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.

Genetic screening of liver cancer:State of the art

Liver cancer,primarily hepatocellular carcinoma,remains a global health challenge with rising incidence and limited therapeutic options.Genetic factors play a pivotal role in the development and progression of liver cancer.This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer.We discuss the genetic underpinnings of liver cancer,emphasizing the critical role of risk-associated genetic variants,somatic mutations,and epigenetic alterations.We also explore the intricate interplay between environmental factors and genetics,highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy,and advancements in high-throughput sequencing technologies.By synthesizing the latest research findings,we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer,shedding light on their potential to revolutionize early detection,risk assessment,and targeted therapies in the fight against this devastating disease.

Hydro-uvarovite from Mantle Peridotites of Naga Hills Ophiolite: A Mineral Tracer for Neo-Tethyan Mantle Wedge Metasomatism

Hydrous Cr-bearing uvarovite garnets are rare in natural occurrences and belong to the ugrandite series and exist in binary solid solutions with grossular and andradite garnets. Here, we report the occurrence of hydrous uvarovite garnet having Cr_(2)O_(3) upto 19.66 wt% and CaO of 32.12–35.14 wt% in the serpentinized mantle peridotites of Naga Hills Ophiolite(NHO), India. They occur in association with low-Cr diopsides. They are enriched in LILE(Ba, Sr), LREEs, with fractionating LREE-MREE [avg.(La/Sm)_(N) = 2.16] with flat MREE/HREE patterns [avg.(Sm/Yb)_(N) = 0.95]. Raman spectra indicate the presence of hydroxyl(OH^(–)) peaks from 3500 to 3700 cm^(-1). Relative abundances in fluid mobile elements and their close association with clinopyroxenes are suggestive of the formation of uvarovite garnets through low temperature metasomatic alteration of low-Cr diopsides by hydrothermal slab fluids. The high LREE concentration and absence of Eu anomaly in the garnet further attest to alkaline nature of the transporting slab dehydrated fluid rather the involvement of low-p H solution. The chemical characteristics of the hydroxyl bearing uvarovite hosted by the mantle peridotite of NHO deviate from the classical features of uvarovite garnet, and their origin is attributed to the fluid-induced metasomatism of the sub arc mantle wedge in a suprasubduction zone regime.

Decoding Subsurface Secondary Mineralisation and its Impact on Cohesive Strength:An Outcome of the Deep Scientific Drilling Program in the Koyna-Warna Seismogenic Region,Western India

The Koyna-Warna seismogenic region overlying the Deccan volcanic province of Western India has been experiencing the recurrence of earthquakes since 1967 soon after the impoundment of the Koyna Dam.A large number of small to medium-magnitude shallow focus earthquakes(>100,000)have been detected in this intraplate region during the last six decades.In the present study,the core samples recovered from the borehole‘KBH3’drilled upto 1134 m depth in the pre-Deccan granitoids basement rocks of this region have been subjected to mineralogical and geochemical studies.

New insights into the effects of APP gene dose on synapse in Down syndrome

Synaptic dysfunction:Alzheimer’s disease(AD)is a prevalent form of dementia,affecting over 35 million people worldwide(Tzioras et al.,2023).A synapse serves as the connection point between neurons,facilitating the transmission of information from one neuron to another.Dynamic alterations in synapses,known as synaptic plasticity,play a pivotal role in cognitive processes such as learning and memory.Synaptic loss has been identified as a key contributor to cognitive decline in AD patients.Studies have shown that the soluble forms of amyloid-beta(Aβ)and tau proteins are toxic to synapses,leading to cognitive impairment in animal models(Spires-Jones and Hyman,2014).Additionally,the formation of oligomers of tau and Aβcan spread pathology through synaptic connections in the brain,emphasizing the vital role of synapses in disease progression.

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.

