Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer

BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.

Discontinuous polyostotic fibrous dysplasia with multiple systemic disorders and unique genetic mutations:A case report

BACKGROUND Polyostotic fibrous dysplasia(PFD)is an uncommon developmental bone disease in which normal bone and marrow are replaced by pseudotumoral tissue.The etiology of PFD is unclear,but it is generally thought to be caused by sporadic,post-zygotic mutations in the GNAS gene.Herein,we report the case of a young female with bone pain and lesions consistent with PFD,unique physical findings,and gene mutations.CASE SUMMARY A 27-year-old female presented with unbearable bone pain in her left foot for 4 years.Multiple bone lesions were detected by radiographic examinations,and a diagnosis of PFD was made after a biopsy of her left calcaneus with symptoms including pre-axial polydactyly on her left hand and severe ophthalmological problems such as high myopia,vitreous opacity,and choroidal atrophy.Her serum cortisol level was high,consistent with Cushing syndrome.Due to consanguineous marriage of her grandparents,boosted whole exome screening was performed to identify gene mutations.The results revealed mutations in HSPG2 and RIMS1,which may be contributing factors to her unique findings.CONCLUSION The unique findings in this patient with PFD may be related to mutations in the HSPG2 and RIMS1 genes.

Genetic pathways in cerebral palsy:a review of the implications for precision diagnosis and understanding disease mechanisms

Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and posture.Patients with cerebral palsy are often only capable of limited activity,resulting from non-progressive disturbances in the fetal or neonatal brain.These disturbances severely impact the child’s daily life and impose a substantial economic burden on the family.Although cerebral palsy encompasses various brain injuries leading to similar clinical outcomes,the unde rstanding of its etiological pathways remains incomplete owing to its complexity and heterogeneity.This review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy development.It is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development,which can be further influenced by environmental fa ctors.Des pite continuous research endeavors,the underlying fa ctors contributing to cerebral palsy remain are still elusive.However,significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy development.Moreove r,these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping,including thrombosis,angiogenesis,mitochondrial and oxidative phosphorylation function,neuronal migration,and cellular autophagy.Furthermore,exploring targeted genotypes holds potential for precision treatment.In conclusion,advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral palsy.These breakthroughs have the potential to pave the way for new treatments and therapies,consequently shaping the future of cerebral palsy research and its clinical management.The investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management strategies.By elucidating the underlying cellular mechanisms,we can develop to rgeted interventions to optimize outcomes.A continued collaboration between researchers and clinicians is imperative to comprehensively unravel the intricate genetic etiology of cerebral palsy.

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B

Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction(qRT-PCR)and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using twobottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results revealed the changed expression profile of m Tas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105.In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B(CuB).Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.

Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy

Background:Fuchs endothelial corneal dystrophy is a hereditary disease and the most frequent cause of corneal transplantation in the worldwide.Its main clinical signs are an accelerated decrease in the number of endothelial cells,thickening of Descemet’s membrane and formation of guttae in the extracellular matrix.The cornea’s ability to maintain stromal dehydration is impaired,causing painful epithelial bullae and loss of vision at the point when the amount of corneal endothelial cells cannot be compensated.At present,apart from corneal transplantation,there is no other effective treatment that prevents blindness.Main text:In this review,we first summarized the mutations of COL8A2,TCF4,TCF8,SLC4A11 and AGBL1 genes in Fuchs endothelial corneal dystrophy.The molecular mechanisms associated with Fuchs endothelial corneal dystrophy,such as endoplasmic reticulum stress and unfolded protein response pathway,oxidative stress,mitochondrial dysregulation pathway,apoptosis pathway,mitophagy,epithelial-mesenchymal transition pathway,RNA toxicity and repeat-associated non-ATG translation,and other pathogenesis,were then explored.Finally,we discussed several potential treatments related to the pathogenesis of Fuchs endothelial corneal dystrophy,which may be the focus of future research.Conclusions:The pathogenesis of Fuchs endothelial corneal dystrophy is very complicated.Currently,corneal transplantation is an important method in the treatment of Fuchs endothelial corneal dystrophy.It is necessary to continuously explore the pathogenesis of Fuchs endothelial corneal dystrophy and establish the scientific foundations for the development of next-generation corneal therapeutics.

