Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease.

Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin-like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin-based and pannexin-based channels in noncancerous liver disease.

The interval approach: an adaptation of the liver-first approach to treat synchronous liver metastases from rectal cancer.

BACKGROUND: The waiting interval after chemoradiotherapy (CRT) is an interesting therapeutic window to treat patients with synchronous liver metastases (SLM) from rectal cancer. METHODS: A retrospective analysis was performed of 18 consecutive patients (M/F 10/8, age (range) 60 (51-75) years) from five institutions who underwent liver resection of SLM during the waiting interval after CRT for rectal adenocarcinoma. RESULTS: All patients underwent interval liver surgery for a median (range) of 4 (2-14) liver metastases. Metastases involved a median (range) of 4 (1-7) liver segments. Median (range) time between end of CRT and liver surgery was 22 (6-45) days. Laparoscopic liver surgery was performed in 12 (67%) patients. No severe complications (Clavien-Dindo ≥ 3b) occurred after liver surgery. Median (range) length of hospital stay after liver surgery was 5 (1-10) days. All patients subsequently underwent rectal resection at a median (range) of 10 (8-13) weeks after end of CRT. Median (IQR) time-to-progression after liver surgery was 4.2 (2.8-9.2) months. CONCLUSIONS: The waiting interval after neoadjuvant CRT is a valuable option to treat SLM from rectal cancer. More data are necessary to confirm its oncological efficacy.

Experimental models of liver fibrosis.

Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.

Holmium-166 Transarterial Radioembolization for the Treatment of Intrahepatic Cholangiocarcinoma: A Case Series.

BACKGROUND: Transarterial radioembolization (TARE) is used to treat primary and secondary malignancies in the liver that are not amenable to curative resection. Accumulating evidence demonstrates the efficacy and safety of TARE with yttrium-90 (90Y), which is the most widely used radionuclide for TARE, and later with holmium-166 (166Ho) for various indications. However, the safety and efficacy of 166Ho TARE in patients with intrahepatic cholangiocarcinoma (ICC) remains to be studied. METHODS: This was a retrospective case series study of seven consecutive patients with ICC who were treated with 166-Ho-TARE in our center. We recorded the clinical parameters and outcomes of the TARE procedures, the tumor response according to mRECIST, subsequent treatments, and adverse events. RESULTS: Three out of the seven patients had a partial or complete response. Two patients had stable disease after the first TARE procedure, and two of the patients (one with a complete response, and one with stable disease) were alive at the time of analysis. No serious adverse events related to the procedure were recorded. CONCLUSIONS: This is the first case series reporting the safety and tumor response outcomes of 166Ho-TARE for ICC. The treatment demonstrated its versatility, allowing for reaching a high tumor dose, which is important for improving tumor response and treating patients in a palliative setting, where safety and the preservation of quality of life are paramount.

Expression of connexins and pannexins in diseased human liver.

Connexin proteins can form hexameric hemichannels and gap junctions that mediate paracrine and direct intercellular communication, respectively. Gap junction activity is crucial for the maintenance of hepatic homeostasis, while connexin hemichannels become particularly active in liver disease, such as hepatitis, fibrosis, cholestasis or even hepatocellular carcinoma. Channels consisting of connexin-like proteins named pannexins have been directly linked to liver inflammation and cell death. The goal of the present study was to characterize the expression and subcellular localization of connexins and pannexins in liver of patients suffering from various chronic and neoplastic liver diseases. Specifically, real-time quantitative reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry analyses were performed on human liver biopsies. It was found that pannexin1 and pannexin2 gene expression are correlated to a certain degree, as is pannexin1 protein expression with connexin32 and connexin43 protein expression. Furthermore, this study is the first to detect pannexin3 in human patient liver biopsies via both immunoblot and immunohistochemistry.

Laparoscopic evaluation shows deficiencies in memory ring deployment during small ventral hernia repair.

BACKGROUND: With the introduction of a self-expanding, memory-containing, circular hernia patch, surgeons have been enthusiastic about its use to repair ventral hernias smaller than 3 cm in diameter. The aim of this study was to evaluate the efficiency, reliability, and safety of the device laparoscopically with respect to adequate deployment of the patch. METHODS: During 1 year all patients with small ventral hernias were treated with this memory-containing patch and were inspected by laparoscopy. Just prior to insertion of the patch, remaining adhesions on top of the peritoneum were analyzed, as was the interference of the umbilical ligament. The final position of the patch was monitored, identifying the cupping phenomenon, exposure of the polypropylene to the viscera, and the amount of tension on the straps. All patients were followed for 2 years and postoperative complications and recurrence rate were monitored. RESULTS: Twenty-eight patients were operated on for repair of a small ventral hernia with laparoscopic control. Adhesions, not digitally palpable, that interfered with adequate patch deployment were observed in more than 80% of the cases. After a median follow-up of 25 months a 14.8% recurrence rate was observed. CONCLUSIONS: The patch, consisting of both polypropylene and ePTFE, leads to unacceptable morbidity and a high rate of recurrences. By laparoscopic evaluation, these recurrences are probably based on a combination of material characteristics and unavoidable technical errors.

Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research.

Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and '-omics'-based read-outs are still in their infancy, but show great promise. In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed.