Post metabolic bariatric surgery weight regain: the importance of GLP-1 levels.

Weight regain and insufficient weight loss are essential problems after metabolic bariatric surgery (MBS) in people living with obesity. Changes in the level of glucagon-like peptide-1 (GLP-1) secreted from the gut after bariatric surgery are one of the underlying mechanisms for successful initial weight loss. Studies and meta-analyses have revealed that postprandial GLP-1 levels increase after the Roux-en-Y gastric bypass and sleeve gastrectomy, but fasting GLP-1 levels do not increase significantly. Some observational studies have shown the relationship between higher postprandial GLP-1 levels and successful weight loss after bariatric surgery. There is growing evidence that GLP-1-receptor agonist (GLP-1-RA) use in patients who regained weight after bariatric surgery has resulted in significant weight loss. In this review, we aimed to summarize the changes in endogenous GLP-1 levels and their association with weight loss after MBS, describe the effects of GLP-1-RA use on weight loss after MBS, and emphasize metabolic adaptations in light of the recent literature. We hypothesized that maintaining higher basal-bolus GLP-1-RA levels may be a promising treatment choice in people with obesity who failed to lose weight after bariatric surgery.

Increased prevalence of metabolic syndrome in female patients with overactive bladder: A population-based study.

OBJECTIVES: To assess the association between overactive bladder syndrome (OAB) and the metabolic syndrome (MetS). PATIENTS AND METHODS: A population-based study was conducted to compare OAB patients with age-, sex- and ethnicity-matched control subjects regarding the prevalence of the parameters of the MetS, with respect to obesity, hyperlipidemia, hypertension and diabetes mellitus. The characteristics of the OAB population were assessed. Adjusted odds ratios (OR) were calculated by logistic regression. RESULTS: 110 024 OAB patients and 220 455 controls. were identified. OAB was associated with a higher prevalence of MetS (35.4% vs. 27.5%, p < 0.001). The fully adjusted OR for MetS in patients with OAB compared to controls was 1.44; 95% confidence interval (CI) 1.42-1.46; p < 0.001. Among metabolic parameters, obesity was found to be the strongest factor associated with OAB (OR 1.55, 95% CI 1.53-1.58, p < 0.001), and higher high-density lipoprotein cholesterole levels (>50) had a protective effect on the risk of OAB (OR 0.75, 95% CI 0.73-0.76, p < 0.001). CONCLUSIONS: Data from this cohort suggest that OAB is positively associated with MetS. Clinicians approaching patients with OAB should be aware of this association. A multimodal treatment focusing on the MetS may be considered in these patients.

The Association Between Hypothyroidism Treatment and Mortality in Patients Hospitalized in Surgical Wards.

Limited data are available regarding the association between pre-admission thyroid-stimulating hormone (TSH) levels and prognosis in hospitalized surgical patients treated for hypothyroidism. We retrospectively evaluated a cohort of 1,451 levothyroxine-treated patients, hospitalized to general surgery wards. The 30-day mortality risk was 2-fold higher for patients with TSH of 5.0-10.0 mIU/L (adjusted OR, 2.3; 95% CI 1.1-5.1), and 3-fold higher for those with TSH > 10.0 mIU/L (3.4; 95% CI 1.3-8.7). Long-term mortality risk was higher in patients with TSH of 5.0-10.0 and above 10.0 mIU/L (adjusted HR, 1.2; 95% CI, 1.0-1.6, and 1.7; 95% CI 1.2-2.4, respectively). We found that in levothyroxine-treated adults hospitalized to surgical wards, increased pre-admission TSH levels are associated with increased short- and long-term mortality.

The Association Between BMI and Mortality in Surgical Patients.

