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Medicina (Kaunas, Lithuania) Jun 2024Hepatocellular carcinoma is the most common primary liver tumor. Orthotopic liver transplant is one of the best treatment options, but its waiting list has to be... (Review)
Review
Hepatocellular carcinoma is the most common primary liver tumor. Orthotopic liver transplant is one of the best treatment options, but its waiting list has to be considered. Bridge therapies have been introduced in order to limit this issue. The aim of this study is to evaluate if bridge therapies in advanced hepatocellular carcinoma can improve overall survival and reduce de-listing. We selected 185 articles. The search was limited to English articles involving only adult patients. These were deduplicated and articles with incomplete text or irrelevant conclusions were excluded. Sorafenib is the standard of care for advanced hepatocellular carcinoma and increases overall survival without any significant drug toxicity. However, its survival benefit is limited. The combination of transarterial chemoembolization + sorafenib, instead, delays tumor progression, although its survival benefit is still uncertain. A few studies have shown that patients undergoing transarterial chemoembolization + radiation therapy have similar or even better outcomes than those undergoing transarterial chemoembolization or sorafenib alone for rates of histopathologic complete response (89% had no residual in the explant). Also, the combined therapy of transarterial chemoembolization + radiotherapy + sorafenib was compared to the association of transarterial chemoembolization + radiotherapy and was associated with a better survival rate (24 vs. 17 months). Moreover, immunotherapy revealed new encouraging perspectives. Combination therapies showed the most encouraging results and could become the gold standard as a bridge to transplant for patients with advanced hepatocellular carcinoma.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Liver Transplantation; Sorafenib; Chemoembolization, Therapeutic; Combined Modality Therapy; Antineoplastic Agents; Bridge Therapy
PubMed: 38929627
DOI: 10.3390/medicina60061010 -
International Journal of Environmental... Jun 2024The emerging concern about chemicals in electronic cigarettes, even those without nicotine, demands the development of advanced criteria for their exposure and risk...
The emerging concern about chemicals in electronic cigarettes, even those without nicotine, demands the development of advanced criteria for their exposure and risk assessment. This study aims to highlight the sensitivity of lung nuclear receptors (NRs) to electronic cigarette e-liquids, independent of nicotine presence, and the influence of the sex variable on these effects. Adult male and female C57BL/6J mice were exposed to electronic cigarettes with 0%, 3%, and 6% nicotine daily (70 mL, 3.3 s, 1 puff per min/30 min) for 14 days, using the inExpose full body chamber (SCIREQ). Following exposure, lung tissues were harvested, and RNA extracted. The expression of 84 NRs was determined using the RT profiler mRNA array (Qiagen). Results exhibit a high sensitivity to e-liquid exposure irrespective of the presence of nicotine, with differential expression of NRs, including one (females) and twenty-four (males) in 0% nicotine groups compared to non-exposed control mice. However, nicotine-dependent results were also significant with seven NRs (females), fifty-three NRs (males) in 3% and twenty-three NRs (female) twenty-nine NRs (male) in 6% nicotine groups, compared to 0% nicotine mice. Sex-specific changes were significant, but sex-related differences were not observed. The study provides a strong rationale for further investigation.
Topics: Animals; Female; Male; Electronic Nicotine Delivery Systems; Mice, Inbred C57BL; Pilot Projects; Mice; Lung; Aerosols; Nicotine; Receptors, Cytoplasmic and Nuclear; Sex Factors
PubMed: 38929056
DOI: 10.3390/ijerph21060810 -
International Journal of Molecular... Jun 2024Hexaazamacrocyclic Schiff bases have been extensively combined with lanthanoid (Ln) ions to obtain complexes with a highly axial geometry. However, the use of flexible...
Hexaazamacrocyclic Schiff bases have been extensively combined with lanthanoid (Ln) ions to obtain complexes with a highly axial geometry. However, the use of flexible hexaazatetraamine macrocycles containing two pyridines and acyclic spacers is rather uncommon. Accordingly, we obtained [DyL(OAc)]OAc·7HO·EtOH and [DyL(Cl)]Cl·2HO, where L and L are the 18-membered macrocycles 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane and 3,10-dimethyl-3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane, respectively, which contain ethylene and methylethylene spacers between their moieties. [DyL(OAc)]OAc·7HO·EtOH represents the first crystallographically characterized lanthanoid complex of L, while [DyL(Cl)]Cl·2HO contributes to increasing the scarce number of Ln compounds containing L. Furthermore, the crystal structure of L·12HO was solved, and it was compared with those of other related macrocycles previously published. Likewise, the crystal structures of the Dy complexes were compared with those of the lanthanoid and -metal complexes of other 18-membered donor macrocycles. This comparison showed some effect of the spacers employed, as well as the influence of the size of the ancillary ligands and the metal ion. Additionally, the distinct folding behaviors of these macrocycles influenced their coordination geometries. Moreover, the luminescent properties of [DyL(OAc)]OAc·7HO·EtOH and [DyL(Cl)]Cl·2HO were also investigated, showing that both complexes are fluorescent, with the emission being sensitized by the ligands.
Topics: Macrocyclic Compounds; Ligands; Coordination Complexes; Lanthanoid Series Elements; Crystallography, X-Ray; Models, Molecular; Molecular Structure
PubMed: 38928512
DOI: 10.3390/ijms25126802 -
International Journal of Molecular... Jun 2024Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic...
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
Topics: Humans; Crizotinib; Thyroid Carcinoma, Anaplastic; Anaplastic Lymphoma Kinase; Cell Proliferation; Protein Kinase Inhibitors; Apoptosis; Thyroid Neoplasms; Male; Female; Antineoplastic Agents; Middle Aged; Cell Movement; Aged; Oncogene Proteins, Fusion; Tumor Cells, Cultured; Cell Line, Tumor; Calmodulin-Binding Proteins; Membrane Proteins; Nerve Tissue Proteins
PubMed: 38928438
DOI: 10.3390/ijms25126734 -
International Journal of Molecular... Jun 2024The levels of the MMPs in the biological samples of confirmed patients with gastric cancer are significantly elevated compared to those found in healthy people....
Determination of Matrix Metalloproteinase 2 in Biological Samples Using a 3D Stochastic Microsensor Based on Graphene Oxide/AuNanoparticles/(Z)-N-(pyridin-4-yl-methyl) Octadec-9-enamide.
The levels of the MMPs in the biological samples of confirmed patients with gastric cancer are significantly elevated compared to those found in healthy people. Therefore, a novel 3D stochastic microsensor based on graphene oxide, modified with gold nanoparticles and (Z)-N-(pyridin-4-yl-methyl) octadec-9-enamide (namely N2-AuNP/GO), was designed for the determination of MMP-2 in biological samples, and validated for the screening tests of biological samples in order to be used for the early diagnosis of gastric cancer. The proposed sensor presents a low limit of quantification (1.00 × 10 g mL), high sensitivity (1.84 × 10 s g mL), and a wide working concentration range (1.00 × 10-1.00 × 10 g mL). Recovery values higher than 99.15% were recorded for the assay of MMP-2 in whole blood, gastric tissue tumors, saliva, and urine samples.
Topics: Graphite; Humans; Matrix Metalloproteinase 2; Metal Nanoparticles; Gold; Stomach Neoplasms; Biosensing Techniques
PubMed: 38928425
DOI: 10.3390/ijms25126720 -
International Journal of Molecular... Jun 2024The lumen of the endoplasmic reticulum (ER) is usually considered an oxidative environment; however, oxidized thiol-disulfides and reduced pyridine nucleotides occur...
The lumen of the endoplasmic reticulum (ER) is usually considered an oxidative environment; however, oxidized thiol-disulfides and reduced pyridine nucleotides occur there parallelly, indicating that the ER lumen lacks components which connect the two systems. Here, we investigated the luminal presence of the thioredoxin (Trx)/thioredoxin reductase (TrxR) proteins, capable of linking the protein thiol and pyridine nucleotide pools in different compartments. It was shown that specific activity of TrxR in the ER is undetectable, whereas higher activities were measured in the cytoplasm and mitochondria. None of the Trx/TrxR isoforms were expressed in the ER by Western blot analysis. Co-localization studies of various isoforms of Trx and TrxR with ER marker Grp94 by immunofluorescent analysis further confirmed their absence from the lumen. The probability of luminal localization of each isoform was also predicted to be very low by several in silico analysis tools. ER-targeted transient transfection of HeLa cells with Trx1 and TrxR1 significantly decreased cell viability and induced apoptotic cell death. In conclusion, the absence of this electron transfer chain may explain the uncoupling of the redox systems in the ER lumen, allowing parallel presence of a reduced pyridine nucleotide and a probably oxidized protein pool necessary for cellular viability.
Topics: Humans; Thioredoxins; Endoplasmic Reticulum; Oxidation-Reduction; HeLa Cells; Thioredoxin-Disulfide Reductase; Mitochondria; Apoptosis; Cell Survival
PubMed: 38928353
DOI: 10.3390/ijms25126647 -
International Journal of Molecular... Jun 2024Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor...
Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor helix distortions effectively inhibits DNA transcription. In our study, we synthesized and characterized three monofunctional Pt(II) complexes with the general formula [Pt(en)(L)Cl]NO, where en = ethylenediamine, and L = pyridine (py), 2-methylpyridine (2-mepy), and 2-phenylpyridine (2-phpy). The hydrolysis rates of [Pt(en)(py)Cl]NO () and [Pt(en)(2-mepy)Cl]NO () decrease with the bulkiness of the auxiliary ligand with k() = 2.28 ± 0.15 × 10 s and k() = 8.69 ± 0.98 × 10 s at 298 K. The complex [Pt(en)(2-phpy)Cl]Cl () demonstrated distinct behavior. Upon hydrolysis, an equilibrium (K = 0.385 mM) between the complexes [Pt(en)(2-phpy)Cl] and [Pt(en)(2-phpy-H)] was observed with no evidence (NMR or HR-ESI-MS) for the presence of the aquated complex [Pt(en)(2-phpy)(HO)]. Despite the kinetic similarities between phenanthriplatin and (), complexes () and () exhibit minimal activity against A549 lung cancer cell line (IC > 100 μΜ), whereas complex () exhibits notable cytotoxicity (IC = 41.11 ± 2.1 μΜ). In examining the DNA binding of () and () to the DNA model guanosine (guo), we validated their binding through guoN7, which led to an increased population of the C3'- sugar conformation, as expected. However, we observed that the rapid transition E (C2') ↔ E (C3'), in the case of [Pt(en)(py)(guo)](NO) ([-guo]), slows down in the case of [Pt(en)(2-mepy)(guo)](NO) ([-guo]), resulting in separate signals for the two conformers in the H NMR spectra. This phenomenon arises from the steric hindrance between the methyl group of pyridine and the sugar moiety of guanosine. Notably, this hindrance is absent in [-(9-MeG)] (9-MeG = 9-methylguanine), probably due to the absence of a bulky sugar unit in 9-MeG. In the case of (), where the bulkiness of the substitution on the pyridine is further increased by a phenyl group, we observed a notable proximity between 9-MeGH8 and the phenyl ring of 2-phpy. Considering that only () exhibited good cytotoxicity against the A549 cancer cell line, it is suggested that auxiliary ligands, L, with an extended aromatic system and proper orientation in complexes of the type cis-[Pt(en)(L)Cl]NO, may enhance the cytotoxic activity of such complexes.
Topics: Antineoplastic Agents; DNA; Humans; Ligands; Organoplatinum Compounds; Cell Line, Tumor; Hydrolysis; Platinum; A549 Cells
PubMed: 38928230
DOI: 10.3390/ijms25126526 -
Journal of Nanobiotechnology Jun 2024The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell...
BACKGROUND
The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application.
RESULTS
The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest.
CONCLUSIONS
The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization.
Topics: Exosomes; Wound Healing; Mesenchymal Stem Cells; Humans; Animals; Wnt Signaling Pathway; Mice; Umbilical Cord; Pyridines; Diabetes Mellitus, Experimental; Pyrimidines; Male; Cells, Cultured; Cell Movement
PubMed: 38926800
DOI: 10.1186/s12951-024-02650-x -
Journal of Medical Case Reports Jun 2024Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial,...
BACKGROUND
Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial, hypoglycemic episodes. We report a case of a previously healthy 67-year-old man presenting with recurrent fasting hypoglycemia culminating in a diagnosis of insulin autoimmune syndrome linked to omeprazole and probably spices, namely, coriander, and ginger.
CASE PRESENTATION
A previously healthy 67-year-old Sinhalese man presented with recurrent syncopal attacks for 3 months, which were found to be hypoglycemic episodes. He experienced mainly fasting hypoglycemic attacks, at a frequency gradually increasing to daily attacks. His cardiovascular, respiratory, abdominal, and neurologic examinations were normal. He was found to have insulin levels > 6000 mU/L and a post-polyethylene glycol insulin recovery of less than 9.5%. Contrast-enhanced computed tomography of the pancreas was normal. The diagnosis of insulin autoantibody syndrome was confirmed by testing for the insulin autoantibody level, yielding a level of > 300 U/mL. With regard to a possible trigger, he had a history of omeprazole intake for 2 weeks, 4 weeks prior to the onset of symptoms. He also consumed an herbal supplement containing coriander and ginger extracts daily for a period of 1 year, approximately 2 years prior to the onset of hypoglycemic attacks. He was commenced on prednisolone 30 mg daily, and hypoglycemic episodes responded dramatically, and thus he was tapered off corticosteroids.
CONCLUSION
Omeprazole-induced insulin autoantibody syndrome is likely in this patient; however, the known hypoglycemic effects of coriander and ginger make it worthwhile to consider a possible association with insulin autoantibody syndrome. In addition, this case report highlights the need to consider insulin autoantibody syndrome even in patients presenting with fasting hypoglycemic attacks.
Topics: Humans; Male; Aged; Hypoglycemia; Insulin Antibodies; Omeprazole; Autoimmune Diseases; Insulin; Zingiber officinale; Syndrome; Autoantibodies
PubMed: 38926797
DOI: 10.1186/s13256-024-04616-x -
BMC Neuroscience Jun 2024Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This...
BACKGROUND
Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons.
RESULT
The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes.
CONCLUSION
Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.
Topics: Animals; Astrocytes; Rats, Wistar; Microglia; Receptor, Angiotensin, Type 2; Telmisartan; Angiotensin II Type 1 Receptor Blockers; Neurons; Receptor, Angiotensin, Type 1; Ischemic Stroke; Angiotensin II Type 2 Receptor Blockers; Rats; Cells, Cultured; Pyridines; Imidazoles; Animals, Newborn; Benzimidazoles; Cell Communication
PubMed: 38926677
DOI: 10.1186/s12868-024-00876-x