Invitation Only Research Event

We aimed to evaluate the diagnostic performance of ¹⁸F-FDG PET/CT for the detection of post-transplantation lymphoproliferative disorder (PTLD) in a pediatric population and explore its feasibility during response assessment. Methods: This retrospective study included 28 pediatric transplant recipients who underwent a total of 32 ¹⁸F-FDG PET/CT scans due to clinical suspicion of PTLD within an 8-year period. Pathology reports and 2-year follow-up were used as reference standard. Twenty-one response assessment ¹⁸F-FDG PET/CT scans were re-evaluated according to the Lugano criteria. Results: The diagnosis of PTLD was established in 14 patients (49%). Sensitivity, specificity, positive predictive value, and negative predictive value of ¹⁸F-FDG PET/CT for the detection of PTLD in children with a clinical suspicion of this disease, was 50% (7/14), 100% (18/18), 100% (7/7), and 72% (18/25), respectively. False-negative results occurred in patients with PTLD in the Waldeyer’s ring, cervical lymph nodes or small bowel with either non-destructive or polymorphic PTLD. Two of 5 interim ¹⁸F-FDG PET/CT scans and 3 of 9 end-of-treatment ¹⁸F-FDG PET/CT scans were false-positive. Conclusion: ¹⁸F-FDG PET/CT had good specificity and positive predictive value but low to moderate sensitivity and negative predictive value for the detection of PTLD in a 28 pediatric patient cohort with a clinical suspicion of this disease. False-negative results were confirmed in the Waldeyer’s ring, cervical lymph nodes and small bowel with either non-destructive or polymorphic PTLD subtypes. ¹⁸F-FDG PET/CT appears to have a limited role in the response assessment setting of pediatric PTLD, given the observed high proportions of false-positives both at interim and end-of-treatment evaluations.

6 November 2019 , Volume 95, Number 6

Oh boy what a meaty session we have for you as Christina Mercer, Somrata Sarkar, David Price and Henry Burrell tackle three whopics (whopping topics) head on.

Somrata takes us into the sometimes scary thoughts of our own digital afterlives. Should we be worried that we'll end up as misrepresentative chat bots one day? Who will have the authority to police the companies that harvest our data?

Then Christina explains the knife edge America is on when it comes to net neutrality. Despite recent hope, there's still a chance the web across the pond will be ruthlessly metered and segmented.

Finally David asks us if we've checked our unused email accounts recently, as there might be a lot of desperate noodle companies in there begging you to stay on their mailing lists.

See acast.com/privacy for privacy and opt-out information.

A fundamental feature of the eukaryotic cell membrane is the asymmetric arrangement of lipids in its two leaflets. A cell invests significant energy to maintain this asymmetry and uses it to regulate important biological processes, such as apoptosis and vesiculation. The dynamic coupling of the inner or cytoplasmic and outer or exofacial leaflets is a challenging open question in membrane biology. Here, we combined fluorescence lifetime imaging microscopy (FLIM) with imaging total internal reflection fluorescence correlation spectroscopy (ITIR-FCS) to differentiate the dynamics and organization of the two leaflets of live mammalian cells. We characterized the biophysical properties of fluorescent analogs of phosphatidylcholine, sphingomyelin, and phosphatidylserine in the plasma membrane of two mammalian cell lines (CHO-K1 and RBL-2H3). Because of their specific transverse membrane distribution, these probes allowed leaflet-specific investigation of the plasma membrane. We compared the results of the two methods having different temporal and spatial resolution. Fluorescence lifetimes of fluorescent lipid analogs were in ranges characteristic for the liquid ordered phase in the outer leaflet and for the liquid disordered phase in the inner leaflet. The observation of a more fluid inner leaflet was supported by free diffusion in the inner leaflet, with high average diffusion coefficients. The liquid ordered phase in the outer leaflet was accompanied by slower diffusion and diffusion with intermittent transient trapping. Our results show that the combination of FLIM and ITIR-FCS with specific fluorescent lipid analogs is a powerful tool for investigating lateral and transbilayer characteristics of plasma membrane in live cell lines.

An early exposure to lipid biochemistry in the laboratory of Konrad Bloch resulted in a fascination with the biosynthesis, structures, and functions of bacterial lipids. The discovery of plasmalogens (1-alk-1'-enyl, 2-acyl phospholipids) in anaerobic Gram-positive bacteria led to studies on the physical chemistry of these lipids and the cellular regulation of membrane lipid polymorphism in bacteria. Later studies in several laboratories showed that the formation of the alk-1-enyl ether bond involves an aerobic process in animal cells and thus is fundamentally different from that in anaerobic organisms. Our work provides evidence for an anaerobic process in which plasmalogens are formed from their corresponding diacyl lipids. Studies on the roles of phospholipases in Listeria monocytogenes revealed distinctions between its phospholipases and those previously discovered in other bacteria and showed how the Listeria enzymes are uniquely fitted to the intracellular lifestyle of this significant human pathogen.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.

I don’t have friends, I do not think. Friends get married, and Drive bigger cars and, Have more intelligent things to talk about, better Places to go, are Becoming lawyers and doctors and ministers, Big people, and It sort of interrupts things. ♦photos♦ Jacob’s Ladder -short evocative poetry-

When I tell people that I do not remember learning how to read, they laugh. But I really do not recall learning to read. Reading was an activity that excited my family, and so it was no surprise that I would love reading. The love of books and...

