Risk factors for primary gout and hyperuricemia

Objective:Through epidemiological investigation,to investigate the etiology and influencing factors of primary gout and hyperuricemia(HUA).Methods:Using case-control methods,designed questionnaires on gout and/or HUA related factors(living habits,eating habits and environmental factors,etc).Logistic regression analysis of the survey results was performed with SPSS 19.0 software.Results:(1)Univariate Logistic regression analysis:11 risk factors with statistical significance(P<0.05),often eat sauce food,often eat Fried food,often eat asparagus,often eat nuts,often drink,smoking,drink water<1000ml per day,residential temperature≤17℃in winter,work environment average temperature≤17℃in winter,often exposure to toxic and harmful substances,often use induction cooker or microwave oven(P<0.05),the OR values were 2.063,1.701,3.242,1.560,2.055,1.338,5.700,5.330,2.305,2.821,1.701;3 protective factors,occasionally eat fresh fruit,wake up between 5 and 7 am,use the computer less than 1 hour per day(P<0.05),OR values were 0.723,0.611 and 0.558,respectively.(2)Multivariate Logistic regression analysis was performed for all factors:6 risk factors,The risk factors were often drink,drink water<1000ml per day,residential temperature≤17℃in winter,work environment average temperature≤17℃in winter,use mobile network cellphones and use unicom network cellphones(P<0.05),OR values are 2.008,4.240,4.034,1.889,2.207 and 1.891,respectively;2 protective factors:occasionally eat agaric and use the computer less than 1 hour per day(P<0.05),OR values were 0.551 and 0.536,respectively.Conclusions:Proper improvement of diet structure,adjustment of life and behavior,and avoidance of environmental risk factors can effectively reduce uric acid level,control the incidence of HUA and gout,and improve health level.

Research status of genes related to primary gout and hyperuricemia

Objective:Existing studies have shown that primary gout and hyperuricemia are a group of polygenetic hereditary diseases,which are the results of the combination of genetic and environmental factors.However,the study on the genetic susceptibility of gout and hyperuricemia is not yet complete and it is not yet possible to predict which populations are susceptible to gout and hyperuricemia.Genome-wide association study(GWAS),a method developed in recent years,is used to identify susceptibility genes for complex disease pathogenesis.Through screening patients and the normal control,and combined with computer technology and statistical analysis,genome-wide variation can be used to identify minor gene and its interaction with related diseases.In our study,we summarized and classified uric acid related genes discovered in recent years,so as to provide a basis for further understanding of the molecular mechanism of gout and hyperuricemia,and provide a beneficial reference for further study on the etiology of gout and hyperuricemia.

Three-dimensional choroidal vascularity index and choroidal thickness in fellow eyes of acute and chronic primary angle-closure using swept-source optical coherence tomography

AIM:To compare the three-dimensional choroidal vascularity index(CVI)and choroidal thickness between fellow eyes of acute primary angle-closure(F-APAC)and chronic primary angle-closure glaucoma(F-CPACG)and the eyes of normal controls.METHODS:This study included 37 patients with unilateral APAC,37 with asymmetric CPACG without prior treatment,and 36 healthy participants.Using swept-source optical coherence tomography(SS-OCT),the macular and peripapillary choroidal thickness and three-dimensional CVI were measured and compared globally and sectorally.Pearson’s correlation analysis and multivariate regression models were used to evaluate choroidal thickness or CVI with related factors.RESULTS:The mean subfoveal CVIs were 0.35±0.10,0.33±0.09,and 0.29±0.04,and the mean subfoveal choroidal thickness were 315.62±52.92,306.22±59.29,and 262.69±45.55μm in the F-APAC,F-CPACG,and normal groups,respectively.All macular sectors showed significantly higher CVIs and choroidal thickness in the F-APAC and F-CPACG eyes than in the normal eyes(P<0.05),while there were no significant differences between the F-APAC and F-CPACG eyes.In the peripapillary region,the mean overall CVIs were 0.21±0.08,0.20±0.08,and 0.19±0.05,and the mean overall choroidal thickness were 180.45±54.18,174.82±50.67,and 176.18±37.94μm in the F-APAC,F-CPACG,and normal groups,respectively.There were no significant differences between any of the two groups in all peripapillary sectors.Younger age,shorter axial length,and the F-APAC or F-CPACG diagnosis were significantly associated with higher subfoveal CVI and thicker subfoveal choroidal thickness(P<0.05).CONCLUSION:The fellow eyes of unilateral APAC or asymmetric CPACG have higher macular CVI and choroidal thickness than those of the normal controls.Neither CVI nor choroidal thickness can distinguish between eyes predisposed to APAC or CPACG.A thicker choroid with a higher vascular volume may play a role in the pathogenesis of primary angle-closure glaucoma.

Acute primary angle closure during the Omicron outbreak

AIM:To investigate Omicron’s impact on clinical presentation of acute primary angle closure(APAC)in China.METHODS:A consecutive case series with historical controls was conducted at Shenzhen Eye Hospital,the largest specialized hospital in Shenzhen,China.Medical records from a two-month period during the Omicron pandemic(December 1,2022,to January 31,2023)were compared with records from two control groups(12/2018–1/2019 and 12/2021–1/2022)before pandemic.Patients with APAC were included,and the prevalence of APAC and demographic characteristics in Omicron-infected and noninfected patients were compared.RESULTS:Seventy-one(23.43%)out of 303 patients were diagnosed with APAC in the pandemic cohort,which was 2.98 and 2.61 times higher than that in control cohorts(7.87%in 2019,8.96%in 2022,P<0.001).The pandemic cohort has significantly higher Omicron-infected rate(78.87%vs 0 vs 0;P<0.001),lower proportion of glaucoma history(16.90%vs 42.86%vs 41.67%,P=0.005),higher surgical rate(95.77%vs 83.33%vs 78.57%,P=0.024),higher total medical costs and larger pupil diameter(5.63±0.15 vs 4.68±0.15 vs 4.69±0.22 mm,P<0.01).In 83%Omicron-infected patients,ocular symptoms appeared within 3d after systemic symptoms onset.In multivariate analysis,Omicron infection(P<0.001)was the only independent predictor of pupil diameter.CONCLUSION:In the Omicron epidemic in China,there is an increase of prevalence and severity of APAC,particularly focusing on the first 3d following infection.

Clinical analysis of multiple primary gastrointestinal malignant tumors:A 10-year case review of a single-center

BACKGROUND Multiple primary malignant tumors(MPMTs)was first described by Billroth as early as 1889,with the first report published by Warren and Gates in 1932.Since then,numerous cases have been reported.A literature review of 1104269 patients with cancer revealed that the incidence of MPMTs ranged from 0.73 to 11.7%.In recent years,however,there has been a significant upward trend in the incidence of this phenomenon,which may be associated with many different factors,including the advancement of modern diagnostic procedures facilitating the examination and diagnosis of more MPMTs,increased exposure to chemotherapy and radiotherapy that exacerbate the risk of new malignant tumors in patients with cancer,and prolonged survival of patients with cancer allowing sufficient time for the development of new primary cancers.AIM To analyze the incidence,clinical features,treatment factors,prevalence,and prognosis of patients with MPMTs in the gastrointestinal tract treated in a single center.Additionally,we analyzed the different tumor combinations,time interval between the occurrence of tumors,and staging.METHODS This retrospective cohort study analyzed 8059 patients with pathologically confirmed gastrointestinal malignant tumors treated at the Gansu Province Hospital in Lanzhou,Gansu,China between June 2011 and June 2020.Of these,85 patients had MPMTs.The clinical features,treatment factors,prevalence,and prognosis of this latter cohort were analyzed.RESULTS The incidence of MPMTs in patients with gastrointestinal malignant tumors was 1.05%(85/8059),including 83 double primary malignant tumors and two triple primary malignant tumors of which 57(67.06%)were synchronous MPMTs(SMPMTs)and 28(32.94%)were metachronous MPMTs(MMPMTs).The most frequent associations were found between the rectum colon cancers within the SMPMT category and the gastric-colon cancers within the MMPMT category.For the MMPMTs,the median interval was 53 months.The overall 1-,3-and 5-year survival rates from diagnosis of the first primary cancer were 91.36%,65.41%,and 45.97%,respectively;those from diagnosis of the second primary cancer were 67.90%,29.90%,and 17.37%,respectively.CONCLUSION MPMTs in the gastrointestinal tract have a high incidence and poor prognosis.Thus,it is necessary to perform both gastroscopy and colonoscopy in patients with gastrointestinal tumors.Multidisciplinary comprehensive diagnosis and treatment may improve the diagnosis rate and treatment efficiency of MPMTs.

MP-3 microperimeter in early primary open angle glaucoma with a new pattern

AIM:To investigate macular microperimetry in patients with early primary open angle glaucoma(POAG)using a new custom-made pattern,and analyze the characteristics of macular sensitivity.METHODS:This case-control study included 38 patients with POAG,who were divided into pre-perimetric glaucoma(18 eyes of 18 patients),early-stage(20 eyes of 20 patients),and control(20 eyes of 20 patients)groups.All subjects underwent standard 24-2 humphrey visual field test.An MP-3 microperimeter with a new custom-made pattern(28 testing points distributed in four quadrants,covering the central 10°of the retina)was used to evaluate macular sensitivity.Ganglion cell complex(GCC)thicknesses were examined using an RS-3000 Advance OCT system.The features of structure and function were analysed per quadrant.RESULTS:The pre-perimetric glaucoma group had significantly lower inferior hemifield macular sensitivity compared to controls(P<0.05).The early-stage POAG group had significantly lower average,inferior hemifield,inferonasal,and inferotemporal mean sensitivities compared to the pre-perimetric glaucoma group(P<0.05),and lower macular sensitivity in all sectors compared to controls(P<0.05).Regarding GCC thickness,all sectors in the early-stage POAG group became thinner compared to those in controls(P<0.05);whereas all sectors in the early-stage POAG group,except the superonasal quadrant,became thinner compared to those in the pre-perimetric glaucoma group(P<0.05).Macular sensitivity and GCC thickness were significantly associated in each sector.The inferotemporal quadrant had the highest correlation coefficients(0.840).The structure-function relationship for the inferonasal and inferotemporal sectors was stronger compared to the corresponding superior sectors.CONCLUSION:Microperimetry reveals variations in macular sensitivity in patients with early glaucoma earlier than conventional perimetry,particularly in pre-perimetric glaucoma cases in which it might be undetectable by conventional methods.The new custom-made pattern may improve the accuracy of microperimetry by enhancing point arrangement and reducing fatigue effects.Macular sensitivity measured by MP-3 with this pattern shows statistically significant structural and functional associations with the thicknesses of the GCC.

Evaluation of Well Spacing for Primary Development of Fractured Horizontal Wells in Tight Sandstone Gas Reservoirs

Methods for horizontal well spacing calculation in tight gas reservoirs are still adversely affected by the complexity of related control factors,such as strong reservoir heterogeneity and seepage mechanisms.In this study,the stress sensitivity and threshold pressure gradient of various types of reservoirs are quantitatively evaluated through reservoir seepage experiments.On the basis of these experiments,a numerical simulation model(based on the special seepage mechanism)and an inverse dynamic reserve algorithm(with different equivalent drainage areas)were developed.The well spacing ranges of Classes I,II,and III wells in the Q gas field are determined to be 802–1,000,600–662,and 285–400 m,respectively,with their average ranges as 901,631,and 342.5 m,respectively.By considering both the pairs of parallel well groups and series well groups as examples,the reliability of the calculation results is verified.It is shown that the combination of the two models can reduce errors and provide accurate results.