BACKGROUND: While obesity is commonly associated with increased morbidity and mortality, in patients with chronic diseases, it has have been associated with a better prognosis, a phenomenon known as the 'obesity paradox'. OBJECTIVE: We investigated the relationship between mortality, length of hospital stay (LOHS), and body mass index (BMI) in patients hospitalized to general surgical wards. METHODS: We extracted data of patients admitted to the hospital between January 2011 and December 2017. BMI was classified according to the following categories: underweight (< 18.5), normal weight (18.5-24.9), overweight (25-29.9), obesity (30-34.9) and severe obesity (≥ 35). Main outcomes were mortality at 30-day mortality and at the end-of-follow-up mortality), as well as LOHS. RESULTS: A total of 27,639 patients (mean age 55 ± 20 years; 48% males; 19% had diabetes) were included in the study. Median LOHS was longer in patients with diabetes vs. those without diabetes (4.0 vs 3.0 days, respectively), with longest LOHS among underweight patients. A 30-day mortality was 2% of those without (371/22,297) and 3% of those with diabetes (173/5,342). In patients with diabetes, 30-day mortality risk showed a step-wise decrease with increased BMI: 10% for underweight, 6% for normal weight, 3% for overweight, 2% for obese and only 1% for severely obese patients. In patients without diabetes, 30-day mortality was found to be 6% for underweight, 3% for normal weight and 1% across the overweight and obese categories. Mortality rate at the end-of-follow-up was 9% of patients without diabetes and 18% of those with diabetes (adjusted OR = 1.3, 95% CI, 1.2-1.5). In patients with diabetes, mortality risk showed an inverse association with respect to BMI: 52% for underweight, 29% for normal weight, 17% for overweight, 14% for obesity and 7% for severely obese patients, with similar trend in patients without diabetes. CONCLUSIONS: The results support the 'obesity paradox' in the general surgical patients as those with and without diabetes admitted to surgical wards, BMI had an inverse association with short- and long-term mortality.

Prevalence and characteristics of fibromyalgia among HIV-positive patients in southern Israel.

OBJECTIVES: Fibromyalgia and chronic pain have previously associated with HIV infection for over two decades. We aimed to evaluate the prevalence of FMS symptoms in an ethnically heterogeneous population of HIV-infected individuals in southern Israel, applying the proposed new diagnostic criteria for diagnosis of fibromyalgia symdrome (FMS). METHODS: 156 HIV-positive patients followed at the AIDS clinic of the Soroka University Medical Center (SUMC) who gave written informed consent were recruited in the trial. FMS was diagnosed based on the widespread pain index (WPI) and the Symptom Severity Score (SSS) comprising the modified 2011 diagnostic criteria for FMS. CD4 levels ad viral load were obtained. RESULTS: One hundred and thirty-nine patients (89.1%) were receiving HAART (Highly Active Antiretroviral Therapy). A total of 22 patients (14.1%) were found to fulfill current criteria for diagnosis of FMS. FMS-criteria positive individuals were slightly younger than criteria-negative individuals (40.3±9.2 vs. 42.6±11.9, p=0.39), but this difference did not reach statistical significance. There was no significant difference between the groups regarding gender, family status, religion, occupation or education. No correlation was found between CD4 and viral load levels and symptoms of FMS. CONCLUSIONS: Despite the dramatic improvement in management of HIV, FMS symptoms remain highly prevalent among these patients and are not directly correlated with indices of active disease. FMS is an important clinical issue to address among patients suffering from HIV infection.

Glycemic Management Among Adults With Type 1 Diabetes During Passover: A Pre-Post Single-center Study.

OBJECTIVES: No data are available regarding glycemic management of individuals with type 1 diabetes (T1D) during Passover. Our aim in this study was to assess the effect of Passover on diabetes management and glycemic management in adults with T1D with nutritional changes during Passover (observant) compared with those who did not change their dietary habits during Passover (nonobservant). METHODS: We conducted an observational pre-post study of adults with T1D, followed in a diabetes clinic in Israel. Data were downloaded from insulin pumps and continuous glucose monitoring for 37 days: 2 weeks before Passover, 9 days of Passover, and 2 weeks thereafter. Differences in percentage of time spent above target (>10.0 to >13.9 mmol/L), at target (3.9 to 10.0 mmol/L), and below target (<3.9 to <3.0 mmol/L) were compared using paired t tests or paired signed rank tests. RESULTS: The study cohort included 43 individuals with T1D (23 observant, 20 nonobservant). The average blood glucose was significantly higher during Passover compared with the period before Passover---in nonobservant patients 8.2±1.5 mmol/L and 7.9±1.3 mmol/L (p=0.043), respectively, and in observant patients 8.7±1.6 mmol/L and 8.4±1.6 mmol/L (p=0.048), respectively. Time above range 10 to 13.9 mmol/L was increased in observant individuals during Passover, as compared with the period before Passover, at 24.9±16.2% and 20.6±12.4% (p=0.04), respectively. The dose of bolus insulin had increased significantly in observant individuals: 27.4±13.9 units during Passover, as compared with 24.2±11.2 units before Passover (p=0.02). CONCLUSIONS: Passover alters glycemic management and insulin needs in Jewish adults with T1D. It is advisable to make specific adjustments to maintain the recommended glycemic management.

