Promotion of perineural invasion of cholangiocarcinoma by Schwann cells via nerve growth factor.

Background: Cholangiocarcinoma (CCA), a highly lethal tumor of the hepatobiliary system originating from bile duct epithelium, can be divided into the intrahepatic, hilar, and extrahepatic types. Due to its insidious onset and atypical early clinical symptoms, the overall prognosis is poor. One of the important factors contributing to the poor prognosis of CCA is the occurrence of perineural invasion (PNI), but the specific mechanisms regarding how it contributes to the occurrence of PNI are still unclear. The main purpose of this study is to explore the molecular mechanism leading to the occurrence of PNI and provide new ideas for clinical treatment. Methods: CCA cell lines and Schwann cells (SCs) were stimulated to observe the changes in cell behavior. SCs cocultured with tumor supernatant and SCs cultured in normal medium were subjected to transcriptome sequencing to screen the significantly upregulated genes. Following this, the two types of tumor cells were cultured with SC supernatant, and the changes in behavior of the tumor cells were observed. Nonobese diabetic-severe combined immunodeficiency disease (NOD-SCID) mice were injected with cell suspension supplemented with nerve growth factor (NGF) via the sciatic nerve. Four weeks later, the mice were euthanized and the tumor sections were removed and stained. Results: Nerve invasion by tumor cells was common in CCA tissues. SCs were observed in tumor tissues, and the number of SCs in tumor tissues and the degree of PNI were much higher than were those in normal tissues or tissues without PNI. The overall survival time was shorter in patients with CCA with PNI than in patients without PNI. SCs were enriched in CCA tissues, indicating the presence of PNI and associated with poor prognosis in CCA patients. CCA was found to promote NGF secretion from SCs in vitro. After the addition of exogenous NGF in CCA cell culture medium, the proliferation activity and migration ability of CCA cells were significantly increased, suggesting that SCs can promote the proliferation and migration of CCA through the secretion of NGF. NGF, in turn, was observed to promote epithelial-mesenchymal transition in CCA through tropomyosin receptor kinase A (TrkA), thus promoting its progression. Tumor growth in mice shows that NGF can promote PNI in CCA. Conclusions: In CCA, tumor cells can promote the secretion of NGF by SCs, which promotes the progression of CCA and PNI by binding to its high-affinity receptor TrkA, leading to poor prognosis.

Fluorescent quantum dot-based nanotool for targeted identification and evaluation of the schistosomiasis circulating cathodic antigen in tissue samples.

Schistosomiasis represents a serious public health problem, a disease for which the circulating cathodic antigen (CCA) is a relevant biomarker. Quantum dots (QDs) are advantageous fluorescent nanoparticles that can be used as specific nanoprobes. In this study, a nanotool based on QDs and anti-CCA antibodies was developed, which, in association with fluorescence microscopy, was applied to trace and evaluate the CCA profile in schistosomiasis-infected tissue samples. Kidney and liver tissues from mice at different disease phases were used as models. QDs and the conjugates were characterized by absorption and emission spectroscopies. Microscopy analyses were used to map and assess CCA accumulation in infected tissue slices in respect to non-infected control samples. The fluorescent microplate assay (FMA) and Zeta potential (ζ) analyses indicated an effective conjugation, which was corroborated by the absence of labeling in non-infected tissue slices (which lack CCA) after incubation with the nanoprobe. Infected liver and kidney tissues exhibited notable staining by the QDs-anti-CCA conjugate. The CCA accumulation increased as follows: 30 < 60 = 120 days post-infection, with 30, 60, and 120 days corresponding to the pre-patent, acute, and beginning of chronic disease phases, respectively. Therefore, this innovative approach, combining imaging acquisition with the sensitivity and specificity of the QDs-anti-CCA conjugate, demonstrated efficiency in locating and comparatively evaluating CCA deposition in biological samples, thereby opening new possibilities for schistosomiasis research.

Mechanisms of Sorafenib Resistance in HCC Culture Relate to the Impaired Membrane Expression of Organic Cation Transporter 1 (OCT1).

