Parathyroid carcinoma: molecular therapeutic targets.

Parathyroid carcinoma (PC) is an extremely rare malignant tumor of the parathyroid glands, accounting for less than 1% of primary hyperparathyroidism, commonly characterized by severe and unmanageable hypercalcemia, aggressive behavior, high metastatic potential, and poor prognosis. PC manifests prevalently as a sporadic tumor and only occasionally it is part of congenital syndromic and non-syndromic endocrine diseases. Molecular pathogenesis of this form of parathyroid tumor is not fully elucidated and it appears to be caused by multiple genetic and epigenetic drivers, differing among affected patients and not yet clearly stated in distinguishing PC from the benign parathyroid adenoma (PA). Congenital forms of PC have been prevalently associated with germline heterozygous loss-of-function mutations of the CDC73 tumor suppressor gene, both in the context of the hyperparathyroidism jaw-tumor syndrome (HPT-JT) and of the isolated familial hyperparathyroidism (FIPH). Currently, surgical en bloc resection of affected gland(s) and other involved structures is the elective therapy for both primary and recurrent PC. However, it usually results ineffective for advance and metastatic disease, and a high percentage of post-operative recurrence is reported. Targeted medical therapies for surgically untreatable PC, based on the molecular profile of PC samples, are, therefore, needed. The characterization of genetic and epigenetic alterations and deregulated pathways in PC samples will be of fundamental importance to tailor treatment for each patient. Here, we reviewed main findings on molecular pathogenetic aspects of PC, and the current state of the art of therapies.

The transcription factor ATF4 mediates endoplasmic reticulum stress-related podocyte injury and slit diaphragm defects.

Mutations in OSGEP and four other genes that encode subunits of the KEOPS complex cause Galloway-Mowat syndrome, a severe, inherited kidney-neurological disease. The complex catalyzes an essential posttranscriptional modification of tRNA and its loss of function induces endoplasmic reticulum (ER) stress. Here, using Drosophila melanogaster garland nephrocytes and cultured human podocytes, we aimed to elucidate the molecular pathogenic mechanisms of KEOPS-related glomerular disease and to test pharmacological inhibition of ER stress-related signaling as a therapeutic principle. We found that ATF4, an ER stress-mediating transcription factor, or its fly orthologue Crc, were upregulated in both fly nephrocytes and human podocytes. Knockdown of Tcs3, a fly orthologue of OSGEP, caused slit diaphragm defects, recapitulating the human kidney phenotype. OSGEP cDNA with mutations found in patients lacked the capacity for rescue. Genetic interaction studies in Tcs3-deficient nephrocytes revealed that Crc mediates not only cell injury, but surprisingly also slit diaphragm defects, and that genetic or pharmacological inhibition of Crc activation attenuates both phenotypes. These findings are conserved in human podocytes where ATF4 inhibition improved the viability of podocytes with OSGEP knockdown, with chemically induced ER stress, and where ATF4 target genes and pro-apoptotic gene clusters are upregulated upon OSGEP knockdown. Thus, our data identify ATF4-mediated signaling as a molecular link among ER stress, slit diaphragm defects, and podocyte injury, and our data suggest that modulation of ATF4 signaling may be a potential therapeutic target for certain podocyte diseases.

SARS-CoV-2 Variants, Current Vaccines and Therapeutic Implications for COVID-19.

Over the past two years, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of infections, resulting in an unprecedented pandemic of coronavirus disease 2019 (COVID-19). As the virus spreads through the population, ongoing mutations and adaptations are being discovered. There is now substantial clinical evidence that demonstrates the SARS-CoV-2 variants have stronger transmissibility and higher virulence compared to the wild-type strain of SARS-CoV-2. Hence, development of vaccines against SARS-CoV-2 variants to boost individual immunity has become essential. However, current treatment options are limited for COVID-19 caused by the SARS-CoV-2 variants. In this review, we describe current distribution, variation, biology, and clinical features of COVID-19 caused by SARS-CoV-2 variants (including Alpha (B.1.1.7 Lineage) variant, Beta (B.1.351 Lineage) variant, Gamma (P.1 Lineage) variant, Delta (B.1.617.2 Lineage) variant, and Omicron (B.1.1.529 Lineage) variant and others. In addition, we review currently employed vaccines in clinical or preclinical phases as well as potential targeted therapies in an attempt to provide better preventive and treatment strategies for COVID-19 caused by different SARS-CoV-2 variants.

