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Approximately 62-72 million people are infected worldwide with HDV. Patients with chronic hepatitis D (CHD) have a higher risk of developing cirrhosis or hepatocellular carcinoma (HCC) and an increased mortality rate compared to those with chronic hepatitis B (CHB). The stage of liver fibrosis or the risk of developing HCC can also be estimated by non-invasive scores, which are cost effective, easier to apply, and reproducible. In this study, we aimed to evaluate the predictive value of four non-invasive scores (FIB-4, APRI, AST/ALT ratio, and aMAP) in assessing severe fibrosis/cirrhosis and the presence of HCC in patients with HBV/HDV superinfection, as compared with HBV mono-infection. Our 8-year retrospective analysis revealed that HDV-infected patients had a 2-3 times higher risk of developing cirrhosis and HCC than HBV-mono-infected subjects. High AST and ALT baseline levels qualified as independent predictors for cirrhosis development in both groups. The following fibrosis scores, FIB-4, APRI score, and AAR, were significantly increased when cirrhosis was present at baseline and showed a good prediction for developing cirrhosis in the CHD group. The aMAP score, a risk predictor for HCC, showed significantly higher values in patients with HCC in both groups. Nonetheless, non-invasive scores should always be considered for monitoring patients with CHB and CHD, but only when associated with other diagnosis methods.

Background: In this study, we compared programmed death-ligand 1 (PD-L1) expression in primary tissue samples and its soluble form (sPD-L1) concentration in matched preoperative plasma samples from gastric cancer patients to understand the relationship between tissue and plasma PD-L1 expression and to determine its diagnostic and prognostic value., Methods: PD-L1 expression in tissue was assessed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), and sPD-L1 concentration in plasma was quantified by ELISA. The levels of the CD274 gene, which encodes for PD-L1 protein, were examined as part of bulk tissue RNA-sequencing analyses. Additionally, we evaluated the association between sPD-L1 levels and various laboratory parameters, disease characteristics, and patient outcomes., Results: GC patients had significantly higher levels of sPD-L1 in their plasma (71.69 pg/mL) compared to healthy controls (35.34 pg/mL) (p < 0.0001). Moreover, sPD-L1 levels were significantly correlated with tissue PD-L1 protein, CD274 mRNA expression, larger tumor size, advanced tumor stage, and lymph node metastasis. Elevated sPD-L1 levels (> 103.5 ng/mL) were associated with poor overall survival (HR = 2.16, 95%CI 1.15-4.08, p = 0.017). Furthermore, intratumoral neutrophil and dendritic cell levels were directly correlated with plasma sPD-L1 concentration in the GC patients., Conclusions: sPD-L1 was readily measurable in GC patients, and its level was associated with GC tissue PD-L1 expression, greater inflammatory cell infiltration, disease progression, and survival. Thus, sPD-L1 may be a useful minimally invasive diagnostic and prognostic biomarker in GC patients., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Although treatment with fixed or mobile appliances has become an important part of modern orthodontics, side effects such as white spot lesions (WSLs) have a negative impact on the aesthetic outcome of orthodontic treatment. The purpose of this article was to review current evidence on the diagnosis, risk assessment, prevention, management and post-orthodontic treatment of these lesions. Data collection was performed electronically, and the initial search using the keywords "white spot lesions", "orthodontics", "WSL", "enamel" and "demineralization" in different combinations resulted in 1032 articles for the two electronic databases used. Ultimately, a total of 47 manuscripts were considered relevant to the aim of this research and included in this review. The results of the review indicate that WSLs remain a significant problem during orthodontic treatment. According to studies in the literature, the severity of WSLs correlates to the duration of treatment. Using toothpaste with more than 1000 ppm fluoride at home reduces the frequency of WSL separation and regular application of varnishes in the office reduces the frequency of the occurrence of WSLs only in the context of maintaining a strict hygiene regime. The old hypothesis that elastomeric ligatures retain more dental plaque than metal ones has been refuted. There are no differences in the appearance of WSLs between conventional brackets and self-ligating brackets. Clear aligner mobile devices develop fewer WSLs but are more extensive as opposed to conventional fixed devices, while lingual orthodontic appliances have a lower incidence of WSLs, and the most effective device for preventing these lesions is WIN, followed by Incognito.

Experimental models of a clinical, pathophysiological context are used to understand molecular mechanisms and develop novel therapies. Previous studies revealed better outcomes for spinal cord injury chronic ethanol-consuming patients. This study evaluated cellular and molecular changes in a model mimicking spinal cord injury (hypoxic stress induced by treatment with deferoxamine or cobalt chloride) in chronic ethanol-consuming patients (ethanol-exposed neural cultures (SK-N-SH)) in order to explain the clinical paradigm of better outcomes for spinal cord injury chronic ethanol-consuming patients. The results show that long-term ethanol exposure has a cytotoxic effect, inducing apoptosis. At 24 h after the induction of hypoxic stress (by deferoxamine or cobalt chloride treatments), reduced ROS in long-term ethanol-exposed SK-N-SH cells was observed, which might be due to an adaptation to stressful conditions. In addition, the HIF-1α protein level was increased after hypoxic treatment of long-term ethanol-exposed cells, inducing fluctuations in its target metabolic enzymes proportionally with treatment intensity. The wound healing assay demonstrated that the cells recovered after stress conditions, showing that the ethanol-exposed cells that passed the acute step had the same proliferation profile as the cells unexposed to ethanol. Deferoxamine-treated cells displayed higher proliferative activity than the control cells in the proliferation-migration assay, emphasizing the neuroprotective effect. Cells have overcome the critical point of the alcohol-induced traumatic impact and adapted to ethanol (a chronic phenomenon), sustaining the regeneration process. However, further experiments are needed to ensure recovery efficiency is more effective in chronic ethanol exposure.

