Adiponectin is an important marker of anthropometric profiles of adipose tissue. However, association of adiponectin and adiposity in HIV mono- and co-infected and hepatitis (HCV) injection drug users (IDUs) has not been elucidated. Therefore, the relationship of total adiponectin levels with anthropometric indices of adiposity was examined in HIV mono-infected (anti-retroviral treatment, ART-naive, n=16 and -experienced, n=34); HCV mono-infected, n=36; HIV and HCV co-infected (ART-naive, n=5 and -experienced, n=13); uninfected, n=19 IDUs; and healthy controls, n=16 from coastal Kenya. Anthropometric indices of adiposity were recorded and total circulating adiponectin levels were measured in serum samples using enzyme-linked immunosorbent assay. Adiponectin levels differed significantly amongst the study groups (P<0.0001). Post-hoc analyses revealed decreased levels in HIV mono-infected ART-naive IDUs in comparison to uninfected IDUs (P<0.05) and healthy controls (P<0.05). However, adiponectin levels were elevated in HCV mono-infected IDUs relative to HIV mono-infected ART-naive (P<0.001) and -experienced (P<0.001) as well as HIV and HCV co-infected ART-naive (P<0.05) IDUs. Furthermore, adiponectin correlated with weight (ρ=0.687; P=0.003) and BMI (ρ=0.598; P=0.014) in HIV mono-infected ART-naive IDUs; waist circumference (ρ=−0.626; P<0.0001), hip (ρ=−0.561; P=0.001) circumference, and bust-to-waist ratio (ρ=0.561; P=0.001) in HIV mono-infected ART-experienced IDUs; waist girth (ρ=0.375; P=0.024) in HCV mono-infected IDUs; and waist-to-hip ratio (ρ=−0.872; P=0.048) in HIV and HCV co-infected ART-naive IDUs. Altogether, these results suggest suppression of adiponectin production in treatment-naive HIV mono-infected IDUs and that circulating adiponectin is a useful surrogate marker of altered adiposity in treatment-naive and -experienced HIV and HCV mono- and co-infected IDUs.
Eric M Ndombi, Valentine Budambula, Mark K Webale, Francis O Musumba, Jesca O Wesongah, Erick Mibei, Aabid A Ahmed, Raphael Lihana, and Tom Were
M L Gild, M Bullock, C K Pon, B G Robinson, and R J Clifton-Bligh
Metastatic differentiated thyroid cancers (DTC) are resistant to traditional chemotherapy. Kinase inhibitors have shown promise in patients with progressive DTC, but dose-limiting toxicity is commonplace. HSP90 regulates protein degradation of several growth-mediating kinases such as RET, and we hypothesized that HSP90 inhibitor (AUY922) could inhibit RET-mediated medullary thyroid cancer (MTC) as well as papillary thyroid cancer (PTC) cell growth and also radioactive iodine uptake by PTC cells. Studies utilized MTC cell lines TT (C634W) and MZ-CRC-1 (M918T) and the PTC cell line TPC-1 (RET/PTC1). Cell viability was assessed with MTS assays and apoptosis by flow cytometry. Signaling target expression was determined by western blot and radioiodine uptake measured with a gamma counter. Prolonged treatment of both MTC cell lines with AUY922 simultaneously inhibited both MAPK and mTOR pathways and significantly induced apoptosis (58.7 and 78.7% reduction in MZ-CRC-1 and TT live cells respectively, following 1 μM AUY922; P<0.02). Similarly in the PTC cell line, growth and signaling targets were inhibited, and also a 2.84-fold increase in radioiodine uptake was observed following AUY922 administration (P=0.015). AUY922 demonstrates in vitro activity against MTC and PTC cell lines. We observed a potent dose-dependent increase in apoptosis in MTC cell lines following drug administration confirming its anti-tumorigenic effects. Western blots confirm inhibition of pro-survival proteins including AKT suggesting this as the mechanism of cell death. In a functional study, we observed an increase in radioiodine uptake in the PTC cell line following AUY922 treatment. We believe HSP90 inhibition could be a viable alternative for treatment of RET-driven chemo-resistant thyroid cancers.
