P53: A key player in diverse cellular processes including nuclear stress and ribosome biogenesis, highlighting potential therapeutic compounds.

The tumor suppressor proteins are key transcription factors involved in the regulation of various cellular processes, such as apoptosis, DNA repair, cell cycle, senescence, and metabolism. The tumor suppressor protein p53 responds to different type of stress signaling, such as hypoxia, DNA damage, nutrient deprivation, oncogene activation, by activating or repressing the expression of different genes that target processes mentioned earlier. p53 has the ability to modulate the activity of many other proteins and signaling pathway through protein-protein interaction, post-translational modifications, or non-coding RNAs. In many cancers the p53 is found to be mutated or inactivated, resulting in the loss of its tumor suppressor function and acquisition of new oncogenic properties. The tumor suppressor protein p53 also plays a role in the development of other metabolic disorders such as diabetes, obesity, and fatty liver disease. In this review, we will summarize the current data and knowledge on the molecular mechanisms and the functions of p53 in different pathways and processes at the cellular level and discuss the its implications for human health and disease.

Advances in molecular function of UPF1 in Cancer.

It is known that more than 10 % of genetic diseases are caused by a mutation in protein-coding mRNA (premature termination codon; PTC). mRNAs with an early stop codon are degraded by the cellular surveillance process known as nonsense-mediated mRNA decay (NMD), which prevents the synthesis of C-terminally truncated proteins. Up-frameshift-1 (UPF1) has been reported to be involved in the downregulation of various cancers, and low expression of UPF1 was shown to correlate with poor prognosis. It is known that UPF1 is a master regulator of nonsense-mediated mRNA decay (NMD). UPF1 may also function as an E3 ligase and degrade target proteins without using mRNA decay mechanisms. Increasing evidence indicates that UPF1 could serve as a good biomarker for cancer diagnosis and treatment for future therapeutic applications. Long non-coding RNAs (lncRNAs) have the ability to bind different proteins and regulate gene expression; this role in cancer cells has already been identified by different studies. This article provides an overview of the aberrant expression of UPF1, its functional properties, and molecular processes during cancer for clinical applications in cancer. We also discussed the interactions of lncRNA with UPF1 for cell growth during tumorigenesis.

En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa.

Severe junctional epidermolysis bullosa is a rare genetic, postpartum lethal skin disease, predominantly caused by nonsense/premature termination codon (PTC) sequence variants in LAMB3 gene. LAMB3 encodes LAMB3, the ß subunit of epidermal-dermal skin anchor laminin 332. Most translational reads of a PTC mRNA deliver truncated, nonfunctional proteins, whereas an endogenous PTC readthrough mechanism produces full-length protein at minimal and insufficient levels. Conventional translational readthrough-inducing drugs amplify endogenous PTC readthrough; however, translational readthrough-inducing drugs are either proteotoxic or nonselective. Ribosome editing is a more selective and less toxic strategy. This technique identified ribosomal protein L35/uL29 (ie, RpL35) and RpL35-ligands repurposable drugs artesunate and atazanavir as molecular tools to increase production levels of full-length LAMB3. To evaluate ligand activity in living cells, we monitored artesunate and atazanavir treatment by dual luciferase reporter assays. Production levels of full-length LAMB3 increased up to 200% upon artesunate treatment, up to 150% upon atazanavir treatment, and up to 170% upon combinatorial treatment of RpL35 ligands at reduced drug dosage, with an unrelated PTC reporter being nonresponsive. Proof of bioactivity of RpL35 ligands in selective increase of full-length LAMB3 provides the basis for an alternative, targeted therapeutic route to replenish LAMB3 in severe junctional epidermolysis bullosa.

An intricate rewiring of cancer metabolism via alternative splicing.

All human genes undergo alternative splicing leading to the diversity of the proteins. However, in some cases, abnormal regulation of alternative splicing can result in diseases that trigger defects in metabolism, reduced apoptosis, increased proliferation, and progression in almost all tumor types. Metabolic dysregulations and immune dysfunctions are crucial factors in cancer. In this respect, alternative splicing in tumors could be a potential target for therapeutic cancer strategies. Dysregulation of alternative splicing during mRNA maturation promotes carcinogenesis and drug resistance in many cancer types. Alternative splicing (changing the target mRNA 3'UTR binding site) can result in a protein with altered drug affinity, ultimately leading to drug resistance.. Here, we will highlight the function of various alternative splicing factors, how it regulates the reprogramming of cancer cell metabolism, and their contribution to tumor initiation and proliferation. Also, we will discuss emerging therapeutics for treating tumors via abnormal alternative splicing. Finally, we will discuss the challenges associated with these therapeutic strategies for clinical applications.

Mucopolysaccharidosis type III (subtype IIIB) diagnosis as a spectrum disorder: A case report from Kosovo.

