Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.

Genomic alterations in oral multiple primary cancers

Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer, while some patients may develop oral multiple primary cancers (MPCs) with unclear etiology. This study aimed to investigate the clinicopathological characteristics and genomic alterations of oral MPCs. Clinicopathological data from patients with oral single primary carcinoma (SPC, n=202) and oral MPCs (n=34) were collected and compared. Copy number alteration (CNA) analysis was conducted to identify chromosomal-instability differences among oral MPCs, recurrent OSCC cases, and OSCC patients with lymph node metastasis. Whole-exome sequencing was employed to identify potential unique gene mutations in oral MPCs patients. Additionally, CNA and phylogenetic tree analyses were used to gain preliminary insights into the molecular characteristics of different primary tumors within individual patients. Our findings revealed that, in contrast to oral SPC, females predominated the oral MPCs (70.59%), while smoking and alcohol use were not frequent in MPCs.Moreover, long-term survival outcomes were poorer in oral MPCs. From a CNA perspective, no significant differences were observed between oral MPCs patients and those with recurrence and lymph node metastasis. In addition to commonly mutated genes such as CASP8, TP53 and MUC16, in oral MPCs we also detected relatively rare mutations, such as HS3ST6 and RFPL4A. Furthermore, this study also demonstrated that most MPCs patients exhibited similarities in certain genomic regions within individuals, and distinct differences of the similarity degree were observed between synchronous and metachronous oral MPCs.

Clinicopathological alterations in wild mammals from the reservoir system of Trypanosoma cruzi:a scoping review

Trypanosoma cruzi is the etiologic agent of Chagas disease.This flagellated protozoan is transmitted to humans as well as different species of domestic and wild animals via vectors from the Reduviidae family(known as"kissing bugs").Despite the fact that hundreds of species of wild mammals are part of the reservoir system,the morphologi-cal changes and clinical manifestations resulting from the pathogenesis of the infection have been largely neglected.The aim of this review is to systematically compile the available information regarding clinicopathological altera-tions in wild mammals due to natural infection by T.cruzi.Information was obtained from six online bibliographic data search platforms,resulting in the identification of 29 publications that met the inclusion criteria.Mortality was the most common clinical manifestation,cardiac damage was the main finding at necropsy,and lymphoplas-macytic inflammation was the most frequent microscopic injury.Thus,regardless of its role as a reservoir,T.cruzi has the potential to affect the health status of wild mammals,a situation that highlights the need for further research to analyze,measure,and compare its effects at both the individual and population levels.

Sex-dependent alterations in extracellular vesicles linking chronic spinal cord injury to brain neuroinflammation and neurodegeneration

Traumatic spinal cord injury(SCI)is a devastating exogenous injury with long-lasting consequences and a leading cause of death and disability worldwide.Advances in assistive technology,rehabilitative interventions,and the ability to identify and intervene in secondary conditions have significantly increased the long-term survival rate of SCI patients,with some people even living well into their seventh or eighth decade.These survival changes have led neurotrauma researchers to examine how SCI interacts with brain aging.Public health and epidemiological data showed that patients with long-term SCI can have a lower life expectancy and quality of life,along with a higher risk of comorbidities and complications.

Bilateral meibomian gland morphological alterations in unilateral herpes simplex keratitis based on artificial intelligence analysis

AIM:To explore whether unilateral herpes simplex keratitis(HSK)can cause morphological changes of bilateral meibomian glands(MGs)based on artificial intelligence(AI)analytical system.METHODS:In the retrospective study,29 patients with unilateral HSK and 29 participants matched in terms of age and sex were included as control group.Meibographic images of the upper eyelid using Keratograph 5M and assessed ocular surface parameters including tear meniscus height and tear break-up time.MG density and vagueness values were automatically analyzed and calculated using an AI analytical system.We compared the differences between the affected and the contralateral unaffected eyes in HSK patients,and the normal control eyes.We employed either the paired t-test or the Wilcoxon signed-rank test to compare significant difference between the affected and unaffected eyes in HSK patients or between the HSK group and control group.RESULTS:The MG density was 0.19±0.09 in the HSKaffected eye and 0.18±0.07 in contralateral unaffected eye,which had no significant difference(P=0.616).The MG density between the affected eye with HSK and the normal control group was statistically significant(P=0.028).There was a significant difference in MG density between the contralateral unaffected eye and the normal control group(P=0.012).However,no significant difference in vagueness value was observed between the eye with HSK and the control group or between HSK eye and contralateral eye.CONCLUSION:The MG density between the HSKaffected eye and the contralateral unaffected eye don’t significantly differ,whereas there is a significant decrease in the HSK group compared to that of the normal participants.Unilateral HSV keratitis may suffer from bilateral changes of MG morphology indicating bilateral dry eye.Therefore,the fellow eye of patients with unilateral HSK should be considered a potential case of MG dysfunction,necessitating early treatment for bilateral dry eye in the clinic.

Hematological Alterations in an Eastern Sudanese Chronic Kidney Disease Patient Population

Background: Chronic Kidney Disease (CKD), associated with a slow and progressive loss of kidney function over a period of several years, is an important clinical disaster with an increasing rate of morbidity and mortality especially in the least developed countries. Many hematological parameters are thought to alter dramatically during the course of the disease. These include white blood cells, red blood cells, and platelets. Methods: We tried, retrospectively, to evaluate the peripheral blood hematological alterations in a group of patients undergoing hemodialysis in an eastern Sudan dialysis center to add local medical information. Results: Anemia (Low hemoglobin and hematocrit) was detected in 94% of the patients’ group. Mean Erythrocyte count (3.32vs.4.76 (×109/L)), Hemoglobin concentration (9.4vs.13 (g/dl)), Hematocrit (28.7vs.38.7 (L/L)) and platelet count (296 vs. 238 (×109/L)) were significantly lower in the patients’ group than in the control group (P-values Conclusion: Five out of eight studied parameters (Red cell count, hemoglobin, hematocrit, mean cell hemoglobin concentration, and platelets count) have shown a significant alteration in CKD patients. As the complete blood count (CBC) test is the most utilized test in clinical laboratory practice, these alterations may be considered as early indicators for CKD. Furthermore, all patients with CKD must be routinely checked for these alterations.

Identifying Comprehensive Genomic Alterations and Potential Neoantigens for Cervical Cancer Immunotherapy in a Cohort of Chinese Squamous Cell Carcinoma of the Cervix

Objective Genomic alterations and potential neoantigens for cervical cancer immunotherapy were identified in a cohort of Chinese patients with cervical squamous cell carcinoma(CSCC).Methods Whole-exome sequencing was used to identify genomic alterations and potential neoantigens for CSCC immunotherapy.RNA Sequencing was performed to analyze neoantigen expression.Results Systematic bioinformatics analysis showed that C>T/G>A transitions/transversions were dominant in CSCCs.Missense mutations were the most frequent types of somatic mutation in the coding sequence regions.Mutational signature analysis detected signature 2,signature 6,and signature 7 in CSCC samples.PIK3CA,FBXW7,and BICRA were identified as potential driver genes,with BICRA as a newly reported gene.Genomic variation profiling identified 4,960 potential neoantigens,of which 114 were listed in two neoantigen-related databases.Conclusion The present findings contribute to our understanding of the genomic characteristics of CSCC and provide a foundation for the development of new biotechnology methods for individualized immunotherapy in CSCC.

Synaptic alterations as a common phase in neurological and neurodevelopmental diseases: JNK is a key mediator in synaptic changes

Brain synapses play a key role in neuronal communication:this“conversation”is at the basis of all brain activities and synaptic dysfunction leads to brain disorders.We study the modulators of this crucial synaptic function and we here present the evidence supporting the c-Jun N-terminal kinase(JNK)pathway as a pivotal actor in this scenario.

Insight into the evolution of breast cancer driven by genetic alterations

Breast cancer originates primarily from the epithelial cells of the mammary gland.Repeated mammary gland expansion and degeneration are accompanied by an increased risk of genetic alterations in the breast1.These mutations in breast epithelial cells dynamically occur in response to pregnancy,labor and delivery,breastfeeding,and the menstrual cycle,with a decline in mutation rates after menopause,which may be related to a decrease in estrogen levels.The breast epithelial cell mutations are also consistent with epidemiologic observations2.

Molecular alterations in gastric cancer with special reference to the early-onset subtype

Currently, gastric cancer(GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the procarcinogenic activity of important genes. These factors include genetic susceptibility expressed in a singlenucleotide polymorphism, various acquired mutations(chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances(e.g., helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma(EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesisare modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.