Muthiah Subramanian, Manu Kurian Baby, and Krishna G Seshadri
Antithyroid drugs (ATDs) have been shown to attenuate the effectiveness of radioiodine (radioiodine ablation, RIA) therapy in Graves' disease. We undertook a study to look at the impact of iodine uptakes on the outcome of 131I therapy. To determine the effect of prior ATD use on the duration of time to achieve cure in patients with high vs intermediate uptake Graves' disease who received a fixed dose (15 mCi) of 131I radioiodine. In a retrospective study of patients with Graves' disease, 475 patients who underwent RIA were followed-up on a two-monthly basis with thyroid function tests. Of the 123 patients with a documented preablation RAIU and consistent follow-up it was observed that 40 patients had an intermediate RAIU (10–30%) and 83 subjects had a distinctly increased uptake (>30%). Successful cure was defined as the elimination of thyrotoxicosis in the form of low free thyroxin and rising TSH levels. When a standard dose of 15 mCi 131I was administered, a cure rate of 93% was achieved. The median duration of time to cure (TC) was 129 days. Surprisingly, a direct proportional linear relationship (R 2=0.92) was established between time to cure and radioiodine uptake (TC> 3 0%=172days, TC10 – 3 0%=105 days, P<0.001). Patients who used ATD medications took a proportionately longer duration to achieve remission (TCNO ATD=102days, TCATD=253days, P<0.001). The effect of prior ATD therapy in delaying remission was amplified in the subset of patients with higher uptakes (TC> 3 0% + ATD=310days, TC> 3 0% + NO ATD=102days, P<0.001) compared to those with the intermediate uptakes (TC10 – 3 0% + ATD=126 days, TC10 – 3 0% + NO ATD=99 days, P<0.001). RIA, using a dose of 15 mCi achieved a high cure rate. Higher uptakes predicted longer time to achieve remission, with prior ATD use amplifying this effect.
Sarah J Delforce, Eugenie R Lumbers, Celine Corbisier de Meaultsart, Yu Wang, Anthony Proietto, Geoffrey Otton, Jim Scurry, Nicole M Verrills, Rodney J Scott, and Kirsty G Pringle
A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.
Martin Zweifel, Beat Thürlimann, Salome Riniker, Patrik Weder, Roger von Moos, Olivia Pagani, Martin Bigler, Karin M Rothgiesser, Christiane Pilop, Hanne Hawle, Peter Brauchli, Coya Tapia, Wolfgang Schoenfeld, Cristiana Sessa, and for the Swiss Group for Clinical Cancer Research (SAKK)
CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo. In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.
Riying Liang, Meijun Wang, Chang Fu, Hua Liang, Hongrong Deng, Ying Tan, Fen Xu, and Mengyin Cai
Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated.
Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated.
Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked.
Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.
Jia Liu, Min Liu, Zhe Chen, Yumei Jia, and Guang Wang
Autoimmune thyroiditis (AIT) is the most common autoimmune thyroid disease. Longitudinal relaxation time mapping (T1-mapping) measured by MRI is a new technique for assessing interstitial fibrosis of some organs, such as heart and liver. This study aimed to evaluate the relationship between T1-mapping value and thyroid function and determine the usefulness of T1-mapping in identifying thyroid destruction in AIT patients.
This case–control study recruited 57 drug-naïve AIT patients and 17 healthy controls. All participants were given thyroid MRI, and T1-mapping values were measured using a modified look-locker inversion-recovery sequence.
AIT patients had significantly higher thyroid T1-mapping values than the healthy controls (1.077 ± 177 vs 778 ± 82.9 ms; P < 0.01). A significant increase in thyroid T1-mapping values was presented along with the increased severity of thyroid dysfunction (P < 0.01). Correlation analyses showed that increased thyroid T1-mapping values were associated with higher TSH and lower FT3 and FT4 levels (TSH: r = 0.75; FT3: r = −0.47; FT4: r = −0.72; all P < 0.01). Receiver-operating characteristic curve analysis revealed a high diagnostic value of T1-mapping values for the degree of thyroid destruction (area under the curve was 0.95, 95% CI: 0.90–0.99, P < 0.01).