Bruton’s tyrosine kinase inhibitors in primary central nervous system lymphoma:New hopes on the horizon

In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.

Spatiotemporal changes of gross primary productivity and its response to drought in the Mongolian Plateau under climate change

Gross primary productivity(GPP)of vegetation is an important constituent of the terrestrial carbon sinks and is significantly influenced by drought.Understanding the impact of droughts on different types of vegetation GPP provides insight into the spatiotemporal variation of terrestrial carbon sinks,aiding efforts to mitigate the detrimental effects of climate change.In this study,we utilized the precipitation and temperature data from the Climatic Research Unit,the standardized precipitation evapotranspiration index(SPEI),the standardized precipitation index(SPI),and the simulated vegetation GPP using the eddy covariance-light use efficiency(EC-LUE)model to analyze the spatiotemporal change of GPP and its response to different drought indices in the Mongolian Plateau during 1982-2018.The main findings indicated that vegetation GPP decreased in 50.53% of the plateau,mainly in its northern and northeastern parts,while it increased in the remaining 49.47%area.Specifically,meadow steppe(78.92%)and deciduous forest(79.46%)witnessed a significant decrease in vegetation GPP,while alpine steppe(75.08%),cropland(76.27%),and sandy vegetation(87.88%)recovered well.Warming aridification areas accounted for 71.39% of the affected areas,while 28.53% of the areas underwent severe aridification,mainly located in the south and central regions.Notably,the warming aridification areas of desert steppe(92.68%)and sandy vegetation(90.24%)were significant.Climate warming was found to amplify the sensitivity of coniferous forest,deciduous forest,meadow steppe,and alpine steppe GPP to drought.Additionally,the drought sensitivity of vegetation GPP in the Mongolian Plateau gradually decreased as altitude increased.The cumulative effect of drought on vegetation GPP persisted for 3.00-8.00 months.The findings of this study will improve the understanding of how drought influences vegetation in arid and semi-arid areas.

Heterochronous multiple primary prostate cancer and lymphoma:A case report

BACKGROUND Multiple primary malignant tumors(MPMTs)are rare type of cancer,especially when solid tumors are the first and lymphoma is the second primary malignancy.We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma(DLBCL).CASE SUMMARY We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide(50 mg per day)and an extended-release implant of goserelin(1/28 d).Seven years later,rectal DLBCL with lung metastases was found.CONCLUSION Although rare,the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

Three novel rare TP53 fusion mutations in a patient with multiple primary cancers:a case report

As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.

Experience of primary intestinal lymphangiectasia in adults: Twelve case series from a tertiary referral hospital

BACKGROUND While primary intestinal lymphangiectasia(PIL)is considered a rare condition,there have been several reported cases in adults.Nevertheless,the absence of clear guidance from diagnosis to treatment and prognosis poses challenges for both physicians and patients.AIM To enhance understanding by investigating clinical presentation,diagnosis,treatment,complications,and prognoses in adult PIL cases.METHODS We enrolled adult patients diagnosed with PIL between March 2016 and September 2021.The primary outcome involved examining the diagnosis and treatment process of these patients.The secondary outcomes included identifying complications(infections,thromboembolism)and assessing prognoses(frequency of hospitalization and mortality)during the follow-up period.RESULTS Among the 12 included patients,peripheral edema(100%)and diarrhea(75%)were the main presenting complaints.Laboratory tests showed that all the pati-ents exhibited symptoms of hypoalbuminemia and hypogammaglobulinemia.Radiologically,the predominant findings were edema of the small intestine(67%)and ascites(58%).The typical endoscopic finding with a snowflake appearance was observed in 75%of patients.Among the 12 patients,two responded positive-ly to octreotide and sirolimus,and eight who could undergo maintenance therapy discontinued subsequently.Complications due to PIL led to infection in half of the patients,thromboembolism in three patients,and one death.CONCLUSION PIL can be diagnosed in adults across various age groups,with different severity and treatment responses among patients,leading to diverse complications and prognoses.Consequently,tailored treatments will be necessary.We anticipate that our findings will contribute to the management of PIL,an etiology of protein-losing enteropathy.

Role of lipids in the control of autophagy and primary cilium signaling in neurons

The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human body.In neurons,lipids are involved in signaling pathways controlling autophagy,a lysosome-dependent catabolic process essential for the maintenance of neuronal homeostasis and the function of the primary cilium,a cellular antenna that acts as a communication hub that transfers extracellular signals into intracellular responses required for neurogenesis and brain development.A crosstalk between primary cilia and autophagy has been established;however,its role in the control of neuronal activity and homeostasis is barely known.In this review,we briefly discuss the current knowledge regarding the role of autophagy and the primary cilium in neurons.Then we review the recent literature about specific lipid subclasses in the regulation of autophagy,in the control of primary cilium structure and its dependent cellular signaling in physiological and pathological conditions,specifically focusing on neurons,an area of research that could have major implications in neurodevelopment,energy homeostasis,and neurodegeneration.

Autoimmune hepatitis and primary sclerosing cholangitis after direct-acting antiviral treatment for hepatitis C virus:A case report

BACKGROUND Chronic hepatitis C virus(HCV)infection is a major global health concern that leads to liver fibrosis,cirrhosis,and cancer.Regimens containing direct-acting antivirals(DAAs)have become the mainstay of HCV treatment,achieving a high sustained virological response(SVR)with minimal adverse events.CASE SUMMARY A 74-year-old woman with chronic HCV infection was treated with the DAAs ledipasvir,and sofosbuvir for 12 wk and achieved SVR.Twenty-four weeks after treatment completion,the liver enzyme and serum IgG levels increased,and antinuclear antibody became positive without HCV viremia,suggesting the development of autoimmune hepatitis(AIH).After liver biopsy indicated AIH,a definite AIH diagnosis was made and prednisolone was initiated.The treatment was effective,and the liver enzyme and serum IgG levels normalized.However,multiple strictures of the intrahepatic and extrahepatic bile ducts with dilatation of the peripheral bile ducts appeared on magnetic resonance cholangiopancreatography after 3 years of achieving SVR,which were consistent with primary sclerosing cholangitis.CONCLUSION The potential risk of developing autoimmune liver diseases after DAA treatment should be considered.

Significance of Primary Treatment Selection in the Efficiency of Wastewater Treatment in Constructed Wetlands (CWs)

This research explores strategies to enhance the efficiency of secondary treatment in Vertical Flow Constructed Wetlands (CW) in Montenegro. The focus is on selecting appropriate primary treatment methods alongside three distinct substrate types to improve wastewater treatment efficacy. The study examines the combination of two primary treatments with different substrate types in constructed wetlands (CW1, CW2, and CW3). The primary treatments include the existing wastewater treatment plant (WWTP) in Podgorica, involving coarse material removal through screens, inert material separation in aerated sand traps, and sediment and suspended matter removal in primary sedimentation tanks. The Extreme Separator (ExSep) was employed to evaluate its efficacy as a primary treatment method. The research demonstrates that the efficiency of CW can be significantly enhanced by selecting suitable primary treatment methods and substrates in Podgorica’s conditions. The most promising results were achieved by combining ExSep as a primary treatment with secondary treatment in CW-3. The removal efficiencies after CW3 for COD, BOD, and TSS exceeded 89%, 93%, and 91%, respectively. The outcomes underscore the significance of primary treatment in mitigating pollutant loads before discharge into the constructed wetlands, emphasizing potential areas for further optimization in wastewater treatment practices to enhance environmental sustainability and water quality management.

One Case of Primary Thrombocythemia with Concealed Hypokalemia Complicated by Acute Myocardial Infarction

Medical history summary: Male, 47 years old, was admitted to the hospital due to “dizziness accompanied by chest tightness and pain for more than 8 days”. One week ago, the patient experienced chest tightness, chest pain accompanied by profuse sweating for 3 hours and underwent emergency percutaneous coronary intervention (PCI) at a local hospital. The procedure revealed left main stem occlusion with subsequent left main stem to left anterior descending artery percutaneous transluminal coronary angioplasty (PTCA). After the procedure, the patient experienced hemodynamic instability, recurrent ventricular fibrillation, and critical condition, thus transferred to our hospital for further treatment. Symptoms and signs: The patient is in a comatose state, unresponsive to stimuli, with bilateral dilated pupils measuring 2.0 mm, exhibiting reduced sensitivity to light reflex, and recurrent fever. Coarse breath sounds can be heard in both lungs, with audible moist rales. Irregular breathing pattern is observed, and heart sounds vary in intensity. No pathological murmurs are auscultated in any valve auscultation area. Diagnostic methods: Coronary angiography results at the local hospital showed complete occlusion of the left main stem, and left main stem to left anterior descending artery percutaneous transluminal coronary angioplasty (PTCA) was performed. However, the distal guidewire did not pass through. After admission, blood tests showed a Troponin T level of 1.44 ng/ml and a Myoglobin level of 312 ng/ml. The platelet count was 1390 × 109/L. Von Willebrand factor (vWF) activity was measured at 201.9%. Bone marrow aspiration biopsy showed active bone marrow proliferation and platelet clustering. The peripheral blood smear also showed platelet clustering. JAK-2 gene testing was positive, confirming the diagnosis of primary thrombocytosis. Treatment methods: The patient is assisted with mechanical ventilation and intra-aortic balloon counterpulsation to improve coronary blood flow. Electrolyte levels are closely monitored, especially maintaining plasma potassium levels between 4.0 and 4.5 mmol/l. Hydroxyurea 500 mg is administered for platelet reduction. Anticoagulants and antiplatelet agents are used rationally to prevent further infarction or bleeding. Antiarrhythmic, lipid-lowering, gastroprotective, hepatoprotective, and heart failure treatment are also provided. Clinical outcome: The family members chose to withdraw treatment and signed for discharge due to a combination of reasons, including economic constraints and uncertainty about the prognosis due to the long disease course. Acute myocardial infarction has gradually become one of the leading causes of death in our country. As a “green channel” disease, corresponding diagnostic and treatment protocols have been established in China, and significant progress has been made in emergency care. There are strict regulations for the time taken from the catheterization lab to the cardiac intensive care unit, and standardized treatments are provided to patients once they enter the intensive care unit. Research results show that the incidence of acute myocardial infarction in patients with primary thrombocythemia within 10 years is 9.4%. This type of disease is rare and difficult to cure, posing significant challenges to medical and nursing professionals. In order to benefit future patients, we have documented individual cases of treatment and nursing care for these patients. The research results show that these patients exhibit resistance to traditional oral anticoagulant drugs and require alternative anticoagulants. Additionally, there are significant differences in serum and plasma potassium levels among patients. Therefore, when making clinical diagnoses, it is necessary to carefully distinguish between the two. Particularly, nursing personnel should possess dialectical thinking when supplementing potassium levels in patients in order to reduce the incidence of malignant arrhythmias and mortality rates.

Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) and rat sarcoma virus(RAS)/rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)/extracellular-signal regulated kinase(ERK)pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension

Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis.Although primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related contraindications.With recent advances in precision medicine,precise drug treatment provides better treatment efficacy.Data sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May 2022.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs.According to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and others.All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.Conclusions:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.