Epigenetic alterations in gastric carcinogenesis

Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a varietyof methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play impor-tant roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpGisland methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesisand its relevance of clinical implications.

Genomic and genetic alterations influence the progression of gastric cancer

Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.

Genetic alterations in hepatocellular carcinoma: An update

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.

Bone alterations in inflammatory bowel diseases

Inflammatory bowel diseases(IBDs)are characterized by a multifactorial partially unknown etiology that involves genetic,immunological and environmental factors.Up to 50%of IBD patients experience at least one extraintestinal manifestation;among them is the involvement of bone density which is referred to as metabolic bone disease(MBD),including osteopenia and osteoporosis.Bone alterations in IBDs population appear to have a multifactorial etiology:Decreased physical activity,inflammation-related bone resorption,multiple intestinal resections,dietary malabsorption of minerals and vitamin D deficiency,genetic factors,gut-bone immune signaling interaction,steroid treatment,microbiota and pathogenic micro-organisms interaction,and dietary malabsorption of minerals,that,all together or individually,may contribute to the alteration of bone mineral density.This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility.We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.

A study on p53 gene alterations in esophageal squamous cell carcinoma and their correlation to common dietary risk factors among population of the Kashmir valley

AIM： To systematically examine the extent of correlation of risk factors, such as age, consumed dietary habit and familial predisposition with somatic Tp53 molecular lesion causal to elevate carcinogenesis severity of esophageal squamous cell carcinoma （ESCC） among the Kashmiri population of Northern India. METHODS： All cases （n = 51） and controls （n = 150） were permanent residents of the Kashmir valley. Genetic alterations were determined in exons 5-8 of Tp53 tumor suppressor gene among 45 ESCC cases histologically confirmed by PCR-SSCP analysis. Data for individual cancer cases （n = 45） and inpatient controls （n = 150） with non-cancer disease included information on family history of cancer, thirty prevailing common dietary risk factors along with patient＇s age group. Correlation of genetic lesion in p53 exons to animistic data from these parameters was generated by Chi-square test to all 45 histologically confirmed ESCC cases along with healthy controls.RESULTS： Thirty-five of 45 （77.8%） histologically characterized tumor samples had analogous somatic mutation as opposed to 1 of 45 normal sample obtained from adjacent region from the same patient showed gerrnline mutation. The SSCP analysis demonstrated that most common p53 gene alterations were found in exon 6 （77.7%）, that did not correlate with the age of the individual and clinicopathological parameters but showed significant concordance （P 〈 0.05） with familial history of cancer （CD = 58）, suggesting germline predisposition at an unknown locus, and dietary habit of consuming locally grown Brassica vegetable ＂Hakh＂ （CD = 19.5）, red chillies （CD = 20.2）, hot salty soda tea （CD = 2.37） and local baked bread （CD = 1.1）. CONCLUSION： Our study suggests that somatic chromosomal mutations, especially in exon 6 of Tp53 gene, among esophageal cancer patients of an ethnically homogenous population of Kashmir valley are closely related to continued exposure to various common dietary risk factors, especially hot salty tea, meat, baked bread and ＂Hakh＂, that are rich in nitrosoamines and familial cancer history.

DMP1 prevents osteocyte alterations,FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease

During chronic kidney disease (CKD),alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality.The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization,but its effects in CKD are unknown.We tested the hypothesis that DMP1 supplementation in CKD would improve bone health,prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes.We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3^-/- mouse model of CKD.Col4a3^-/- mice demonstrated impaired kidney function,reduced bone DMP1 expression,reduced bone mass,altered osteocyte morphology and connectivity,increased osteocyte apoptosis,increased serum FGF23,hyperphosphatemia,left ventricular hypertrophy (LVH),and reduced survival.Genetic or pharmacological supplementation of DMP1 in Col4a3^-/- mice prevented osteocyte apoptosis,preserved osteocyte networks,corrected bone mass,partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription,and further increased serum phosphate.Despite impaired kidney function and worsened hyperphosphatemia,DMP1 prevented development of LVH and improved Col4a3^-/- survival.Our data suggest that CKD reduces DMP1 expression,whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

Inflammation-associated microsatellite alterations:Mechanisms and significance in the prognosis of patients with colorectal cancer

Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono-and di-nucleotide frameshifts to classify it as microsatellite instability-high(MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic nonMSI-H CRCs demonstrate frameshifts at di-and tetra-nucleotide microsatellites to classify it as MSIlow/elevated microsatellite alterations at selected tetranucleotide repeats(EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.

