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.

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.

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.

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.

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.

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.

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.

A Blade Altering Toolbox for Automating Rotor Design Optimization

The Blade Altering Toolbox(BAT)described in this paper is a tool designed for fast reconstruction of an altered blade geometry for design optimization purposes.The BAT algorithm is capable of twisting a given rotor’s angle of attack and stretching the chord length along the span of the rotor.Several test cases were run using the BAT’s algorithm.The BAT code’s twisting,stretching,and mesh reconstruction capabilities proved to be able to handle reasonably large geometric alterations to a provided input rotor geometry.The test examples showed that the toolbox’s algorithm could handle any stretching of the blade’s chord as long as the blade remained within the original bounds of the unaltered mesh.The algorithm appears to fail when the net twist angle applied the geometry exceeds approximately 30 degrees,however this limitation is dependent on the initial geometry and other input parameters.Overall,the algorithm is a very powerful tool for automating a design optimization procedure.

Application of Remote Sensing and GIS in Mineral Alteration Mapping and Lineament Extraction Case of Oudiane Elkharoub (Requibat Shield, Northern of Mauritania)

The integration of remotely sensed data allowed the successful characterization of the mineral alteration zones of the Oudiane Elkharoub area in the Northeastern part of Reguibat Shield using image transformation techniques. As both chemical and geochemical analyses showed significant Au, Ag, Cu, Pb, Mn, Cr, Ni, Th and Y anomalies, it’s very interesting to apply the remote sensing and GIS in mineral resources mapping. The remote sensing is a direct adjunct to the field, lithologic and structural mapping, and more recently, GIS has played an important role in the study of mineralization areas. The integration of several evidential maps highlighted the plausible areas with high concentrations of chlorite, epidote, kaolinite, calcite, alunite, hematite, illite and sulfur among other key mineral alterations that reflect the intensity of hydrothermal effects and the probable sites of ore bodies. The methodological approach integrates geological information acquired from Aster and Landsat 8 OLI/TIRS (Operational Land Imager/Thermal InfraRed Sensor) images and a multi-criteria GIS analysis. The superimposition of various lineament and hydrothermal alteration maps and the consideration of precious and base metal indicators allowed the zoning of sites likely to contain mineral concentrations. Remote sensing becomes an important tool for locating mineral deposits in its own right, when the primary and secondary processes of mineralization result in the formation of spectral anomalies. Reconnaissance lithological mapping is usually the first step of mineral resource mapping. This is complimented with structural mapping, as mineral deposits usually occur along or adjacent to geologic structures, and alteration mapping, as mineral deposits are commonly associated with hydrothermal alteration of the surrounding rocks. Ground truthing and laboratory studies including XRD analysis were utilized to verify the results.

Multi-scale data joint inversion of minerals and porosity in altered igneous reservoirs—A case study in the South China Sea

There are abundant igneous gas reservoirs in the South China Sea with significant value of research,and lithology classification,mineral analysis and porosity inversion are important links in reservoir evaluation.However,affected by the diverse lithology,complicated mineral and widespread alteration,conventional logging lithology classification and mineral inversion become considerably difficult.At the same time,owing to the limitation of the wireline log response equation,the quantity and accuracy of minerals can hardly meet the exploration requirements of igneous formations.To overcome those issues,this study takes the South China Sea as an example,and combines multi-scale data such as micro rock slices,petrophysical experiments,wireline log and element cutting log to establish a set of joint inversion methods for minerals and porosity of altered igneous rocks.Specifically,we define the lithology and mineral characteristics through core slices and mineral data,and establish an igneous multi-mineral volumetric model.Then we determine element cutting log correction method based on core element data,and combine wireline log and corrected element cutting log to perform the lithology classification and joint inversion of minerals and porosity.However,it is always difficult to determine the elemental eigenvalues of different minerals in inversion.This paper uses multiple linear regression methods to solve this problem.Finally,an integrated inversion technique for altered igneous formations was developed.The results show that the corrected element cutting log are in good agreement with the core element data,and the mineral and porosity results obtained from the joint inversion based on the wireline log and corrected element cutting log are also in good agreement with the core data from X-ray diffraction.The results demonstrate that the inversion technique is applicable and this study provides a new direction for the mineral inversion research of altered igneous formations.