Genetic mutations associated with chemical resistance in the cytochrome P450 genes of invasive and native Bemisia tabaci （Hemiptera： Aleyrodidae） populations in China

Bemisia tabaci （Gennadius） is a species complex, and its two most damaging biotypes B and Q are globally distributed pests. Despite increasing biological and economic impacts, little is known about the evolutionary mechanisms that favor their competition with native populations. Here, we investigated the genetic mutations in the P450 gene of the invasive B, Q biotypes and the native Cv population. Four mutations associated with chemical resistance, Pro-Leu, Ala-Ser, Ser-Phe and Trp-Leu, were found in the cytochrome P450 CYP6C and CYP9F genes of the B and Q biotypes. Bioassay results also revealed that both the B and Q biotypes have about 12-47 times more resistance to acephate, beta- cypermethrin, methomyl, and 5-7 times more resistance to imidacloprid insecticide than Cv population. Our results provide a molecular approach for better understanding and monitoring the pesticide resistances of invasive and native B. tabaei populations in China.

Genetic perspectives on childhood monogenic diabetes:Diagnosis,management,and future directions

Monogenic diabetes is caused by one or even more genetic variations, which maybe uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1 to 5% of children, and early detection and geneticallyfocused treatment of neonatal diabetes and maturity-onset diabetes of theyoung can significantly improve long-term health and well-being. The etiology ofmonogenic diabetes in childhood is primarily attributed to genetic variationsaffecting the regulatory genes responsible for beta-cell activity. In rare instances,mutations leading to severe insulin resistance can also result in the developmentof diabetes. Individuals diagnosed with specific types of monogenic diabetes,which are commonly found, can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguishindividuals with type 1 or 2 diabetes from those more prone to monogenicdiabetes. Genetic screening with appropriate findings and interpretations isessential to establish a prognosis and to guide the choice of therapies andmanagement of these interrelated ailments. This review aims to design a comprehensiveliterature summarizing genetic insights into monogenetic diabetes inchildren and adolescents as well as summarizing their diagnosis and management.

Uveal melanoma:Recent advances in immunotherapy

Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

Exploring Biocomplexity in Cancer: A Comprehensive Review

Living objects have complex internal and external interactions. The complexity is regulated and controlled by homeostasis, which is the balance of multiple opposing influences. The environmental effects finally guide the self-organized structure. The living systems are open, dynamic structures performing random, stationary, stochastic, self-organizing processes. The self-organizing procedure is defined by the spatial-temporal fractal structure, which is self-similar both in space and time. The system’s complexity appears in its energetics, which tries the most efficient use of the available energies;for that, it organizes various well-connected networks. The controller of environmental relations is the Darwinian selection on a long-time scale. The energetics optimize the healthy processes tuned to the highest efficacy and minimal loss (minimalization of the entropy production). The organism is built up by morphogenetic rules and develops various networks from the genetic level to the organism. The networks have intensive crosstalk and form a balance in the Nash equilibrium, which is the homeostatic state in healthy conditions. Homeostasis may be described as a Nash equilibrium, which ensures energy distribution in a “democratic” way regarding the functions of the parts in the complete system. Cancer radically changes the network system in the organism. Cancer is a network disease. Deviation from healthy networking appears at every level, from genetic (molecular) to cells, tissues, organs, and organisms. The strong proliferation of malignant tissue is the origin of most of the life-threatening processes. The weak side of cancer development is the change of complex information networking in the system, being vulnerable to immune attacks. Cancer cells are masters of adaptation and evade immune surveillance. This hiding process can be broken by electromagnetic nonionizing radiation, for which the malignant structure has no adaptation strategy. Our objective is to review the different sides of living complexity and use the knowledge to fight against cancer.

