The role of living donor liver transplantation in treating intrahepatic cholangiocarcinoma.

Introduction: Intrahepatic cholangiocarcinoma (iCC) is the liver's second most common neoplasm. Until now, surgery is the only curative option, but only 35% of the cases are considered resectable at the diagnosis, with a post-resection survival of around 30%. Advancements in surgical techniques and perioperative care related to liver transplantation (LT) have facilitated the expansion of indications for hepatic neoplasms. Method: This study is a comprehensive review of the global experience in living donor LT (LDLT) for treating iCC and describes our first case of LDLT for an unresectable iCC. Results: While exploring LT for intrahepatic cholangiocarcinoma dates to the 1990s, the initial outcomes were discouraging, marked by poor survival and high recurrence rates. Nevertheless, contemporary perspectives underscore a reinvigorated emphasis on extending the frontiers of LT indications within the context of the "oncologic era." The insights gleaned from examining explants, wherein incidental iCC was categorized as hepatocellular carcinoma in the preoperative period, have demonstrated comparable survival rates to small hepatocellular carcinoma. These findings substantiate the potential viability of LT as a curative alternative for iCC. Another investigated scenario pertains to "unresectable tumors with favorable biological behavior," LT presents a theoretical advantage by providing free margins without the concern of a small future liver remnant. The constraint of organ shortage persists, particularly in nations with low donation rates. LDLT emerges as a viable and secure alternative for treating iCC. Conclusion: LDLT is an excellent option for augmenting the graft pool, particularly in carefully selected patients.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review.

BACKGROUND: Perihilar cholangiocarcinoma (phCCC) is a dismal malignancy. There is no consensus regarding the best treatment for patients with unresectable phCCC. The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice. DATA SOURCES: The search was conducted in PubMed, Embase, Cochrane, and LILACS. The related references were searched manually. Inclusion criteria were: reports in English or Portuguese literature that a) patients with confirmed diagnosis of phCCC; b) patients treated with a curative intent; c) patients with the outcomes of liver resection and liver transplantation. Case reports, reviews, letters, editorials, conference abstracts and papers with full-text unavailability were excluded from the analysis. RESULTS: Most of the current literature is based on observational retrospective studies with low grades of evidence. Liver resection has better long-term outcomes than systemic chemotherapy or palliation therapy and liver transplantation is a good alternative for selected patients with unresectable phCCC. All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahepatic diseases. As a general rule, patients presenting with a tumor having a longitudinal size > 3 cm or extending below the cystic duct, lymph node disease, confirmed extrahepatic dissemination; intraoperatively diagnosed metastatic disease; a history of other malignancies within the last five years, and did not complete chemoradiation regimen and were medically unfit should not be considered for transplantation. Some of these criteria should be individually assessed. Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers, and any decision-making must be based on a multidisciplinary evaluation. CONCLUSIONS: phCCC is a complex condition with high morbidity. Surgical therapies, including hepatectomy and liver transplantation, are the best option for better long-term disease-free survival.

Melanin's Journey from Melanocytes to Keratinocytes: Uncovering the Molecular Mechanisms of Melanin Transfer and Processing.

Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in melanocytes are now well characterized, much less is known about melanin transfer and processing within keratinocytes. Over the past few decades, distinct models have been proposed to explain how melanin transfer occurs at the cellular and molecular levels. However, this remains a debated topic, as up to four different models have been proposed, with evidence presented supporting each. Here, we review the current knowledge on the regulation of melanin exocytosis, internalization, processing, and polarization. Regarding the different transfer models, we discuss how these might co-exist to regulate skin pigmentation under different conditions, i.e., constitutive and facultative skin pigmentation or physiological and pathological conditions. Moreover, we discuss recent evidence that sheds light on the regulation of melanin exocytosis by melanocytes and internalization by keratinocytes, as well as how melanin is stored within these cells in a compartment that we propose be named the melanokerasome. Finally, we review the state of the art on the molecular mechanisms that lead to melanokerasome positioning above the nuclei of keratinocytes, forming supranuclear caps that shield the nuclear DNA from UV radiation. Thus, we provide a comprehensive overview of the current knowledge on the molecular mechanisms regulating skin pigmentation, from melanin exocytosis by melanocytes and internalization by keratinocytes to processing and polarization within keratinocytes. A better knowledge of these molecular mechanisms will clarify long-lasting questions in the field that are crucial for the understanding of skin pigmentation and can shed light on fundamental aspects of organelle biology. Ultimately, this knowledge can lead to novel therapeutic strategies to treat hypo- or hyper-pigmentation disorders, which have a high socio-economic burden on patients and healthcare systems worldwide, as well as cosmetic applications.

Crosstalk between cilia and autophagy: implication for human diseases.

Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders.

Molecular Profile of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease's underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), and AT-rich interactive domain-containing protein 1A (ARID1A). The rate of mutations varies significantly for each population. Targeting TP53 and KRAS is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated IDH1 and target therapy for ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC's molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy.

RAB3A Regulates Melanin Exocytosis and Transfer Induced by Keratinocyte-Conditioned Medium.

Skin pigmentation is imparted by melanin and is crucial for photoprotection against UVR. Melanin is synthesized and packaged into melanosomes within melanocytes and is then transferred to keratinocytes (KCs). Although the molecular players involved in melanogenesis have been extensively studied, those underlying melanin transfer remain unclear. Previously, our group proposed that coupled exocytosis/phagocytosis is the predominant mechanism of melanin transfer in human skin and showed an essential role for RAB11B and the exocyst tethering complex in this process. In this study, we show that soluble factors present in KC-conditioned medium stimulate melanin exocytosis from melanocytes and transfer to KCs. Moreover, we found that these factors are released by differentiated KCs but not by basal layer KCs. Furthermore, we found that RAB3A regulates melanin exocytosis and transfer stimulated by KC-conditioned medium. Indeed, KC-conditioned medium enhances the recruitment of RAB3A to melanosomes in melanocyte dendrites. Therefore, our results suggest the existence of two distinct routes of melanin exocytosis: a basal route controlled by RAB11B and a RAB3A-dependent route, stimulated by KC-conditioned medium. Thus, this study provides evidence that soluble factors released by differentiated KCs control skin pigmentation by promoting the accumulation of RAB3A-positive melanosomes in melanocyte dendrites and their release and subsequent transfer to KCs.

Melanocore uptake by keratinocytes occurs through phagocytosis and involves protease-activated receptor-2 internalization.

In the skin epidermis, melanin is produced and stored within melanosomes in melanocytes, and then transferred to keratinocytes. Different models have been proposed to explain the melanin transfer mechanism, which differ essentially in how melanin is transferred-either in a membrane-bound melanosome or as a melanosome core, that is, melanocore. Here, we investigated the endocytic route followed by melanocores and melanosomes during internalization by keratinocytes, by comparing the uptake of melanocores isolated from the supernatant of melanocyte cultures, with melanosomes isolated from melanocytes. We show that inhibition of actin dynamics impairs the uptake of both melanocores and melanosomes. Moreover, depletion of critical proteins involved in actin-dependent uptake mechanisms, namely Rac1, CtBP1/BARS, Cdc42 or RhoA, together with inhibition of Rac1-dependent signaling pathways or macropinocytosis suggest that melanocores are internalized by phagocytosis, whereas melanosomes are internalized by macropinocytosis. Interestingly, we found that Rac1, Cdc42 and RhoA are differently activated by melanocore or melanosome stimulation, supporting the existence of two distinct routes of melanin internalization. Furthermore, we show that melanocore uptake induces protease-activated receptor-2 (PAR-2) internalization by keratinocytes to a higher extent than melanosomes. Because skin pigmentation was shown to be regulated by PAR-2 activation, our results further support the melanocore-based mechanism of melanin transfer and further refine this model, which can now be described as coupled melanocore exo/phagocytosis.

Rab11 is required for lysosome exocytosis through the interaction with Rab3a, Sec15 and GRAB.

Lysosomes are dynamic organelles, capable of undergoing exocytosis. This process is crucial for several cellular functions, namely plasma membrane repair. Nevertheless, the molecular machinery involved in this process is poorly understood. Here, we identify Rab11a and Rab11b as regulators of Ca2+-induced lysosome exocytosis. Interestingly, Rab11-positive vesicles transiently interact with lysosomes at the cell periphery, indicating that this interaction is required for the last steps of lysosome exocytosis. Additionally, we found that the silencing of the exocyst subunit Sec15, a Rab11 effector, impairs lysosome exocytosis, suggesting that Sec15 acts together with Rab11 in the regulation of lysosome exocytosis. Furthermore, we show that Rab11 binds the guanine nucleotide exchange factor for Rab3a (GRAB) as well as Rab3a, which we have previously described to be a regulator of the positioning and exocytosis of lysosomes. Thus, our study identifies new players required for lysosome exocytosis and suggest the existence of a Rab11-Rab3a cascade involved in this process.

