Safety and effectiveness of vonoprazan-based rescue therapy for Helicobacter pylori infection

BACKGROUND Vonoprazan(VPZ)-based regimens are an effective first-line therapy for Helicobacter pylori(H.pylori)infection.However,their value as a rescue therapy needs to be explored.AIM To assess a VPZ-based regimen as H.pylori rescue therapy.METHODS This prospective,single-center,clinical trial was conducted between January and August 2022.Patients with a history of H.pylori treatment failure were administered 20 mg VPZ twice daily,750 mg amoxicillin 3 times daily,and 250 mg Saccharomyces boulardii(S.boulardii)twice daily for 14 d(14-d VAS regimen).VPZ and S.boulardii were taken before meals,while amoxicillin was taken after meals.Within 3 d after the end of eradication therapy,all patients were asked to fill in a questionnaire to assess any adverse events they may have experienced.At least 4-6 wk after the end of eradication therapy,eradication success was assessed using a 13C-urea breath test,and factors associated with eradication success were explored.RESULTS Herein,103 patients were assessed,and 68 patients were finally included.All included patients had 1-3 previous eradication failures.The overall eradication rates calculated using intention-to-treat and per-protocol analyses were 92.6%(63/68)and 92.3%(60/65),respectively.The eradication rate did not differ with the number of treatment failures(P=0.433).The rates of clarithromycin,metronidazole,and levofloxacin resistance were 91.3%(21/23),100.0%(23/23),and 60.9%(14/23),respectively.There were no cases of resistance to tetracycline,amoxicillin,or furazolidone.In 60.9%(14/23)patients,the H.pylori isolate was resistant to all 3 antibiotics(clarithromycin,metronidazole,and levofloxacin);however,eradication was achieved in 92.9%(13/14)patients.All patients showed metronidazole resistance,and had an eradication rate of 91.3%(21/23).The eradication rate was higher among patients without anxiety(96.8%)than among patients with anxiety(60.0%,P=0.025).No severe adverse events occurred;most adverse events were mild and disappeared without intervention.Good compliance was seen in 95.6%(65/68)patients.Serological examination showed no significant changes in liver and kidney function.CONCLUSION VAS is a safe and effective rescue therapy,with an acceptable eradication rate(>90%),regardless of the number of prior treatment failures.Anxiety may be associated with eradication failure.

Next-generation antibody-drug conjugates revolutionize the precise classification and treatment of HER2-expressing breast cancer

The concept of antibody±drug conjugations(ADCs)can be tracked back to the early 20^(th) century when the renowned immunologist,Paul Ehrlich,proposed the idea of a"magic bullet",which utilizes ADCs for targeted destruction of microorganisms and tumor cells^(1).After nearly one century of development,ADCs have emerged as a rather promising approach in the treatment of cancer,especially breast cancer,which is the most common malignant tumor in women^(2).

Conceptualizing the complexity of ferroptosis to treat triple-negative breast cancer:theory-to-practice

Ferroptosis,a type of regulated cell death named one decade ago,is a unique type driven by lipid peroxidation in an iron-dependent manner.Ferroptosis differs radically from apoptosis and other regulated forms of cell death in both morphology and molecular underpinning.Ferroptosis can be triggered by a variety of physiologic conditions and pathologic stresses.There has been growing interest in ferroptosis in recent years,and research on ferroptosis is productive.

Breast cancer screening and early diagnosis in Chinese women

Breast cancer is the most common malignant tumor in Chinese women,and its incidence is increasing.Regular screening is an effective method for early tumor detection and improving patient prognosis.In this review,we analyze the epidemiological changes and risk factors associated with breast cancer in China and describe the establishment of a screening strategy suitable for Chinese women.Chinese patients with breast cancer tend to be younger than Western patients and to have denser breasts.Therefore,the age of initial screening in Chinese women should be earlier,and the importance of screening with a combination of ultrasound and mammography is stressed.Moreover,Chinese patients with breast cancers have several ancestry-specific genetic features,and aiding in the determination of genetic screening strategies for identifying high-risk populations.On the basis of current studies,we summarize the development of risk-stratified breast cancer screening guidelines for Chinese women and describe the significant improvement in the prognosis of patients with breast cancer in China.

AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs

AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFF1 and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFFI and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.

Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.

Bidirectional crosstalk between therapeutic cancer vaccines and the tumor microenvironment:Beyond tumor antigens

Immunotherapy has rejuvenated cancer therapy,especially after anti-PD-(L)1 came onto the scene.Among the many therapeutic options,therapeutic cancer vaccines are one of the most essential players.Although great progress has been made in research on tumor antigen vaccines,few phase III trials have shown clinical benefits.One of the reasons lies in obstruction from the tumor microenvironment(TME).Meanwhile,the therapeutic cancer vaccine reshapes the TME in an ambivalent way,leading to immune stimulation or immune escape.In this review,we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME.With respect to vaccine resistance,innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved.Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

Prognostic Factors Related to In-hospital Death in Children with Biliary Atresia:Analysis of a Nationwide Inpatient Database

Background and Aims:Patients with biliary atresia(BA)are prone to hepatic decompensation,which might eventually lead to death.This study aimed to identify the possible risk factors affecting in-hospital death in BA patients in China.Methods:We collected data from the Hospital Quality Monitoring System,a national inpatient database.All patients aged up to 2 years old with a diagnosis of BA were included.The subjects were divided to three groups,including Kasai portoenterostomy(KP),liver transplantation(LT),and no surgery.Logistic regression with Firth’s method was performed to identify potential influencing variables associated with in-hospital death.Results:During the year 2013 to 2017,there were 14,038 pediatric admissions with a diagnosis of BA.The proportion of in-hospital death in pediatric BA admissions was 1.08%.Compared with patients under six months,there was a higher risk of in-hospital death for children aged six months to 1 year and 1–2 years old.Clinical signs,including cirrhosis,variceal bleeding,and hepatic encephalopathy,were significantly associated with the risk of in-hospital death.In no surgery group,compared to those in Beijing and Shanghai,BA patients admitted in other districts had a lower risk of in-hospital death(OR=0.39,95%CI:0.21,0.70).However,in the LT group,patients admitted in other districts had a higher risk of in-hospital death(OR=9.13,95%CI:3.99,20.87).Conclusions:In-hospital survival remains unsatisfactory for pediatric BA patients with severe complications.Furthermore,more resources and training for BA treatment,especially LT,are essential for districts with poor medical care in the future.

Inflammatory response-based subtyping and potential therapeutic strategies for triple-negative breast cancer

objective:Inflammatory response plays a crucial role in the development and treatment of cancer.However,the role of inflammatory response in triple-negative breast cancer(TNBC)remains unclear.Based on the heterogeneity of the inflammatory response,we classified TNBC,elucidated its subtype features,and revealed potential therapeutic strategies.Methods:We established inflammatory response subtyping based on the RNA sequencing data of TNBCs derived from a cohort at the Fudan University Shanghai Cancer Center(FUSCC).Next,we explored the features and potential therapeutic strategies for each subgroup by analyzing transcriptome data.Using a machine-learning method,we validated and generalized the TNBC inflammatory response subtypes in an external dataset.Results:A total of 360 TNBC samples and 88 normal tissues were collected from a cohort at FUSCC.Patients with TNBC were divided into four inflammatory response groups(IRGs)based on the expression of inflammatory response genes:high inflammatory response gene expression with pronounced pyroptosis phenotype and high immune cellinfiltration(IRG 1),low inflammatory response gene expression and low immune cell infiltration(IRG 2),ITGB8 specific inflammatory response with a predominant proliferation phenotype(IRG 3),and low M1/M2 ratio with a marked angiogenesis phenotype(IRG 4).Relapse-free survival(RFS)was better in iRG 1 and 2 and worse in IRG 3 and 4.Owing to their poor prognosis,we mainly focused on IRG 3 and IRG 4 to investigate potential treatment strategies.ITGB8 was highly expressed in IRG 3;thus,targeting ITGB8 may be a potential therapeutic strategy for patients in IRG 3.IRG 4 had a lower M1/M2 ratio and a marked angiogenesis phenotype;therefore,therapeutic strategies,such as anti-angiogenesis or M2 to M1 repolarization of macrophages,could be recommended for these patients.Additionally,we validated and generalized the TNBC inflammatory response subtyping in an external dataset using a machine-learning method.Conclusion:TNBC patients with different inflammatory response subtypes have different characteristics and may need subtype-specific treatment strategies.

Deep learning framework for comprehensive molecular and prognostic stratifications of triple-negative breast cancer

Triple-negative breast cancer(TNBC)is the most challenging breast cancer subtype.Molecular stratification and target therapy bring clinical benefit for TNBC patients,but it is difficult to implement comprehensive molecular testing in clinical practice.Here,using our multi-omics TNBC cohort(N=425),a deep learning-based framework was devised and validated for comprehensive predictions of molecular features,subtypes and prognosis from pathological whole slide images.The framework first incorporated a neural network to decompose the tissue on WSIs,followed by a second one which was trained based on certain tissue types for predicting different targets.Multi-omics molecular features were analyzed including somatic mutations,copy number alterations,germline mutations,biological pathway activities,metabolomics features and immunotherapy biomarkers.It was shown that the molecular features with therapeutic implications can be predicted including the somatic PIK3CA mutation,germline BRCA2 mutation and PD-L1 protein expression(area under the curve[AUC]:0.78,0.79 and 0.74 respectively).The molecular subtypes of TNBC can be identified(AUC:0.84,0.85,0.93 and 0.73 for the basal-like immune-suppressed,immunomodulatory,luminal androgen receptor,and mesenchymal-like subtypes respectively)and their distinctive morphological patterns were revealed,which provided novel insights into the heterogeneity of TNBC.A neural network integrating image features and clinical covariates stratified patients into groups with different survival outcomes(log-rank P<0.001).Our prediction framework and neural network models were externally validated on the TNBC cases from TCGA(N=143)and appeared robust to the changes in patient population.For potential clinical translation,we built a novel online platform,where we modularized and deployed our framework along with the validated models.It can realize real-time one-stop prediction for new cases.In summary,using only pathological WSIs,our proposed framework can enable comprehensive stratifications of TNBC patients and provide valuable information for therapeutic decision-making.It had the potential to be clinically implemented and promote the personalized management of TNBC.

Triple-negative breast cancer:new treatment strategies in the era of precision medicine

Triple-negative breast cancer(TNBC)remains the most aggressive cluster of all breast cancers,which is due to its rapid progression,high probabilities of early recurrence,and distant metastasis resistant to standard treatment.Following the advances in cancer genomics and transcriptomics that can illustrate the comprehensive profiling of this heterogeneous disease,it is now possible to identify different subclasses of TNBC according to both intrinsic signals and extrinsic microenvironment,which have a huge influence on predicting response to established therapies and picking up novel therapeutic targets for each cluster.In this review,we summarize basic characteristics and critical subtyping systems of TNBC,and particularly discuss newly found prospective targets and relevant medications,which were proved promising in clinical trials,thus shedding light on the future development of precision treatment strategies.

Comparision between portosystemic shunts and endoscopic therapy for prevention of variceal re-bleeding:a systematic review and meta-analysis

