Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role, and that hepatic amino acid metabolism and glucagon are linked in a mutual feed-back cycle, the liver-alpha cell axis. On this background, we hypothesized that hepatic steatosis might impair glucagon’s action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia.

We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism during basal and high physiological levels of glucagon. The degree of steatosis was evaluated from liver biopsies.

Total RNA sequencing of liver biopsies revealed perturbations in the expression of genes predominantly involved in amino acid metabolism in the obese steatotic individuals. This group was also characterized by fasting hyperglucagonemia, hyperaminoacidemia and an absent lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals.

Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism resulting in increased amino acid concentrations as well as increased glucagon secretion providing a likely explanation of fatty liver-associated hyperglucagonemia.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

Ole Schmitz
Dec 1, 2004; 53:S233-S238
Section V: The Incretin Pathway

David J. Hodson
May 1, 2020; 69:864-866
Commentaries

Jens Juul Holst
Dec 1, 2004; 53:S197-S204
Section V: The Incretin Pathway

Mariam Alatrach
Apr 1, 2020; 69:681-688
Pathophysiology

The Giants added another arm into their bullpen mix Wednesday, acquiring right-hander Trevor Gott from the Nationals for cash considerations.

Hillel Furstenberg and Grigoriĭ Margulis have been announced as the winners of the 2020 Abel Prize.  You can read the official announcement here.   There is a news item about the prize on the AMS website.  Needless to say, they have … Continue reading →

10 January 2020

Invitation Only Research Event

Event participants

Professor Philippe Sands QC, Professor of Law, UCL 
Richard Burt, Managing Partner, McLarty Associates
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme; Dean, Queen Elizabeth II Academy, Chatham House

A gofundme account has been launched with the hope of keeping animals feed and to preserve endangered wildlife at the Hope Zoo in St Andrew. Curator, Joey Brown, organiser of the fundraiser, indicated that as a non-profit organisation,...

Invitation Only Research Event

Event participants

Invitation Only Research Event

It does not matter that he does not listen to you, That you’d rather he say your neck Is as graceful as an antelopes, Perhaps he’s not accustomed to lying. If he bought you an expensive phone you, Dropped in the bath the next day, would You, In yellow, Say he does not love you? […]

A time will come, When you don’t even, Own your own body, On the side of the road, A full breakdown not a common, Puncture, Leave your heart, it’s broken, Total mechanical failure. What will you do? Trust what you have given? Love, a blue opinion? You have only what you spent. You think you […]

The broom slices across the floor,Cutting a precise path through the mess,Clean swathe through the valley,Creating mounds of discarded,Clothing,Pieces,Returning slowly to their original state while,Still holding plastic memories of the night out,A strong attempt at cleaning up,A fine start. Loose Birthday cards too, Steal up on you, Perched as they are atop, Passports from a […]

  My shoes are not where I left them. There is a dog howling in the distance, And the sound reverberates, Lifting the dew off the dense canopy of trees outside. The bamboo lamp beside the sofa, Sheds dull orange light across the Persian carpet, And I am not casting a shadow. I have, A […]

It’s a revolt. A revolution. And in the name of God, they are building schools, Delivering doctors, door to door. They are conveying the message that people care, And that no one is forgotten but, Cameras are not allowed in some places. People hoist burning American Flags, Which melt and spit plastic, Scarring children with […]

Did you hear me? Within the bounds of righteousness, you May do as you please, I miss you. Finish and come back to me, I am always here. Have fun. Be happy. Photo – MoisesGomes – African Women -short evocative poetry-

Life is easy, when you’re up on the mountain And you’ve got peace of mind, like you’ve never known But things change, when you’re down in the valley Don’t lose faith, for you’re never alone For the God on the mountain, is the God in the valley When things go wrong, He’ll make them right […]

Director's Breakfast Briefing

Event participants

James Bacchus, Chair, Global Agenda Council on Governance for Sustainability, World Economic Forum; Chair, Appellate Body, World Trade Organization (1995-2003); Chair, Global Practice, Greenberg Taurig LLP

Invitation Only Research Event

Event participants

Shane Tomlinson, Senior Research Fellow, Energy, Environment and Resources Department, Chatham House

Just the mention of the name Marvia Providence sends a tingle to the toes and, immediately, feet start tapping and bodies begin swaying. Before you know it, all the ‘warriors’ – prayer and otherwise – are in full flight. That’s the effect of the...

Choreographer and designer Barry Moncrieffe; actress Lois Kelly Miller; New York-based broadcaster Gil Bailey; and actor and teacher Carl Samuels will all be remembered with a special tribute at Saturday’s staging of the annual Actor Boy Awards....

WHAT STARTED as an idea of two Barbadians – Ian Webster and Cheyne Jones – transformed into We Got This, a song which proved enough to stir the collective imagination of 25 recording artistes from 14 countries across the region, disseminating the...

“The United States has launched a stunning attack on Cuba’s medical-aid missions, with the Trump administration pressing countries to reject them during the coronavirus pandemic,” Steve Sweeny reported in the Morning Star, March 26, 2020. Given...

Government, having said bye, bye to the International Monetary Fund (IMF), declared quite boldly that it was ready to take charge and defend, on its own, the country’s economic independence. For the Government to swallow its pride and say, “Please...

Here's a look at 10 stars that you may have forgotten played for the Braves.