Mucopolysaccharidosis type IIIB (MPS IIIB), also known as Sanfilippo syndrome type B, is a metabolic disease caused by mutations in both alleles of the NAGLU gene encoding for the enzyme α-N-acetylglucosaminidase. A malfunction of this enzyme causes  inability to degrade heparan sulfate, which leads to accumulation of glycosaminoglycans in the cells. MPS IIIB is associated with different symptoms such as neurodegeneration, extreme hyperactivity, sleeping problems, aggressive behavior, reduced fear, and cognitive  deterioration. The condition is by now not curable. Here we describe a patient with MPS IIIB diagnosed at the age of 5 presenting with communication problems, motor dysfunctions, and speech and sleeping problems.Standard biochemical tests for neurodegenerative disorders and DNA analyses including NAGLU mutation screening were performed. We also did some psychological tests assessing the patient's communication skills and behavior. The patient was heterozygote for two mutations in the gene NAGLU (Y140C and Ser169fs). Thus, he suffered from MPS IIIB due to two mutations in the disease-causing gene.The patient presented with clear signs and symptoms of MPS IIIB with at least one of the two mutations affecting the α-N-acetylglucosaminidase protein function severely. Here we report the combination of a well-known and previously unreported mutation in the NAGLU gene; this could be dependent on geographical origin of the patient, which needs to be clarified by molecular studies of more MPS IIIB patients from Southeast Europe.

Recoding of Nonsense Mutation as a Pharmacological Strategy.

Approximately 11% of genetic human diseases are caused by nonsense mutations that introduce a premature termination codon (PTC) into the coding sequence. The PTC results in the production of a potentially harmful shortened polypeptide and activation of a nonsense-mediated decay (NMD) pathway. The NMD pathway reduces the burden of unproductive protein synthesis by lowering the level of PTC mRNA. There is an endogenous rescue mechanism that produces a full-length protein from a PTC mRNA. Nonsense suppression therapies aim to increase readthrough, suppress NMD, or are a combination of both strategies. Therefore, treatment with translational readthrough-inducing drugs (TRIDs) and NMD inhibitors may increase the effectiveness of PTC suppression. Here we discuss the mechanism of PTC readthrough and the development of novel approaches to PTC suppression. We also discuss the toxicity and bioavailability of therapeutics used to stimulate PTC readthrough.

Targeted Treatment and Immunotherapy in High-risk and Relapsed/ Refractory Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most frequent pediatric malignancy in children, comprising 30% of all pediatric malignancies; adult ALL comprises 5% of all ALL cases, which have a 186.6 per 1 million incidence. In pediatric ALL (pALL), on which this review focuses, approximately 1 in 285 children are diagnosed with cancer before the age of 20, and approximately 1 in 530 young adults between the ages of 20 and 39 years old is a childhood cancer survivor. The survival probability in pALL is now very high, approximately 80-90%. Thus, the most important is to improve supportive care and treatment based on relapse risk, optimally being based on the genetic feature of malignant cells. Improvements made by now are mainly the classifying of subgroups based on genetic characteristics such as aneuploidy or translocation and aligning them with treatment response. Relevant genetic changes in ALL pathogenesis are transcription regulators of lymphoid development (PAX5, IKZF1, EBF1, and LEF1) and/or coactivators (TBL1XR1 and ERG), lymphoid signaling (BTLA, and CD200 TOX), and tumor suppressor genes (CDKN2A, CDKN2B, RB1, and TP53). This review aims to summarize treatment strategies inhibiting tyrosine kinases, influencing different signaling pathways, BCL inhibitors, and anti-CD therapy (anti-cluster differentiation therapy) in pALL. CAR T-cell therapy (chimeric antigen receptors T-cell therapy) is under research and requires further development.

Ribosome-Directed Therapies in Cancer.

The human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis and mutation of ribosomal proteins. The ribosome represents an attractive anti-cancer therapy target and several strategies are used to identify specific drugs. Here we review the role of different drugs that may decrease ribosome biogenesis and cancer cell proliferation.

Correlation between level of vitamin D in serum and value of lung function in children diagnosed with bronchial asthma.

INTRODUCTION: Many authors in their research have suggested an association between vitamin D and asthma, but the results from these publications are sometimes confusing. AIM: Our aim was to assess the relationship between serum vitamin D and lung function in patients previously diagnosed with asthma. MATERIALS AND METHODS: The present study started in September 2019 and was completed in May 2020. All patients were diagnosed at the University Clinical Center-Prishtina, Kosovo. Spirometry was performed on children of ages 6-16 years old with a spirometer according to the recommendations of the American Thoracic Society. RESULTS: Of the 57 children who visited the University Clinical Center of Kosovo-Department of Pediatrics, 29 were diagnosed with asthma. The Spearman coefficient correlation showed statistical significance between vitamin D and body weight, and vitamin D and FEF75% at level 0.05. Other parameters did not show statistical significance with vitamin D, but such statistical significance was found in other parameters between asthma and healthy groups. CONCLUSIONS: Our data suggested that serum vitamin D level was insignificant for FVC%, FEV1%, Tiffeneau Index values, and PEF. Statistical significance was observed between vitamin D and body weight; vitamin D and FEF75% (p=0.05).