Introduction: Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC) treatment, encounters resistance in many patients. Deciphering the mechanisms underlying sorafenib resistance is crucial for devising alternative strategies to overcome it. Aim: This study aimed to investigate sorafenib resistance mechanisms using a diverse panel of HCC cell lines. Methods: HCC cell lines were subjected to continuous sorafenib treatment, and stable cell lines (Huh 7.5 and Huh 7PX) exhibiting sustained growth in its presence were isolated. The investigation of drug resistance mechanisms involved a comparative analysis of drug-targeted signal transduction pathways (EGFR/RAF/MEK/ERK/Cyclin D), sorafenib uptake, and membrane expression of the drug uptake transporter. Results: HCC cell lines (Huh 7.5 and Huh 7PX) with a higher IC50 (10µM) displayed a more frequent development of sorafenib resistance compared to those with a lower IC50 (2-4.8µM), indicating a potential impact of IC50 variation on initial treatment response. Our findings reveal that activated overexpression of Raf1 kinases and impaired sorafenib uptake, mediated by reduced membrane expression of organic cation transporter-1 (OCT1), contribute to sorafenib resistance in HCC cultures. Stable expression of the drug transporter OCT1 through cDNA transfection or adenoviral delivery of OCT1 mRNA increased sorafenib uptake and successfully overcame sorafenib resistance. Additionally, consistent with sorafenib resistance in HCC cultures, cirrhotic liver-associated human HCC tumors often exhibited impaired membrane expression of OCT1 and OCT3. Conclusion: Intrinsic differences among HCC cell clones, affecting sorafenib sensitivity at the expression level of Raf kinases, drug uptake, and OCT1 transporters, were identified. This study underscores the potential of HCC tumor targeted OCT1 expression to enhance sorafenib treatment response.

Decoding temporal muscle synergy patterns based on brain activity for upper extremity in ADL movements.

Muscle synergies have been hypothesized as specific predefined motor primitives that the central nervous system can reduce the complexity of motor control by using them, but how these are expressed in brain activity is ambiguous yet. The main purpose of this paper is to develop synergy-based neural decoding of motor primitives, so for the first time, brain activity and muscle synergy map of the upper extremity was investigated in the activity of daily living movements. To find the relationship between brain activities and muscle synergies, electroencephalogram (EEG) and electromyogram (EMG) signals were acquired simultaneously during activities of daily living. To extract the maximum correlation of neural commands with muscle synergies, application of a combined partial least squares and canonical correlation analysis (PLS-CCA) method was proposed. The Elman neural network was used to decode the relationship between extracted motor commands and muscle synergies. The performance of proposed method was evaluated with tenfold cross-validation and muscle synergy estimation of brain activity with R, VAF, and MSE of 84 ± 2.6%, 70 ± 4.7%, and 0.00011 ± 0.00002 were quantified respectively. Furthermore, the similarity between actual and reconstructed muscle activations was achieved more than 92% for correlation coefficient. To compare with the existing methods, our results showed significantly more accuracy of the model performance. Our results confirm that use of the expression of muscle synergies in brain activity can estimate the neural decoding performance for motor control that can be used to develop neurorehabilitation tools such as neuroprosthesis.

In situ decrease in rhodolith growth associated with Arctic climate change.

Rhodoliths built by crustose coralline algae (CCA) are ecosystem engineers of global importance. In the Arctic photic zone, their three-dimensional growth emulates the habitat complexity of coral reefs but with a far slower growth rate, growing at micrometers per year rather than millimeters. While climate change is known to exert various impacts on the CCA's calcite skeleton, including geochemical and structural alterations, field observations of net growth over decade-long timescales are lacking. Here, we use a temporally explicit model to show that rising ocean temperatures over nearly 100 years were associated with reduced rhodolith growth at different depths in the Arctic. Over the past 90 years, the median growth rate was 85 µm year-1 but each °C increase in summer seawater temperature decreased growth by a mean of 8.9 µm (95% confidence intervals = 1.32-16.60 µm °C-1, p < .05). The decrease was expressed for rhodolith occurrences in 11 and 27 m water depth but not at 46 m, also having the shortest time series (1991-2015). Although increasing temperatures can spur plant growth, we suggest anthropogenic climate change has either exceeded the population thermal optimum for these CCA, or synergistic effects of warming, ocean acidification, and/or increasing turbidity impair rhodolith growth. Rhodoliths built by calcitic CCA are important habitat providers worldwide, so decreased growth would lead to yet another facet of anthropogenic habitat loss.

Point-of-care circulating cathodic antigen positivity and associated factors in school children one year after mass praziquantel administration in an endemic district in Ghana.

Background: Mass drug administration of praziquantel is expected to reduce Schistosome carriage in treated children in endemic communities. However, the effectiveness of this annual exercise has not been assessed in Ghana. Therefore, this study aimed to detect viable Schistosoma mansoni infection using point-of-care circulating cathodic antigen (POC-CCA) positivity as proxy and associated factors in children previously treated with praziquantel in an endemic municipality in Ghana. Materials and methods: This cross-sectional study was done in the Assin Central municipality in the Central Region of Ghana. School children, less than 16 years of age, treated with 40 mg/kg of praziquantel (treatment period: February-March 2019), provided early morning urine (∼40 mL) and stool (∼4 g) samples. Immediately, POC-CCA (ICT International, South Africa) was done, while S. mansoni ova were detected in formalin fixed samples using microscopy later. Additionally, participant's socio-demographic information and factors associated with S, mansoni infection transmission were collected from each child. Results: A total of 520 children participated in the study (males-51.9%, majority age range [9-11 years, 34.4%]). Overall, 244 (46.9%) were positive for urinary CCA with no S. mansoni detected by microscopy. POC-CCA positivity was higher in females (48.4%), children with 2-3 siblings (49.3%), children aged 6-8-year range (55.4%) and residents of Brofoyedur (52%). However, age (x2 = 16.1, p = 0.0003) and town of residence (x2 = 11.7, p = 0.019) associated with CCA positivity. Further, location of water body (x2 = 16.4, p = 0.008), frequency of water contact (x2 = 12.3, p = 0.015) and handling of the Biomphalaria intermediate host (x2 = 5.1, p = 0.024) associated with POC-CCA outcome. Conclusion: About 47% of the school children were positive for CCA, one year after mass praziquantel administration in the Assin Central municipality. Varied factors associated with the post-praziquantel administration POC-CCA positivity. This study should be replicated in other endemic areas to identify groups at risk of parasite persistence or reinfection to inform modification of control and preventive measures.

Vegetation-edaphic correlation and importance value index in himalayan 'ecotone' temperate conifer forest using the multivariate technique.

Himalayan 'Ecotone' temperate conifer forest is the cradle of life for human survival and wildlife existence. In spite of the importance of these areas, they have not been studied in depth. This study aimed to quantify the floristic structure, important value index (IVI), topographic and edaphic variables between 2019 and 2020 utilizing circular quadrant method (10 m x 10 m). The upper-storey layer consisted of 17 tree species belongs to 12 families and 9 orders. Middle-storey shrubs comprised of 23 species representing 14 families and 12 orders. A total of 43 species of herbs, grasses, and ferns were identified from the ground-storey layer, representing 25 families and 21 orders. Upper-storey vegetation structure was dominated by Pinus roxburghii (22.45 %) and middle-storey by Dodonaea viscosa (7.69 %). However, the ground layer vegetation was diverse in species composition (43 species) and distribution. The floral vegetation structure was encompassing of three floral communities which were diverse in IVI, such as, in Piro-Aial (Group 2), Pinus roxburghii (54.46 x 15.94) had the highest IVI value, followed by Pinus wallichiana (45.21 x 14.85) in Piwa-Quin (Group 3) and Ailanthus altissima (22.84 x 19.25) in Aial-Qugal (Group 1). However, the IVI values for Aesculus indica, Celtis australis, and Quercus incana in Aial-Qugal (Group 1) were not determined due to low detection rate. Nevertheless, eleven of these species showed 0 IVI values in Piro-Aial (Group 2) and Piwa-Quin (Group 3). CCA ordination biplot illustrated the significant differences among floral communities and its distribution, which impacted by temperature, rainfall, soil pH, altitude, and topographic features. Ward's agglomerative clustering finding reflected 'Ecotone' temperate conifer forest is rich and diverse floristic structure.