Brian McCann still laughs about what transpired as he learned the Braves were calling him up to the Majors during the 2005 season. He remembers being summoned to Brian Snitker's room, where he found the then Double-A manager eating pizza while wearing nothing more than his underwear.

Having seen what Luiz Gohara had done upon his introduction to the big leagues the previous September, Freddie Freeman told Alex Anthopoulos the big left-hander might immediately became an All-Star. Instead, it became a year of awakening for the young hurler, who remains fueled by last year's disappointments.

Orioles right-hander Hunter Harvey had hopped off a backfield mound at the club's Spring Training complex and exhaled. He was one of 14 pitchers scheduled to face hitters as part of the club's first full-squad workout on Monday, and now that he had, Harvey was asked to recall when was the last time he threw competitive pitches.

JERUSALEM (AP): Israeli Prime Minister Benjamin Netanyahu formally received the support of a majority of lawmakers to lead a new government yesterday, paving the way for a controversial power-sharing deal with rival-turned-partner Benny Gantz....

Western Bureau: A number of swimming officials in western Jamaica say that the region’s struggles with underdevelopment will continue even if the COVID-19 pandemic is brought under control. They say this is because they still lack proper pools to...

Western Bureau: THE MOBAY City Run organisers have reconsidered the event’s cancellation. Organising committee chair­person Janet Silvera said on Sunday, the day the event was to have taken place, that the seventh staging of the 5K/10K Walk and Run...

Waiting times in theatre can be a source of friction – but is the delay due to mandatory anaesthetic faff around time (MAFAT), or AWOL surgeons? Elizabeth Travis, and orthopaedic house officer in New Zealand and colleagues, have been trying to create and evidence base to argue the toss, and she joins me now to discuss her study, Operating...

Martin McShane, medical director of long term conditions at NHS England, questions the validity of the Quality and Outcomes Framework and suggests how it should change in the future. Read the related article: http://www.bmj.com/content/350/bmj.h2540

We're creating a manifesto for better evidence. The centre for Evidence Based Medicine at the University of Oxford, and the BMJ, are asking what are the problem with medical evidence, and how can we fix them? In this third discussion we went to Scotland, to find out what the people who create policy think about the issues with evidence synthesis,...

The increase in life expectancy in England has almost “ground to a halt” since 2010 and austerity measures are likely to be a significant contributor. In this podcast Michael Marmot, director at University College London’s Institute of Health Equity, joins us to discuss what might be causing that drop off, and why a decrease in early life chances...

It’s been 10 years since electronic cigarettes hit the shelves in a big way - and since there controversy has reigned about their health effects - are they less unhealthy than smoking traditional tobacco cigarettes, and will they increase nicotine dependence? Its to that last point that new research, published on BMJ.com is looking into -...

A new Rapid Recommendation from The BMJ suggests that for pregnant women, they may wish to avoid certain antiviral treatments for HIV. This recommendation differs from the WHO's, and to discuss why that is, and what makes that difference important, we're joined by Reed Siemieniuk, a physician and methodologist from McMaster University, and Alice...

Who better to kick off a series on all things health and evidence than the exceptional and erudite Editor-in-Chief of The BMJ, Dr Fiona Godlee. In this episode, Fiona chats to Ray about the BMJ's ongoing and often controversial campaigns to change medicine - and broader society - for the better. She also looks to a future that addresses the...

The Three Talk Model of shared decision is a framework to help clinicians to think about how to structure their consultation to ensure that shared decision making can most usefully take place. The model is based around 3 concepts - option talk, decision talk, and team talk - with active listening at the centre. Three Talk was first proposed in...

Healthy self confidence has an important role in surgery, but what came first - the surgeon or the ego? In this conversation, Christopher Myers, Yemeng Lu-Myers, and Amir Ghaferi join us to talk about the (very few) surgeons who behave badly in theatre, and why that behaviour has persisted, and can be detrimental. Read their full...

Jönköping has been at the centre of the healthcare quality improvement movement for years - but how did a forested region of Sweden, situated between it's main cities, come to embrace the philosophy of improvement so fervently? Goran Henriks, chief executive of learning and innovation at Qulturum in Jönköping joins us to explain. He also tells...

In 2001, Gottfried Hirnschall joined the WHO to work on the global response to HIV/AIDs, 18 years later he just retired as the director of WHO’s department for HIV and Hepatitis. The intervening period, almost half the time we’ve been aware of the disease the fight against the infection has been characterised by scientific breakthroughs, and...

Brexit. Who knows what’s going to happen in the next few weeks, months, years - the uncertainty is high. In the face of that, you’d hope that the government was doing all it could to plan for any eventuality - let alone for a massive, country altering one like suddenly crashing out without a deal - but Martin McKee, professor of public health at...

Statins are now the most commonly used drug in the UK and one of the most commonly used medicines in the world, but debate remains about their use for primary prevention for people without cardiovascular disease. Paula Byrne from the National University of Ireland Galway, joins us to talk about the evidence of benefit for low risk individuals,...

In many countries (including the UK and Australia) it is still common practice for hospital doctors to write letters to patients’ general practitioners (GPs) following outpatient consultations, and for patients to receive copies of these letters. However, Hugh Rayner, consultant nephrologist, and Peter Rees, former Chair of the Academy of...