Ribosomopathies and cancer: pharmacological implications.

INTRODUCTION: The ribosome is a ribonucleoprotein organelle responsible for protein synthesis, and its biogenesis is a highly coordinated process that involves many macromolecular components. Any acquired or inherited impairment in ribosome biogenesis or ribosomopathies is associated with the development of different cancers and rare genetic diseases. Interference with multiple steps of protein synthesis has been shown to promote tumor cell death. AREAS COVERED: We discuss the current insights about impaired ribosome biogenesis and their secondary consequences on protein synthesis, transcriptional and translational responses, proteotoxic stress, and other metabolic pathways associated with cancer and rare diseases. The modulation of different therapeutic chemical entities targeting cancer in in vitro and in vivo models have also been detailed. EXPERT OPINION: Despite the association between inherited mutations affecting ribosome biogenesis and cancer biology, the development of therapeutics targeting the essential cellular machinery has only started to emerge. New chemical entities should be designed to modulate different checkpoints (translating oncoproteins, dysregulation of specific ribosome-assembly machinery, ribosomal stress, and rewiring ribosomal functions). Although safe and effective therapies are lacking, consideration should be given to using existing drugs alone or in combination for long-term safety, with known risks for feasibility in clinical trials and synergistic effects.

Suspicions regarding the genetic inheritance of acute lymphoblastic leukemia in patients with down syndrome.

Children with Down syndrome (DS) are at markedly increased risk for acute lymphoblastic leukaemia (ALL). DS is caused by trisomy of chromosome 21 affecting approximately 1 in 732 newborns in the USA. ALL is the most common cancer in children and constitutes approximately 25% of cancer diagnoses among children under the age of 15. Different protocols for treatment and management of paediatric ALL are available; however, DS children with ALL (DS-ALL) have increased risk of therapy-related toxicity compared to those without DS. Herein, we summarize the available literature on inherited predisposition for ALL, and possibilities for molecular therapy and treatment for DS-ALL patients.

Case Report: Identification of likely recurrent CEP290 mutation in a child with Joubert syndrome and cerebello-retinal-renal features.

Background. Joubert syndrome (JS) is a rare autosomal recessive ciliopathy with an estimated prevalence of 1 in 100,000. JS is characterized by hyperpnoea, hypotonia, ataxia, developmental delay and various neuropathological abnormalities in the brain including cerebellar hypoplasia and cerebellar vermis aplasia. JS can also have variable multi-organ involvement, including the retina, kidneys, liver, and musculoskeletal system. Methods and Results. Here we report a clinical description of two-year-old girl presenting with breathing difficulties, hyperechoic kidneys with loss of corticomedullary differentiation. Brain magnetic resonance imaging revealed the typical molar tooth sign consistent with a clinical diagnosis of JS and retinal examination showed severe retinal dystrophy leading to blindness. Molecular genetic analysis using whole exome sequencing and Sanger sequence confirmation demonstrated a homozygous mutation (c.5493delA, p.(A1832fs*19) in CEP290 which segregated from either parent and was consistent with the multisystem ciliopathy phenotype. This precise variant has been described previously in 2 families from the Kosovar-Albanian region suggesting this allele is a recurrent mutation in this population. Conclusions. Mutations in CEP290 lead to multisystem ciliopathy syndromes and molecular genetic diagnostics of such cases allows precise diagnosis, screening of at risk relatives and appropriate management.

Joubert syndrome: Molecular basis and treatment.

Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the cerebellum and the so-called "molar tooth sign." Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome. This review will describe some characteristics of JS associated with changes in 35 genes, and will also address subtypes of JS, clinical diagnosis, and the future of therapeutic developments.

Mucopolysaccharidosis III: Molecular basis and treatment.

Mucopolysaccharidoses (MPSs) are known as rare genetic diseases which are caused by mutation in the enzyme heparin sulfate, which normally leads to degradation and accumulation of glycosaminoglycans in the cells. There are 11 types of MPSs, whereby neuropathy may occur in seven of them (MPS I, II, IIIA, IIIB, IIIC, IIID and VII). Accumulation of degraded heparin sulfate in lysosomes causes cellular dysfunction and malfunction of several organs. However, the exact molecular mechanism how protein degradation and storage leads to cellular dysfunction is not understood, yet. Nonetheless, several genetic and biochemical methods for diagnosis of MPSs are available nowadays. Here we provide an overview on known molecular basis of MPS in general, including enzyme defects and symptoms of MPS; however, the main focus is on MPS type III together with potential and perspective therapy-options.