Current advances and future directions in combined hepatocellular and cholangiocarcinoma.

The low incidence of combined hepatocellular cholangiocarcinoma (cHCC-CCA) is an important factor limiting research progression. Our study extensively included nearly three decades of relevant literature and assembled the most comprehensive database comprising 5,742 patients with cHCC-CCA. We summarized the characteristics, tumor markers, and clinical features of these patients. Additionally, we present the evolution of cHCC-CCA classification and explain the underlying rationale for these classification standards. We reviewed cHCC-CCA diagnostic advances using imaging features, tumor markers, and postoperative pathology, as well as treatment options such as surgical, adjuvant, and immune-targeted therapies. In addition, recent advances in more effective chemotherapeutic regimens and immune-targeted therapies were explored. Furthermore, we described the molecular mutation features and potential specific markers of cHCC-CCA. The prognostic value of Nestin has been proven, and we speculate that Nestin will also play a role in classification and diagnosis. However, further research is needed. Moreover, we believe that the possibility of using machine learning liquid biopsy for preoperative diagnosis and establishing a scoring system are directions for future research.

Long-Term Intake of Proton-Pump Inhibitors Could Be Associated with an Increased Incidence of Liver Cancer in Women.

BACKGROUND: Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs in gastroenterology. Although PPIs are mostly well tolerated, long-term PPI intake has been linked with diabetes mellitus, osteoporosis and infectious disease. In the present study, we evaluated a potential association between PPI intake and a subsequent diagnosis of liver cancer in a large real-world cohort of outpatients in Germany. METHODS: A total of 1766 patients with liver cancer, as well as 8830 propensity-score-matched controls, were identified from the Disease Analyzer database (IQVIA). The outcome of the study was the association between PPI use and a subsequent diagnosis of liver cancer, which was evaluated using multivariable logistic regression analyses. RESULTS: Overall, 42.9% of the liver cancer patients and 39.0% of the controls received at least one PPI prescription before the index date. PPI prescriptions at any time before the index date were associated with an increased risk of subsequent liver cancer (OR: 1.18; 95% CI: 1.06-1.31). The positive association was observed in all age groups, as well as in women and men, but only in women (OR: 1.30; 95% 1.09-1.55) did it reach the predefined level of significance (p < 0.01). When considering the duration of PPI therapy, only PPI therapy for at least two years was significantly associated with an increased risk of liver cancer (OR: 1.28; 95% 1.09-1.50). In an analysis stratified by age and sex, this association was strongest in the age group < 60 years (OR: 1.99; 95% 1.21-3.26). CONCLUSIONS: Our data suggest that long-term PPI intake in women as well as in patients < 60 years might be associated with an increased risk of liver cancer. These findings support current efforts to reduce the inappropriate use of PPIs in routine clinical practice and to link PPI prescribing to a clear medical indication.

Generation of Metastatic Cholangiocarcinoma Patient-Derived Xenograft Models.

Cholangiocarcinoma (CCA) poses a substantial clinical hurdle as it is often detected at advanced metastatic stages with limited therapeutic options. To enhance our understanding of advanced CCA, it is imperative to establish preclinical models that faithfully recapitulate the disease's characteristics. Patient-derived xenograft (PDX) models have emerged as a valuable approach in cancer research, offering an avenue to reproduce and study the genomic, histologic, and molecular features of the original human tumors. By faithfully preserving the heterogeneity, microenvironmental interactions, and drug responses observed in human tumors, PDX models serve as highly relevant and predictive preclinical tools. Here, we present a comprehensive protocol that outlines the step-by-step process of generating and maintaining PDX models using biopsy samples from patients with advanced metastatic CCA. The protocol encompasses crucial aspects such as tissue processing, xenograft transplantation, and subsequent monitoring of the PDX models. By employing this protocol, we aim to establish a robust collection of PDX models that accurately reflect the genomic landscape, histologic diversity, and therapeutic responses observed in advanced CCA, thereby enabling improved translational research, drug development, and personalized treatment strategies for patients facing this challenging disease.