Let’s face it, ladies: boosting your health is not always your primary priority, but it needs to be. It doesn’t require a long, overbearing and spine-chilling regime. Simple lifestyle changes can get the job done! In the end you’ll be left with a...

A hysterectomy is a surgical procedure that’s done to cure serious problems of the uterus (womb), cervix or even the ovaries. Some women fear that having this procedure done will affect their sex life. Will it truly? Let’s find out. “There are...

A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult Tph1 βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of Htr2b in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

Henry "Hank" Aaron was born in Alabama three years after Willie Mays, 85 years ago Tuesday. Now, all this time later, Aaron is as much the conscience and the soul of baseball as any man alive. But we don't just celebrate a great baseball life today. We celebrate a great American life.

Delirium is common in the last weeks or days of life. It can be distressing for patients and those around them. A clinical update explains why successful management involves excluding reversible causes of delirium and balancing drugs that may provoke or maintain delirium while appreciating that most patients want to retain clear cognition at the...

Scott Murray, professor of primary palliative care at the University of Edinburgh, has written, and talked in this podcast before, about the benefits of early palliative care - and today he’s back to explain how illness trajectory, and the pattern of decline at the end of life, affects 4 main areas of wellness - physical, social, psychological and...

When a person’s heart or breathing stops and the cause is reversible, immediate cardiopulmonary resuscitation (CPR) offers a chance of life. However, when a person is dying—for example, from organ failure, frailty, or advanced cancer—and his or her heart stops as a final part of a dying process, CPR will not prevent death and may do harm. But...

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...

Cardiovascular factors are associated with risk of stroke - and those factors can be mediated by lifestyle and by genetic make up. New research published by The BMJ sets out to explore how these risks combine, and we're joined on the podcast by two of the authors - Loes Rutten-Jacobs, senior postdoctoral researcher at the German Center for...

More doctors are choosing to retire early, doctors who take career breaks find it hard to return to practice, and doctors at all stages of their careers are frustrated by the lack of support given to training and development in today’s NHS. Each year the BMJ holds a roundtable discussion at the Nuffield Summit - where health leaders come...

The engaging storyline and realness of the characters in Barbara Jenkins’ De Rightest Place makes it a book you breeze through in a matter of days. Set mainly in and around a bar called De Rightest Place, in the environs of a working-class...

Sagicor Finance Company has raised doubt about whether the deal to acquire the assets of Scotia Life Trinidad...

DESPITE TUMBLING sales and challenges with hire-purchase accounts, two of the largest retailers of home furniture and appliances, Courts Jamaica and Singer Jamaica, have found glimmers of hope during the COVID-19 pandemic. That’s because work-from...

By: Matt Stamps, Yale-NUS College When Yale-NUS College reviewed the curriculum for its Mathematical, Computational, and Statistical (MCS) Sciences major in the autumn of 2018, I spent several weeks reading about mathematics programs at similar institutions.  A common learning objective … Continue reading →

OBJECTIVE

To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

OBJECTIVE

This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D).

Saila B. Koivusalo
Jan 1, 2016; 39:24-30
Considerations in the Management of Gestational Diabetes Mellitus

TODAY Study Group
Jun 1, 2013; 36:1749-1757
TODAY Study

Alison J. Dunkley
Apr 1, 2014; 37:922-933
Current Concepts of Type 2 Diabetes Prevention

Frank B. Hu
Jun 1, 2011; 34:1249-1257
Kelly West Award Lecture

Jordi Salas-Salvadó
May 1, 2019; 42:777-788
Continuing Evolution of Nutritional Therapy for Diabetes

Frank B. Hu
Jun 1, 2011; 34:1249-1257
Kelly West Award Lecture

OBJECTIVE

To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes.

OBJECTIVE

Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life.

AHP readers will be interested in a review article now available online from History of the Human Sciences “Within a single lifetime: Recent writings on autism.” Written by Gregory Hollin the piece reviews five recent books on autism.

These are unprecedented times. Much of the world is currently living under lockdown conditions and practicing social distancing in order to curb the spread of the COVID-19 coronavirus. So how is this affecting people’s intimate lives? How are our sex lives and relationships holding up, and is there anything we can do to more effectively navigate this complex and challenging situation? For the answers to these questions, I spoke to Dr. Lori Brotto, a Professor at the University of British Columbia, a practicing psychologist, and author of the book Better Sex Through Mindfulness. I asked Dr. Brotto what she has been seeing in her clinical practice since the pandemic began and how it’s different from usual.

By Emily Reynolds. But self-assessed intelligence was not actually related to objective measures of intelligence

Former NFL linebacker talks about growing up with the game of football.

Clarke Island is a windswept place in Eastern Bass Strait. It had no residents and could only be accessed by light plane or boat when weather permitted. Having never seen the place, Dion and his family move there in March of 1984. They arrived with few provisions and few possessions to an old farm house in a poor state of repair. To survive they had to learn to live in harmony with the island by forging a semi self-sufficient life style in which they not only grew a garden and kept milking goats, but learned to live off the bounty of the land and sea.