Three Patterns of Inheritance of Quantitative Dermatoglyphic Traits: Kosovo Albanian Twin Study.

Dermatoglyphs are epidermal ridge configurations on the fingers, palms and soles that are formed during fetal development, and therefore only the intrauterine environment can have any influence on their formation. This study aims at investigating the genetic and environmental contribution in determining quantitative dermatoglyphic traits in 32 monozygotic (MZ) and 35 dizygotic (DZ) same-sex twins from the Albanian population of Kosovo. All genetic analyses were run in the statistical program Mx. After assumptions testing, based on the pattern of MZ-DZ correlations, univariate models were fitted to the data in order to estimate additive genetic (A), common (C) and individual (E) environmental influences for all variables. The exception was the atd-angle for which a model with nonadditive genetic (D) influences was tested, since DZ correlations were less than half of MZ correlations. Goodness of fit of the full ACE or ADE model was compared to the saturated model. The fit of nested models (AE, CE, DE or E) was compared to the full models (ACE or ADE). Our results indicate that additive genetic component strongly contributes to individual differences in finger ridge counts (49-81%), and weakly (0-50%) on the formation of the palmar ridge counts between the palmar triradii a, b, c, and d. The specific pattern found for the atd-angle implies the impact of a nonadditive genetic component, possibly the effect of a major gene. Further, more powered studies are needed to confirm this pattern, especially for resolving the issue of the huge difference in MZ and DZ twin similarity for the atd-angle palmar trait.

A detection of microevolutionary changes by the analysis of qualitative dermatoglyphic traits: an example of Albanians from Kosovo.

In this study we analyzed the qualitative dermatoglyphic traits in the Albanians from three Kosovo distinct regions. We aimed to detect possible microevolutionary changes, which could have happened as a consequence of geographical and cultural isolation. The dermatoglyphic traits were analyzed for total 641 Albanians of both sexes. The analysis included 4 variables on fingers, 8 on palms and terminations of A, B, C, D and T main-lines. The differences in patterns incidence were tested using the chi-square test. The frequencies of several pattern types varied to a great extent between distinct groups with statistically significant difference in most of the cases. Our results indicated that the Albanians from South Morava valley and from Kosovo plain were genetically close, and the population from Dukagjini valley is less close to any of them. The analysis of qualitative dermatoglyphic patterns may be utilized effectively to track the microevolutionary changes. This is especially useful in a developing country like Kosovo, since it is an inexpensive and effective tool for screening and studying the patterns influenced by the divergence of population.

Comparative analysis of qualitative dermatoglyphic traits of Albanian and Turkish populations living in the area of Dukagjin Valley in Kosovo.

Dermatoglyphic prints were collected from 800 inhabitants of Dukagjin valley in Kosovo. The sample consisted of two ethnically different sub-populations who refer themselves as Albanians (N = 400) and Turks (N = 400). Qualitative analysis of prints concerned the frequency of the patterns on fingers (arch, ulnar and radial loop, whorl, accidental whorl) and on palms (Thenar and I, II, III, and IV interdigital area and the hypothenar, main line index, and the axial "t" triradius position). As was expected due to previous study of quantitative dermatoglyphic traits, in the same population the Alba-nians and Turks showed to be significantly different in most explored qualitative dermatoglyphic variables. Found differences indicated that the reproductive isolation between the Albanian and Turkish population in Kosovo is substantial, despite the fact that those two ethnic sub-populations live in the close vicinity through several centuries.

Comparative analysis of dermatoglyphic traits in Albanian and Turkish population living in Kosovo.

The aim of the study was to compare quantitative dermatoglyphic traits of two ethnic groups with different origin and customs, living on the same territory. The dermatoglyphic prints were collected from 800 inhabitants of the Dukagjin valley in southwest Kosovo, of Albanian (400) and Turkish (400) ethnic origin. The quantitative analysis comprised the number of ridges and triradii on the fingers, and the number of ridges in the interdigital areas on the palm (a-b, b-c, and c-d) as well as the size of the atd angle. The statistical analysis showed significant differences between the Albanian and the Turkish males for two fingers and pattern intensity index left, and on palms for a-b rc and c-d rc on both hands and b-c re on the left hand, and between females for six fingers and almost all palmar traits. Significant inter-population variations were observed for most palmar areas in both sexes but more pronouncedly in females. The differences found between the examined population groups show that admixture between Albanian and Turkish population in Kosovo has been small, and the Turks have retained their ethnic identity for several centuries.