Despite advances in cancer detection and therapy, it has been estimated that the incidence of cancers will increase, while the mortality rate will continue to remain high, a fact explained by the large number of patients diagnosed in advanced stages when therapy is often useless. Therefore, it is necessary to invest knowledge and resources in the development of new non-invasive biomarkers for the early detection of cancer and new therapeutic targets for better health management. In this review, we provided an overview on the collagen family as promising biomarkers and on how they may be exploited as therapeutic targets in cancer. The collagen family tridimensional structure, organization, and functions are very complex, being in a tight relationship with the extracellular matrix, tumor, and immune microenvironment. Moreover, accumulating evidence underlines the role of collagens in promoting tumor growth and creating a permissive tumor microenvironment for metastatic dissemination. Knowledge of the molecular basis of these interactions may help in cancer diagnosis and prognosis, in overcoming chemoresistance, and in providing new targets for cancer therapies.

The continuous variability of SARS-CoV-2 and the rapid waning of specific antibodies threatens the efficacy of COVID-19 vaccines. We aimed to evaluate antibody kinetics one year after SARS-CoV-2 vaccination with an mRNA vaccine in healthcare workers (HCW), with or without a booster. A marked decline in anti-Spike(S)/Receptor Binding Domain (RBD) antibody levels was registered during the first eight months post-vaccination, followed by a transitory increase after the booster. At three months post-booster an increased antibody level was maintained only in HCW vaccinated after a prior infection, who also developed a higher and long-lasting level of anti-S IgA antibodies. Still, IgG anti-nucleocapsid (NCP) fades five months post-SARS-CoV-2 infection. Despite the decline in antibodies one-year post-vaccination, 68.2% of HCW preserved the neutralization capacity against the ancestral variant, with a decrease of only 17.08% in the neutralizing capacity against the Omicron variant. Nevertheless, breakthrough infections were present in 6.65% of all participants, without any correlation with the previous level of anti-S/RBD IgG. Protection against the ancestral and Omicron variants is maintained at least three months after a booster in HCW, possibly reflecting a continuous antigenic stimulation in the professional setting.

This paper aimed to develop two types of support materials with a mesoporous structure of mobile crystalline matter (known in the literature as MCM, namely MCM-41 and MCM-48) and to load them with gallic acid. Soft templating methodology was chosen for the preparation of the mesoporous structures-the cylindrical micelles with certain structural characteristics being formed due to the hydrophilic and hydrophobic intermolecular forces which occur between the molecules of the surfactants (cetyltrimethylammonium bromide-CTAB) when a minimal micellar ionic concentration is reached. These mesoporous supports were loaded with gallic acid using three different types of MCM-gallic acid ratios (1:0.41; 1:0.82 and 1:1.21)-and their characterizations by FTIR, SEM, XRD, BET and drug release were performed. It is worth mentioning that the loading was carried out using a vacuum-assisted methodology: the mesoporous materials are firstly kept under vacuum at ~0.1 barr for 30 min followed by the addition of the polyphenol solutions. The concentration of the solutions was adapted such that the final volume covered the wet mesoporous support and-in this case-upon reaching normal atmospheric pressure, the solution was pushed inside the pores, and thus the polyphenols were mainly loaded inside the pores. Based on the S BET data, it can be seen that the specific surface area decreased considerably with the increasing ratio of gallic acid; the specific surface area decreased 3.07 and 4.25 times for MCM-41 and MCM-48, respectively. The sample with the highest polyphenol content was further evaluated from a biological point of view, alone or in association with amoxicillin administration. As expected, the MCM-41 and MCM-48 were not protective against infections-but, due to the loading of the gallic acid, a potentiated inhibition was recorded for the tested gram-negative bacterial strains. Moreover, it is important to mention that these systems can be efficient solutions for the recovery of the gut microbiota after exposure to antibiotics, for instance.

Gastric cancer has remained in the top five cancers for over ten years, both in terms of incidence and mortality due to the shortage of biomarkers for disease follow-up and effective therapies. Aiming to fill this gap, we performed a bioinformatics assessment on our data and two additional GEO microarray profiles, followed by a deep analysis of the 40 differentially expressed genes identified. PPI network analysis and MCODE plug-in pointed out nine upregulated hub genes coding for proteins from the collagen family (COL12A1, COL5A2, and COL10A1) or involved in the assembly (BGN) or degradation of collagens (CTHRC1), and also associated with cell adhesion (THBS2 and SPP1) and extracellular matrix degradation (FAP, SULF1). Those genes were highly upregulated at the mRNA and protein level, the increase being correlated with pathological T stages. The high expression of BGN ( p = 8 × 10 -12 ), THBS2 ( p = 1.2 × 10 -6 ), CTHRC1 ( p = 1.1 × 10 -4 ), SULF1 ( p = 3.8 × 10 -4 ), COL5A1 ( p = 1.3 × 10 -4 ), COL10A1 ( p = 5.7 × 10 -4 ), COL12A1 ( p = 2 × 10 -3 ) correlated with poor overall survival and an immune infiltrate based especially on immunosuppressive M2 macrophages ( p -value range 4.82 × 10 -7 -1.63 × 10 -13 ). Our results emphasize that these genes could be candidate biomarkers for GC progression and prognosis and new therapeutic targets.

SARS-CoV-2 vaccines are highly efficient against severe forms of the disease, hospitalization and death. Nevertheless, insufficient protection against several circulating viral variants might suggest waning immunity and the need for an additional vaccine dose. We conducted a longitudinal study on the kinetics and persistence of immune responses in healthcare workers vaccinated with two doses of BNT162b2 mRNA vaccine with or without prior SARS-CoV-2 infection. No new infections were diagnosed during follow-up. At 6 months, post-vaccination or post-infection, despite a downward trend in the level of anti-S IgG antibodies, the neutralizing activity does not decrease significantly, remaining higher than 75% (85.14% for subjects with natural infection, 88.82% for vaccinated after prior infection and 78.37% for vaccinated only). In a live-virus neutralization assay, the highest neutralization titres were present at baseline and at 6 months follow-up in persons vaccinated after prior infection. Anti-S IgA levels showed a significant descending trend in vaccinated subjects (p < 0.05) after 14 weeks. Cellular immune responses are present even in vaccinated participants with declining antibody levels (index ratio 1.1-3) or low neutralizing activity (30%-40%) at 6 months, although with lower T-cell stimulation index (p = 0.046) and IFN-γ secretion (p = 0.0007) compared to those with preserved humoral responses., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Liquid biopsy represents an exciting new area in the field of cancer diagnosis and management, offering a less invasive and more convenient approach to obtain a time-point image of the tumor burden and its genomic profile. Samples collected from several body fluids, mostly blood, can be used to gain access to circulating tumor cells and DNA, non-coding RNAs, microRNAs, and exosomes, at any moment, offering a dynamic picture of the tumor. For patients with GC, the use of blood-based biopsies may be particularly beneficial since tissue biopsies are difficult to obtain and cause real distress to the patient. With advantages such as repeatability and minimal invasion, it is no wonder that the field of liquid biopsy has received tremendous attention. However, the abundance of studies, involving a wide range of assays with different principles, prevented for the moment the reproducibility of the results and therefore the translation into the clinic of liquid biopsy. In this review, we present the latest technical development and data on circulating biomarkers available through liquid biopsy in gastric cancer with an emphasis on their clinical utility in areas such as cancer screening, prognostic stratification, and therapeutic management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chivu-Economescu, Necula, Matei, Dragu, Bleotu and Diaconu.)

Left ventricular volumes (LVVs) and ejection fraction (LVEF) are key elements in the evaluation and follow-up of patients with heart failure with reduced ejection fraction (HFrEF). Therefore, a feasible and reproducible imaging method to be used by both experienced and in-training echocardiographers is mandatory. Our aim was to establish if, in a large echo lab, echocardiographers in-training provide feasible and more reproducible results for the evaluation of patients with HFrEF when using 3-dimensional echocardiography (3-DE) versus 2-dimensional echocardiography (2-DE). Sixty patients with HFrEF (46 males, age: 58 ± 17 y) underwent standard transthoracic 2-D acquisitions and 3-D multibeat full volumes of the left ventricle. One expert user in echocardiography (expert) and three echocardiographers with different levels of training in 2-DE (beginner, medium and advanced) measured the 2-D LVVs and LVEFs on the same consecutive images of patients with HFrEF. Afterward, the expert performed a 1-mo training in 3-DE analysis of the users, and both the expert and trainees measured the 3-D LVVs and LVEF of the same patients. Measurements provided by the expert and all trainees in echo were compared. Six patients were excluded from the study because of poor image quality. The mean end-diastolic LVV of the remaining 54 patients was 214 ± 75 mL with 2-DE and 233 ± 77 mL with 3-DE. Mean LVEF was 35 ± 10% with 2-DE and 33 ± 10% with 3-DE. Our analysis revealed that, compared with the expert user, the trainees had acceptable reproducibility for the 2-DE measurements, according to their level of expertise in 2-DE (intra-class coefficients [ICCs] ranging from 0.75 to 0.94). However, after the short training in 3-DE, they provided feasible and more reproducible measurements of the 3-D LVVs and LVEF (ICCs ranging from 0.89-0.97) than they had with 2-DE. 3-DE is a feasible, rapidly learned and more reproducible method for the assessment of LVVs and LVEF than 2-DE, regardless of the basic level of expertise in 2-DE of the trainees in echocardiography. In echo labs with a wide range of staff experience, 3-DE might be a more accurate method for the follow-up of patients with HFrEF., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Three novel Co(II) complexes of the type [Co(C 4 H 5 O 2 ) 2 L 2 ] (where C 4 H 5 O 2 is methacrylate anion; L = C 3 H 4 N 2 (imidazole; HIm) ( 1 ), C 4 H 6 N 2 (2-methylimidazole; 2-MeIm) ( 2 ), C 5 H 8 N 2 (2-ethylimidazole; 2-EtIm) ( 3 )) have been synthesized and characterized by elemental analysis, IR and UV-Vis spectroscopic techniques, thermal analysis and single crystal X-ray diffraction. X-ray crystallography revealed for complexes ( 1 ) and ( 2 ) distorted trigonal bipyramid stereochemistry for Co(II), meanwhile for complex ( 3 ) evidenced that the unit cell comprises three molecular units with interesting structural features. In each unit, both stereochemistry adopted by metallic ion and coordination modes of carboxylate anions are different. The screening of antimicrobial activity revealed that Candida albicans planktonic cells were the most susceptible, with minimal inhibitory concentration (MIC) values of 7.8 μg/mL for complexes ( 1 ) and ( 2 ) and 15.6 μg/mL for complex ( 3 ). Complexes ( 1 ) and ( 2 ) proved to be more active than complex ( 3 ) against the tested bacterial strains, both in planktonic and biofilm growth state, with MIC and minimal biofilm eradication concentration (MBEC) values ranging from 15.6 to 62.5 μg/mL, the best antibacterial effects being noticed against Staphylococcus aureus and Pseudomonas aeruginosa . Remarkably, the MBEC values obtained for the four tested bacterial strains were either identical or even lower than the MIC ones. The cytotoxicity assay indicated that the tested complexes affected the cellular cycle of HeLa, HCT-8, and MG63 cells, probably by inhibiting the expression of vimentin and transient receptor potential canonical 1 (TRPC1). The obtained biological results recommend these complexes as potential candidates for the development of novel anti-biofilm agents.