SOX11 as a potential prognostic biomarker in hepatocellular carcinoma linked to immune infiltration and ferroptosis

Objective:SOX11 is expressed in numerous malignancies,including hepatocellular carcinomas(HCC),but its oncogenic function has not been elucidated.Here,we performed a comprehensive bioinformatics analysis of the Liver Hepatocellular Carcinoma(LIHC)dataset to investigate the function of SOX11 in tumorgenesis.Methods:SOX11 expression data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)were validated by immunohistochemistry(IHC).Co-expression,differential expression,and functional analyses utilized TCGA-LIHC,Timer 2.0,Metascape,GTEx,and LinkedOmics databases.Associations with immune infiltration,ferroptosis,and immune checkpoint genes were assessed.Genetic changes were explored via CBioPortal.Logistic regression,receiver operating characteristic curve(ROC),Kaplan-Meier analysis,and nomogram modeling evaluated associations with HCC clinicopathological features.SOX11’s impact on proliferation and migration was studied in HepG2 and HuH7 cell lines.Results:SOX11 was significantly elevated in HCC tumors compared to controls.SOX11-associated genes exhibited differential expression in pathways involving extracellular membrane ion channels.Significant associations were found between SOX11 levels,immune infiltration,ferroptosis,and immune checkpoint genes in HCC tissue.SOX11 levels correlated with HCC stage,histologic grade,and tumor status,and independently predicted overall and disease-specific survival.SOX11 expression effectively distinguished between tumor and normal liver tissue.Spearman correlations highlighted a significant relationship between SOX11 and ferroptosis-associated genes.Decreased SOX11 levels in HepG2 and HuH7 cells resulted in reduced proliferation and migration.Conclusions:SOX11 was found to represent a promising biomarker within HCC diagnosis and prognosis together with being a possible drug-target.

Activity-dependent mechanisms of neuroprotection:promising avenues against dementia

The study of the brain and its complex functions is highly fascinating and,at the same time,extremely important.Indeed,furthering our understanding of the biology of neurons and synapses is a prerequisite to uncover the mechanisms involved in memory formation and the coordination of movement as well as their alterations occurring in several neurological disorders.

Non-linear dynamic state-space network modeling for decoding neurodegeneration

Neurodegenerative disorders represent a pervasive global health challenge,yet therapeutic options remain conspicuously limited.These disorders are inherently dynamic processes within the central nervous system,unfolding across distinct sub-stages:initial structural neuronal alterations(sub-stage 1),functional impairment(sub-stage 2),and culminating in neuronal death(sub-stage 3).

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.

Investigating ischemia and reperfusion-induced organ damage in severe cardiac arrest:A comprehensive proteomics perspective

Cardiac arrest(CA)is a life-threatening condition with complex pathophysiology and limited treatment options.To gain deeper insights into the pathological state of vital organs,we employed a proteomics analysis in rodents to assess proteome alterations in the brain,heart,kidney,and liver using a rat model of CA.The brain displayed severe protein alterations in essential cellular pathways,including three major energy-generating pathways after CA,which worsened after resuscitation,resulting in the most significant overall protein changes among the organs.Conversely,the liver,experiencing the most substantial protein alterations post-CA,demonstrated significant recovery,presenting the least protein changes post-resuscitation.

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.

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas

Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart.Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing(NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC(LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes.Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas.Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC(TERT amplification),colorectal NEC(KRAS mutation), and bile tract NEC(ARID1A mutation). The gene disparities between small-cell NEC(SCNEC) and large-cell NEC(LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in22.2% of the patients, and they had longer progression-free survival(PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40(0.21-0.75), P=0.006].Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

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.

Advances in MET tyrosine kinase inhibitors in gastric cancer

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

How dopamine tunes parvalbumin interneurons in the hippocampus:new experimental observations in Alzheimer's disease

Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.

Calcium-sensitive protein MLC1 as a possible modulator of the astrocyte functional state

Astrocytes,the main population of glial cells in the central nervous system(CNS),exert essential tasks for the control of brain tissue homeostasis,supporting neuron and other glial cell activity from the developmental stage to adult life.To maintain the optimal functionality of the brain,astroglial cells are particularly committed to reacting to every change in tissue homeostatic conditions,from mild modifications of the physiological environment,a process called astrocyte activation,to the more severe alterations occurring in pathological situations causing astrocyte reactivity or reactive astrogliosis(Escartin et al.,2021).During these reactive states,astrocytes mount an active,progressive response encompassing morphological,molecular,and interactional remodeling,leading to the acquisition of new functions and the loss of others,whose intensity,duration,and reversibility are dependent on the nature of the stimulus and regulated in a context-specific manner.

