Scaffold proteins of cancer signaling networks: The paradigm of FK506 binding protein 51 (FKBP51) supporting tumor intrinsic properties and immune escape

Scaffold proteins are crucial regulators of signaling networks,and their abnormal expression may favor the development of tumors.Among the scaffold proteins,immunophilin covers a unique role as‘protein-philin’(Greek‘philin’=friend)that interacts with proteins to guide their proper assembly.The growing list of human syndromes associated with the immunophilin defect underscores the biological relevance of these proteins that are largely opportunistically exploited by cancer cells to support and enable the tumor’s intrinsic properties.Among the members of the immunophilin family,the FKBP5 gene was the only one identified to have a splicing variant.Cancer cells impose unique demands on the splicing machinery,thus acquiring a particular susceptibility to splicing inhibitors.This review article aims to overview the current knowledge of the FKBP5 gene functions in human cancer,illustrating how cancer cells exploit the scaffolding function of canonical FKBP51 to foster signaling networks that support their intrinsic tumor properties and the spliced FKBP51s to gain the capacity to evade the immune system.

Clinical and molecular spectrum of Wiedemann-Steiner syndrome, an emerging member of the chromatinopathy family

Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arched eyebrows with a lateral flare,wide nasal bridge,and downslanting and vertically narrow palpebral fissures;mild to moderate intellectual disability;behavioral difficulties;and hypertrichosis on the back.It is caused by heterozygous pathogenic variants in KMT2A.This gene has an established role in histone methylation,which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies,a heterogeneous group of syndromic conditions that share a common trigger:The disruption of one of the genes involved in chromatin modification,leading to dysfunction of the epigenetic machinery.

liver and the defects of cholesterol and bile acids biosynthesis: rare disorders many diagnostic pitfalls

In recent decades, biotechnology produced a growth of knowledge on the causes and mechanisms of metabolic diseases that have formed the basis for their study, diagnosis and treatment. Unfortunately, it is well known that the clinical features of metabolic diseases can manifest themselves with very different characteristics and escape early detection. Also, it is well known that the prognosis of many metabolic diseases is excellent if diagnosed and treated early. In this editorial we briefly summarized two groups of inherited metabolic diseases, the defects of cholesterol biosynthesis and those of bile acids. Both groups show variable clinical manifestations but some clinical signs and symptoms are common in both the defects of cholesterol and bile acids. The differential diagnosis can be made analyzing sterol profiles in blood and/or bile acids in blood and urine by chromatographic techniques(GC-MS and LC-MS/MS). Several defects of both biosynthetic pathways are treatable so early diagnosis is crucial. Unfortunately their diagnosis is made too late, due either to the clinical heterogeneity of the syndromes(severe, mild and very mild) that to the scarcity of scientific dissemination of these rare diseases. Therefore, the delay in diagnosis leads the patient to the medical observation when the disease has produced irreversible damages to the body. Here, we highlighted simple clinical and laboratory descriptions that can potentially make you to suspect a defect in cholesterol biosynthesis and/or bile acids, as well, we suggest appropriate request of the laboratory tests that along with common clinical features can help to diagnose these defects.

Association of H3K4me3 and CBX7 Levels to the Down-Regulation of <i>GKN</i>1 Gene Expression in Gastric Cancer Cells

Gastrokine 1 (GKN1) is a highly secreted gastric mucosal protein in normal individuals but strongly down-regulated or totally absent in gastric cancer subjects. An epigenetic mechanism might be responsible for GKN1 gene silencing probably through the activity of a transcription factor in association with the enzymes SUV39H1 and HDACs on the GKN1 promoter. In fact, compared to non-tumor tissues, a high increase of H3K9me3 level was observed in the corresponding tumor ones. Because H3K4me3 seems to be a possible epigenetic mark for active euchromatin, we try to verify the H3K4me3 level on the GKN1 promoter in gastric cancer tumor specimens. In addition, we also attempt to highlight if CBX7 could be the possible regulatory transcription factor correlated to GKN1 gene promoter. Therefore, we evaluated if the CBX7 expression levels could be associated with GKN1 down-regulation in gastric cancer. To this purpose, 2 pairs of non-tumor and tumor surgical specimens from patients with gastric cancer were analyzed for H3K4me3 by chromatin immunoprecipitation (ChiP) assays, and 9 pairs were instead analyzed by Western blotting for GKN1, and CBX7 expression levels, respectively. The results suggested that the observed increase of H3K4me3 in tumor samples was not in agreement with its proposed function whereas the expression of CBX7 was not associated with the down-regulation of GKN1. In particular, the expression levels of CBX7 in tumor samples might suggest a survival role in gastric cancer.

