BACKGROUND Ulcerative colitis(UC)is a chronic and debilitating inflammatory bowel disease.Cumulative evidence indicates that excess hydrogen peroxide,a potent neutrophilic chemotactic agent,produced by colonic epithel...BACKGROUND Ulcerative colitis(UC)is a chronic and debilitating inflammatory bowel disease.Cumulative evidence indicates that excess hydrogen peroxide,a potent neutrophilic chemotactic agent,produced by colonic epithelial cells has a causal role leading to infiltration of neutrophils into the colonic mucosa and subsequent development of UC.This evidence-based mechanism identifies hydrogen peroxide as a therapeutic target for reducing agents in the treatment of UC.CASE SUMMARY Presented is a 41-year-old female with a 26-year history of refractory UC.Having developed steroid dependence and never achieving complete remission on treatment by conventional and advanced therapies,she began treatment with oral R-dihydrolipoic acid(RDLA),a lipid-soluble reducing agent with intracellular site of action.Within a week,rectal bleeding ceased.She was asymptomatic for three years until a highly stressful experience,when she noticed blood in her stool.RDLA was discontinued,and she began treatment with oral sodium thiosulfate pentahydrate(STS),a reducing agent with extracellular site of action.After a week,rectal bleeding ceased,and she resumed oral RDLA and discontinued STS.To date,she remains asymptomatic with normal stool calprotectin while on RDLA.CONCLUSION STS and RDLA are reducing agents that serve as highly effective and safe therapy for the induction and maintenance of remission in UC,even in patients refractory or poorly controlled by conventional and advanced therapies.Should preliminary findings be validated by subsequent clinical trials,the use of reducing agents could potentially prevent thousands of colectomies and represent a paradigm shift in the treatment of UC.展开更多
Liver biopsy evaluation plays a critical role in management of patients with viral hepatitis C. In patients with acute viral hepatitis, a liver biopsy, though uncommonly performed, helps to rule out other nonviral cau...Liver biopsy evaluation plays a critical role in management of patients with viral hepatitis C. In patients with acute viral hepatitis, a liver biopsy, though uncommonly performed, helps to rule out other nonviral causes of deranged liver function. In chronic viral hepatitis C, it is considered the gold standard in assessment of the degree of necroinflammation and the stage of fibrosis, to help guide treatment and determine prognosis. It also helps rule out any concomitant diseases such as steatohepatitis, hemochromatosis or others. In patients with chronic progressive liver disease with cirrhosis and dominant nodules, a targeted liver biopsy is helpful in differentiating a regenerative nodule from dysplastic nodule or hepatocellular carcinoma. In the setting of transplantation, the liver biopsy helps distinguish recurrent hepatitis C from acute rejection and also is invaluable in the diagnosis of fibrosing cholestatic hepatitis, a rare variant of recurrent hepatitis C. This comprehensive review discusses the entire spectrum of pathologic findings in the course of hepatitis C infection.展开更多
Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neopl...Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound(EUS)-guided fine-needle aspiration(FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUSguided FNA and the cytological diagnosis for pancreatic cysts.展开更多
The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a ly...The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.展开更多
Acute myeloid leukemia(AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification ...Acute myeloid leukemia(AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification of AML requires clinical and pathologic information, the latter including morphologic, immunophenotypic, cytogenetic and molecular genetic analysis. Risk stratification in AML requires cytogenetics evaluation as the most important predictor, with genetic mutations providing additional necessary information. AML with normal cytogenetics comprises about 40%-50% of all AML, and has been intensively investigated. The currently used 2008 World Health Organization classification of hematopoietic neoplasms has been proposed to be updated in2016, also to include an update on the classification of AML, due to the continuously increasing application of genomic techniques that have led to major advances in our knowledge of the pathogenesis of AML. The purpose of this review is to describe some of these recent major advances in the diagnostic classification and risk stratification of AML.展开更多
Detection of SARS-CoV-2 RNA in wastewater is a promising tool for informing public health decisions during the COVID-19 pandemic.However,approaches for its analysis by use of reverse transcription quantitative polymer...Detection of SARS-CoV-2 RNA in wastewater is a promising tool for informing public health decisions during the COVID-19 pandemic.However,approaches for its analysis by use of reverse transcription quantitative polymerase chain reaction(RT-q PCR)are still far from standardized globally.To characterize inter-and intra-laboratory variability among results when using various methods deployed across Canada,aliquots from a real wastewater sample were spiked with surrogates of SARS-CoV-2(gamma-radiation inactivated SARS-CoV-2 and human coronavirus strain 229E[HCoV-229E])at low and high levels then provided"blind"to eight laboratories.Concentration estimates reported by individual laboratories were consistently within a 1.0-log_(10) range for aliquots of the same spiked condition.All laboratories distinguished between low-and high-spikes for both surrogates.As expected,greater variability was observed in the results amongst laboratories than within individual laboratories,but SARS-CoV-2 RNA concentration estimates for each spiked condition remained mostly within 1.0-log_(10) ranges.The no-spike wastewater aliquots provided yielded non-detects or trace levels(<20 gene copies/mL)of SARS-CoV-2 RNA.Detections appear linked to methods that included or focused on the solids fraction of the wastewater matrix and might represent in-situ SARS-CoV-2 to the wastewater sample.HCoV-229E RNA was not detected in the no-spike aliquots.Overall,all methods yielded comparable results at the conditions tested.Partitioning behavior of SARS-CoV-2 and spiked surrogates in wastewater should be considered to evaluate method effectiveness.A consistent method and laboratory to explore wastewater SARS-CoV-2 temporal trends for a given system,with appropriate quality control protocols and documented in adequate detail should succeed.展开更多
Background & Objective: Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained defic...Background & Objective: Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions. Methods: This study examined the effects of chronic + binge alcohol exposures (8 weeks) and intervention with myriocin, a ceramide inhibitor, on neurobehavioral functions (Open Field, Novel Object Recognition, and Morris Water Maze tests) and frontal lobe white matter myelin lipid biochemical pathology in an adult Long-Evans rat model. Results: The ethanol-exposed group had significant deficits in executive functions with increased indices of anxiety and impairments in spatial learning acquisition. Myriocin partially remediated these effects of ethanol while not impacting behavior in the control group. Ethanol-fed rats had significantly smaller brains with broadly reduced expression of sulfatides and reduced expression of two of the three sphingomyelins detected in frontal white matter. Myriocin partially resolved these effects corresponding with improvements in neurobehavioral function. Conclusion: Therapeutic strategies that support cerebral white matter myelin expression of sulfatide and sphingomyelin may help remediate cognitive-behavioral dysfunction following chronic heavy alcohol consumption in humans.展开更多