The exocyst is required for melanin exocytosis from melanocytes and transfer to keratinocytes.

Skin pigmentation involves the production of the pigment melanin by melanocytes, in melanosomes and subsequent transfer to keratinocytes. Within keratinocytes, melanin polarizes to the apical perinuclear region to form a protective cap, shielding the DNA from ultraviolet radiation-induced damage. Previously, we found evidence to support the exocytosis by melanocytes of the melanin core, termed melanocore, followed by endo/phagocytosis by keratinocytes as a main form of transfer, with Rab11b playing a key role in the process. Here, we report the requirement for the exocyst tethering complex in melanocore exocytosis and transfer to keratinocytes. We observed that the silencing of the exocyst subunits Sec8 or Exo70 impairs melanocore exocytosis from melanocytes, without affecting melanin synthesis. Moreover, we confirmed by immunoprecipitation that Rab11b interacts with Sec8 in melanocytes. Furthermore, we found that the silencing of Sec8 or Exo70 in melanocytes impairs melanin transfer to keratinocytes. These results support our model as melanocore exocytosis from melanocytes is essential for melanin transfer to keratinocytes and skin pigmentation and suggest that the role of Rab11b in melanocore exocytosis is mediated by the exocyst.

In Vitro Susceptibility of Leishmania infantum to Artemisinin Derivatives and Selected Trioxolanes.

Leishmaniasis is among the world's most neglected diseases. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. A small library of artemisinin-derived trioxanes and synthetic trioxolanes was tested against promastigote and intramacrophage amastigote forms of Leishmania infantum. The trioxolanes LC50 and LC95 presented the best activity and safety profiles, showing potential for further studies in the context of leishmanial therapy. Our results indicate that the compounds tested exhibit peroxide-dependent activity.

Echocardiographic assessment of right ventricular contractile reserve in patients with pulmonary hypertension.

INTRODUCTION AND AIM: Right ventricular function is a major determinant of prognosis in pulmonary hypertension. The aim of this study was to assess and compare right ventricular contractile reserve in healthy subjects (controls) and in subjects with pulmonary hypertension (cases). METHODS: In this prospective study of seven cases and seven controls undergoing treadmill stress echocardiography, right ventricular S-wave velocity, tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RVFAC) and stroke volume index were assessed at rest and with exercise. The increase in each parameter between rest and exercise for cases and controls was analyzed and the magnitude of change in each parameter with exercise between cases and controls was compared. RESULTS: A significant increase in S-wave velocity was observed in cases (rest: 9.4 ± 3.1; exercise: 13.7 ± 4.8 cm/s [p < 0.05]). In controls there was a statistically significant increase in S-wave velocity (12.9 ± 2.3 to 23.0 ± 7.2 cm/s [p < 0.005]), TAPSE (25.7 ± 2.4 to 31.0 ± 3.5 mm [p < 0.05]) and RVFAC (53.8 ± 14.7% to 64.4 ± 9.9% [p < 0.005]). The magnitude of change in S-wave velocity (cases: 4.3 ± 3.3; controls: 10.1 ± 5.5 cm/s [p < 0.05]), TAPSE (cases: 0.6 ± 2.5; controls: 5.3 ± 3.8 mm [p < 0.05]) and RVFAC (cases: -0.4 ± 11.8; controls: 10.6 ± 5.9% [p < 0.05]) was significantly different between cases and controls. CONCLUSIONS: S-wave velocity, TAPSE and RVFAC increased significantly with exercise in controls. S-wave velocity was the only parameter that showed a significant increase in cases, although the magnitude of this increase was significantly less than in controls.

[Carcinoid heart - case report]. / Coração carcinóide - a propósito de um caso clínico.