Histological Effect of Viola Odorata Methanolic Extract and Methotraxate Induced in Albino Male Mice

The objective of this study was to considere as an explorer for in vivo studies on the production of some secondary metabolites from local medical plants named Viola odorata. Viola odorata commonly known as “garden violet or sweet violet” belongs to family Violaceae, is a slow growing perennial, with stout rootstock, grows in hedgerows, rough land and margins of woodland. 200 mg/kg of methanol extract for V. odorata was interacted with methotrexate as a drug in albino mice to see the healing capacity for this extract. Different organs were used such as intestine, kidney, spleen, and testes for this experiment. Each organ response was recorded in this experiment. Histopathological section in the intestine of animal treated with MTX and plant showed hypertrophy and hyperplasia of goblet cells and increased cellularity of lamna properia while Histopathological section in the testes of animal treated with MTX and plant showed no sperm in the seminiferous tubules of epididymis with the round multi-nuclei cell in the lumen accompanied by homogeneous material and cellular debris while Histopathological section in the spleen of animal treated with MTX and plant proliferation of lymphocytes in the periarteriolar sheath and proliferation of mononuclear cells around sinus in red pulp and Histopathological section in the kidney of animal treated with MTX and plant mononuclear cells aggregation in the interstitial tissue mainly around blood vessels and in the adipose tissue and renal tubules. Other sections showed hydropic degeneration of renal tubules.

Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis

AIM:To investigated the molecular cause of very early-onset ulcerative colitis(UC)in an 18-mo-old affected child.METHODS:We analysed the interleukin-10(IL10)receptor genes at the DNA and RNA level in the proband and his relatives.Beta catenin and tumor necrosis factor-α(TNFα)receptors were analysed in the proteins extracted from peripheral blood cells of the proband,his relatives and familial adenomatous polyposis(FAP)and PTEN hamartoma tumor syndrome(PHTS)patients.Samples were also collected from the proband’s inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer(CRC).Finally,we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients.RESULTS:Our patient was a compound heterozygote for the IL10RB E47K polymorphism,inherited from his father,and for a novel point mutation within the IL10RA promoter(the-413G->T),inherited from his mother.Beta catenin and tumour necrosis factorαreceptors-Ⅰ(TNFRI)protein were both over-expressed in peripheral blood cells of the proband’s relatives more than the proband.However,TNFRII was over-expressed only in the proband.Finally,both TNFα-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa.Consistent with this observation,mesalazine and azathioprine induced,in primary fibroblasts,IL10RB and TNFRII over-expression and TNFRI and TNFαunder-expression.We suggest thatβ-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.CONCLUSION:A synergistic effect of several variant alleles of the IL10 receptor genes,inherited in a Mende-lian manner,is involved in UC onset in this young child.

Probiotics, prebiotics and their role in Alzheimer's disease

Accumulation of amyloid and dysfunctional tau proteins in the brain, along with the development of dementia, characterizes Alzheimer 's disease(AD). Although the cause of AD is currently unknown, it has been shown that the onset of the disease, with amyloid-beta peptide(Aβ) accumulation, occurs 10–20 years before the development of the clinical signs.