Genitourinary neoplasms,including bladder,prostate,renal,and testicular cancers,represent 25%of all solid tumors worldwide.Great advances have been achieved in the last few decades in diagnostic and therapeutic modali...Genitourinary neoplasms,including bladder,prostate,renal,and testicular cancers,represent 25%of all solid tumors worldwide.Great advances have been achieved in the last few decades in diagnostic and therapeutic modalities.Among these,liquid biopsy(LB)technology has evolved during the past few years and offers emerging and novel modalities in the field of oncology.LB is performed by withdrawing bodily fluids(i.e.,blood or urine)and looking for circulating tumor DNA,circulating tumor cells,extracellular vesicles,and non-coding RNAs,among others.Over the past years,several technologies have been developed to isolate and analyze the tumor burden.LB is less invasive than traditional biopsies and has many applications,including early screening,providing diagnostic cues,predicting disease severity and survival outcomes,assessing response and resistance to treatment,detecting minimal tumor burden before radiological evidence,and monitoring for disease recurrence.However,multiple challenges still need to be addressed,including reduction in variability between assays,standardization of protocols,and validation in large trials to ensure reliability.This review will focus on the latest advancements in LB applications for diagnostic and prognostic characterization of genitourinary cancers.展开更多
BACKGROUND Neuroendocrine tumors(NETs)are rare malignancies arising from the diffuse neuroendocrine system,often in the gastroenteropancreatic(GEP)tract.GEP-NETs,primarily involving the intestines(50%)and pancreas(30%...BACKGROUND Neuroendocrine tumors(NETs)are rare malignancies arising from the diffuse neuroendocrine system,often in the gastroenteropancreatic(GEP)tract.GEP-NETs,primarily involving the intestines(50%)and pancreas(30%),may occa-sionally secrete hormones,causing syndromes.Diagnosis relies on markers like chromogranin A,synaptophysin,and Ki-67,along with imaging modalities.Ri-sing NETs incidence is attributed to advancements in diagnostic modalities,parti-cularly endoscopic ultrasonography(EUS).EUS demonstrates high accuracy in detecting small lesions,assessing tumor depth,and identifying locoregional lymph nodes.Despite its proven diagnostic utility,there is limited data on EUS's role in evaluating GEP-NETs in resource-constrained settings like Pakistan.AIM To evaluate the diagnostic role of EUS in characterizing GEP-NETs based on clinical,histopathological,tumor grading,and site-specific differences.METHODS This single-center retrospective descriptive study was conducted at Aga Khan University Hospital,Karachi,a tertiary care hospital,from January 2021 to December 2023.Fourteen adult patients(≥18 years)with suspected NETs who underwent EUS and were diagnosed via histopathology were included.Data on demographics,clinical features,radiological findings,and histopathological characteristics were collected.Descriptive analysis was performed using SPSS version 23,with descriptive statistics expressed as means±SD for continuous variables and frequencies/percentages for categorical data.RESULTS A total of 14 adult GEP-NETs patients who underwent EUS were included,with a mean age of 52±14 years and the majority being male(71.4%).Common clinical presentations included weight loss(85.7%)and abdominal pain(78.6%).Computed tomography scans were performed in 92.9%of cases,with pancreatic masses detected in 42.9%of patients.EUS-guided fine needle biopsy(FNB)had a 100%diagnostic yield.The pancreas was the most common tumor site(57.1%).Histopathology revealed 78.6%of cases as well-differentiated NETs with 42.9%being grade II.Metastases were seen in 57.1%of patients,with the liver being the most common site.Surgical interventions were performed in 28.6%of patients,and all patients were alive at the time of study analysis.CONCLUSION EUS,with accurate imaging and effective EUS-FNB,is the gold standard for GEP-NET diagnosis,aiding tumor assessment and prognosis.Larger studies are needed to validate its impact on management outcomes.展开更多
Acellular mucin refers to pools of mucin without epithelial component,oftentimes harboring inflammatory cells.Acellular mucin can be observed in both neoplastic and non-neoplastic lower gastrointestinal(GI)conditions....Acellular mucin refers to pools of mucin without epithelial component,oftentimes harboring inflammatory cells.Acellular mucin can be observed in both neoplastic and non-neoplastic lower gastrointestinal(GI)conditions.While mucinous neoplasms are classified and staged using established guidelines,interobserver variability occurs when acellular mucin pools are encountered,leading to inconsistent interpretation and staging.In particular,acellular mucin found in regional lymph nodes of colorectal adenocarcinoma patients who have not received treatment presents a diagnostic challenge,as its prognostic implication is not clearly defined.Acellular mucin is also commonly seen in treated colorectal adenocarcinoma,post neoadjuvant therapy.Although acellular mucin is not counted toward T or N staging in this setting,variation in how pathologists report and stage these cases persists.Acellular mucin can also be seen in non-neoplastic specimens,such as those from interval appendectomies,appendiceal diverticula,colonic diverticulitis,volvulus,and Crohn’s disease where it may mimic a neoplastic lesion.Acellular mucin in this setting is often a byproduct of inflammation,increased luminal pressure,and mural defect.This review highlights the clinical relevance and diagnostic complexity of acellular mucin in pathologic conditions of the lower GI tract.Further studies are needed to clarify its prognostic value and develop standardized guidelines.展开更多
Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, en...Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Gestational dietary soy prevents alcohol-related impairments in placentation and FASD-associated fetal anomalies. Objective: This study was designed to determine if gestational dietary soy would be sufficient to normalize cognitive function in young adolescent offspring after chronic in utero exposure to alcohol. In addition, efforts were made to characterize the mechanisms of FASD prevention by maternal dietary soy. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source from gestation day 6 through delivery/postnatal day 0 (P0). From P24 - P28, the offspring were subjected to Morris water maze (MWM) testing, and on P35, they were sacrificed to harvest temporal lobes for histopathologic and molecular studies. Results: The in-utero ethanol-exposed offspring exhibited significant performance impairments on the MWM test, and they had a significantly reduced mean brain weight with neuronal loss in the CA1 hippocampal region and evidence of white matter myelin loss. Gestational dietary soy nearly normalized MWM performance and preserved brain weight, hippocampal CA1 architecture, and white matter myelin staining in alcohol-exposed offspring. Mechanistically, the main positive effects of soy included increased temporal lobe expression of HES-1 and HIF-1α, reflecting enhanced Notch signaling, and broadly increased expression of GnRH network molecules, including Erb1, Gper1, GnRH, GnRH-R, KiSS, and KiSS-R, irrespective of gestational ethanol exposure. Conclusions: Dietary soy intervention early in pregnancy may reduce FASD-associated cognitive deficits. The findings suggest that targeting Notch and GnRH-related networks may help reduce long-term disability with FASD. Additional mechanistic and experimental research is needed to determine if longer-duration, postnatal dietary soy could prevent the adverse neurobehavioral effects of FASD.展开更多
BACKGROUND Gallbladder mucocele,also known as gallbladder hydrops,is a rare condition characterized by the distention of the gallbladder due to the accumulation of fluid or mucus within its lumen,primarily attributed ...BACKGROUND Gallbladder mucocele,also known as gallbladder hydrops,is a rare condition characterized by the distention of the gallbladder due to the accumulation of fluid or mucus within its lumen,primarily attributed to obstruction arising from a gallstone in the cystic duct or gallbladder neck.CASE SUMMARY We present a case of a 67-year-old woman with an incidentally discovered gallbladder mucocele,shedding light on the clinical presentation,causes,and histopathological findings.We performed a literature review including an analysis of 27 case reports,revealing the diverse spectrum of causative factors,clinical manifestations,diagnosis,and management.CONCLUSION This study underscores the importance of considering alternative diagnoses and highlights the significance of imaging techniques in narrowing down the differential diagnosis and histopathologic examination for a definitive diagnosis.展开更多
BACKGROUND Pancreatic fibrosis,which decreases risk of postoperative pancreatic fistula(POPF),can be estimated using extracellular volume fraction(ECVf).AIM To investigate the correlation between ECVf and pancreatic h...BACKGROUND Pancreatic fibrosis,which decreases risk of postoperative pancreatic fistula(POPF),can be estimated using extracellular volume fraction(ECVf).AIM To investigate the correlation between ECVf and pancreatic histology,as well as the usefulness of ECVf in predicting POPF.METHODS In 71 patients who underwent pancreatic resection,we caluculated pancreatic ECVf by comparing absolute enhancements of the pancreas and aorta between pre-contrast and equilibrium phases.Areas of fibrosis,fat,acini,and islets were calculated based on resection specimens.RESULTS ECVf correlated with fibrosis(r=0.724;P<0.001)and negatively correlated with acini(r=-0.510;P<0.001).Among 48 patients who underwent pancreatoduoden ectomy,21 developed POPF.Main pancreatic duct diameter≤2 mm and ECVf<36%were selected as risk factors by multivariate analysis[respective odds ratios(OR)and P values,4.26 and P=0.048;OR=11.07 and P=0.036].Using these factors as a risk score(0-2 points),POPF occurred in 0%,50%,and 70%of patients with 0,1,and 2 points,respectively.CONCLUSION ECVf is useful in predicting acinar loss and pancreatic fibrosis,and ECVf<36%may be a risk factor for POPF.展开更多
BACKGROUND Fibroadenomas(FA)and phyllodes tumors(PT)are fibroepithelial neoplasms and are difficult to differentiate radiographically and histologically.We present a partially infarcted borderline PT in an adolescent ...BACKGROUND Fibroadenomas(FA)and phyllodes tumors(PT)are fibroepithelial neoplasms and are difficult to differentiate radiographically and histologically.We present a partially infarcted borderline PT in an adolescent with rapid tumor enlargement within 24 hours.Tumor infarction made the diagnostic work-up difficult.Com-plete surgical excision is the standard of care for PTs.There is controversy regar-ding margin re-excision for borderline PTs.In this report,we discuss the diagno-stic challenges of PT and the evolving concept of margin status on PT recurrence rate.CASE SUMMARY A 14-year-old healthy female with no medical history presented with a painful right breast mass with no nipple discharge,trauma,or skin findings.The mass showed rapid enlargement over 24 hours,prompting a workup with ultrasound and core needle biopsy.The initial biopsy was limited due to large areas of in-farction.Based on the scant viable tissue and considering the patient’s age,the mass was favored to be a juvenile FA.The patient underwent excision of the mass.Final pathology confirmed a borderline PT with positive surgical margins.The patient underwent margin re-excision,which did not show any residual tumor.At the 6-month post-op visit,there was a mass-forming lesion on the breast ultrasound.Subsequent core needle biopsy showed benign breast parenchyma with scar formation.The primary goal of evaluation in pediatric breast masses is to do no harm.However,rapidly growing and symptomatic masses require a more extensive work-up including biopsy and surgical excision.We present a rapidly growing breast mass in a 14-year-old female which was diagnosed as a borderline PT on her excision specimen.The mass rapidly enlarged over 24 hours.The initial biopsy pathology was limited due to a large area of infarction.The patient underwent excision of the mass.Final pathology confirmed a borderline PT that extended into the surgical margin,resulting in an additional re-excision procedure.Accurate diagnosis prior to surgical intervention is crucial to avoid additional procedures.Although histological morphology remains the gold standard for diagnosis,immunohistochemistry and molecular studies have recently shown to improve the accuracy of diagnosis of PTs.Long-term clinical and pathologic follow-up of PTs in adolescent patients should be collectively studied to examine whether our current diagnostic criteria for PT can reliably predict tumor behavior in this age group.CONCLUSION Accurate diagnosis of PTs requires surgical excision.Tumor infarction may lead to rapid tumor enlargement,hindering the correct diagnosis.More research is needed on margin status and recurrence rate,especially in adolescent patients,to help establish the best possible care for this age group.展开更多