Starting from isoniazid and carboxylic acids as precursors, thirteen new hydrazides and 1,3,4-oxadiazoles of 2-(4-substituted-phenoxymethyl)-benzoic acids were synthesized and characterized by appropriate means. Their biological properties were evaluated in terms of apoptosis, cell cycle blocking, and drug metabolism gene expression on HCT-8 and HT-29 cell lines. In vitro antimicrobial tests were performed by the microplate Alamar Blue assay for the anti-mycobacterial activities and an adapted agar disk diffusion technique for other non-tubercular bacterial strains. The best antibacterial activity (anti- Mycobacterium tuberculosis effects) was proved by 9 . Compounds 7 , 8 , and 9 determined blocking of G1 phase. Compound 7 proved to be toxic, inducing apoptosis in 54% of cells after 72 h, an effect that can be predicted by the increased expression of mRNA caspases 3 and 7 after 24 h. The influence of compounds on gene expression of enzymes implicated in drug metabolism indicates that synthesized compounds could be metabolized via other pathways than NAT2, spanning adverse effects of isoniazid. Compound 9 had the best antibacterial activity, being used as a disinfectant agent. Compounds 7 , 8 , and 9 , seemed to have antitumor potential. Further studies on the action mechanism of these compounds on the cell cycle may bring new information regarding their biological activity.

Traumatic brain injury (TBI) represents a public healthcare problem and a major economic burden, all over the world. It is estimated that every year, on the globe, there occur about two million severe TBI and over 42 million mild TBI. The main causes of TBI in civil population are fallings, followed by car accidents. In the last decades, the accelerated development of car industry and the poor development of traffic infrastructure in low- and average-income countries led to an increasing number of brain injuries, this becoming a major problem for medical health systems. According to some studies, approximately 1.35 million people die every year because of car accidents. In the last four decades, these types of injuries started to be studied in order to understand the lesion mechanisms for developing new safety equipment that may be installed on vehicles. The device presented by us for causing a TBI in a lab rat (mechanical pendulum) allows the performance of several major types of TBI, according to the kinetic energy, exposure area, contact surface, etc. The impact energies obtained by the device we presented may vary on a large scale, from less than 1 J up to 10 J, according to its weight, launching angle and impact head shape, thus being obtained minor, moderate or severe TBI.

Background: Gastric cancer (GC) remains an aggressive malignancy with a high rate of mortality, being the third leading cause of cancer-related death. More than one million newly diagnosed cases and 782685 deaths due to GC were reported in 2018. GC is characterized by limited effective treatment options and the lack of consistent biomarkers for the diagnosis and prognosis of these patients. The discovery of new biomarkers useful in the early diagnosis of GC is mandatory., Aim: To evaluate the potential of COL10A1 as a circulating biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients., Methods: Plasma and tissue obtained from 49 patients with gastric adenocarcinoma have been used in exploring the expression of COL10A1. Real-time PCR and western blot techniques were used to evaluate COL10A1 level in gastric tumor tissue compared to normal adjacent tissue. The circulating level of COL10A1 was also evaluated by ELISA in plasma of gastric adenocarcinoma patients. Survival analysis was made in order to evaluate the potential of COL10A1 as a biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients., Results: Our results showed a significant increase in COL10A1 gene expression and protein levels in gastric tumor tissue compared to adjacent normal tissue ( P < 0.05). COL10A1 seems to show an elevated expression from the beginning of carcinogenesis, in the early stages, and its increased level remains elevated during cancer progression. A significant increase of COL10A1 plasma level in gastric adenocarcinoma patients was also identified. Moreover, increased COL10A1 plasma level was associated with poor survival of the patients. Plasma COL10A1 performed a diagnostic value in GC with area under the receiver operating characteristic curve (AUC) of 0.9171 ( P = 0.0002), sensitivity of 87.76%, and specificity of 100.0%. Furthermore, this study demonstrated the potential role of plasma COL10A1 in the early detection of GC, as in the early stage, we obtained an AUC of 0.8789 ( P = 0.0030), sensitivity of 81.25%, and specificity of 100.0%., Conclusion: Circulating expression level of COL10A1 is significantly increased in gastric adenocarcinoma patients being associated with poor survival and is a potential biomarker for early detection of GC., Competing Interests: Conflict-of-interest statement: This work was supported by a grant of the Romanian Authority for Scientific Research and Innovation, CNCS - UEFISCDI, No. PN-III-P4-ID-PCCF-2016-0158 (contract PCCF 17/2018), within PNCDI III. All other authors have nothing to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy., Competing Interests: Conflict-of-interest statement: Authors declare no potential conflicts of interest for this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest.

Alterations in the bone marrow niche induced by abnormal production of cytokines and other soluble factors have been associated with disease progression in classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Variations in circulating proteins might reflect local disease processes and plasma proteome profiling could serve to identify possible diagnostic and prognostic biomarkers. We employed a human cytokine array to screen for 105 distinct analytes in pooled plasma samples obtained from untreated young MPN patients (<35 years) with different clinical phenotypes and driver mutations, as well as from healthy individuals. Among molecules that exhibited significantly increased levels in MPN patients versus controls, the top of the list was represented by Dickkopf-related protein 1 (Dkk-1), which also showed the highest potential for discrimination between MPN subtypes. In the next step, a quantitative ELISA was used to measure plasma Dkk-1 levels in 30 young-onset MPN-10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 pre-fibrotic primary myelofibrosis (pre-PMF)-and 10 controls. The results suggested that plasma Dkk-1 levels could differentiate ET from pre-PMF, in JAK2 V617F-positive as well as in CALR-positive patients, and also ET from PV in JAK2 V617F-positive patients., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Acute myeloid leukemia (AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells (LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to introduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest.

Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest.

Gamma-ray detection and spectroscopy is the quantitative determination of their energy spectra, and is of critical value and critically important in diverse technological and scientific fields. Here we report an improved melt growth method for cesium lead bromide and a special detector design with asymmetrical metal electrode configuration that leads to a high performance at room temperature. As-grown centimeter-sized crystals possess extremely low impurity levels (below 10 p.p.m. for total 69 elements) and detectors achieve 3.9% energy resolution for 122 keV 57 Co gamma-ray and 3.8% for 662 keV 137 Cs gamma-ray. Cesium lead bromide is unique among all gamma-ray detection materials in that its hole transport properties are responsible for the high performance. The superior mobility-lifetime product for holes (1.34 × 10 -3  cm 2  V -1 ) derives mainly from the record long hole carrier lifetime (over 25 μs). The easily scalable crystal growth and high-energy resolution, highlight cesium lead bromide as an exceptional next generation material for room temperature radiation detection.

Background: Keratin 17 (KRT17) was shown to be an important molecular marker for predicting the carcinogenesis, progression, and prognosis of various cancer types. Our previous studies identified KRT17 as a possible biomarker for gastric cancer by gene microarray, with an elevated expression that occurred early during tumorigenesis and increased during tumor progression. Based on these findings, we aimed to investigate KRT17 biological functions in gastric adenocarcinoma and its possible use as a rational molecular target for anticancer therapy., Methods: We used RNA interference-mediated knockdown of KRT17 expression and analyzed the effects on cell proliferation, cell migration, and signal transduction in two gastric cell lines (AGS and NCI-N87) in vitro and on xenograft growth in vivo., Results: The functional analysis of KRT17 knockdown cell lines showed a decreased cell proliferation (with 42.36% ± 3.2%) and migration ability (with 37.2% ± 6.2%) relative to scrambled siRNA control. The in vivo tumorigenicity on nude mice exhibited a significant decrease in tumor weight with 69.14% in xenografts obtained from AGS cells and 84.43% in xeno-NCI-N87 tumors. The analysis on KRT17 knockdown outcome on intracellular signaling identifies AKT/mTOR as the main affected pathway that sustains proliferation and survival, and also the AMPKα1/CREB pathway that was recently shown to induce organ protection and antiinflammatory response., Conclusions: Our results highlight KRT17 as a possible biomarker in gastric cancer promoting tumor growth, motility, and invasion, and suggest that KRT17 can be a valuable molecular target for development of anti-gastric cancer-specific therapies.

Despite their commensal status, staphylococci can become problematic pathogens expressing multiple and redundant virulence factors. This study aimed to evaluate aggressiveness markers comparatively in staphylococcal strains isolated from severe infections versus asymptomatic carriage in order to identify clinically relevant bacterial traits that could easily be detected in clinical practice and could be suggestive for particular host-pathogen interactions such as cyto-adhesion or biofilm formation, ultimately orienting the clinical decision-making process. We have used in vitro phenotypic methods to assess adhesion to and invasion of eukaryotic cells, biofilm development, and expression of soluble virulence factors in 92 Staphylococcus spp. strains. The adhesion index, invasion capacity, biofilm formation and expression of soluble factors did not differ significantly between clinical and commensal strains. The major bacterial traits we found to be significantly more prevalent in clinical staphylococci were the aggregative adhesion pattern (P = 0.012), cluster adhesion (P = 0.001) and tetrad morphology (P = 0.018). The aggregative adhesion pattern was correlated with higher cyto-adhesion (P < 0.001), higher invasion capacity (P = 0.003) and lower Carmeli scores (P = 0.002). Three major bacterial traits, namely tetrad morphology, aggregative adhesion pattern, and resistance to methicillin (acronym: TAM), can be used to compute an aggressiveness score (SAS) predictive of the staphylococcal strain's virulence and capacity to initiate and develop a biofilm-driven chronic infectious process versus a fulminant acute infection, in a susceptible host., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The current understanding of BCR-ABL1 negative myeloproliferative neoplasms pathogenesis is centred on the phenotypic driver mutations in JAK2, MPL, or CALR genes, and the constitutive activation of JAK-STAT pathway. Nonetheless, there is still a need to better characterize the cellular processes that are triggered by these genetic alterations, such as apoptosis that might play a role in the pathological expansion of the myeloid lineages and, especially, in the morphological anomalies of the bone marrow megakaryocytes. In this article we will explore the connection between the driver mutations in MPN and the abnormal apoptosis that might be translated in new therapeutic strategies.

We designed and synthesized new pyrazole thiourea chimeric derivatives and confirmed their structures by NMR and IR spectra. Apoptotic effects were studied in human cancer cells. The N-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-N'-(3-bromophenyl)-thiourea compound (4b) exhibited the highest apoptosis-inducing effect. Compound 4b and the thiazole derivatives, 5b and 6b, increased the expression of tumor necrosis factor receptors TRAIL-R2 and TRAIL-R1, accompanied by down-modulation of pro-caspase 3 levels, and the augmentation of cleaved caspase 3. They also reduced the levels of apoptosis inhibitory proteins and the expression of the heat-shock proteins Hsp27 and Hsp70. All the tested pyrazole derivatives induced a concentration-dependent increase of cells in G2/M phases. The analysis of the experimental data indicates the reduction of Akt phosphorylation as the most probable cellular mechanism of action for the tested compounds. The in vitro study indicated that compound 4b could be a promising anti-cancer drug, to be further developed in animal models of cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.0(2.7)]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.0(2.7)]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6. It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3, but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT-8 cell lines. The expression level of CYP3A4 was increased by compounds 1, 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co-administration with new compounds in slow acetylators., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate the response of HeLa cells to the interaction with inactivated Staphylococcus aureus cells and live challenge with herpes simplex virus (HSV).The results of this study are indicating that the interaction between the HeLa cells and S. aureus inactivated whole cells could modulate the host cell apoptosis and cytokine production, and therefore, influence the progression of HSV infection. The pre-treatment of HeLa cells with heat inactivated bacterial whole cells protects them from the occurrence of HSV mediated cytopathic effect, while the post viral infection treatment with bacterial cells prevents the high activation of bax/bcl-2 apoptotic pathway, a process that could change the fate of the infectious process triggered by the virus, and eventually reduce its multiplication rate. The pre-treatment of HeLa monolayer with inactivated bacterial cells 24 hours before the viral infection is increasing the expression level of TNF-a, IL-6 and IL-8 pro-inflammatory cytokines genes, also suggesting that bacterial antigens could contribute to the decrease of viral multiplication rate.

Objectives : To bring a neonatal classification system of unilateral cleft lip and palate and to correlate this classification with the distribution of the permanent lateral incisor and maxillary growth. Design : Retrospective with longitudinal follow-up. Setting : Tertiary. Patients : A total of 112 individuals with treated unilateral cleft lip and palate and 30 controls. Main Outcome Measures : Unilateral cleft lip and palate neonatal casts were classified anatomically in four categories, in which Class 1 corresponds to a maxillary arch with a narrow alveolar cleft; Class 2 corresponds to a balanced form; Class 3 corresponds to a wide cleft and short maxilla; and Class 4 corresponds to a wide cleft and long maxilla. The classification was correlated with the distribution of the permanent lateral incisor. Maxillary growth was evaluated using a cephalometric analysis after the age of 10 years. Results : Clinical classification of unilateral cleft lip and palate found 10 cases of Class 1 (8.9%), 34 cases of Class 2 (30.4%), 46 cases of Class 3 (41.1%), and 22 cases of Class 4 (19.6%). The permanent lateral incisor was most often present in narrower clefts (Classes 1 and 2); whereas, large clefts (Classes 3 and 4) were relatively more frequently associated with an agenesis of the permanent lateral incisor (P = .019). Maxillary growth impairment was most severe in Class 3, with a mean sella-nasion-A point angle at 71.9° ± 4.6° (P < .001). Conclusions : Using the cleft width, arch form, and shape of the nasal septum, unilateral cleft lip and palate can be classified into four different classes at birth, which can all give information about permanent lateral incisor agenesis and maxillary growth.