The covariant structural and functional neuro-correlates of cognitive impairments in patients with end-stage renal diseases.

Introduction: Cognitive impairment (CI) is a common complication of end-stage renal disease (ESRD) that is associated with structural and functional changes in the brain. However, whether a joint structural and functional alteration pattern exists that is related to CI in ESRD is unclear. Methods: In this study, instead of looking at brain structure and function separately, we aim to investigate the covariant characteristics of both functional and structural aspects. Specifically, we took the fusion analysis approach, namely, multimodal canonical correlation analysis and joint independent component analysis (mCCA+jICA), to jointly study the discriminative features in gray matter volume (GMV) measured by T1-weighted (T1w) MRI, fractional anisotropy (FA) in white matter measured by diffusion MRI, and the amplitude of low-frequency fluctuation (ALFF) measured by blood oxygenation-level-dependent (BOLD) MRI in 78 ESRD patients versus 64 healthy controls (HCs), followed by a mediation effect analysis to explore the relationship between neuroimaging findings, cognitive impairments and uremic toxins. Results: Two joint group-discriminative independent components (ICs) were found to show covariant abnormalities across FA, GMV, and ALFF (all p < 0.05). The most dominant joint IC revealed associative patterns of alterations of GMV (in the precentral gyrus, occipital lobe, temporal lobe, parahippocampal gyrus, and hippocampus), alterations of ALFF (in the precuneus, superior parietal gyrus, and superior occipital gyrus), and of white matter FA (in the corticospinal tract and inferior frontal occipital fasciculus). Another significant IC revealed associative alterations of GMV (in the dorsolateral prefrontal and orbitofrontal cortex) and FA (in the forceps minor). Moreover, the brain changes identified by FA and GMV in the above-mentioned brain regions were found to mediate the negative correlation between serum phosphate and mini-mental state examination (MMSE) scores (all p < 0.05). Conclusion: The mCCA+jICA method was demonstrated to be capable of revealing covariant abnormalities across neuronal features of different types in ESRD patients as contrasted to HCs, and joint brain changes may play an important role in mediating the relationship between serum toxins and CIs in ESRD. Our results show the mCCA+jICA fusion analysis approach may provide new insights into similar neurobiological studies.

Cholangiocarcinoma imaging: from diagnosis to response assessment.

Cholangiocarcinoma (CCA), a highly aggressive primary liver cancer arising from the bile duct epithelium, represents a substantial proportion of hepatobiliary malignancies, posing formidable challenges in diagnosis and treatment. Notably, the global incidence of intrahepatic CCA has seen a rise, necessitating a critical examination of diagnostic and management strategies, especially due to presence of close imaging mimics such as hepatocellular carcinoma (HCC) and combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA). Hence, it is imperative to understand the role of various imaging modalities such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), elucidating their strengths, and limitations in diagnostic precision and staging accuracy. Beyond conventional approaches, there is emerging significance of functional imaging tools including positron emission tomography (PET)-CT and diffusion-weighted (DW)-MRI, providing pivotal insights into diagnosis, therapeutic assessment, and prognostic evaluation. This comprehensive review explores the risk factors, classification, clinical features, and role of imaging in the holistic spectrum of diagnosis, staging, management, and restaging for CCA, hence serving as a valuable resource for radiologists evaluating CCA.

Circulating tumor DNA analysis guiding adjuvant treatment in resected stage III cholangiocarcinoma: a case report.

Background: Cholangiocarcinoma (CCA) is a rare and aggressive gastrointestinal cancer. Unfortunately, 60% to 70% of early-stage CCA patients experience disease recurrence after curative resection and standard adjuvant therapy. Currently, there is no reliable tool to identify CCA recurrence before radiographic detection. Longitudinal monitoring of circulating tumor DNA (ctDNA) has shown promising value in molecular identification of relapse prior to conventional surveillance in other solid tumors. However, there is a scarcity of data on ctDNA in CCA after curative surgery. Case Description: An 81-year-old male with stage 3A intrahepatic CCA achieved radiographic remission after curative resection and was started on standard adjuvant capecitabine on post-operative day (POD) 50. Tumor-informed ctDNA tested positive on two consecutive occasions, with the titer increasing from 0.16 mean tumor molecule (MTM)/mL on POD 92 to 0.80 MTM/mL on POD 183, despite being on capecitabine. carbohydrate antigen 19-9 (CA19-9) also continued to increase from 175.6 U/mL on POD 92 to 7,594.9 U/mL on POD 217. Notably, surveillance computed tomography (CT) scans showed no evidence of disease (NED) on POD 126, 186, and 211. Molecular profiling and next-generation sequencing (NGS) panels from CCA tissue revealed microsatellite instability-high (MSI-H). After extensive discussions with the patient regarding the rising ctDNA titer despite being on capecitabine for nearly 6 months, we initiated pembrolizumab on POD 224 prior to radiographic recurrence. Given the tumor is MSI-H, and the preferred toxicity profile compared to the front-line chemotherapy option for CCA, we started pembrolizumab. ctDNA became undetectable, and CA19-9 returned to the reference range with pembrolizumab. As of the last follow-up on POD 876, the patient has continued pembrolizumab without noticeable side effects, and imaging continues to show NED, with persistent negative ctDNA and normal CA19-9 levels. Conclusions: This case demonstrates the potential utility of tumor-informed ctDNA in CCA as (I) an early detection tool before radiographic recurrence; (II) a response monitoring tool as a surrogate biomarker that can guide therapy optimization; and (III) shows that early intervention with immunotherapy or potentially targeted agents based on ctDNA may lead to improved survival outcomes.

Progress in controlling the transmission of schistosome parasites in Southern Ethiopia: the Geshiyaro Project in the Wolaita Zone.

BACKGROUND: This paper describes changes in the prevalence and intensity of schistosome parasite infections in a project integrating mass drug administration (MDA), water, sanitation, and hygiene (WaSH), and behavioral change interventions. METHODS: The Geshiyaro Project comprises three intervention arms. Arm 1 is subdivided into "Arm 1 pilot" (one district) and Arm 1 (four other districts), both receiving integrated community-wide MDA with intensive WaSH interventions. Arm 2 involves 17 districts with community-wide MDA interventions, while Arm 3 serves as a control with school-based MDA interventions in three districts. A total of 150 individuals, stratified by age group, were randomly selected from each of the 45 sentinel sites. Arm sizes were 584 (Arm 1 pilot), 1636 (Arm 1), 2203 (Arm 2), and 2238 (Arm 3). Statistical tests were employed to compare infection prevalence and intensity across the different arms. RESULTS: The prevalence of schistosome parasite infection ranged from 0% to 2.6% and from 1.7% to 25.7% across districts, employing the Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) diagnostics, respectively. The mean infection intensity level showed no marked difference between baseline and follow-up surveys when measured by KK, except in Arm 2 (t = 6.89, P < 0.0001). Infection prevalence decreased significantly in Arm 1 (t = 8.62, P < 0.0001), Arm 2 (t = 6.94, P < 0.0001), and Arm 3 (t = 8.83, P < 0.0001), but not in Arm 1 pilot (t = 1.69, P = 0.09) by POC-CCA, when trace was considered positive. The decrease was significant only in Arm 1 (t = 3.28, P = 0.0001) and Arm 2 (t = 7.62, P < 0.0001) when the trace was considered negative in POC-CCA. Arm 2 demonstrated a significant difference in difference (DID) compared to the control group, Arm 3, regardless of whether trace in POC-CCA was considered positive (DID = 3.9%, df = 8780, P = 0.025) or negative (DID = -5.2, df = 8780, P = 0.0004). CONCLUSIONS: The prevalence of schistosomiasis was low when employing the KK diagnostic but moderate in some locations by the POC-CCA diagnostic. The infection level had decreased across all arms of the Geshiyaro study at mid-term of the 7-year project, but further efforts are needed to reduce the rate of parasite transmission based on the POC-CCA diagnostic scores.

History, Paranoia, Fragmentation1.