Background:The Akreos®AO60 intraocular lens(IOL)has been employed for scleral fixation in eyes without capsular support,although surgical complications,including IOL opacification,have been reported.This study ai...Background:The Akreos®AO60 intraocular lens(IOL)has been employed for scleral fixation in eyes without capsular support,although surgical complications,including IOL opacification,have been reported.This study aims to evaluate the outcomes and complications associated with scleral fixation of the Akreos®AO60 IOL in vitrectomized eyes,with a particular focus on IOL opacification.Methods:Electronic medical records of consecutive eyes that underwent scleral-fixation of the Akreos®AO60 lens using Gore-tex®sutures from 2017 to 2022 were reviewed.The following parameters were collected:age,sex,laterality,past ocular/medical history,surgical indication,pre-operative visual acuity(VA)and intraocular pressure(IOP),surgical procedure,and post-operative VA and IOP.The types of complications,onset,management,and outcomes were also documented.Descriptive statistics,Wilcoxon signed-rank test,and Fisher’s exact test were employed for statistical analysis.Results:Eighty-nine eyes of 86 patients aged 31-100 years were included.The most common surgical indication was non-traumatic IOL displacement.Retinal tears and localized choroidal hemorrhage were found intraoperatively in 7.9%and 1.1%,respectively.The most common post-operative complications were vitreous hemorrhage(13.5%),corneal edema(12.4%),ocular hypotony(11.2%),and IOL opacification(11.2%).IOL opacification was associated with intra-/post-operative exposure to air/gas[odds ratio(OR):12.24;95%confidence interval(CI),1.46-103.0;P=0.006].Mean logarithm of the minimum angle of resolution(logMAR)best-reported VA(BRVA)improved from 1.22±0.77 pre-operatively to 0.56±0.67 on latest follow-up(P<0.001).Conclusions:The majority of the complications from scleral-fixation of the Akreos®AO60 lens in vitrectomized eyes were mild and transient;however,a proportion required surgical intervention.A significant risk for opacification was found in IOLs exposed to air/gas,although VA was often maintained.展开更多
BACKGROUND Discordance between endoscopic and histologic assessments in Crohn’s disease(CD)have been observed,however the prevalence and cause are unclear.AIM To assess if a protocolized approach to biopsy collection...BACKGROUND Discordance between endoscopic and histologic assessments in Crohn’s disease(CD)have been observed,however the prevalence and cause are unclear.AIM To assess if a protocolized approach to biopsy collection facilitates understanding of this discordance in patients with ileal CD.METHODS Patients with known ileal CD underwent colonoscopy with endoscopic disease activity assessment.Three protocolized biopsies were taken respectively from an ulcer edge,7-mm,and 14-mm away from the ulcer edge in patients with discrete ileal ulcer(s).In patients with no ulcers as controls,the same 3-site biopsy protocol was applied in a randomly selected area of endoscopically-unremarkable terminal ileal mucosa.A blinded pathologist assessed mucosal inflammation in each biopsy using 3 validated histologic indices.RESULTS Twenty-four participants had visible ulcer(s)on endoscopy and 12 served as no-ulcer controls.Of biopsies taken from an ulcer edge,only 67%showed histologic evidence of active(neutrophilic)inflammation,and 33%showed histologic features of ulcer or erosion;all were from either large(n=4)or very large(n=4)ulcers.In the no-ulcer controls,no biopsies showed histologic features of ulcer or erosion,but 8%showed active inflammation.CONCLUSION A striking discordance exists between endoscopic and histologic assessments for mucosal inflammation in patients with active ileal CD,even in biopsies targeted at an ulcer edge,while a higher concordance is seen in patients with no endoscopic disease activity.It remains unclear how to incorporate histologic disease activity into the treatment paradigm.Further research is needed to optimize biopsy protocols and histologic assessments for CD.展开更多
N6-methyladenosine(m^(6)A)modification of mRNA is a critical post-transcriptional regulatory mechanism that modulates mRNA metabolism and neuronal function.The m^(6)A reader YTHDF1 has been shown to enhance the transl...N6-methyladenosine(m^(6)A)modification of mRNA is a critical post-transcriptional regulatory mechanism that modulates mRNA metabolism and neuronal function.The m^(6)A reader YTHDF1 has been shown to enhance the translational efficiency of m^(6)A-modified mRNAs in the brain and is essential for learning and memory.However,its role in the mature retina remains unclear.Herein,we report a novel role of Ythdf1 in the maintenance of retinal function using a genetic knockout model.Loss of Ythdf1 resulted in impaired scotopic electroretinogram(ERG)responses and progressive retinal degeneration.Detailed analyses of rod photoreceptors confirmed substantial degenerative changes in the absence of ciliary defects.Single-cell RNA sequencing revealed comprehensive molecular alterations across all retinal cell types in Ythdf1-deficient retinas.Integrative analysis of methylated RNA immunoprecipitation(MeRIP)sequencing and RIP sequencing identified Tulp1 and Dhx38,two inheritable retinal degeneration disease-associated gene homologs,as direct targets of YTHDF1 in the retina.Specifically,YTHDF1 recognized and bound m^(6)A-modified Tulp1 and Dhx38 mRNA at the coding sequence(CDS),enhancing their translational efficiency without altering mRNA levels.Collectively,these findings highlight the essential role of YTHDF1 in preserving visual function and reveal a novel regulatory mechanism of m^(6)A reader proteins in retinal degeneration,identifying potential therapeutic targets for severe retinopathies.展开更多
Given the critical shortage of antibody-drug conjugates(ADCs)for bladder cancer(BCa),we developed a novel FGFR3-targeted ADC,LZU-WZLYFG001,composed of a humanized anti-FGFR3 IgG1 monoclonal antibody,a cleavable GGFG l...Given the critical shortage of antibody-drug conjugates(ADCs)for bladder cancer(BCa),we developed a novel FGFR3-targeted ADC,LZU-WZLYFG001,composed of a humanized anti-FGFR3 IgG1 monoclonal antibody,a cleavable GGFG linker,and the payload DXD.The antibody was engineered in 293 cells and conjugated via thiol-based chemistry,achieving a drug-to-antibody ratio(DAR)of eight.Comprehensive preclinical assessments,including in vitro and in vivo studies using BCa cells,organoids,cell-derived xenograft and patient-derived xenograft(PDX)models,were conducted to evaluate efficacy,targeting ability,mechanism,safety and tissue distribution.LZU-WZLYFG001 demonstrated high purity,targeting specificity and low endotoxin levels,and it significantly inhibited BCa cell proliferation,migration and invasion at nanomolar concentrations,with efficacy strongly associated with FGFR3 expression levels.Mechanistic studies showed binding to FGFR3,internalization and lysosomal release of LZU-WZLYFG001.In organoid and xenograft models,LZU-WZLYFG001 exhibited superior efficacy compared with the gemcitabine+cisplatin(GC)regimen,particularly in GC-resistant PDX tumors,while also showing robust 3D penetration,a bystander effect,and no significant short-term toxicity.展开更多
Although gastric tumors have overlapping radiologic appearances, some unusual tumors may present specific imaging features. Using multidetector computed tomography(MDCT), with water as a negative oral contrast agent a...Although gastric tumors have overlapping radiologic appearances, some unusual tumors may present specific imaging features. Using multidetector computed tomography(MDCT), with water as a negative oral contrast agent and intravenous contrast medium, can provide critical information for the diagnosis of gastric diseases. In addition, MDCT can evaluate the involvement of the gastric wall and extragastric extent of the disease, as compared with gastroenteroscopy and double-contrast upper gastrointestinal study. Regarding lesion location and size, enhancing and growth patterns, presence of calcification or fat, and involvement of the gastric wall and adjacent structures, CT may provide useful information. In this review article, we review the relevant literature and discuss the CT features and the histopathologic findings of different types of gastric lesions. The lesions are divided into benign(glomus tumors, schwannomas, leiomyomas, and lipomas), malignant(gastrointestinal stromal tumors, mucinous carcinomas, lymphomas, and carcinoid tumors), and tumor-like lesions(ectopic pancreas and bezoar). Familiarity with imaging appearances and pathologic findings can help physicians make an accurate diagnosis.展开更多
AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (10...AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 μg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002.CONCLUSIONSitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.展开更多
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and debilitating inflammatory bowel disease.Cumulative evidence indicates that excess hydrogen peroxide,a potent neutrophilic chemotactic agent,produced by colonic epithelial cells has a causal role leading to infiltration of neutrophils into the colonic mucosa and subsequent development of UC.This evidence-based mechanism identifies hydrogen peroxide as a therapeutic target for reducing agents in the treatment of UC.CASE SUMMARY Presented is a 41-year-old female with a 26-year history of refractory UC.Having developed steroid dependence and never achieving complete remission on treatment by conventional and advanced therapies,she began treatment with oral R-dihydrolipoic acid(RDLA),a lipid-soluble reducing agent with intracellular site of action.Within a week,rectal bleeding ceased.She was asymptomatic for three years until a highly stressful experience,when she noticed blood in her stool.RDLA was discontinued,and she began treatment with oral sodium thiosulfate pentahydrate(STS),a reducing agent with extracellular site of action.After a week,rectal bleeding ceased,and she resumed oral RDLA and discontinued STS.To date,she remains asymptomatic with normal stool calprotectin while on RDLA.CONCLUSION STS and RDLA are reducing agents that serve as highly effective and safe therapy for the induction and maintenance of remission in UC,even in patients refractory or poorly controlled by conventional and advanced therapies.Should preliminary findings be validated by subsequent clinical trials,the use of reducing agents could potentially prevent thousands of colectomies and represent a paradigm shift in the treatment of UC.
文摘Liver biopsy evaluation plays a critical role in management of patients with viral hepatitis C. In patients with acute viral hepatitis, a liver biopsy, though uncommonly performed, helps to rule out other nonviral causes of deranged liver function. In chronic viral hepatitis C, it is considered the gold standard in assessment of the degree of necroinflammation and the stage of fibrosis, to help guide treatment and determine prognosis. It also helps rule out any concomitant diseases such as steatohepatitis, hemochromatosis or others. In patients with chronic progressive liver disease with cirrhosis and dominant nodules, a targeted liver biopsy is helpful in differentiating a regenerative nodule from dysplastic nodule or hepatocellular carcinoma. In the setting of transplantation, the liver biopsy helps distinguish recurrent hepatitis C from acute rejection and also is invaluable in the diagnosis of fibrosing cholestatic hepatitis, a rare variant of recurrent hepatitis C. This comprehensive review discusses the entire spectrum of pathologic findings in the course of hepatitis C infection.
文摘Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound(EUS)-guided fine-needle aspiration(FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUSguided FNA and the cytological diagnosis for pancreatic cysts.
文摘The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.
文摘Acute myeloid leukemia(AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification of AML requires clinical and pathologic information, the latter including morphologic, immunophenotypic, cytogenetic and molecular genetic analysis. Risk stratification in AML requires cytogenetics evaluation as the most important predictor, with genetic mutations providing additional necessary information. AML with normal cytogenetics comprises about 40%-50% of all AML, and has been intensively investigated. The currently used 2008 World Health Organization classification of hematopoietic neoplasms has been proposed to be updated in2016, also to include an update on the classification of AML, due to the continuously increasing application of genomic techniques that have led to major advances in our knowledge of the pathogenesis of AML. The purpose of this review is to describe some of these recent major advances in the diagnostic classification and risk stratification of AML.
基金supported by a CHEO (Children’s Hospital of Eastern Ontario) CHAMO (Children’s Hospital Academic Medical Organization) grant, awarded to Dr.Alex E.Mac Kenziesupported by the “Next generation solutions to ensure healthy water resources for future generations” funded by the Global Water Futures program, Canada First Research Excellence Fund (#419205)+7 种基金supported by the Canada Research Chairs Program of the Natural Sciences and Engineering Research Council of Canada (NSERC)supported by funding from NSERC Discovery and Strategic Grant Programssupported by funding from an NSERC Discovery Grantsupported by the NSERC Alliance COVID-19 Grantby Mitacs through the Mitacs Accelerate programsupported by Canadian Institutes of Health Research (CIHR), Alberta Innovates, Alberta Health-Water for Life Strategysupported by the BC center for Disease Control, BC center for Disease Control Foundation for Public Health and Metro Vancouversupported by the Canada Research Chairs Program of NSERC。
文摘Detection of SARS-CoV-2 RNA in wastewater is a promising tool for informing public health decisions during the COVID-19 pandemic.However,approaches for its analysis by use of reverse transcription quantitative polymerase chain reaction(RT-q PCR)are still far from standardized globally.To characterize inter-and intra-laboratory variability among results when using various methods deployed across Canada,aliquots from a real wastewater sample were spiked with surrogates of SARS-CoV-2(gamma-radiation inactivated SARS-CoV-2 and human coronavirus strain 229E[HCoV-229E])at low and high levels then provided"blind"to eight laboratories.Concentration estimates reported by individual laboratories were consistently within a 1.0-log_(10) range for aliquots of the same spiked condition.All laboratories distinguished between low-and high-spikes for both surrogates.As expected,greater variability was observed in the results amongst laboratories than within individual laboratories,but SARS-CoV-2 RNA concentration estimates for each spiked condition remained mostly within 1.0-log_(10) ranges.The no-spike wastewater aliquots provided yielded non-detects or trace levels(<20 gene copies/mL)of SARS-CoV-2 RNA.Detections appear linked to methods that included or focused on the solids fraction of the wastewater matrix and might represent in-situ SARS-CoV-2 to the wastewater sample.HCoV-229E RNA was not detected in the no-spike aliquots.Overall,all methods yielded comparable results at the conditions tested.Partitioning behavior of SARS-CoV-2 and spiked surrogates in wastewater should be considered to evaluate method effectiveness.A consistent method and laboratory to explore wastewater SARS-CoV-2 temporal trends for a given system,with appropriate quality control protocols and documented in adequate detail should succeed.
文摘Background & Objective: Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions. Methods: This study examined the effects of chronic + binge alcohol exposures (8 weeks) and intervention with myriocin, a ceramide inhibitor, on neurobehavioral functions (Open Field, Novel Object Recognition, and Morris Water Maze tests) and frontal lobe white matter myelin lipid biochemical pathology in an adult Long-Evans rat model. Results: The ethanol-exposed group had significant deficits in executive functions with increased indices of anxiety and impairments in spatial learning acquisition. Myriocin partially remediated these effects of ethanol while not impacting behavior in the control group. Ethanol-fed rats had significantly smaller brains with broadly reduced expression of sulfatides and reduced expression of two of the three sphingomyelins detected in frontal white matter. Myriocin partially resolved these effects corresponding with improvements in neurobehavioral function. Conclusion: Therapeutic strategies that support cerebral white matter myelin expression of sulfatide and sphingomyelin may help remediate cognitive-behavioral dysfunction following chronic heavy alcohol consumption in humans.
文摘Genitourinary neoplasms,including bladder,prostate,renal,and testicular cancers,represent 25%of all solid tumors worldwide.Great advances have been achieved in the last few decades in diagnostic and therapeutic modalities.Among these,liquid biopsy(LB)technology has evolved during the past few years and offers emerging and novel modalities in the field of oncology.LB is performed by withdrawing bodily fluids(i.e.,blood or urine)and looking for circulating tumor DNA,circulating tumor cells,extracellular vesicles,and non-coding RNAs,among others.Over the past years,several technologies have been developed to isolate and analyze the tumor burden.LB is less invasive than traditional biopsies and has many applications,including early screening,providing diagnostic cues,predicting disease severity and survival outcomes,assessing response and resistance to treatment,detecting minimal tumor burden before radiological evidence,and monitoring for disease recurrence.However,multiple challenges still need to be addressed,including reduction in variability between assays,standardization of protocols,and validation in large trials to ensure reliability.This review will focus on the latest advancements in LB applications for diagnostic and prognostic characterization of genitourinary cancers.
文摘BACKGROUND Neuroendocrine tumors(NETs)are rare malignancies arising from the diffuse neuroendocrine system,often in the gastroenteropancreatic(GEP)tract.GEP-NETs,primarily involving the intestines(50%)and pancreas(30%),may occa-sionally secrete hormones,causing syndromes.Diagnosis relies on markers like chromogranin A,synaptophysin,and Ki-67,along with imaging modalities.Ri-sing NETs incidence is attributed to advancements in diagnostic modalities,parti-cularly endoscopic ultrasonography(EUS).EUS demonstrates high accuracy in detecting small lesions,assessing tumor depth,and identifying locoregional lymph nodes.Despite its proven diagnostic utility,there is limited data on EUS's role in evaluating GEP-NETs in resource-constrained settings like Pakistan.AIM To evaluate the diagnostic role of EUS in characterizing GEP-NETs based on clinical,histopathological,tumor grading,and site-specific differences.METHODS This single-center retrospective descriptive study was conducted at Aga Khan University Hospital,Karachi,a tertiary care hospital,from January 2021 to December 2023.Fourteen adult patients(≥18 years)with suspected NETs who underwent EUS and were diagnosed via histopathology were included.Data on demographics,clinical features,radiological findings,and histopathological characteristics were collected.Descriptive analysis was performed using SPSS version 23,with descriptive statistics expressed as means±SD for continuous variables and frequencies/percentages for categorical data.RESULTS A total of 14 adult GEP-NETs patients who underwent EUS were included,with a mean age of 52±14 years and the majority being male(71.4%).Common clinical presentations included weight loss(85.7%)and abdominal pain(78.6%).Computed tomography scans were performed in 92.9%of cases,with pancreatic masses detected in 42.9%of patients.EUS-guided fine needle biopsy(FNB)had a 100%diagnostic yield.The pancreas was the most common tumor site(57.1%).Histopathology revealed 78.6%of cases as well-differentiated NETs with 42.9%being grade II.Metastases were seen in 57.1%of patients,with the liver being the most common site.Surgical interventions were performed in 28.6%of patients,and all patients were alive at the time of study analysis.CONCLUSION EUS,with accurate imaging and effective EUS-FNB,is the gold standard for GEP-NET diagnosis,aiding tumor assessment and prognosis.Larger studies are needed to validate its impact on management outcomes.
文摘Acellular mucin refers to pools of mucin without epithelial component,oftentimes harboring inflammatory cells.Acellular mucin can be observed in both neoplastic and non-neoplastic lower gastrointestinal(GI)conditions.While mucinous neoplasms are classified and staged using established guidelines,interobserver variability occurs when acellular mucin pools are encountered,leading to inconsistent interpretation and staging.In particular,acellular mucin found in regional lymph nodes of colorectal adenocarcinoma patients who have not received treatment presents a diagnostic challenge,as its prognostic implication is not clearly defined.Acellular mucin is also commonly seen in treated colorectal adenocarcinoma,post neoadjuvant therapy.Although acellular mucin is not counted toward T or N staging in this setting,variation in how pathologists report and stage these cases persists.Acellular mucin can also be seen in non-neoplastic specimens,such as those from interval appendectomies,appendiceal diverticula,colonic diverticulitis,volvulus,and Crohn’s disease where it may mimic a neoplastic lesion.Acellular mucin in this setting is often a byproduct of inflammation,increased luminal pressure,and mural defect.This review highlights the clinical relevance and diagnostic complexity of acellular mucin in pathologic conditions of the lower GI tract.Further studies are needed to clarify its prognostic value and develop standardized guidelines.
文摘Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Gestational dietary soy prevents alcohol-related impairments in placentation and FASD-associated fetal anomalies. Objective: This study was designed to determine if gestational dietary soy would be sufficient to normalize cognitive function in young adolescent offspring after chronic in utero exposure to alcohol. In addition, efforts were made to characterize the mechanisms of FASD prevention by maternal dietary soy. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source from gestation day 6 through delivery/postnatal day 0 (P0). From P24 - P28, the offspring were subjected to Morris water maze (MWM) testing, and on P35, they were sacrificed to harvest temporal lobes for histopathologic and molecular studies. Results: The in-utero ethanol-exposed offspring exhibited significant performance impairments on the MWM test, and they had a significantly reduced mean brain weight with neuronal loss in the CA1 hippocampal region and evidence of white matter myelin loss. Gestational dietary soy nearly normalized MWM performance and preserved brain weight, hippocampal CA1 architecture, and white matter myelin staining in alcohol-exposed offspring. Mechanistically, the main positive effects of soy included increased temporal lobe expression of HES-1 and HIF-1α, reflecting enhanced Notch signaling, and broadly increased expression of GnRH network molecules, including Erb1, Gper1, GnRH, GnRH-R, KiSS, and KiSS-R, irrespective of gestational ethanol exposure. Conclusions: Dietary soy intervention early in pregnancy may reduce FASD-associated cognitive deficits. The findings suggest that targeting Notch and GnRH-related networks may help reduce long-term disability with FASD. Additional mechanistic and experimental research is needed to determine if longer-duration, postnatal dietary soy could prevent the adverse neurobehavioral effects of FASD.
文摘BACKGROUND Gallbladder mucocele,also known as gallbladder hydrops,is a rare condition characterized by the distention of the gallbladder due to the accumulation of fluid or mucus within its lumen,primarily attributed to obstruction arising from a gallstone in the cystic duct or gallbladder neck.CASE SUMMARY We present a case of a 67-year-old woman with an incidentally discovered gallbladder mucocele,shedding light on the clinical presentation,causes,and histopathological findings.We performed a literature review including an analysis of 27 case reports,revealing the diverse spectrum of causative factors,clinical manifestations,diagnosis,and management.CONCLUSION This study underscores the importance of considering alternative diagnoses and highlights the significance of imaging techniques in narrowing down the differential diagnosis and histopathologic examination for a definitive diagnosis.
文摘BACKGROUND Pancreatic fibrosis,which decreases risk of postoperative pancreatic fistula(POPF),can be estimated using extracellular volume fraction(ECVf).AIM To investigate the correlation between ECVf and pancreatic histology,as well as the usefulness of ECVf in predicting POPF.METHODS In 71 patients who underwent pancreatic resection,we caluculated pancreatic ECVf by comparing absolute enhancements of the pancreas and aorta between pre-contrast and equilibrium phases.Areas of fibrosis,fat,acini,and islets were calculated based on resection specimens.RESULTS ECVf correlated with fibrosis(r=0.724;P<0.001)and negatively correlated with acini(r=-0.510;P<0.001).Among 48 patients who underwent pancreatoduoden ectomy,21 developed POPF.Main pancreatic duct diameter≤2 mm and ECVf<36%were selected as risk factors by multivariate analysis[respective odds ratios(OR)and P values,4.26 and P=0.048;OR=11.07 and P=0.036].Using these factors as a risk score(0-2 points),POPF occurred in 0%,50%,and 70%of patients with 0,1,and 2 points,respectively.CONCLUSION ECVf is useful in predicting acinar loss and pancreatic fibrosis,and ECVf<36%may be a risk factor for POPF.
文摘BACKGROUND Fibroadenomas(FA)and phyllodes tumors(PT)are fibroepithelial neoplasms and are difficult to differentiate radiographically and histologically.We present a partially infarcted borderline PT in an adolescent with rapid tumor enlargement within 24 hours.Tumor infarction made the diagnostic work-up difficult.Com-plete surgical excision is the standard of care for PTs.There is controversy regar-ding margin re-excision for borderline PTs.In this report,we discuss the diagno-stic challenges of PT and the evolving concept of margin status on PT recurrence rate.CASE SUMMARY A 14-year-old healthy female with no medical history presented with a painful right breast mass with no nipple discharge,trauma,or skin findings.The mass showed rapid enlargement over 24 hours,prompting a workup with ultrasound and core needle biopsy.The initial biopsy was limited due to large areas of in-farction.Based on the scant viable tissue and considering the patient’s age,the mass was favored to be a juvenile FA.The patient underwent excision of the mass.Final pathology confirmed a borderline PT with positive surgical margins.The patient underwent margin re-excision,which did not show any residual tumor.At the 6-month post-op visit,there was a mass-forming lesion on the breast ultrasound.Subsequent core needle biopsy showed benign breast parenchyma with scar formation.The primary goal of evaluation in pediatric breast masses is to do no harm.However,rapidly growing and symptomatic masses require a more extensive work-up including biopsy and surgical excision.We present a rapidly growing breast mass in a 14-year-old female which was diagnosed as a borderline PT on her excision specimen.The mass rapidly enlarged over 24 hours.The initial biopsy pathology was limited due to a large area of infarction.The patient underwent excision of the mass.Final pathology confirmed a borderline PT that extended into the surgical margin,resulting in an additional re-excision procedure.Accurate diagnosis prior to surgical intervention is crucial to avoid additional procedures.Although histological morphology remains the gold standard for diagnosis,immunohistochemistry and molecular studies have recently shown to improve the accuracy of diagnosis of PTs.Long-term clinical and pathologic follow-up of PTs in adolescent patients should be collectively studied to examine whether our current diagnostic criteria for PT can reliably predict tumor behavior in this age group.CONCLUSION Accurate diagnosis of PTs requires surgical excision.Tumor infarction may lead to rapid tumor enlargement,hindering the correct diagnosis.More research is needed on margin status and recurrence rate,especially in adolescent patients,to help establish the best possible care for this age group.
文摘Background:The Akreos®AO60 intraocular lens(IOL)has been employed for scleral fixation in eyes without capsular support,although surgical complications,including IOL opacification,have been reported.This study aims to evaluate the outcomes and complications associated with scleral fixation of the Akreos®AO60 IOL in vitrectomized eyes,with a particular focus on IOL opacification.Methods:Electronic medical records of consecutive eyes that underwent scleral-fixation of the Akreos®AO60 lens using Gore-tex®sutures from 2017 to 2022 were reviewed.The following parameters were collected:age,sex,laterality,past ocular/medical history,surgical indication,pre-operative visual acuity(VA)and intraocular pressure(IOP),surgical procedure,and post-operative VA and IOP.The types of complications,onset,management,and outcomes were also documented.Descriptive statistics,Wilcoxon signed-rank test,and Fisher’s exact test were employed for statistical analysis.Results:Eighty-nine eyes of 86 patients aged 31-100 years were included.The most common surgical indication was non-traumatic IOL displacement.Retinal tears and localized choroidal hemorrhage were found intraoperatively in 7.9%and 1.1%,respectively.The most common post-operative complications were vitreous hemorrhage(13.5%),corneal edema(12.4%),ocular hypotony(11.2%),and IOL opacification(11.2%).IOL opacification was associated with intra-/post-operative exposure to air/gas[odds ratio(OR):12.24;95%confidence interval(CI),1.46-103.0;P=0.006].Mean logarithm of the minimum angle of resolution(logMAR)best-reported VA(BRVA)improved from 1.22±0.77 pre-operatively to 0.56±0.67 on latest follow-up(P<0.001).Conclusions:The majority of the complications from scleral-fixation of the Akreos®AO60 lens in vitrectomized eyes were mild and transient;however,a proportion required surgical intervention.A significant risk for opacification was found in IOLs exposed to air/gas,although VA was often maintained.
文摘BACKGROUND Discordance between endoscopic and histologic assessments in Crohn’s disease(CD)have been observed,however the prevalence and cause are unclear.AIM To assess if a protocolized approach to biopsy collection facilitates understanding of this discordance in patients with ileal CD.METHODS Patients with known ileal CD underwent colonoscopy with endoscopic disease activity assessment.Three protocolized biopsies were taken respectively from an ulcer edge,7-mm,and 14-mm away from the ulcer edge in patients with discrete ileal ulcer(s).In patients with no ulcers as controls,the same 3-site biopsy protocol was applied in a randomly selected area of endoscopically-unremarkable terminal ileal mucosa.A blinded pathologist assessed mucosal inflammation in each biopsy using 3 validated histologic indices.RESULTS Twenty-four participants had visible ulcer(s)on endoscopy and 12 served as no-ulcer controls.Of biopsies taken from an ulcer edge,only 67%showed histologic evidence of active(neutrophilic)inflammation,and 33%showed histologic features of ulcer or erosion;all were from either large(n=4)or very large(n=4)ulcers.In the no-ulcer controls,no biopsies showed histologic features of ulcer or erosion,but 8%showed active inflammation.CONCLUSION A striking discordance exists between endoscopic and histologic assessments for mucosal inflammation in patients with active ileal CD,even in biopsies targeted at an ulcer edge,while a higher concordance is seen in patients with no endoscopic disease activity.It remains unclear how to incorporate histologic disease activity into the treatment paradigm.Further research is needed to optimize biopsy protocols and histologic assessments for CD.
基金supported by the National Natural Science Foundation of China(82371083,82471100,82121003,82271084)Program of Science and Technology International Cooperation Project of Qinghai province(China)(2022-HZ-814)。
文摘N6-methyladenosine(m^(6)A)modification of mRNA is a critical post-transcriptional regulatory mechanism that modulates mRNA metabolism and neuronal function.The m^(6)A reader YTHDF1 has been shown to enhance the translational efficiency of m^(6)A-modified mRNAs in the brain and is essential for learning and memory.However,its role in the mature retina remains unclear.Herein,we report a novel role of Ythdf1 in the maintenance of retinal function using a genetic knockout model.Loss of Ythdf1 resulted in impaired scotopic electroretinogram(ERG)responses and progressive retinal degeneration.Detailed analyses of rod photoreceptors confirmed substantial degenerative changes in the absence of ciliary defects.Single-cell RNA sequencing revealed comprehensive molecular alterations across all retinal cell types in Ythdf1-deficient retinas.Integrative analysis of methylated RNA immunoprecipitation(MeRIP)sequencing and RIP sequencing identified Tulp1 and Dhx38,two inheritable retinal degeneration disease-associated gene homologs,as direct targets of YTHDF1 in the retina.Specifically,YTHDF1 recognized and bound m^(6)A-modified Tulp1 and Dhx38 mRNA at the coding sequence(CDS),enhancing their translational efficiency without altering mRNA levels.Collectively,these findings highlight the essential role of YTHDF1 in preserving visual function and reveal a novel regulatory mechanism of m^(6)A reader proteins in retinal degeneration,identifying potential therapeutic targets for severe retinopathies.
基金supported by the Major Science and Technology Special Project of Gansu Province(24ZDFA002)the National Natural Science Foundation of China(82060459)+1 种基金the Key Research and Development Program of Gansu Province(23YFFA0007)the Joint Research Fund of Gansu Province(23JRRA1511)。
文摘Given the critical shortage of antibody-drug conjugates(ADCs)for bladder cancer(BCa),we developed a novel FGFR3-targeted ADC,LZU-WZLYFG001,composed of a humanized anti-FGFR3 IgG1 monoclonal antibody,a cleavable GGFG linker,and the payload DXD.The antibody was engineered in 293 cells and conjugated via thiol-based chemistry,achieving a drug-to-antibody ratio(DAR)of eight.Comprehensive preclinical assessments,including in vitro and in vivo studies using BCa cells,organoids,cell-derived xenograft and patient-derived xenograft(PDX)models,were conducted to evaluate efficacy,targeting ability,mechanism,safety and tissue distribution.LZU-WZLYFG001 demonstrated high purity,targeting specificity and low endotoxin levels,and it significantly inhibited BCa cell proliferation,migration and invasion at nanomolar concentrations,with efficacy strongly associated with FGFR3 expression levels.Mechanistic studies showed binding to FGFR3,internalization and lysosomal release of LZU-WZLYFG001.In organoid and xenograft models,LZU-WZLYFG001 exhibited superior efficacy compared with the gemcitabine+cisplatin(GC)regimen,particularly in GC-resistant PDX tumors,while also showing robust 3D penetration,a bystander effect,and no significant short-term toxicity.
文摘Although gastric tumors have overlapping radiologic appearances, some unusual tumors may present specific imaging features. Using multidetector computed tomography(MDCT), with water as a negative oral contrast agent and intravenous contrast medium, can provide critical information for the diagnosis of gastric diseases. In addition, MDCT can evaluate the involvement of the gastric wall and extragastric extent of the disease, as compared with gastroenteroscopy and double-contrast upper gastrointestinal study. Regarding lesion location and size, enhancing and growth patterns, presence of calcification or fat, and involvement of the gastric wall and adjacent structures, CT may provide useful information. In this review article, we review the relevant literature and discuss the CT features and the histopathologic findings of different types of gastric lesions. The lesions are divided into benign(glomus tumors, schwannomas, leiomyomas, and lipomas), malignant(gastrointestinal stromal tumors, mucinous carcinomas, lymphomas, and carcinoid tumors), and tumor-like lesions(ectopic pancreas and bezoar). Familiarity with imaging appearances and pathologic findings can help physicians make an accurate diagnosis.
基金the Physicians’Services Incorporated Foundation 10q2083(Joy TR and Beaton MD)Academic Medical Organization of Southwestern Ontario,No.F10-002(Beaton MD)+1 种基金partly funded through academic research funds from the Program of Experimental Medicine(Joy TR)Department of Medicine Academic Funds(Joy TR)from Western University,London,Ontario,Canada
文摘AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 μg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002.CONCLUSIONSitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.