Prognostic value of BCL2 and TP53 genetic alterations for diffuse large B-cell lymphoma patients treated with R-CHOP

Objective:Limited data about the prognostic significance of BCL2 mutations and BCL2 copy number variations in diffuse large B-cell lymphoma(DLBCL)are available.This study aimed to comprehensively describe BCL2 genetic alterations in DLBCL patients,and examine correlation of BCL2,TP53 and other genetic alterations with outcomes in patients treated with R-CHOP.Methods:Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLBCL.MYC,BCL2,and BCL6 protein expressions were detected by immunohistochemistry.Results:The presence of BCL2 alterations significantly correlated with poor progression-free survival(PFS)(5-year PFS:13.7%vs.40.8%;P=0.003)and overall survival(OS)(5-year OS:34.0%vs.70.9%;P=0.036).Importantly,patients who harbored BCL2 gain/amplifications(BCL2GA/AMP)also had a remarkably inferior 5-year PFS(11.1%vs.38.3%;P<0.001)and OS(22.1%vs.69.6%;P=0.009).In contrast,neither BCL2 mutations nor BCL2 translocations were significantly prognostic for survival.Multivariable analyses showed that the presence of BCL2 alterations,especially BCL2GA/AMP,TP53 mutations,and International Prognostic Index(IPI)were significantly associated with inferior PFS and OS.Novel prognostic models for OS were constructed based on 3 risk factors,including BCL2 alterations(Model 1)or BCL2GA/AMP(Model 2),TP53 mutations,and IPI,to stratify patients into 4 risk groups with different survival outcomes.Conclusions:This study showed that DLBCL patients treated with R-CHOP,BCL2 alterations,especially BCL2GA/AMP and TP53 mutations were significantly associated with inferior outcomes,which were independent of the IPI.The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP,but further validation of the prognostic models is still warranted.

Genetic alterations of hepatocellular carcinoma by random amplified polymorphic DNA analysis and cloning sequencing of tumor differential DNA fragment

AIM: To study the genetic alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC), and to find the tumor related DNA fragments.METHODS: DNA isolated from tumors and corresponding noncancerous liver tissues of 56 HCC patients was amplified by random amplified polymorphic DNA (RAPD)with 10 random 10-mer arbitrary primers. The RAPD bands showing obvious differences in tumor tissue DNA corresponding to that of normal tissue were separated,purified, cloned and sequenced. DNA sequences were analyzed and compared with GenBank data.RESULTS: A total of 56 cases of HCC were demonstrated to have genetic alterations, which were detected by at least one primer. The detestability of genetic alterations ranged from 20% to 70% in each case, and 17.9% to 50% in each primer. Serum HBV infection, tumor size,histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with genetic alterations on certain primers. A band with a higher intensity of 480 bp or so amplified fragments in tumor DNA relative to normal DNA could be seen in 27 of 56 tumor samples using primer 4. Sequence analysis of these fragments showed 91% homology with Homo sapiens double homeobox protein DUX10 gene.CONCLUSION: Genetic alterations are a frequent event in HCC, and tumor related DNA fragments have been found in this study, which may be associated with hepatocarcinogenesis. RAPD is an effective method for the identification and analysis of genetic alterations in HCC, and may provide new information for further evaluating the molecular mechanism of hepatocarcinogenesis.

Neuropsychological alterations in hepatitis C infection:The role of inflammation

About 50% of patients with hepatitis C virus(HCV)infection complain of neuropsychiatric symptoms,"brain fog",weakness,fatigue,and exhibit some degree of quality of life impairment,irrespective of the severity of liver disease.Since the first observation of HCV-related cognitive deficits,10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment.Unfortunately,these have often included patients with cirrhosis,patients who had acquired the infection through previous intravenous drug misuse,who had a history of relatively recent treatment with interferon,or were on psychoactive medication.In addition,different neuropsychological batteries and tests that explored different cognitive domains were used,which makes the results of the studies difficult to compare.Finally,limited information is available on the pathogenesis of HCV-related cognitive impairment.Cerebral and/or systemic inflammation may be important players but their potential role has not been substantiated by experimental data.The present review outlines the available evidence of the presence of cognitive impairment in patients with HCV infection,with a focus on the potential relationship with cerebral and/or systemic inflammation.