Background:Portosystemic shunts,including surgical portosystemic shunts and transjugular intra-hepatic portosystemic shunt (TIPS),may have benefit over endoscopic therapy (ET) for treatment of variceal bleeding in patients with cirrhotic portal hypertension;however,whether there being a survival benefit among them remains unclear.This study was to compare the effect of three above-mentioned therapies on the short-term and long-term survival in patient with cirrhosis.Methods:Using the terms "variceal hemorrhage or variceal bleeding or variceal re-bleeding" OR "esophageal and gastric varices" OR "portal hypertension" and "liver cirrhosis," the Cochrane Central Register of Controlled Trials,PubMed,Embase,and the references of identified trials were searched for human randomized controlled trials (RCTs) published in any language with full texts or abstracts (last search June 2017).Risk ratio (RR) estimates with 95% confidence interval (CI) were calculated using random effects model by Review Manager.The quality of the included studies was evaluated using the Cochrane Collaboration’s tool for the assessment of the risk of bias.Results:Twenty-six publications comprising 28 RCTs were included in this analysis.These studies included a total of 2845 patients:496 (4 RCTs) underwent either surgical portosystemic shunts or TIPS,1244 (9 RCTs) underwent either surgical portosystemic shunts or ET,and 1105 (15 RCTs) underwent either TIPS or ET.There was no significant difference in overall mortality and 30-day or 6-week survival among three interventions.Compared with TIPS and ET,separately,surgical portosystemic shunts were both associated with a lower bleeding-related mortality (RR = 0.07,95% CI = 0.01–0.32;P<0.001;RR = 0.17,95% CI = 0.06–0.51,P<0.005) and rate of variceal re-bleeding (RR = 0.23,95% CI = 0.10–0.51,P<0.001;RR = 0.10,95% CI = 0.04–0.24,P<0.001),without a significant difference in the rate of postoperative hepatic encephalopathy (RR = 0.52,95% CI = 0.25–1.00,P = 0.14;RR = 1.09,95% CI = 0.59–2.01,P = 0.78).TIPS showed a trend toward lower variceal re-bleeding (RR = 0.46,95% CI = 0.36–0.58,P<0.001),but a higher incidence of hepatic encephalopathy than ET (RR = 1.78,95% CI = 1.34–2.36,P<0.001).Conclusions:The overall analysis revealed that there seem to be no short-term and long-term survival advantage,but surgical portosystemic shunts are with the lowest bleeding-related mortality among the three therapies.Surgical portosystemic shunts may be the most effective without an increased risk of hepatic encephalopathy and TIPS is superior to ET but at the cost of a higher incidence of hepatic encephalopathy.However,some of findings should be interpreted with caution due to the lower level of evidence and the existence of significant heterogeneity.

Technological advances in cancer immunity:from immunogenomics to single-cell analysis and artificial intelligence

Immunotherapies play critical roles in cancer treatment.However,given that only a few patients respond to immune checkpoint blockades and other immunotherapeutic strategies,more novel technologies are needed to decipher the complicated interplay between tumor cells and the components of the tumor immune microenvironment(TIME).Tumor immunomics refers to the integrated study of the TIME using immunogenomics,immunoproteomics,immune-bioinformatics,and other multi-omics data reflecting the immune states of tumors,which has relied on the rapid development of next-generation sequencing.High-throughput genomic and transcriptomic data may be utilized for calculating the abundance of immune ceils and predicting tumor antigens,referring to immunogenomics.However,as bulk sequencing represents the average characteristics of a heterogeneous cell population,it fails to distinguish distinct cell subtypes.Single-cell-based technologies enable better dissection of the TIME through precise immune cell subpopulation and spatial architecture investigations.In addition,radiomics and digital pathology-based deep learning models largely contribute to research on cancer immunity.These artificial intelligence technologies have performed well in predicting response to immunotherapy,with profound significance in cancer therapy.In this review,we briefly summarize conventional and state-of-the-art technologies in the field of immunogenomics,single-cell and artificial intelligence,and present prospects for future research.

