA),and serine palmitoyltransferase(SPT))were assessed using real-time quantitative polymerase chain reaction on day 3 and 8 after wounding,while transepidermal water loss(TEWL)rates were measured in wounded areas.Results TASE accelerated WH both in vivo(40%vs.22%reduction in wound area,P<0.01)and in vitro(90%vs.65%reduction in wound area,P<0.01).Moreover,topical applications of TASE upregulated the expression levels of epidermal mRNA for ELOVL4,HMGCoA,SPT,filaggrin,loricrin and involucrin(P<0.05 vs.vehicle-treated controls)on day 3 after wounding.Likewise,TASE significantly lowered TEWL rates in comparison with vehicle alone on day 8(33.06±2.09 g/(m^2·h)vs.24.60±2.04 g/(m^2·h),P<0.01).Conclusions Topical applications of TASE stimulated keratinocyte proliferation and formation of epidermal permeability barrier function,leading to acceleration of acute cutaneous WH.Topical products containing TASE could be used to manage acute cutaneous WH.
文摘Pancreatic cancer remains a disease with an overall grim prognosis,even in the limited number of patients who are amenable for resection attempted at cure.Indeed,pancreatic cancer demonstrate a predisposition for invasive growth and distant metastasis-even in the very early stages of the disease.Alas,while surgical resection is the strongest factor for long-term survival,early recurrence after surgery is associated with a poor prognosis(1).In light of this knowledge and,despite the lack of good level I data,it seems that patients and practitioners have been voting with their feet regarding systemic therapy;an increasing number of institutions are giving systemic treatment before surgery with the hopes of better disease control and avoiding futile surgery.However,the contemporary practice is based on an“radiant autonomy”-as it would seem,that pretty much any regimen and combination of drugs and modalities will be offered in current practice,with the lack of randomized studies for most options but often with an institutional signature to preference and delivery.
基金NHMRC grants APP1113577(MCC,CGV)and APP1079648(MCC,CGV)grant APP1130330 awarded through the Priority-drive Collaborative Cancer Research Scheme and funded by Cancer Australia(MCC,DY,SY).
文摘As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57^(+)CD4^(+)T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell RNA-seq analysis of matched CD57^(+)CD4^(+)T cells from blood and tonsil samples.Circulating CD57^(+)CD4^(+)T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8^(+)effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a preexhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57^(+)CD4^(+)T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4^(+)T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.
文摘Hepatocellular carcinoma(HCC)stands as a primary malignant liver tumor characterized by chronic inflammation and complex alterations within the tumor microenvironment(TME).Lymphocyte activation gene 3(LAG-3),also known as CD223,has gained prominence as a potential next-generation immune checkpoint,maintaining continuous expression in response to persistent antigen exposure within the TME,warranting our attention.In patients with HCC,LAG-3 expression on T cells,regulatory T cells(Tregs),and natural killer(NK)cells contributes to immune evasion,while high expression of LAG-3 leads to increased angiogenesis and poor prognosis.By interacting with major histocompatibility complex class II molecules,LAG-3 promotes T cell exhaustion and suppresses antitumor responses,often in collaboration with other immune checkpoints like programmed cell death protein 1(PD-1),while on Tregs and NK cells,LAG-3 modulates their suppressive functions,indirectly facilitating tumor immune escape.LAG-3 expression may offer prognostic insights,correlating with disease progression and outcomes in HCC patients,while various preclinical studies highlight the potential of LAG-3-targeted therapies in reinvigorating immune responses against HCC,with a few combination approaches targeting LAG-3 alongside other checkpoints demonstrating synergistic effects in restoring T cell function.Therefore,harnessing LAG-3 as a therapeutic target holds promise for enhancing antitumor immunity and potentially improving HCC treatment outcomes.Our narrative review aims to delve into the full spectrum of LAG-3 signaling in HCC,with the goal of a better understanding of the pathophysiological and immunological basis of its use to arrest HCC growth and development.