Germline mutations in hereditary diffuse gastric cancer

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Among which, about 1%–3% of gastric cancer patients were characterized by inherited gastric cancer predisposition syndromes, knowing as hereditary diffuse gastric cancer（HDGC）. Studies reported that CDH1 germline mutations are the main cause of HDGC. With the help of rapid development of genetic testing technologies and data analysis tools, more and more researchers focus on seeking candidate susceptibility genes for hereditary cancer syndromes. In addition, National Comprehensive Cancer Network（NCCN） guidelines recommend that the patients of HDGC carrying CDH1 mutations should undergo prophylactic gastrectomy or routine endoscopic surveillances. Therefore, genetic counseling plays a key role in helping individuals with pathogenic mutations make appropriate risk management plans. Moreover, experienced and professional genetic counselors as well as a systematic multidisciplinary team（MDT） are also required to facilitate the development of genetic counseling and benefit pathogenic mutation carriers who are in need of regular and standardized risk management solutions. In this review, we provided an overview about the germline mutations of several genes identified in HDGC, suggesting that these genes may potentially act as susceptibility genes for this malignant cancer syndrome. Furthermore, we introduced information for prevention, diagnosis and risk management of HDGC. Investigations on key factors that may have effect on risk management decision-making and genetic data collection of more cancer syndrome family pedigrees are required for the development of HDGC therapeutic strategies.

Mutations of the AAAS gene in an Indian family with Allgrove's syndrome

The triple A or AIIgrove＇s syndrome is an autosomal recessive disorder characterized by the triad of achalasia cardia, alacrima and ACTH resistant adrenocortical insufficiency. Mutations of the Achalasia-AddisonianismAlacrima-Syndrome （AAAS） gene on chromosome 12q13 are associated with this syndrome. We report an Indian family where two siblings were homozygous for a known mutation of the AAAS gene and presented with the classical triad of symptoms. The mother and the brother were heterozygous and asymptomatic. The affected siblings had iron deficiency anemia and the younger sister had pes cavus and palmoplantar keratosis. Neurological symptoms were absent in both affected children. Recognition of this syndrome can lead to early treatment of adrenal insufficency and genetic counselling.

COVID-2019 Genome Sequence Analysis: Phylogenetic Molecular Evolution and Docking of Structural Modelling of Receptor Binding Domain of S Protein in Active Site of ACE2

Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the nearest family member of the virus and its receptor binding domain of S protein including its model structure and function of its active sites were naked through Multiple Sequence Alignment, modelling and molecular docking software accordingly its repository genome databases. The virus was genetically associated and molecular evolutionary related with (RaTG13) and it scores 96.12% homology with 99% query coverage followed by bat-SL-CoVZC45 and bat-SL-CoVZXC21 notch 89.12% and 88.65% respectively. However, SARS and MERS corona type virus those outbreak earlier respectively less likely family members of 2019-nCoV. Though the virus has a close genetic association with those previous SARS coronaviruses, and certainly the spike protein used as a binding receptor to fight against human receptor protein of ACE 2, but on the basis of FRODOC and HDOCK server analysis multi favorable active sites of S protein was discovered such GLN493 shown as a finest key in both model and possessed a unique traits on it resulting unexpected rate of transmission and number of people died while compared to the previous one. TYR500, ASN501, GLN498 and others residues preferably contemplate site also. In particular, the diversity of the virus in the world may be due to the genome structure of the virus and S gene changed over the time, across the world against to host of human genetic diversity, which may be more robust, and may be a new and unique feature. This is because it is characterized close to contact with distance divergence between wild type novel coronavirus which was risen from China against to the genomes from Lebanon, India, Italy, and USA and so on. Thus, the World Health Organization and its researchers should focus on immunologic research and effective drug and vaccine development that will help to address the epidemiology of the virus, which can provide a long-term solution.

Presenilin and Alzheimer’s disease interactions with aging,exercise and high-fat diet:A systematic review

Presenilin(Psn)protein is associated with organismal aging.Mutations in the Psn gene may lead to Alzheimer’s disease(AD),dilated cardiomyopathy(DCM),and many age-dependent degenerative diseases.These diseases seriously affect the quality of life and longevity of the population and place a huge burden on health care and economic systems around the world.Humans have two types of Psn,presenilin-1(PSEN1)and presenilin-2(PSEN2).Mutations in the genes encoding PSEN1,PSEN2,and amyloid precursor protein(APP)have been identified as the major genetic causes of AD.Psn is a complex gene strongly influenced by genetic and environmental factors.The effects of exercise,training,and a high-fat diet on the Psn gene expressed in the heart and its related pathways are not fully understood.Fortunately,relevant aspects of the mutational effects on Psn can be studied experimentally in easily handled animal models,including Drosophila,mice,and other animals,all of which share orthologous genes of Psn with humans.Many previous studies have linked aging,exercise training,and a high-fat diet to the Psn gene.This review discusses the interrelationship between aging,exercise training,and a high-fat diet on the Psn gene and its associated disease,AD.The aim is to understand the adverse effects of Psn gene mutations on the body and the diseases caused by AD,find ways to alleviate the adverse effects and provide new directions for the improvement of treatment strategies for diseases caused by Psn gene mutations.

