Perturbations in ribosome biogenesis have been associated with cancer. Such aberrations activate p53 through the RPL5/RPL11/5S rRNA complex-mediated inhibition of HDM2. Studies using animal models ...have suggested that this signaling pathway might constitute an important anticancer barrier. To gain a deeper insight into this issue in humans, here we analyze somatic mutations in RPL5 and RPL11 coding regions, reported in The Cancer Genome Atlas and International Cancer Genome Consortium databases. Using a combined computational and statistical approach, complemented by a range of biochemical and functional analyses in human cancer cell models, we demonstrate the existence of several mechanisms by which RPL5 mutations may impair wild-type p53 upregulation and ribosome biogenesis. Unexpectedly, the same approach provides only modest evidence for a similar role of RPL11, suggesting that RPL5 represents a preferred target during human tumorigenesis in cancers with wild-type p53. Furthermore, we find that several functional cancer-associated RPL5 somatic mutations occur as rare germline variants in general population. Our results shed light on the so-far enigmatic role of cancer-associated mutations in genes encoding ribosomal proteins, with implications for our understanding of the tumor suppressive role of the RPL5/RPL11/5S rRNA complex in human malignancies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Toll-like receptors (TLRs), as a family of pattern recognition receptors, play an important role in the recognition of HIV-1 molecular structures by various cells of the innate immune system, but ...also provide a functional association with subsequent mechanisms of adaptive immunity. TLR7 and TLR8 play a particularly important role in the innate immune response to RNA viruses due to their ability to recognise GU-rich single-stranded RNA molecules and subsequently activate intracellular signalling pathways resulting in expression of genes coding for various biological response modifiers (interferons, proinflammatory cytokines, chemokines). The aim of this review is to summarise the most recent knowledge on the role of TLRs in the innate immune response to HIV-1 and the role of TLR gene polymorphisms in the biology and in the clinical aspects of HIV infections. In addition, the role of TLR agonists as latency reversing agents in research to treat HIV infections and as immunomodulators in HIV vaccine research will be discussed.
This is the first report of anisakiasis in a Croatian patient, evidenced from an archival paraffin-embedded and hematoxylin-eosin stained tissue section. Anisakiasis has been only suspected in the ...country based on previously detected anti-Anisakis IgE seroprevalence in the healthy coastal population, as well as an acute case where pathohistological and serological findings suggested the diseases, but the migrating larva has not been retrieved.
Seventy years-old female, operated in 1998 for pulmonary carcinoma, was admitted to the General hospital Šibenik, Croatia in 2003, because of gastric pain and nausea that lasted for couple of days. She was showing good general condition, full mobility and lucidity, subfebrile status. Abdominal palpation inferred acute pain in paraumbilical and ileocecal region. Exploratory right pararectal laparotomy revealed a hardened, 5 cm-long structure, located intraluminally in the sigmoid colon, not perforating colon serosa. The process has been dissected and sent for patohistological diagnosis. Results showed a 2 mm-long whitish nematode spiralised in muscular layer of colon mucosa surrounded by granulomatous inflammation.
After genomic DNA isolation of the nematode from the histological section, and amplification at the mitochondrial cytochrome oxidase 2 locus, etiological agent has been identified as Anisakis pegreffii. Used methodology suggests that screening of archival suspicious sections is feasible in order to study epidemiology of this zoonotic disease poorly recognised in Croatia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oxidative stress and oxidative protein damage occur in various biological processes and diseases. The carbonyl group on amino acid side chains is the most widely used protein oxidation biomarker. ...Carbonyl groups are commonly detected indirectly through their reaction with 2,4-dinitrophenylhydrazine (DNPH) and subsequent labeling with an anti-DNP antibody. However, the DNPH immunoblotting method lacks protocol standardization, exhibits technical bias, and has low reliability. To overcome these shortcomings, we have developed a new blotting method in which the carbonyl group reacts with the biotin-aminooxy probe to form a chemically stable oxime bond. The reaction speed and the extent of the carbonyl group derivatization are increased by adding a p-phenylenediamine (pPDA) catalyst under neutral pH conditions. These improvements are crucial since they ensure that the carbonyl derivatization reaction reaches a plateau within hours and increases the sensitivity and robustness of protein carbonyl detection. Furthermore, derivatization under pH-neutral conditions facilitates a good SDS-PAGE protein migration pattern, avoids protein loss by acidic precipitation, and is directly compatible with protein immunoprecipitation. This work describes the new Oxime blot method and demonstrates its use in detecting protein carbonylation in complex matrices from diverse biological samples.