In his book Aion, Jung describes something like a quasi-Hegelian progressive historical realization of the Self in a perspective similar to Fernand Braudel's longue durée history. This article deals with a similar perspective, as it tries to focus on what we may call a "cultural complex" yet within its unfolding in historical time and belonging not to just one specific cultural group, but to a large cultural basin, which we may indicate as the "West". This complex marks the birth and development of modernity. The depth, pervasiveness and duration of this cultural complex permeates the lives and psychologies of all of those that are part of it. Therefore, every analytical project must take into account the underlying emotional, epistemic and social field within which this complex constellates. One of the main features of this (trans)cultural complex, strictly connected with the progressive fragmentation of the self and the transformation of the numinosum with its meaning-giving force, is paranoia. This article analyses the historical and cultural features that produce paranoia and fragmentation and determine paranoid symptoms and attitudes.

Dans son livre Aïon, Jung décrit quelque chose comme une réalisation historique progressive quasi hégélienne du Soi dans une perspective similaire à l'histoire de longue durée de Fernand Braudel. Cet article aborde une perspective semblable, car il tente de se concentrer sur ce que nous pouvons appeler un « complexe culturel ¼. Mais ici il s'agit de son déroulement dans le temps historique et de son appartenance non pas à un groupe culturel spécifique, mais à un grand bassin culturel, que nous pouvons désigner comme « l'Occident ¼. Ce complexe marque la naissance et le développement de la modernité. La profondeur, l'omniprésence et la durée de ce complexe culturel imprègnent la vie et la psychologie de tous ceux qui en font partie. Par conséquent, tout projet analytique doit prendre en compte le champ émotionnel, épistémique et social sous­jacent dans lequel ce complexe se constelle. L'une des principales caractéristiques de ce complexe (trans)culturel, étroitement lié à la fragmentation progressive du soi et à la transformation du numinosum et de sa capacité à donner du sens, c'est la paranoïa. Cet article analyse les caractéristiques historiques et culturelles qui produisent la paranoïa et la fragmentation et déterminent les symptômes et les attitudes paranoïdes.

En su libro 'Aion', Jung describe algo así como una realización histórica progresiva cuasi­hegeliana del Self en una perspectiva similar a la historia 'longue durée' de Fernand Braudel. El presente artículo aborda una perspectiva similar, ya que trata de centrarse en lo que podríamos denominar un "complejo cultural", pero dentro de su despliegue en el tiempo histórico y perteneciente no sólo a un grupo cultural concreto, sino a una gran cuenca cultural, que podríamos señalar como "Occidente". Este complejo marca el nacimiento y el desarrollo de la modernidad. La profundidad, la omnipresencia y la duración de este complejo cultural impregnan la vida y la psicología de todos los que forman parte de él. Por lo tanto, todo proyecto analítico debe tener en cuenta el campo emocional, epistémico y social subyacente en el que se inscribe este complejo. Uno de los principales rasgos de este complejo (trans)cultural, estrictamente relacionado con la progresiva fragmentación del self y la transformación de lo numinoso con su fuerza dadora de sentido, es la paranoia. Este artículo analiza los rasgos históricos y culturales que producen la paranoia y la fragmentación y determinan síntomas y actitudes paranoides.

Harnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies.

Evidence suggests that long non-coding RNAs (lncRNAs) play a pivotal role in the carcinogenesis and progression of various human malignancies including gastrointestinal malignancies. This comprehensive review reports the functions and mechanisms of the lncRNA maternally expressed gene 3 (MEG3) involved in gastrointestinal malignancies. It summarizes its roles in mediating the regulation of cellular proliferation, apoptosis, migration, invasiveness, epithelial-to-mesenchymal transition, and drug resistance in several gastrointestinal cancers such as colorectal cancer, gall bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, gastrointestinal stromal tumors and most importantly, hepatocellular carcinoma. In addition, the authors briefly highlight its implicated mechanistic role and interactions with different non-coding RNAs and oncogenic signaling cascades. This review presents the rationale for developing non coding RNA-based anticancer therapy via harnessing the power of MEG3 in gastrointestinal malignancies.

Transplant oncology - Current indications and strategies to advance the field.

Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.