Research on the Application of Electromagnetic Method in the Exploration of Altered Rock-type Gold Deposits in the East Kunlun Metallogenic Belt

Introduction The East Kunlun Orogenic Belt is located in the northeastern part of the Qinghai–Tibet Plateau(Li et al.,2007),stretching from the East Kunlun to the Elashan area in an east–west direction(Guo et al.,2018).It is an important part of the Central Orogenic Belt(Xiong et al.,2023).It is considered one of the important gold mineralization regions in the Tethys tectonic domain(Norbu et al.,2023)and an essential potential base for mineral resources in China.Wulonggou and Gouli gold mines have been discovered successively,earning the reputation of the"Golden Belt of Qinghai Province"(Feng et al.,2004;He et al.,2023).

Novel cyber-physical collaborative detection and localization method against dynamic load altering attacks in smart energy grids

Owing to the integration of energy digitization and artificial intelligence technology,smart energy grids can realize the stable,efficient and clean operation of power systems.However,the emergence of cyber-physical attacks,such as dynamic load-altering attacks(DLAAs)has introduced great challenges to the security of smart energy grids.Thus,this study developed a novel cyber-physical collaborative security framework for DLAAs in smart energy grids.The proposed framework integrates attack prediction in the cyber layer with the detection and localization of attacks in the physical layer.First,a data-driven method was proposed to predict the DLAA sequence in the cyber layer.By designing a double radial basis function network,the influence of disturbances on attack prediction can be eliminated.Based on the prediction results,an unknown input observer-based detection and localization method was further developed for the physical layer.In addition,an adaptive threshold was designed to replace the traditional precomputed threshold and improve the detection performance of the DLAAs.Consequently,through the collaborative work of the cyber-physics layer,injected DLAAs were effectively detected and located.Compared with existing methodologies,the simulation results on IEEE 14-bus and 118-bus power systems verified the superiority of the proposed cyber-physical collaborative detection and localization against DLAAs.

Characteristics of Element Migration in the Process of Wall-Rock Alteration in the Shibangou Gold Deposit,Western Henan

Abstract The Shibangou gold deposit in western Henan is associated with irregular quartz veinlets occurring in altered shear zones dissecting a dioritic intrusion. The altered shear zones are characterized by silicification, pyritization, sericilization, chloritization and K-feldspar alteration. Zoning of altered rocks adjacent to the Au-bearing quartz veins is obviously exhibited. Fine-grained sulphides and quartz veinlets of different ages and small-scale fissures are widely distributed in the central part of the altered zones. Major mineralization types in this gold deposit are Au-bearing quartz veinlets and altered rocks in the shear zones. Samples were collected from drilling cores according to the alteration zoning and mineralization type and all samples were analyzed for major and trace elements. Mass balance, volume change (fv=97.3–71.9%) and major element variation sequences are studied in terms of major elements. The changes of mobile components (SiO2, K2O, Fe2O3) and CaO) and immobile component (Al2O3) in the wall-rock alteration are discussed. The gold mineralization is associated with the enrichment of As, Ag, Hg and Pb and depletion of Cu and Zn. The study of compositional variation of altered rocks proves to be a very efficient method for defining the extent of wall-rock alteration, fluid activity and mineralization and enrichment.

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.

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.

Mineralogical Zonation of Wall-Rock Alteration in Jiaodong Gold Province, North China

Mineralogical zonation of wall rock alterations in Mesozoic granitoids is summarized from 18 gold deposits in Jiaodong gold province on the Asian mobile continental margin of the west circum Pacific rim. This paper deals with wall rock alterations developed around gold mineralizations of the quartz vein type in granitoids and the wall rock alteration type in granitoid basement contacts along Mesozoic fault zones trending mostly NNE SSW and NE SW. Five alteration zones are distinguished from host rock to ore zone, namely the chloritization and sericitization zone, the hematitization rutilization and microclinization zone, the quartz sericitization zone, the pyrite quartz sericitization zone and the pyrite silicification zone. The former two are outer zones marked by incomplete alteration of first mafic and then felsic minerals of the granitoids, while the later three are inner zones marked by complete alteration of both mafic and felsic minerals of the granitoids leading to retrogressive sericitization and progressive silicification with participation of ore elements. The whole process proceeds under dynamometamorphism with high fugacity of volatiles. Wall rock alteration is the intermediate link between unaltered host rock and ore mineralization both in time and space. Development of the alteration zonation and its mineral composition controls genetic type of mineralization, size and grade of the deposit and location of the ore zones.

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.

Genomic alterations in pancreatic cancer and their relevance to therapy

Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.