Plasma metabolites and risk of myocardial infarction:a bidirectional Mendelian randomization study

BACKGROUND Myocardial infarction(MI)is a critical cardiovascular event with multifaceted etiology,involving several genetic and environmental factors.It is essential to understand the function of plasma metabolites in the development of MI and unravel its complex pathogenesis.METHODS This study employed a bidirectional Mendelian randomization(MR)approach to investigate the causal relationships between plasma metabolites and MI risk.We used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa.In addition,the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite(1400 metabolites)and MI(20,917 individuals with MI and 440,906 individuals without MI)susceptibility.Inverse variance weighted was the primary method for estimating causal effects.MR estimates are expressed as beta coefficients or odds ratio(OR)with 95%CI.RESULTS We identified 14 plasma metabolites associated with the occurrence of MI(P<0.05),among which 8 plasma metabolites[propionylglycine levels(OR=0.922,95%CI:0.881–0.965,P<0.001),gamma-glutamylglycine levels(OR=0.903,95%CI:0.861–0.948,P<0.001),hexadecanedioate(C16-DC)levels(OR=0.941,95%CI:0.911–0.973,P<0.001),pentose acid levels(OR=0.923,95%CI:0.877–0.972,P=0.002),X-24546 levels(OR=0.936,95%CI:0.902–0.971,P<0.001),glycine levels(OR=0.936,95%CI:0.909–0.964,P<0.001),glycine to serine ratio(OR=0.930,95%CI:0.888–0.974,P=0.002),and mannose to trans-4-hydroxyproline ratio(OR=0.912,95%CI:0.869–0.958,P<0.001)]were correlated with a decreased risk of MI,whereas the remaining 6 plasma metabolites[1-palmitoyl-2-arachidonoyl-GPE(16:0/20:4)levels(OR=1.051,95%CI:1.018–1.084,P=0.002),behenoyl dihydrosphingomyelin(d18:0/22:0)levels(OR=1.076,95%CI:1.027–1.128,P=0.002),1-stearoyl-2-docosahexaenoyl-GPE(18:0/22:6)levels(OR=1.067,95%CI:1.027–1.109,P=0.001),alpha-ketobutyrate levels(OR=1.108,95%CI:1.041–1.180,P=0.001),5-acetylamino-6-formylamino-3-methyluracil levels(OR=1.047,95%CI:1.019–1.076,P<0.001),and N-acetylputrescine to(N(1)+N(8))-acetylspermidine ratio(OR=1.045,95%CI:1.018–1.073,P<0.001)]were associated with an increased risk of MI.Furthermore,we also observed that the mentioned relationships were unaffected by horizontal pleiotropy(P>0.05).On the contrary,MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites(P>0.05 for each comparison).CONCLUSIONS Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI,among which 13 plasma metabolites have not been reported previously.These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.

Endoscopic treatment of biliopancreatic pathology in patients with Whipple's pancreaticoduodenectomy surgical variants: Lessons learned from single-balloon enteroscopy-assisted ERCP

Background: Endoscopic treatment of biliopancreatic pathology is challenging due to surgically altered anatomy after Whipple's pancreaticoduodenectomy. This study aimed to evaluate the feasibility and safety of single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography(SBE-ERCP) to treat biliopancreatic pathology in patients with Whipple's pancreaticoduodenectomy surgical variants. Methods: We retrospectively analyzed 106 SBE-ERCP procedures in 46 patients with Whipple's variants. Technical and clinical success rates and adverse events were evaluated. Results: Biliary SBE-ERCP was performed in 34 patients and pancreatic SBE-ERCP in 17, including 5 with both indications. From a total of 106 SBE-ERCP procedures, 76 were biliary indication with technical success rate of 68/76(90%) procedures and clinical success rate of 30/34(88%) patients. Mild adverse event rate was 8/76(11%), without serious adverse events. From a total of 106 SBE-ERCP procedures, 30 were pancreatic indication with technical success rate of 24/30(80%) procedures( P = 0.194 vs. biliary SBEERCP) and clinical success rate of 11/17(65%) patients( P = 0.016 vs. biliary SBE-ERCP). Mild adverse event rate was 6/30(20%)( P = 0.194 vs. biliary SBE-ERCP), without serious adverse events. After SBE-ERCP failure, endoscopic ultrasound-guided drainage, percutaneous drainage and redo surgery were alternative therapeutic options. Conclusions: Biliopancreatic pathology after Whipple's pancreaticoduodenectomy variants can be treated using SBE-ERCP without serious adverse events. Technical and clinical success rates are high for biliary indications, whereas clinical success rate of pancreatic indications is significantly lower. SBE-ERCP can be considered as first-line treatment option in this patient group with surgically altered anatomy.

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.