AIT patients have higher thyroid T1-mapping values than the healthy controls, and the T1-mapping values increased with the progression of thyroid dysfunction. Thyroid T1-mapping value might be a new index to quantitatively evaluate the degree of thyroid destruction in AIT patients.
Monia Cito, Silvia Pellegrini, Lorenzo Piemonti, and Valeria Sordi
The experience in the field of islet transplantation shows that it is possible to replace β cells in a patient with type 1 diabetes (T1D), but this cell therapy is limited by the scarcity of organ donors and by the danger associated to the immunosuppressive drugs. Stem cell therapy is becoming a concrete opportunity to treat various diseases. In particular, for a disease like T1D, caused by the loss of a single specific cell type that does not need to be transplanted back in its originating site to perform its function, a stem cell-based cell replacement therapy seems to be the ideal cure. New and infinite sources of β cells are strongly required. In this review, we make an overview of the most promising and advanced β cell production strategies. Particular hope is placed in pluripotent stem cells (PSC), both embryonic (ESC) and induced pluripotent stem cells (iPSC). The first phase 1/2 clinical trials with ESC-derived pancreatic progenitor cells are ongoing in the United States and Canada, but a successful strategy for the use of PSC in patients with diabetes has still to overcome several important hurdles. Another promising strategy of generation of new β cells is the transdifferentiation of adult cells, both intra-pancreatic, such as alpha, exocrine and ductal cells or extra-pancreatic, in particular liver cells. Finally, new advances in gene editing technologies have given impetus to research on the production of human organs in chimeric animals and on in situ reprogramming of adult cells through in vivo target gene activation.
Anastasia P Athanasoulia-Kaspar, Matthias K Auer, Günter K Stalla, and Mira Jakovcevski
Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing’s disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing’s disease).
Here, we examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case–control (n = 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.
We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; P = 0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres.
These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.
Soraya Puglisi, Paola Perotti, Mattia Barbot, Paolo Cosio, Carla Scaroni, Antonio Stigliano, Pina Lardo, Valentina Morelli, Elisa Polledri, Iacopo Chiodini, Giuseppe Reimondo, Anna Pia, and Massimo Terzolo
Metyrapone has been approved for the treatment of patients with Cushing’s syndrome (CS), but only few retrospective clinical studies are available. The aim of our study was the prospective assessment of metyrapone as pre-operative treatment.
Design and methods
Before adrenalectomy, seven patients with ACTH-independent CS due to adrenal adenoma were prospectively treated with metyrapone for 3 months in three tertiary academic centers, with endocrine work-up and clinical evaluation at screening and at predefined evaluation time points (Days 14, 31, 48, 65, 82).
In all patients, UFC levels decreased up to normal range from baseline to Day 82 (609 (188–1476) vs 69 (28–152) nmol/24 h, P < 0.02), with a reduction of serum and salivary cortisol levels, and no significant increase of plasma ACTH and serum DHEAS levels. Clinical improvement was reported on quality of life (+16.7 (+4.2; +52.00) points, P < 0.04) and pressure control (systolic pressure, −25 (−52; −10) mmHg, P < 0.01; diastolic pressure, −16 (−50; +2 mmHg), P < 0.03). No significant change in weight, electrolytes, glycemic and lipid profile was reported. Although in women a significant increase of testosterone and androstenedione was reported, no worsening of clinical hyperandrogenism was observed. All drug-related adverse events (nausea, fatigue, low grade fever, edema of lower limbs and facial rash) were grade 1 or 2 and generally transient.
This prospective pilot study demonstrated that metyrapone is effective in normalizing biochemical and clinical parameters in patients with CS due to adrenal adenoma before surgical intervention, with minimal side effects.