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•Optimized protein carbonyl derivatization protocol.•A simple, versatile, and reliable method, suitable for detecting protein oxidation in a range of biological matrices.•Detection of low-abundance protein carbonylation following immunoprecipitation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pojam trombofilija obično se koristi za opisivanje nasljednih i/ili stečenih stanja povezanih s povećanom sklonošću za nastanak tromboze i klinički se odnosi na pacijente koji razvijaju spontanu ...vensku tromboemboliju (VTE). VTE u dječjoj dobi jest multifaktorijalna bolest, a u većine djece prisutan je jedan ili više kliničkih čimbenika rizika. Osim stečenih čimbenika, kao što su primjena centralnoga venskog katetera, maligne bolesti, teške infekcije, nefrotski sindrom i nasljedni trombofilni poremećaji mogu pridonijeti razvoju VTE-a u novorođenčadi. Nasljedna trombofilija uključuje nedostatak antitrombina (AT), proteina C (PC), proteina S (PS) te mutacije gena za faktor V (FV G1691A, Leiden) i protrombin (FII G20210A). Druge trombofilije, koje su slabije karakterizirane i nisu nužno genetički uvjetovane, uključuju povišenu razinu homocisteina, lipoproteina(a), disfibrinogenemije, antifosfolipidni sindrom i povećane razine faktora VIII, IX i XI. Sukladno najnovijim smjernicama, novorođenčad i djeca s purpurom fulminans trebaju biti odmah testirana na nedostatak PC-a i PS-a, dok se probir na trombofiliju u djece s moždanim udarom ne preporučuje rutinski. U djece s višestrukim neobjašnjivim trombozama, posebice ako ukazuju na katastrofični antifosfolipidni sindrom, treba razmotriti testiranje na antifosfolipidna protutijela i nasljednu trombofiliju. Skupine pedijatrijskih pacijenata koje će najvjerojatnije imati koristi od testiranja na trombofiliju jesu adolescenti sa spontanim nastankom VTE-a, djeca/adolescenti s pozitivnom obiteljskom anamnezom te tinejdžerice s poznatom pozitivnom obiteljskom anamnezom koje planiraju uzimanje oralnih kontraceptiva koji sadrže estrogen. Manje je korisno testiranje provesti u novorođenčadi i djece u kojih je nastanak VTE-a povezan s primjenom venskog katetera. Zaključno, može se reći da testiranje na nasljednu trombofiliju treba provesti individualiziranim pristupom i samo u slučaju kada bi dobiveni rezultati mogli utjecati na poboljšanje ili promjenu tijeka liječenja.
To determine variations in allele and genotype frequencies between keratoacanthoma (KA) and common warts (CW), compared with the control group, in three single nucleotide polymorphisms (SNPs) within ...the TLR2, TLR3, and TLR9 genes.AIMTo determine variations in allele and genotype frequencies between keratoacanthoma (KA) and common warts (CW), compared with the control group, in three single nucleotide polymorphisms (SNPs) within the TLR2, TLR3, and TLR9 genes.This case-control study involved samples from 161 patients with KA, 152 patients with CW, and 469 controls. DNA was isolated from formalin-fixed paraffin-embedded tissue sections. Three SNPs - rs4696480 in TLR2, rs7657186 in TLR9, and rs35213 in TLR3 - were genotyped with TaqMan Genotyping Assays on the 7500 Real-Time PCR System.METHODSThis case-control study involved samples from 161 patients with KA, 152 patients with CW, and 469 controls. DNA was isolated from formalin-fixed paraffin-embedded tissue sections. Three SNPs - rs4696480 in TLR2, rs7657186 in TLR9, and rs35213 in TLR3 - were genotyped with TaqMan Genotyping Assays on the 7500 Real-Time PCR System.TLR2 rs4696480 and TLR3 rs7657186 were significantly overrepresented in KA and CW compared with controls (P<0.001). The association was stronger for CW than for KA, as evidenced by higher frequencies of the A allele and AA genotype for rs4696480. Both KA and CW patients had higher frequencies of the G allele and GG genotype for rs7657186 than controls. rs7657186 was moderately associated with KA and CW, with the G allele and GG genotype being more prevalent in CW cases, where no AA homozygotes were found.RESULTSTLR2 rs4696480 and TLR3 rs7657186 were significantly overrepresented in KA and CW compared with controls (P<0.001). The association was stronger for CW than for KA, as evidenced by higher frequencies of the A allele and AA genotype for rs4696480. Both KA and CW patients had higher frequencies of the G allele and GG genotype for rs7657186 than controls. rs7657186 was moderately associated with KA and CW, with the G allele and GG genotype being more prevalent in CW cases, where no AA homozygotes were found.Genetic variants in TLR2 (rs4696480) and TLR3 (rs7657186) genes may affect KA and CW development, influencing immune responses and susceptibility to these skin lesions. Further research is required to elucidate TLR expression patterns and their role in KA development.CONCLUSIONGenetic variants in TLR2 (rs4696480) and TLR3 (rs7657186) genes may affect KA and CW development, influencing immune responses and susceptibility to these skin lesions. Further research is required to elucidate TLR expression patterns and their role in KA development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
The aim of this study was to investigate the effect of urapidil and low-molecular weight heparin (LMWH) on testicular torsion–detorsion injury in rats.
Methods
Thirty-two male Sprague–Dawley ...rats were used. In the torsion–detorsion (T/D) group, the left testis was twisted at 720° for 3 h. After 3 h of reperfusion, the testis was removed. Urapidil or LMWH was administered intraperitoneally 30 min before detorsion in the treatment groups.
Results
Unilateral testicular torsion–detorsion caused significant increases in the malondialdehyde level and apoptosis and significant decreases in the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in ipsilateral testes (
p
< 0.001). The rats treated with urapidil had a significant decrease in the malondialdehyde level and apoptosis and significant increases in the SOD and GPx activities in ipsilateral testes compared to the T/D group (
p
< 0.001). Animals treated with LMWH showed non-significant reductions in malondialdehyde levels and apoptosis compared to the T/D group. In addition, no significant difference in the SOD activities (
p
= 0.52) between the groups was found. The increase in the GPx activities was significant in the LMWH group compared to the T/D group (
p
< 0.001).
Conclusion
The administration of urapidil before detorsion prevents ischemia/reperfusion cellular damage in testicular tissue. LMWH was not found to have a beneficial effect on testicular T/D injury in rats.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective To investigate the effect of nifedipine on testicular torsion-detorsion injury. Materials and Methods Twenty-four adult male Sprague-Dawley rats were randomly divided into 3 groups, each ...containing 8 rats. Rats in the control group underwent a sham operation of the left testis. In the torsion-detorsion (T/D) group, the left testis was twisted at 720° for 3 hours. After 3 hours of reperfusion, at the end of the experiment, the testes were removed. Rats in the treatment group received the same surgical procedure as the T/D group, but nifedipine was administered intraperitoneally (100 μg/kg) 30 minutes before the time of detorsion. Results Unilateral testicular torsion-detorsion caused a significant increase in the malondialdehyde level and apoptosis and caused significant decreases in superoxide dismutase and glutathione peroxidase activities in ipsilateral testes. The rats treated with nifedipine had a significant decrease in malondialdehyde level and apoptosis and had significant increases in superoxide dismutase and glutathione peroxidase activities in ipsilateral testes compared with those of the T/D group. Conclusion These results suggest that biochemical and histological torsion-detorsion injury occurs in the ipsilateral testes after a 3-hour torsion and 3-hour detorsion and that administration of nifedipine before detorsion prevents ischemia/reperfusion cellular damage in the testicular tissue.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The aim of the study was to examine basal hypothalamic-pituitary-adrenal (HPA) axis activity and to determine associations of various covariates (gender, sleep-wake rhythm, demographic, academic, ...life style and health-related characteristics) with altered daily salivary cortisol profiles in late adolescence.
The total analytic sample consisted of 903 Croatian secondary school students aged 18 - 21 years (median 19 years). Salivary cortisol was sampled at home at three time points over the course of one week and its concentrations were measured by using the enzyme immunoassay.
In comparison to males, female students had a higher cortisol awakening response (CAR) (median 4.69, IQR 10.46 and median 3.03, IQR 8.94, respectively; P < 0.001), a steeper ("healthier") diurnal cortisol slope (DCS) (median 0.51, IQR 0.55 and median 0.44, IQR 0.51, respectively; P = 0.001), and a greater area under curve with respect to ground (AUC
) (median 206.79, IQR 111.78 and median 191.46, IQR 104.18, respectively; P < 0.001). Those students who woke-up earlier and were awake longer, had a higher CAR (P < 0.001), a flatter ("less healthy") DCS (P < 0.001), and a greater AUCG (P < 0.001), than students who woke-up later and were awake shorter. Less consistent but still significant predictors of salivary cortisol indexes were age, school behaviour, friendship, diet healthiness and drug abuse.
Gender and sleep-wake up rhythm were major determinants of the altered daily salivary cortisol profiles in late adolescence. The predictive power of other covariates, although less clear, has a potential for identifying vulnerable subgroups such as male drug users and females without a best friend.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite progress in adjuvant chemotherapy in the recent decades, pancreatic and colon cancers remain common causes of death worldwide. Bacterial toxins, which specifically bind to cell ...surface-exposed glycosphingolipids, are a potential novel therapy. We determined the expression of globotriaosylceramide (Gb3Cer/CD77), the Shiga toxin receptor, in human pancreatic and colon adenocarcinomas.
Tissue lipid extracts of matched pairs of cancerous and adjacent normal tissue from 21 pancreatic and 16 colon cancer patients were investigated with thin-layer chromatography overlay assay combined with a novel mass spectrometry approach. Gb3Cer/CD77 was localized by immunofluorescence microscopy of cryosections from malignant and corresponding healthy tissue samples. 62% of pancreatic and 81% of colon adenocarcinomas showed increased Gb3Cer/CD77 expression, whereas 38% and 19% of malignant pancreas and colon tissue, respectively, did not, indicating an association of this marker with neoplastic transformation. Also, Gb3Cer/CD77 was associated with poor differentiation (G>2) in pancreatic cancer (P = 0.039). Mass spectrometric analysis evidenced enhanced expression of Gb3Cer/CD77 with long (C24) and short chain fatty acids (C16) in malignant tissues and pointed to the presence of hydroxylated fatty acid lipoforms, which are proposed to be important for receptor targeting. They could be detected in 86% of pancreatic and about 19% of colon adenocarcinomas. Immunohistology of tissue cryosections indicated tumor-association of these receptors.
Enhanced expression of Gb3Cer/CD77 in most pancreatic and colon adenocarcinomas prompts consideration of Shiga toxin, its B-subunit or B-subunit-derivatives as novel therapeutic strategies for the treatment of these challenging malignancies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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