Drug-Drug Interactions Between Glucagon-Like Peptide 1 Receptor Agonists and Oral Medications: A Systematic Review.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1RAs) are used in the treatment of diabetes and obesity. Their slowing effect of gastric emptying might change oral drug absorption, potentially affecting pharmacokinetics, particularly in the case of medications with a narrow therapeutic index. PURPOSE: The purpose of this systematic review is to summarize data on drug-drug interactions between GLP1RAs and oral drugs. DATA SOURCES: The PubMed and EMBASE databases were searched up to November, 1st 2023. STUDY SELECTION: We selected pharmacokinetic studies of any injectable GLP1RA given with an oral medication, and product prescribing sheets reporting data without access to the original study. DATA EXTRACTION: Two authors independently extracted the data. DATA SYNTHESIS: Twenty-two reports and six prescribing sheets were included. Treatment with GLP1RAs resulted in unaffected or reduced Cmax and delayed tmax of drugs with high solubility and permeability (warfarin, contraceptive pills, acetaminophen), drugs with high solubility and low permeability (angiotensin converting enzyme inhibitors), drugs with low solubility and high permeability (statins) and drugs with low solubility and permeability (digoxin). However, the use of GLP1RAs did not exert clinically significant changes in the AUC or differences in clinically relevant endpoints. LIMITATIONS: The major limitations of the studies that are included in this systematic review are the enrollment of healthy subjects and insufficient data in conditions that might affect pharmacokinetics (e.g., kidney dysfunction). CONCLUSIONS: To conclude, reduced Cmax and delayed tmax of drugs co-administered with GLP1RAs are consistent with the known delayed gastric output by the latter. Nevertheless, the overall drug exposure was not considered clinically significant. Dose adjustments are probably not required for simultaneous use of GLP1RAs with oral medications. Still, results should be carefully generalized to cases of background kidney dysfunction or when using drugs with narrow therapeutic index. The study is registered in PROSPERO: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022332339 .

Glucagon-like Peptide 1 Receptor Agonists and Cardiovascular Outcomes in Solid Organ Transplant Recipients With Diabetes Mellitus.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in type 2 diabetes. Limited data are available on diabetes treatment after solid organ transplantation. We aimed to explore the effect of GLP1-RAs on cardiovascular outcomes in transplanted recipients with diabetes. METHODS: We extracted data on adult transplant recipients (kidney, lungs, liver, heart) insured in a large health maintenance organization. Death-censored patients with diabetes treated with GLP1-RAs were matched with nonusers. The primary outcome was a composite of major cardiovascular events (MACEs): a nonfatal cardiac event (myocardial infarction, stable/unstable angina, coronary bypass, and coronary angiography), ischemic stroke and all-cause mortality. Secondary outcomes were MACE or peripheral vascular disease (MACE-PVD), and all-cause mortality. Safety outcomes included biliopancreatic adverse events. RESULTS: We included 318 patients (69% males, average age 58.3 ±â€…11.0 y) with a 3.1-y median follow-up. The incidence of MACE was 101 of 1000 patient-years in GLP1-RAs users compared with 134 of 1000 in controls (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.27-0.78). GLP1-RAs similarly reduced the risk of MACE-PVD (HR 0.53; 95% CI, 0.33-0.88) and the risk of all-cause mortality (HR 0.39; 95% CI, 0.18-0.84). Biliopancreatic adverse events occurred less in GLP1-RA users. CONCLUSIONS: Transplant recipients with diabetes who used GLP1-RAs had lower risks for MACE and all-cause mortality. These results may profoundly implicate the daily management of posttransplant recipients with diabetes, a population with a high prevalence of cardiometabolic risk factors and cardiovascular death. Transplant patients are usually excluded from randomized controlled trials and, hence might be undertreated with disease-modifying drugs. Larger prospective studies are needed in this unique population.

Clinical Study and Systematic Review of Pituitary Microadenomas vs. Macroadenomas in Cushing's Disease: Does Size Matter?

Background: Reports on clinical and biochemical differences between adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas and macroadenomas are limited and inconsistent. Objective: Compare clinical and biochemical characteristics of patients with corticotroph microadenomas and macroadenomas and assess predictive factors for biochemical response to dynamic testing for Cushing's disease (CD) in a clinical trial and a systematic review. A second aim was to evaluate differences between macroadenomas with and without cavernous and sphenoid sinus invasion. Methods: Retrospective charts review of patients with CD, treated at Rabin Medical Center between 2000 and 2020 or at Maccabi Healthcare Services in Israel between 2005 and 2017. Clinical and biochemical factors were compared between patients with corticotroph microadenomas and macroadenomas. We have also performed a systematic review of all studies (PRISMA guidelines) comparing corticotroph microadenomas with macroadenomas up to 31 November 2021. Results: The cohort included 105 patients (82 women, 78%; mean age, 41.5 ± 14.5 years), including 80 microadenomas (mean size, 5.2 ± 2.2 mm) and 25 macroadenomas (mean size, 18.0 ± 7.7 mm). Other baseline characteristics were similar between groups. Most common presentation suggestive for hypercortisolemia among patients with both micro- and macroadenomas were weight gain (46.3% vs. 48.0%, p = NS) and Cushingoid features (27.5% vs. 20.0%, p = NS). Mean 24 h urinary free cortisol (5.2 ± 5.4 × ULN vs. 7.8 ± 8.7 × ULN) and serum cortisol following low-dose dexamethasone (372.0 ± 324.5 vs. 487.6 ± 329.8 nmol/L), though higher for macroadenomas, were not significant. Levels of ACTH were greater for macroadenomas (1.9 ± 1.2 × ULN vs. 1.3 ± 0.8 × ULN, respectively, p = 0.01). Rates of recurrent/persistent disease were similar, as were rates of post-operative adrenal insufficiency and duration of post-operative glucocorticoid replacement. Macroadenomas with sphenoid or cavernous sinus invasion were associated with higher ACTH, 24 h free urinary cortisol, and serum cortisol following low-dose dexamethasone, compared with suprasellar or intrasellar macroadenomas. Conclusions: While ACTH-secreting macroadenomas exhibit higher plasma ACTH than microadenomas, there was no association between tumor size with cortisol hypersecretion or clinical features of hypercortisolemia. Though overall rare, increased awareness is needed for patients with CD with tumor extension in the cavernous or sphenoid sinus, which displays increased biochemical burden, highlighting that extent/location of the adenoma may be more important than size per se. Our systematic review, the first on this topic, highlights differences and similarities with our study.

Comparison of Insulin Dose Adjustments Made by Artificial Intelligence-Based Decision Support Systems and by Physicians in People with Type 1 Diabetes Using Multiple Daily Injections Therapy.

Objective: Artificial intelligence-based decision support systems (DSS) need to provide decisions that are not inferior to those given by experts in the field. Recommended insulin dose adjustments on the same individual data set were compared among multinational physicians, and with recommendations made by automated Endo.Digital DSS (ED-DSS). Research Design and Methods: This was a noninterventional study surveying 20 physicians from multinational academic centers. The survey included 17 data cases of individuals with type 1 diabetes who are treated with multiple daily insulin injections. Participating physicians were asked to recommend insulin dose adjustments based on glucose and insulin data. Insulin dose adjustments recommendations were compared among physicians and with the automated ED-DSS. The primary endpoints were the percentage of comparison points for which there was agreement on the trend of insulin dose adjustments. Results: The proportion of agreement and disagreement in the direction of insulin dose adjustment among physicians was statistically noninferior to the proportion of agreement and disagreement observed between ED-DSS and physicians for basal rate, carbohydrate-to insulin ratio, and correction factor (P < 0.001 and P ≤ 0.004 for all three parameters for agreement and disagreement, respectively). The ED-DSS magnitude of insulin dose change was consistently lower than that proposed by the physicians. Conclusions: Recommendations for insulin dose adjustments made by automatization did not differ significantly from recommendations given by expert physicians regarding the direction of change. These results highlight the potential utilization of ED-DSS as a useful clinical tool to manage insulin titration and dose adjustments.

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

The Biochemical Diagnosis of Acromegaly.

BACKGROUND: The diagnosis of acromegaly still poses a clinical challenge, and prolonged diagnostic delay is common. The most important assays for the biochemical diagnosis and management of acromegaly are growth hormone (GH) and insulin-like growth factor-1 (IGF-1). OBJECTIVE: Discuss the role of IGF-1, basal serum GH, and nadir GH after oral glucose tolerance test (OGTT) for the diagnosis, management, and treatment of patients with acromegaly. METHODS: We performed a narrative review of the published data on the biochemical diagnosis and monitoring of acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 January 2021. The reference lists of relevant studies were also reviewed. RESULTS: Serum IGF-1 levels, basal GH values, and nadir GH after OGTT play a major role in the diagnosis, management, and treatment of patients with acromegaly. Measurement of IGF-1 levels is the key factor in the diagnosis and monitoring of acromegaly, but basal and nadir GH following OGTT are also important. However, several factors may significantly influence the concentrations of these hormones, including assay methods, physiologic and pathologic factors. In some cases, discordant GH and IGF-1 levels may be challenging and usually requires additional data and monitoring. CONCLUSION: New GH and IGF-1 standards are much more precise and provide more accurate tools to diagnose and monitor patients with acromegaly. However, all these biochemical tools have their limitations, and these should be taken under consideration, along with the history, clinical features and imaging studies, when assessing patients for acromegaly.