We describe the case of a 76-year-old woman, diagnosed with a neuroendocrine tumor of the cecum in 2004, with liver metastases and carcinoid syndrome since September 2010. The patient had been treated intermittently with chemotherapy cycles, and remained symptomatic, with worsening secondary lesions. In June 2011 she began to present signs and symptoms of right heart failure and was hospitalized in September 2011. Transthoracic two- and three-dimensional echocardiography revealed enlarged right atrium and ventricle and thickened and fixed tricuspid and pulmonary valve leaflets, causing severe tricuspid regurgitation and mild pulmonary regurgitation and stenosis, suggestive of carcinoid heart disease. The authors discuss the clinical importance of transthoracic echocardiography, and the more recent three-dimensional echocardiography, as the diagnostic exam of choice in these cases, as it is especially suitable for assessing the valves and subvalvular apparatus.

Intraventricular gradients and acute coronary syndromes: a case report.

Left ventricular outflow tract obstruction (LVOTO) has traditionally been associated with hypertrophic obstructive cardiomyopathy, but can occur in other clinical scenarios such as acute myocardial infarction (AMI). In some patients, LVOTO is absent at rest, being detectable only with provocation tests such as stress echocardiography. Timely diagnosis of this phenomenon is very important, as it has therapeutic implications, and relies on clinical suspicion and on recognizing substrates in which LVOTO can occur. We report a case of syncope and AMI associated with LVOTO with systolic anterior motion of the mitral valve and a significant intraventricular gradient.

Ultrasonografía fetal: exámen del corazón normal (Parte I) / Fetal ultrasonography: the normal heart (Part I)

El propósito de éste trabajo de revisión es el de brindar una sistemática clara, sencilla y completa para un adecuado estudio ecográfico del corazón fetal. La circulación fetal difiere de la del adulto en que no es "secuencial" sino "en paralelo", con una bifurcación que se produce en la aurícula derecha hacia el corazón derecho o izquierdo y con un bypass en el ducto arterioso, esquivando al corazón izquierdo. Otra diferencia es la presencia del ductus venoso, que permite a la sangre oxigenada, proveniente de la placenta, realizar un bypass al hígado. En la práctica ecográfica fetal, unos pocos planos constituyen la base de la mayoría de los diagnósticos. Estos son: la vista de las cuatro cámaras, la vista del eje largo (con barrido del corazón derecho e izquierdo), la vista del eje corto (o plano axial) y la vista de los grandes vasos. Se revisa la importancia del ultrasonido en tiempo real en el reconocimiento de las estructuras cardíacas de acuerdo con sus relaciones para proseguir su estudio en modo M y Doppler. Se concluye ésta primera parte valorizando una sistemática "paso a paso" en el estudio detallado, donde el primer paso estaría limitado a la identificación de la posición fetal y cardíaca. El segundo paso es el reconocimiento de las estructuras intracardíacas y sus conexiones. El tercer paso es el estudio de los grandes vasos. El cuarto paso es el estudio del ritmo cardíaco (AU)

Ultrasonografía fetal: exámen del corazón normal (Parte I) / Fetal ultrasonography: the normal heart (Part I)

El propósito de éste trabajo de revisión es el de brindar una sistemática clara, sencilla y completa para un adecuado estudio ecográfico del corazón fetal. La circulación fetal difiere de la del adulto en que no es "secuencial" sino "en paralelo", con una bifurcación que se produce en la aurícula derecha hacia el corazón derecho o izquierdo y con un bypass en el ducto arterioso, esquivando al corazón izquierdo. Otra diferencia es la presencia del ductus venoso, que permite a la sangre oxigenada, proveniente de la placenta, realizar un bypass al hígado. En la práctica ecográfica fetal, unos pocos planos constituyen la base de la mayoría de los diagnósticos. Estos son: la vista de las cuatro cámaras, la vista del eje largo (con barrido del corazón derecho e izquierdo), la vista del eje corto (o plano axial) y la vista de los grandes vasos. Se revisa la importancia del ultrasonido en tiempo real en el reconocimiento de las estructuras cardíacas de acuerdo con sus relaciones para proseguir su estudio en modo M y Doppler. Se concluye ésta primera parte valorizando una sistemática "paso a paso" en el estudio detallado, donde el primer paso estaría limitado a la identificación de la posición fetal y cardíaca. El segundo paso es el reconocimiento de las estructuras intracardíacas y sus conexiones. El tercer paso es el estudio de los grandes vasos. El cuarto paso es el estudio del ritmo cardíaco