Thrombotic events are highly prevalent in systemic lupus erythematosus (SLE). Antiphospholipid antibodies play an essential role in promoting thrombosis by activating several intracellular signaling pathways (TLR4, p38MAPK, NFkB) in platelets, monocytes and endothelial cells. New therapeutic opportunities might be offered by addressing these molecular targets. Chronic inflammatory status, the degree of disease activity and accelerated atherosclerosis are also responsible for the thrombotic phenotype in patients with SLE. The aim of this review is to highlight thrombosis mechanisms and to look for possible connection between SLE, antiphospholipid antibodies and cancer, especially myeloproliferative neoplasms.

The aim of the study was to synthesize some new compounds with potential anti-tuberculosis activity, containing isoniazid and α,β-unsaturated thiocinnamamide-like thioamides as precursors. The obtained derivatives were evaluated regarding their biological activity (antioxidant and antibacterial), as well as their influence on the eukaryotic cell cycle. The results suggested that the newly obtained derivatives of isoniazid exhibited different biological activities, depending on their structure; thus, the most active compound in terms of anti-oxidant and anti-Mycobacterium tuberculosis effects proved to be the isonicotinic acid N'-(1-amino-1-mercapto-3-phenyl-propen-1-yl)-hydrazide. This compound also increased the expression of NAT1 and NAT2 genes, which are implicated in the metabolism of the isoniazid, demonstrating that it could be rapidly metabolized, and thus well tolerated. The largest spectrum of antibacterial activity (excluding M. tuberculosis) was noticed for the isonicotinic acid N'-[1-amino-1-mercapto-3-(p-chloro-phenyl)-propen-1-yl]-hydrazide, which was also the most cytotoxic, especially at high concentrations, although not significantly affecting the cellular cycle phases. The obtained results showed that the new derivatives could represent potential candidates for the treatment of M. tuberculosis infections, but further research is needed in order to improve their pharmacological properties, by increasing their antimicrobial activity and reducing the risk of side-effects., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The number of evidences regarding the role of tumor stem cells (TSC) in the initiation and progression of high-grade astrocytomas became more and more numerous in the last years. This issue has been intensively tested in glioblastoma, but little attention has been paid for anaplastic astrocytoma. The main objective of this paper was to study the morphological characteristics of the xenografts developed from glioblastoma and anaplastic astrocytoma derived cancer stem cells., Methods: The authors of this study successfully isolated and partial characterized primary cultures of glioblastoma and anaplastic astrocytoma derived TSC. Tumors stem cells have been stereotactically inoculated in nude mice brains and the xenografts have been studied using morphological and imunohistochemistry techniques., Results: The tumor xenografts which have been established in nude mice using TSC had different characteristics when compared with U87 xenografts previously developed by our group, and depend of the origin type of the tumors (glioblastoma versus anaplastic astrocytoma). The diffuse growing pattern and cells infiltration have been more pronounced in both anaplastic astrocytoma and glioblastoma derived TSC xenografts compared with U87 line xenografts., Conclusion: Our results support the hypothesis regarding the role of TSC in the infiltration process of glioblastoma and anaplastic astrocytoma. The extensive infiltration growing patterns of these types of xenografts make them useful models for studying the invasion mechanisms in gliomas.

Although significant progresses were made in the field of molecular biology of malignant cerebral gliomas, the prognostic of these tumors continues to be reserved. One of the therapeutic failure reasons is the incomplete knowledge regarding the origin of these tumors and cells features, which in fact represent an obstacle in developing a cell and molecular therapy guided against malignant cells responsible for the tumor development and for the therapeutic resistance. Initiation and characterization of glioblastoma cell lines represents an essential step in order to obtain a better in vitro and in vivo experimental model for glioblastoma. We describe here a new glioblastoma line, named T11, which was successfully isolated in our laboratories starting with a tumor sample obtained intraoperative from a 58 years-old female patient. The histopathological evaluation showed a grad IV WHO glioma (glioblastoma). The sample was prepared by manual fragmentation, followed by enzymatic digestions using different concentration of trypsin. The cell line has been cultivated for more than 150 passages. The characterization of the glioblastoma line consisted in the evaluation of cells proliferation capacity (growth curve), morphological features, karyotyping and identification of specific markers. We found that T11 expressed specific markers for glial progenitors and astrocytes (glial fibrillary acidic protein-GFAP); oligodendrocites (A2B5; O4), and microglia (CD45, CD 11b). Cells were negative for neuronal lineage markers like beta3-tubulin and NCAM. In order to evaluate the differentiation grade of T11 cell line, the presence of stem cell markers (nestin, CD133) was explored. T11l cells expressed higher level of nestin and lower level of CD133 comparing with standard glioblastoma cell line U87. T11 cell line expressed VEGF and Bcl-2, but not EGFR and Mdrl and Bax. This new line has distinct and unique characteristics when compared with standard glioblastoma cell line (e.g., U87) and may become a new and useful in vitro model for glioblastoma.