Association of Haplotypes in Exon 4 of KLK2 Gene with Raised Serum Prostate-Specific Antigen

The standard diagnostic modalities for Prostate Cancer (PC) include serum Prostate-Specific Antigen (PSA) assay, Digital Rectal Examination (DRE), and histological examination of prostate biopsy. They are limited by low predictive potential and inability to predict which patients are at risk of developing metastatic disease. The aim of this study is to investigate the exon 4 of the KLK2 gene of subjects for changes in its nucleotide sequences (SNPs) and determine the correlation of these changes with serum PSA in an Igbo population of Nigeria. One hundred male subjects aged 40 years and above, who gave their consent, were used for the study. Their PSA determinations were done using ELISA technique while genetic studies were carried out using real-time PCR. tPSA, fPSA, and % fPSA of the subjects ranged between 0.8% - 18.30%, 0.10% - 1.60% and 0.0% - 0.7% respectively. Of the 100 subjects, 28 subjects had tPSA levels above 4.0 ng/ml with a mean of 7.10 (±3.30) ng/ml. Those with tPSA less than 4 ng/ml had a mean of 1.87 (±0.85) ng/m. 15 subjects showed SNPs with a mean tPSA of 6.87 (±4.82) ng/ml while the remaining 85 subjects without SNPs had a mean of 1.86 (±0.80) ng/ml. Results from direct DNA sequencing showed 11 SNPs. Ten subjects are curated in SNP database while one is uncurated. The Chi-square test showed significant association (p = 0.00) between tPSA levels and SNPs mutation (X2 = 17.35, p = 0.00). A Kruskal-Wallis test demonstrated that the positional arrangement of the SNP mutations had no effect on PSA-total or free-values (H (10) = 10.92, p = 0.28;H (10) = 10.07, p = 0.38 respectively). Two SNPs: rs6072 and rs74478031 were associated with elevated PSA levels (p < 0.05). Their presence, therefore, has the potential to serve, in conjunction with raised PSA, as biomarkers of prostate cancer in the study population.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas

Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.

Malignant hyperthermia as a rare complication of local lidocaine injection:A case report

BACKGROUND Malignant hyperthermia(MH)is a hypermetabolic disorder of skeletal muscles triggered by exposure to volatile anesthetics and depolarizing muscular relaxants.It manifests with clinical presentations such as tachycardia,muscle rigidity,hyperpyrexia,and rhabdomyolysis in genetically predisposed individuals with ryanodine receptor or calcium voltage-gated channel subunit alpha1 S mutations.Local anesthetics,such as lidocaine,are generally considered safe;however,complications can arise,albeit rarely.Lidocaine administration has been reported to induce hypermetabolic reactions resembling MH in susceptible individuals.The exact mechanism by which lidocaine might trigger MH is not fully understood.Although some mechanisms are postulated,further research is needed for a better understanding of this.CASE SUMMARY We present the case of MH in a 43-year-old male patient with an unknown genetic predisposition following a lidocaine injection during a dental procedure.This case serves as a reminder that while the occurrence of lidocaine-induced MH is rare,lidocaine can still trigger this life-threatening condition.Therefore,caution should be exercised when administering lidocaine to individuals who may be susceptible to MH.It is important to note that prompt intervention played a crucial role in managing the patient’s symptoms.Upon recognizing the early signs of MH,aggressive measures were initiated,including vigorous intravenous normal saline administration and lorazepam.Due to the effectiveness of these interventions,the administration of dantrolene sodium,a specific antidote for MH,was deferred.CONCLUSION This case highlighted the significance of vigilant monitoring and swift action in mitigating the detrimental effects of lidocaine-induced MH.Caution should be exercised when administering lidocaine to individuals who may be predisposed to MH.It is very important to be aware and vigilant of the signs and symptoms of MH as early recognition and treatment intervention are important to prevent serious complications to decrease mortality.