Long-term safety and efficacy of long-acting pasireotide in acromegaly.

BACKGROUND: Pasireotide long acting (LAR) can be effective in normalizing insulin-like growth factor (IGF)-1 level in acromegaly patients inadequately controlled by octreotide or lanreotide. OBJECTIVE: Determine the long-term efficacy and safety of pasireotide, including time to biochemical control and time to best response, and risk for diabetes mellitus. METHODS: A retrospective multicenter study investigating the efficacy and safety of pasireotide LAR treatment in patients with active acromegaly treated for >12 months. RESULTS: The study included 19 patients (10 men; mean age ± SD, 48.0 ± 12.9 years) treated with pasireotide for a mean of 50 ± 36 months. During the follow-up, 4 patients discontinued pasireotide treatment. Pasireotide LAR produced a tolerable and long-term significant biochemical response in 15 of 19 patients (79.0%). Mean time to IGF-1 normalization from pasireotide LAR initiation was 13.6 ± 16.9 months with early biochemical normalization (<12 months) evident in 11 (64.7%) patients and delayed IGF-1 normalization in 6 (35.2%) patients. Nadir IGF-1 values were recorded within the first 12 months in 6 patients (35.3%), while in 11 patients (64.7%) lowest values were reported after >12 months of treatment, including 4 of 11 patients with early IGF-1 normalization. New-onset diabetes was documented in 5 of 7 patients with pre-diabetes and in 1 of 5 patients with normal glucose homeostasis at baseline. Among patients with pre-diabetes or diabetes mellitus prior to initiating pasireotide, mean HbA1c increase was 0.56 ± 1.0%. CONCLUSIONS: The results support the long-term efficacy and safety of pasireotide LAR for acromegaly and support the potential delayed effect of treatment on IGF-1 normalization.

Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages.

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1-/-Apoe-/-). After 21 weeks of atherogenic diet, Dj1-/- Apoe-/-mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

Glycemic variability and mortality in patients hospitalized in general surgery wards.

BACKGROUND: Glucose variability is common among hospitalized patients, but the prognostic implications among patients hospitalized in surgical wards are unknown. The objective of this study was to investigate the association between glucose variability, length of stay, and mortality. METHODS: Historical prospectively collected data of patients ≥18 years of age, hospitalized in general surgery wards between January 2011 and December 2017. Glucose variability was assessed by coefficient of variance and standard deviation of glucose values during hospitalization. The main outcomes were length of stay and 30-day and end-of-follow-up mortality. RESULTS: The cohort included 8,894 patients (mean age 63 ± 19 years, 48% male, mean follow-up 3.0 ± 1.8 years). A total of 2,012 (23%) patients had diabetes mellitus. The mean length of stay was longer with a higher coefficient of variance or standard deviation in patients without and with diabetes mellitus. The 30-day mortality was 6%, associated with a higher versus a lower coefficient of variance (9% vs 3%) and standard deviation (9% vs 3%) in patients without diabetes mellitus and with diabetes mellitus (9% vs 5%; 8% vs 5%, respectively). Mortality at the end of follow-up was increased in patients without diabetes mellitus with a higher coefficient of variance (27% vs 18%) and standard deviation (29% vs 17%) and in patients with diabetes mellitus (33% vs 24% and 32% vs 21%, respectively). Multivariate analysis indicated an increased risk for 30-day and end-of-follow-up mortality, in both groups. Adjustment for glucocorticoid treatment or hypoglycemia did not affect the results. In patients with a high or low coefficient of variance, mortality was higher with median glucose levels during hospitalization ≥180 mg/dl, compared with <180 mg/dl. CONCLUSION: In patients with and without diabetes mellitus hospitalized in general surgery wards, increased glucose variability is associated with longer hospitalization and increased short-term and long-term mortality.

Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid) act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches. METHODS: Thyroid Stimulating Hormone Receptor (TSHR) was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin) were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm) was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining. RESULTS: TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls. CONCLUSION: A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with fewer side effects and improved quality of life.

Correction: Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

[This corrects the article DOI: 10.1371/journal.pone.0149723.].