Human-correlated genetic HCC models identify combination therapy for precision medicine [Pre-print]

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. Despite an increasing range of systemic treatment options for advanced HCC outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with histopathology. In a proof-of-principle analysis, we verified response to standard of care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy

Targeting epigenetics in preclinical models of HCC for translational therapy

Abstract not currently available

Impact of a Single-Tube PCR Assay for the Detection of Haemophilus influenzae Serotypes a, c, d, e and f on the Epidemiological Surveillance in Greece

Background: The decrease in the rate of meningitis due to Haemophilus influenzae type b after vaccine introduction and a possible change in epidemiology of H. influenzae disease highlights the need for continuous serotype surveillance. Methods: A single-tube multiplex PCR assay for serotyping of H. influenzae was developed and deployed. Results: During 2003–2020, 108 meningitis cases due to H. influenzae were notified; 86 (80%) were confirmed and serotyped by molecular methods. The overall specificity and sensitivity of the assay were estimated (100% PPV and NPV respectively). The overall mean annual reported incidence for H. influenzae was 0.02, while for Hib and non-b meningitis equaled 0.02 and 0.03 per 100 000, respectively. Analysis by age group revealed that H. influenzae peaks in toddlers and children 0–4 years and in adults >45 years old. Among the serotyped cases, 39.8% were identified as Hib, 46.3% as NTHi, and 0.9% and 2.8% as serotypes a (Hia) and f (Hif)) respectively. Conclusions: Low incidence due to Hib was observed while non-typeable H. influenzae (NTHi) and serotypes Hia and Hif seem to emerge. The application of the current assay discloses the ongoing change of invasive H. influenzae disease trends during the Hib post-vaccine era

Genetic Insights into the Molecular Pathophysiology of Depression in Parkinson’s Disease

Background and Objectives: Parkinson’s disease (PD) is a clinically heterogeneous disorder with poorly understood pathological contributing factors. Depression presents one of the most frequent non-motor PD manifestations, and several genetic polymorphisms have been suggested that could affect the depression risk in PD. Therefore, in this review we have collected recent studies addressing the role of genetic factors in the development of depression in PD, aiming to gain insights into its molecular pathobiology and enable the future development of targeted and effective treatment strategies. Materials and Methods: we have searched PubMed and Scopus databases for peer-reviewed research articles published in English (pre-clinical and clinical studies as well as relevant reviews and meta-analyses) investigating the genetic architecture and pathophysiology of PD depression. Results: in particular, polymorphisms in genes related to the serotoninergic pathway (sodium-dependent serotonin transporter gene, SLC6A4, tryptophan hydrolase-2 gene, TPH2), dopamine metabolism and neurotransmission (dopamine receptor D3 gene, DRD3, aldehyde dehydrogenase 2 gene, ALDH2), neurotrophic factors (brain-derived neurotrophic factor gene, BDNF), endocannabinoid system (cannabinoid receptor gene, CNR1), circadian rhythm (thyrotroph embryonic factor gene, TEF), the sodium-dependent neutral amino acid transporter B(0)AT2 gene, SLC6A15), and PARK16 genetic locus were detected as altering susceptibility to depression among PD patients. However, polymorphisms in the dopamine transporter gene (SLC6A3), monoamine oxidase A (MAOA) and B (MAOB) genes, catechol-O-methyltransferase gene (COMT), CRY1, and CRY2 have not been related to PD depression. Conclusions: the specific mechanisms underlying the potential role of genetic diversity in PD depression are still under investigation, however, there is evidence that they may involve neurotransmitter imbalance, mitochondrial impairment, oxidative stress, and neuroinflammation, as well as the dysregulation of neurotrophic factors and their downstream signaling pathways

First report of meningococcal ciprofloxacin resistance in Greece due to invasive isolates of the sequence type ST-3129

International audienceA local outbreak caused by Neisseria meningitidis occurred in the migration camp in the Greek island of Lesbos during January-February 2020 (4 of 5 cases). In total, 5 samples positive for N. meningitidis were further investigated for sero-/genogroup, PorA, and WGS analysis. MenB was found among 3 cases, while in two cases, MenY was identified. WGS analysis and antibiotic susceptibility testing on the 2 culture positive MenB samples showed the new ST-3129, ciprofloxacin-resistant clone was circulating among the immigrants in the aforementioned camp. This is the first report of ciprofloxacin resistance in Greece

Pharmacological and Non-Pharmacological Treatments for Depression in Parkinson’s Disease: An Updated Review

Depression represents one of the most common non-motor disorders in Parkinson’s disease (PD) and it has been related to worse life quality, higher levels of disability, and cognitive impairment, thereby majorly affecting not only the patients but also their caregivers. Available pharmacological therapeutic options for depression in PD mainly include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants; meanwhile, agents acting on dopaminergic pathways used for motor symptoms, such as levodopa, dopaminergic agonists, and monoamine oxidase B (MAO-B) inhibitors, may also provide beneficial antidepressant effects. Recently, there is a growing interest in non-pharmacological interventions, including cognitive behavioral therapy; physical exercise, including dance and mind–body exercises, such as yoga, tai chi, and qigong; acupuncture; therapeutic massage; music therapy; active therapy; repetitive transcranial magnetic stimulation (rTMS); and electroconvulsive therapy (ECT) for refractory cases. However, the optimal treatment approach for PD depression is uncertain, its management may be challenging, and definite guidelines are also lacking. It is still unclear which of these interventions is the most appropriate and for which PD stage under which circumstances. Herein, we aim to provide an updated comprehensive review of both pharmacological and non-pharmacological treatments for depression in PD, focusing on recent clinical trials, systematic reviews, and meta-analyses. Finally, we discuss the pharmacological agents that are currently under investigation at a clinical level, as well as future approaches based on the pathophysiological mechanisms underlying the onset of depression in PD

Field Application of SD Bioline Malaria Ag Pf/ Pan Rapid Diagnostic Test for Malaria in Greece Field Application of SD Bioline Malaria Ag Pf/ Pan Rapid Diagnostic Test for Malaria in Greece

Abstract Greece, a malaria-free country since 1974, has experienced re-emergence of Plasmodium vivax autochthonous malaria cases in some agriculture areas over the last three years. In early 2012, an integrated control programme (MALWEST Project) was launched in order to prevent re-establishment of the disease. In the context of this project, the rapid diagnostic tests (RDT) of SD Bioline Malaria Ag Pf/Pan that detects hrp-2 and pan-LDH antigens were used. The aim of this study was to assess the field application of the RDT for the P. vivax diagnosis in comparison to light microscopy and polymerase chain reaction (PCR). A total of 955 samples were tested with all three diagnostic tools. Agreement of RDT against microscopy and PCR for the diagnosis of P. vivax was satisfactory (K value: 0.849 and 0.976, respectively). The sensitivity, specificity and positive predictive value of RDT against PCR was 95.6% (95% C.I.: 84.8-99.3), 100% (95% C.I.: 99.6-100.0) and 100% (95% CI: 91.7-100.0) respectively, while the sensitivity, specificity and positive predictive value of RDT against microscopic examination was 97.4% (95% C.I.: 86.1-99.6), 99.4% (95% C.I.: 98.6-99.8) and 86.1% (95% CI: 72.1-94.7), respectively. Our results indicate that RDT performed satisfactory in a non-endemic country and therefore is recommended for malaria diagnosis, especially in areas where health professionals lack experience on light microscopy