Gene mutations in newly diagnosed multiple myeloma patients detected by next-generation sequencing technology

Background:Multiple myeloma(MM)is a heterogeneous plasma-derived hematopoietic malignancy with complex genetic mutation contributing to the pathogenesis.Though gene sequencing has been applied in MM,genetic features from Chinese MM patients are reported less.We investigated the genetic mutation of newly diagnosed multiple myeloma(NDMM)patients and explore its correlation with cytogenetic abnormalities detected by fluorescence in situ hybridization(FISH).Methods:A total of 206 patients with NDMM were enrolled.After enriching plasma cells with CD138 magnetic beads,92 MM-related target gene mutations were detected by the Illumina sequencing platform,and six common genetic abnormalities were detected by FISH.Results:162 cases(78.6%)had at least one gene mutation detected by NDMM.The top 5 mutated genes were KRAS,NRAS,TRAF3,BRAF,and TP53.Cytogenetic abnormalities detected by FISH have a certain correlation with gene mutations,t(11;14)translocations are often accompanied by CCND1 and TP53 mutations,KLHL6 in t(4;14),SP140,CDKN1B and PRKD2 in t(14;16)and t(14;20)translocations.The mutation ratio was higher for EGR1,while lower of CCND1 in patients with gain 1q21.The TP53 mutation was more likely in patients with 17p deletion.The gene mutation affects the pathway of the RNA process is more frequently occurring in males and age less than 70 years patients.The International Staging System(ISS)Stage Ⅲ correlated with gene mutations in the NK-κB pathway while Revised ISS(R-ISS)Stage Ⅲ correlated with the DNA damage repair pathway.Conclusions:There are various gene mutations in NDMM patients,mainly RAS/MAPK and NF-κB pathway gene pathways.

Blastic Plasmacytoid Dendritic Cell Neoplasm:Progress in Cell Origin,Molecular Biology,Diagnostic Criteria and Therapeutic Approaches

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)is a rare hematological malignancy characterized by recurrent skin nodules,an aggressive clinical course with rapid involvement of hematological organs,and a poor prognosis with poor overall survival.BPDCN is derived from plasmacytoid dendritic cells(pDCs)and its pathogenesis is unclear.The tumor cells show aberrant expression of CD4,CD56,interleukin-3 receptor alpha chain(CD 123),blood dendritic cell antigen 2(BDCA 2/CD303),blood dendritic cell antigen 4(BDCA4)and transcription factor(E protein)E2-2(TCF4).The best treatment drugs are based on experience by adopting those used for either leukemia or lymphoma.Relapse with drug resistance generally occurs quickly.Stem cell transplantation after the first complete remission is recommended and tagraxofusp is the first targeted therapy.In this review,we summarize the differentiation of BPDCN from its cell origin,its connection with normal pDCs,clinical characteristics,genetic mutations and advances in treatment of BPDCN.This review provides insights into the mechanisms of and new therapeutic approaches for BPDCN.

Exploring the genetic basis of childhood monogenic diabetes

Monogenic diabetes is caused by one or even more genetic variations,which may be uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1%to 5%of children,and early detection and genetically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being.The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity.In rare instances,mutations leading to severe insulin resistance can also result in the development of diabetes.Individuals diagnosed with specific types of monogenic diabetes,which are commonly found,can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes.Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments.This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and management.

Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed.Unfunctional GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of misdiagnosis.Therefore,many GEP-NEN patients present with later staged tumors.Motivated hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent years.The result of which is great progress in clinical diagnosis and treatment.According to the most recent clinical guidelines,improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas(NECs),which are subclassified into large and small cell NECs.Combining different functional imaging methods facilitates precise diagnosis.The expression of somatostatin receptors helps to predict prognosis.Genetic analyses of mutations affecting death domain associated protein(DAXX),multiple endocrine neoplasia type 1(MEN 1),alpha thalassemia/intellectual disability syndrome X-linked(ATRX),retinoblastoma transcriptional corepressor 1(RB 1),and mothers against decapentaplegic homolog 4(SMAD 4)help distinguishing grade 3 NENs from poorly differentiated NECs.The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.