Mutational Profile and Potential Molecular Therapeutic Targets of Pheochromocytoma.

Purpose: Pheochromocytoma/paraganglioma (PCC/PGL; collectively known as PPGL) can be driven by germline and somatic mutations in susceptibility genes. We aimed to investigate the mutation profile and clinical features of pathogenic genes in highly genetically heterogeneous PPGL and to preliminary explore molecular therapeutic targets in PPGL. Methods: We established a panel of 260 genes, including susceptibility genes of PPGL and other important tumorigenic genes to sequence 107 PPGL tissues. Results: Overall, 608 genomic mutations were identified in 107 PPGL tissues. Almost 57% of PPGL tissue samples exhibited pathogenic mutations, and the most frequently mutated gene was SDHB (15/107, 14%). SDHB and HRAS were the most commonly mutated genes in germline-mutated PPGL (25/107, 23%) and nongermline-mutated PPGL (36/107, 34%), respectively. In addition, novel pathogenic mutations were detected in sporadic PPGL. PPGL with mutations in the hypoxia pathway had an earlier onset and higher norepinephrine level than those in the kinase pathway. Receptor tyrosine kinase (RTK; 22%, 24/107), mitogen-activated protein kinase (MAPK; 14%, 15/107), and tyrosine kinase (TK; 2%, 2/107) pathways were the most frequently mutated pathways in PPGL. Conclusion: Our results provided the genetic mutation profile in PPGL tissues. Genetic mutations in PPGL were mainly concentrated in the RTK, TK, and MAPK pathways, suggesting potential molecular therapeutic targets for PPGL.

[Molecular pathogenesis and therapeutic targets in acute erythroid leukemia].

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by erythroid predominance and dysplasia. It is classified into two subtypes: pure erythroid (PEL) and erythroid/myeloid (EML) phenotypes. To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed 105 AEL and 214 non-AEL cases using whole-genome/exome and/or targeted-capture sequencing, with SNP probes for detecting copy number abnormalities. We also performed a transcriptome analysis of 12 AEL samples. Combining publicly available sequencing data, AEL was genetically clustered into four groups according to mutational status in TP53, STAG2, and NPM1 genes. Conspicuously, highly recurrent gains and amplifications affecting EPOR, JAK2, and/or ERG/ETS2 were recurrently detected in AEL cases, almost exclusively found in TP53-mutated cases. Among these, gains/amplifications of EPOR/JAK2 were more highly enriched in PEL than EML cases. Along with the activated STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism, and they showed high sensitivity to ruxolitinib in in vitro and in xenograft models, highlighting the potential role of JAK2 inhibition in AEL therapeutics.

Identification of targetable kinases in idiopathic pulmonary fibrosis.

BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4.

BACKGROUND: Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression. AIM: Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways. METHODS: Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software. RESULTS: Six genes - AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 - were significantly overexpressed. Thirteen genes - ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1 - were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive. CONCLUSIONS: The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.

ADAMTS4 and ADAMTS5 may be considered as new molecular therapeutic targets for cartilage damages with Kashin-Beck Disease.

There are a pretty number of research demonstrating that ADAMTS4 and ADAMTS5 playing primary roles in the degradation of cartilage during inflammatory joint diseases like osteoarthritis (OA). Because Kashin-Beck Disease (KBD) has been found to own the common pathological changes and symptoms with OA, and is regarded as the specific type of osteoarthritis, it's reasonable to believe that ADAMTS4 and ADAMTS5 may exert an enormous functions on the injury of cartilage of the KBD and may be potential molecular therapeutic targets for KBD.

Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets.

Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.

Current Position of the Molecular Therapeutic Targets for Ovarian Clear Cell Carcinoma: A Literature Review.