Cytokines are a large family of small proteins secreted by leukocytes and having an essential role in mediating the immune function. Many cytokines have multiple cellular sources and targets, as well as many natural inducers and inhibitors. These features and moreover the functional particularities of cytokines (autocrine and paracrine mode of action, overlapped activities, pleiotropic action, functioning as a complex regulatory network, and reciprocal down-regulation of the Th1 and Th2 cytokine groups) hampered the investigation of cytokines' role in autoimmune diseases (ADs). Despite this, the experimental and clinical studies have firmly documented the implication of cytokines in major pathophysiological and pathogenetic mechanisms associated with both the acute (onset and/or recurrence) and the chronic stages of ADs. The enhanced production of cytokines during the acute phase of systemic lupus erythematosus, rheumatoid arthritis and vasculitis has pathogenic effects such as appearance of anti-neutrophil cytoplasmic antibodies, initiation of vascular thrombosis and/or an increased production of autoantigens. The potent proinflammatory cytokines IL-1 and TNFalpha and also IL-8 and IFNalpha,gamma stimulate cells in different tissues to release harmful proteinases and reactive oxygen species, contributing to tissue damage. Some correlations have been found between serum cytokine levels and disease activity in certain systemic ADs. Studies investigating the cytokine pattern in ADs revealed the prevalence of the proinflammatory Th1-type cytokines in the target organ of patients with organ-specific ADs, such as multiple sclerosis and autoimmune thyroid disease, and heterogeneous cytokine profiles in patients with systemic ADs. A lot of factors, including the mechanism of tissue damage, the type of antigen-presenting cells and costimulatory molecules, and also the hormonal status, favor secretion of cytokines of Th1- or Th2-type in these patients. Beneficial effects have been obtained in patients with rheumatoid arthritis and Crohn disease by administering biotechnologically manufactured anti-TNFalpha antibodies or TNFalpha receptors. The risks of these cytokine-targeting therapeutical interventions are also discussed.

In many pathological states changes in the carbohydrate part of serum glycoproteins occur, the etiopathogenic role or diagnosis significance of these abnormally glycosylated glycoproteins being relevant in many instances. The aim of this study was to determine the glycosylation pattern of the serum immunoglobulin A (IgA) in young women suffering from systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), by comparison with that in healthy ones. We used lectin proteins as bivalent reagents to selectively and specifically recognize and bind the different oligosaccharides at the surface of the IgA molecules and precipitate them. The serum IgA level in the SLE and RA women included in this study was of 4 and respectively 6 times greater than in control women. Our experiments revealed for the IgA isolated from SLE women a very low degree of glycosylation, as follows: in the Fc region, we detected a markedly reduced level of the unbisected, biantennary oligosaccharides (by 72.8%) and of the unbisected, tri- and tetraantennary oligosaccharides (by 40%), accompanied by a slightly increased level of the bisected (by 14.7%) and fucosylated (by 13.3%) oligosaccharides; in the hinge region, a marked degalactosylation (by 74.4%) of the oligosaccharides was revealed; the sialylation degree of the IgA molecules was thus reduced by 71.2%. Related to it, it is reasonable to presume a certain role of the degalactosylated IgA fraction in renal tissue deposition of IgA in SLE patients, as it has been ascribed to this fraction in IgA nephropathy. Referring to the IgA isolated from RA women, we showed that it selectively bound the lectins, but lacked the property to be lectin-precipitated, most probably due to an altered arrangement of the oligosaccharide chains at the surface of the glycoprotein.

Most plasma proteins are glycoproteins, that is, they possess oligosaccharide chains attached to the polypeptide core. These oligosaccharides have important structural and functional roles; they serve as recognition markers (ligands), especially for lectin receptors, thus modulating the glycoprotein interactions. Protein glycosylation is a posttranslational event which depends on the proteic core and biosynthetic cell type and results in a set of microheterogeneous forms (glycoforms) of an individual glycoprotein. Under pathological conditions an alteration of the glycosylation pattern of plasma glycoproteins occurs. So, degalactosylated IgG and IgA1 detected in rheumatoid arthritis and IgA nephropathy, respectively, are implicated in the pathogenic mechanisms. Alteration of transferrin, alpha 1-acid glycoprotein and alpha-fetoprotein glycosylation (reduced sialylation and increased branching of oligosaccharide chains) occurs in liver diseases. In inflammations and infections the alteration is dependent on the disease studied, while increased sialylation and fucosylation of acute-phase proteins are detected in cancer sera. Lectin-based methods have been developed for clinical purposes, in order to improve the diagnosis, prognosis evaluation, or treatment monitoring.

The interaction of lactoperoxidase with lysozyme and ribonuclease as well as immunoglobulins from cow milk has been investigated. As gel filtration and enzyme kinetics experiments have shown, the lactoperoxidase was slightly activated by complexing to lysozyme, while IgA and IgM were inhibitory for the peroxidase. Oh the other hand, IgG and ribonuclease had no effect on the enzyme activity although the latter did form a complex with the lactoperoxidase. The interaction between the lysozyme and lactoperoxidase appears to be rather specific since the alteration of the lactoperoxidase sugar moiety by periodate oxidation, prevented the formation of the lactoperoxidase-lysozyme complex.