Novel biomarkers of fibrosis in Crohn's disease

Fibrosis represents a major challenge in Crohn's disease(CD),and many CD patients will develop fibrotic strictures requiring treatment throughout their lifetime.There is no drug that can reverse intestinal fibrosis,and so endoscopic balloon dilatation and surgery are the only effective treatments.Since patients may need repeated treatments,it is important to obtain the diagnosis at an early stage before strictures become symptomatic with extensive fibrosis.Several markers of fibrosis have been proposed,but most need further validation.Biomarkers can be measured either in biological samples obtained from the serum or bowel of CD patients,or using imaging tools and tests.The ideal tool should be easily obtained,costeffective,and reliable.Even more challenging is fibrosis occurring in ulcerative colitis.Despite the important burden of intestinal fibrosis,including its detrimental effect on outcomes and quality of life in CD patients,it has received less attention than fibrosis occurring in other organs.A common mechanism that acts via a specific signaling pathway could underlie both intestinal fibrosis and cancer.A comprehensive overview of recently introduced biomarkers of fibrosis in CD is presented,along with a discussion of the controversial areas remaining in this field.

Down-Regulation of GKN1 in Gastric Cancer Is Not Associated with the RUNX3 Expression

Gastrokine 1 (GKN1) is a gastric mucosal protein highly expressed and secreted in normal individuals but during Helicobacter pylori infection or in gastric carcinogenesis it is strongly down-regulated or totally absent. In gastric cancer, the GKN1 gene is silenced through an epigenetic mechanism most likely mediated by a transcription factor that promotes on GKN1 promoter the activity of the enzymes SUV39H1 and HDACs. Because RUNX3 is a potential candidate in the regulation of molecular carcinogenesis process of stomach cancers, we tried to assess if RUNX3 could be involved in GKN1 down-regulation in GC. 17 paired of non-tumoral and tumoral surgical specimens from patients with gastric cancer were analyzed for GKN1 and RUNX3 by Western blotting and chromatin immunoprecipitation (Chip) assays. The overall results indicated that RUNX3 expression was not associated with the down-regulation of GKN1. The expression levels of RUNX3 in non-tumoral and tumoral samples suggest that RUNX3 does not act as a tumor suppressor but that it might play a complex oncogenic role in gastric cancer cells.

Antibacterial Activity of Silver Nanoparticles Using Salvia officinalis Extract on Some Pathogenic Bacteria

This study included evaluation for the effects of green synthetic nanoparticles of Salvia officinalis aqueous leaf extract loaded with silver nitrate on antibacterial activity. Green synthetic nanoparticles were synthesized by mixing the plant extract with different AgNO3 concentrations (1 mM, 1.5 mM, 1.75 mM, and 2 Mm) then they were detected by color changing and UV visible spectroscopy, which gave indication for the creation of silver nanoparticles. A characteristic and definite surface plasmon resonance (SPR) band for silver nanoparticles was obtained at around 433 nm. The SPR peak of silver nanoparticles extreme peak intensity was obtained at 1.75 mM of AgNO3. Atomic Force Microscopy analysis was used to characterize silver nanoparticles which declared that the shape of green synthetic nanoparticles had different average size depending on sliver concentrations. Since it was observed that the shape and size of green synthetic nanoparticles were concentrations dependent (89.69 nm, 80.94 nm, 76.98 nm and 60.28 nm) respectively for AgNO3 concentrations tested (1 mM, 1.5 mM, 1.75 mM and 2 mM). The antibacterial activity of green synthetic sliver nanoparticles was studied for all G+ve and G-ve selected isolates (Staphylococcus aureus, Staphylococcus heamolytics, Streptococcus pnemoniae, Enterococcus faecalis) and others G-ve bacterial isolates (Escherichi coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa) and the result showed that different green synthetic nanoparticles concentrations (1, 1.5, 1.75, 2 mM) have the ability to inhibit all bacterial isolates with varying zones of inhibition higher than the inhibition observed by ready to use sliver nanoparticles. Minimum inhibitory concentrations (MIC) of green synthetic nanoparticles were obtained in concentration of (31, 27, 23 and 16 μm/mL) for G+ve (S. auerus) and (187, 125, 125, 109 μm/mL) for G-ve (E. coli) at (1, 1.5, 1.75, 2 mM) respectively. The activity of green synthetic sliver nanoparticles in inhibition S. auerus and E. coli, biofilm formation was studied and the result showed that 2 mM nanoparticles could inhibit 75% of S. auerus biofilm and 50% of E. coli biofilm respectively.