Perioperative characteristics and management of liver transplantation for isolated methylmalonic acidemia—the largest experience in China

Background:There are few detailed consensus and guidelines on perioperative clinical characteristicsof liver transplantation(LT)in patients with methylmalonic acidemia(MMA).This retrospective studyinvestigated details of the clinical course and individualized treatment plan of the center with largestexperience in China.Methods:A total of 7 MMA patients undergoing LT in Beijing Friendship Hospital from June 2013 toDecember 2017 were enrolled in the study,whose clinical data(clinical characteristics,laboratory findings,chronological changes in urine MMA levels,treatment,etc.)during perioperative period were analyzedretrospectively.All the patients received strict postoperative management.Results:All the 7 cases were confirmed to have isolated MMA,among which,3 cases received livingdonor liver transplantation(LDLT),4 cases received deceased donor liver transplantation(DDLT).A wildfluctuate of metabolic condition was observed within the first few days after surgery and two weeks afterLT,the mean base excess of blood value(BE-B)restored to normal whereas plasma bicarbonate(HCO3-)was still below normal value even with intermittent sodium bicarbonate correction.It also showed markedreduction in propionylcarnitine(C3)and C3/C2 level and the mean urine MMA by gas chromatographymassspectrometry(GC-MS)was reduced by 81.7%(P<0.01)but remained>72×higher than upper limitof normal.The metabolism-correcting medications were administered as before.The renal function ofone case with renal insufficiency before LT(serum creatinine rising)maintained stable by adjusting theimmunosuppressive regimen during the observation period.All patients survive to date.Conclusions:LT is an effective treatment to prevent metabolic crisis,but patients with MMA tend to bemetabolically fragile even after surgery.During perioperative period,close monitoring should be given foracidosis episodes so as to implement sodium bicarbonate correction.Metabolism-correcting medications arestill needed.Special immunosuppressive regimen is an effective way of maintaining renal function for thosewith kidney dysfunction.

Mettl5 mediated 18S rRNA N6-methyladenosine(m^(6)A)modification controls stem cell fate determination and neural function

Ribosome RNA(rRNA)accounts for more than 80%of the cell's total RNA,while the physiological functions of rRNA modifications are poorly understood.Mutations of 18S rRNA m6A methyltransferase METTL5 cause intellectual disability,microcephaly,and facial dysmorphisms in patients,however,little is known about the underlying mechanisms.In this study,we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins.Functionally,we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development.Moreover,using Mettl5 knockout mouse model,we further demonstrated that Mettl5 knockout mice exhibit intellectual disability,recapitulating the human phenotype.Mechanistically,we found that Mettl5 maintains brain function and intelligence by regulating the myelination process.Our study uncovered the causal correlation between mis-regulated 18S rRNA m6A modification and neural function defects,supporting the important physiological functions of rRNA modifications in human diseases.

Extracellular viscosity:a potential therapeutic target to combat cancer metastasis

Aberrant migration plays a key role in cancer development and is particularly significant during invasion,which is the initial step of metastasis.Research over the past decade has shown that cancer cell migration is affected by several physical stimuli within the tumor microenvironment.For example,tumor metastasis is driven by interstitial flow caused by high intertumoral interstitial fluid pressure1.Shellard et al.showed that cells follow gradients in the stiffness of the substrates to prompt collective cell migration in vitro2.However,the effect of extracellular viscosities on cell function remains unclear.

Effects of dietary intervention on human diseases:molecular mechanisms and therapeutic potential

Diet,serving as a vital source of nutrients,exerts a profound influence on human health and disease progression.Recently,dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases,autoimmune diseases,cardiovascular diseases,and metabolic disorders.These interventions have demonstrated substantial potential in modulating metabolism,disease trajectory,and therapeutic responses.Metabolic reprogramming is a hallmark of malignant progression,and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication.Dietary intake,as a key environmental factor,can influence tumor metabolism.Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors,thereby increasing the efficacy of cancer treatments.However,the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex.Despite encouraging results,the mechanisms underlying diet-based therapeutic strategies remain largely unexplored,often resulting in underutilization in disease management.In this review,we aim to illuminate the potential effects of various dietary interventions,including calorie restriction,fasting-mimicking diet,ketogenic diet,protein restriction diet,high-salt diet,high-fat diet,and high-fiber diet,on cancer and the aforementioned diseases.We explore the multifaceted impacts of these dietary interventions,encompassing their immunomodulatory effects,other biological impacts,and underlying molecular mechanisms.This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.