Ovarian clear cell carcinoma (OCCC) shows low sensitivity to conventional chemotherapy and has a poor prognosis, especially in advanced stages. Therefore, the development of innovative therapeutic strategies and precision medicine for the treatment of OCCC are important. Recently, several new molecular targets have been identified for OCCC, which can be broadly divided into four categories: a) downstream pathways of receptor tyrosine kinases, b) anti-oxidative stress molecules, c) AT-rich interactive domain 1A-related chromatin remodeling errors, and d) anti-programmed death ligand 1/programmed cell death 1 agents. Several inhibitors have been discovered for these targets, and the suppression of OCCC cells has been demonstrated both in vitro and in vivo. However, no single inhibitor has shown a sufficient effectiveness in clinical pilot studies. This review outlines recent progress regarding the molecular biological characteristics of OCCC to identify future directions for the development of precision medicine and combinatorial therapies to treat OCCC.

Patent landscape of molecular and cellular targeted therapies for recessive dystrophic epidermolysis bullosa.

INTRODUCTION: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a monogenetic inherited genodermatosis associated with deleterious mutations in the gene encoding type VII collagen (COL7A1). COL7A1 is essential for promoting attachment of the epidermis to the dermis, and its dysfunction may lead to generalized mucosal and cutaneous blistering associated to severe deformities. Currently, management of RDEB patients is limited to supportive care, being aimed at treating and preventing common complications associated with this condition. There is a great demand to develop targeted therapies for this devastating disease and RDEB research advances are currently being translated into clinical trials. AREAS COVERED: Based on the literature and patent search, the authors have grouped the RDEB targeted therapies into five categories: a) cell-based therapies; b) gene therapy; c) protein replacement therapy; d) molecular therapy based on exon skipping; and e) drug-mediated premature termination codon read-through. The patent searching strategy involved inquiring Google and USPTO patent databases to reveal companies and institutions that are active in the area of RDEB targeted therapies. EXPERT OPINION: The patent landscape related to targeted therapies for RDEB is quite heterogeneous, with each targeted therapeutic approach being associated with its own challenges in achieving robust patent protection and identifying opportunities for future development.

The Cancer Genome Atlas Project in Bladder Cancer.

Bladder cancer (BC) remains an aggressive disease with a poor prognosis, especially for patients with metastatic disease who have a limited median overall survival of 14 months. Urothelial carcinomas harbor frequent molecular dysregulations including recurrent mutations and copy number alteration, some of which could be potential therapeutic targets. However, no molecularly targeted agents have been approved to date for the treatment of advanced BC. Gaining new insights into the molecular landscape of BC will be critical to tailor future targeted agents for the treatment of advanced disease. The Cancer Genome Atlas (TCGA) project is cataloguing the genetic and epigenetic alterations responsible for cancer through the application of high-throughput genome analysis techniques. After the landmark paper profiling 131 patients was published in 2014, additional patients have been added with an updated TCGA analysis now including 412 patients. This chapter will review the previously described genomic alterations reported in the first manuscript and the new major highlights found in the expanded analyses recently published. The aim will be to review how this comprehensive integrated genomic analysis can inform the design of precision medicine targeted therapy for the treatment of advanced disease.

The regulatory interplay between Oct-1 isoforms contributes to hematopoiesis and the isoforms imbalance correlates with a malignant transformation of B cells.

Oct-1(POU2F1) is a DNA-binding transcription regulator and its level being highly increased in many human cancers. Oct-1 is present in the human cells as a family of functionally different isoforms which are transcribed from alternative promoters. Here, we have demonstrated that expression patterns of Oct-1 isoforms change during differentiation of hematopoetic progenitor cells (CD34+) (HPCs) to the B (CD19+) and T (CD3+) cells. While Oct-1L is expressed at a high level in the CD34+ HPCs, its expression level drops dramatically during the T-cell differentiation, although remains nearly the same in B-cells. We have described the novel human Oct-1R isoform which is conserved in mammals and is B cell-specific. Oct-1R was found in B cells, but not in HPCs. Oct-1R is transcribed from the same promoter as Oct-1L, another lymphocyte-specific isoform. Overexpression of Oct-1R and Oct-1L in the Namalwa cells leads to the repression of many genes involved in B-lymphocyte differentiation and signal transduction. Thus these isoforms may regulate the particular stages of development of normal B cells and maintain their proper differentiation status. However the extremely high level of Oct-1L isoform observed in the B-lymphoblast tumor cell lines indicated that the excess of Oct-L seem likely to considerably decrease the differentiation ability of these cells. Oct-1 may serve as a therapeutic target for many tumors, but it should be noted that in a tumor the content of a certain isoform Oct-1, rather than the total Oct-1 protein, can be increased.

PRDM14: A Potential Target for Cancer Therapy.

PRDM14 belongs to the PR domain-containing (PRDM) family. Although a precise understanding focused on the function of PRDM14 to maintain stemness and pluripotency in embryonic stem cells via epigenetic mechanisms, growing experimental evidence has been linked PRDM14 to human cancers. In adults, PRDM14 has low expression in human tissues. Aberrant PRDM14 expression is connected with various malignant histological types and solid cancers, where PRDM14 can act as a driver of oncogenic processes. Overexpression of RPDM14 enhanced cancer cells growth and reduced cancer cells sensitive to chemotherapeutic agents. Reducing the expression of PRDM14 in cancer cells can enhance the therapeutic sensitivity of drugs to cancer cells, suggesting that aberrant PRDM14 may have a carcinogenic characteristic in tumor therapy and as a new molecular target. This review summarizes the structure and oncogenic properties of PRDM14 in different malignancies and suggests that PRDM14 may be a potential therapeutic molecular target for tumor treatment.

[Advance in the biology of pancreatic of cancer]. / Nouveautés dans la biologie du cancer du pancréas.

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic/epigenetic alterations and molecular expression in experimental models as well as precancerous and cancerous tissues by mean of molecular amplification and large-scale transcriptoma analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating point mutation of the KRAS oncogene on codon 12 is the major event and occurs early in pancreatic carcinogenesis. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, Nerve Growth Factor, gastrin), of pro-angiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, tissue plasminogen activators) occurs. The microenvironment plays also a key role in the invasive and metastatic process of pancreatic carcinoma with a strong relationship between cancerous cells and pancreatic stellate cells as well as extracellular matrix. This microenvironment strongly participates to the tumor fibrosis, hypoxia and hypovascularization inducing an inaccessibility of drugs. Nowadays, the targeting of microenvironment takes a special place in the new therapeutic strategies of pancreatic cancer in combination with chemotherapy.

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome.

Rett Syndrome is a neurodevelopmental disorder that arises from mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). MeCP2 has a large number of targets and a wide range of functions, suggesting the hypothesis that functional signaling mechanisms upstream of synaptic and circuit maturation may contribute to our understanding of the disorder and provide insight into potential treatment. Here, we show that insulin-like growth factor-1 (IGF1) levels are reduced in young male Mecp2-null (Mecp2(-/y)) mice, and systemic treatment with recombinant human IGF1 (rhIGF1) improves lifespan, locomotor activity, heart rate, respiration patterns, and social and anxiety behavior. Furthermore, Mecp2-null mice treated with rhIGF1 show increased synaptic and activated signaling pathway proteins, enhanced cortical excitatory synaptic transmission, and restored dendritic spine densities. IGF1 levels are also reduced in older, fully symptomatic heterozygous (Mecp2(-/+)) female mice, and short-term treatment with rhIGF1 in these animals improves respiratory patterns, reduces anxiety levels, and increases exploratory behavior. In addition, rhIGF1 treatment normalizes abnormally prolonged plasticity in visual cortex circuits of adult Mecp2(-/+) female mice. Our results provide characterization of the phenotypic development of Rett Syndrome in a mouse model at the molecular, circuit, and organismal levels and demonstrate a mechanism-based therapeutic role for rhIGF1 in treating Rett Syndrome.

Molecular Pathology of Ovarian Carcinomas.

This content presents a review of molecular pathology of ovarian cancer. The authors present key molecular features for high-grade and low-grade serous carcinomas, endometrioid carcinomas, clear cell carcinomas, and mucinous carcinomas. Cell lineage, mutation and gene expression, pathway alterations, risk factors, prognostic markers, and treatment targets are discussed.