Preliminary focus on the mechanical and antibacterial activity of a PMMA-based bone cement loaded with gold nanoparticles

In total knee arthroplasty(TKA)and total hip replacement(THR)the restoration of the normal joint function represents a fundamental feature.A prosthetic joint must be able to provide motions and to transmit functional loads.As reported in the literature,the stress distribution may be altered in bones after the implantation of a total joint prosthesis.Some scientific works have also correlated uncemented TKA to a progressive decrease of bone density below the tibial component.Antibiotic-loaded bone cements are commonly employed in conjunction with systemic antibiotics to treat infections.Furthermore,nanoparticles with antimicrobial activity have been widely analysed.Accordingly,the current research was focused on a preliminary analysis of the mechanical and antibacterial activity of a PMMA-based bone cement loaded with gold nanoparticles.The obtained results demonstrated that nanocomposite cements with a specific concentration of gold nanoparticles improved the punching performance and antibacterial activity.However,critical aspects were found in the optimization of the nanocomposite bone cement.

Cancer chemotherapy and beyond:Current status,drug candidates,associated risks and progress in targeted therapeutics

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year.With the new understanding of the molecular mechanism(s)of disease progression,our knowledge about the disease is snowballing,leading to the evolution of many new therapeutic regimes and their successive trials.In the past few decades,various combinations of therapies have been pro-posed and are presently employed in the treatment of diverse cancers.Targeted drug therapy,immunotherapy,and personalized medicines are now largely being employed,which were not common a few years back.The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies,extending patients’disease-free survival thereafter.Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine,chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient’s physical and psychological health.Chemother-apeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons.The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals;it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

Corrigendum to'Cancer chemotherapy and beyond:Current status,drug candidates,associated risks and progress in targeted therapeutics'[Genes&Diseases 10(2023)1367-1401]

In the published article,there was an error in the affiliation information about the first author Uttpal Anand[a].Instead of"Department of Life Sciences,Ben-Gurion University of the Negev,Beer-Sheva 84105,Israel",it should be"CytoGene Research&Development LLP,K-51,UPSIDA Industrial Area,Kursi Road(Lucknow),Dist.Barabanki,225001,Uttar Pradesh,India".The authors would like to apologize for any inconvenience caused and state that this does not change the scientific conclusions of thearticle inanyway.

Tomographic flow cytometry by digital holography

High-throughput single-cell analysis is a challenging task.Label-free tomographic phase microscopy is an excellent candidate to perform this task.However,in-line tomography is very difficult to implement in practice because it requires a complex set-up for rotating the sample and examining the cell along several directions.We demonstrate that by exploiting the random rolling of cells while they are flowing along a microfluidic channel,it is possible to obtain in-line phase-contrast tomography,if smart strategies for wavefront analysis are adopted.In fact,surprisingly,a priori knowledge of the three-dimensional position and orientation of rotating cells is no longer needed because this information can be completely retrieved through digital holography wavefront numerical analysis.This approach makes continuous-flow cytotomography suitable for practical operation in real-world,single-cell analysis and with a substantial simplification of the optical system;that is,no mechanical scanning or multi-direction probing is required.A demonstration is given for two completely different classes of biosamples:red blood cells and diatom algae.An accurate characterization of both types of cells is reported,despite their very different nature and material content,thus showing that the proposed method can be extended by adopting two alternate strategies of wavefront analysis to many classes of cells.

Targeting histone lysine-specific demethylase KDM1A/LSD1 to control epithelial-mesenchymal transition program in breast cancers

Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes. Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Specifically, the lysine specific demethylase 1 (LSD1, also known as KDM1A) plays a pivotal role in the regulation of EMT. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer.