ResearchPad - insight https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[How HIV exploits T cells in the endometrium]]> https://www.researchpad.co/article/elastic_article_12718 Immune cells in the endometrium are targeted by HIV and re-programmed to allow them to survive and spread the virus throughout the body.

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<![CDATA[OR28-01 Constitutive Activation of NRF2 Antioxidant Response Leads to Age-Dependent Goiter and Compensated Hypothyroidism in Male Mice]]> https://www.researchpad.co/article/elastic_article_7026 Background: Familial non-toxic multinodular goiter (MNG) is a rare disease. KEAP1 gene (Kelch-like ECH-associated protein 1) that encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses, has been found to be one of the mutated genes that lead to familial MNG. The proposed association of KEAP1 with familial MNG is based on only two loss-of-function mutations in respective Japanese families, only one of which included proper phenotyping and demonstration of co-segregation of phenotype and mutation. To date, there is no experimental evidence from model organisms to support that decreased Keap1 levels can cause goiter. Hypothesis: We hypothesized that enhanced Nrf2 signaling induced by loss of Keap1 function in mice can lead to goiter. Methods: To this end, male Keap1 hypomorphic C57BL/6J mice that express ~80% less Keap1 in their tissues (Keap1 knockdown mice:“Keap1KD”) were studied at 3 and 12 months of age and compared to wild-type mice (WT). Plasma, thyroids and pituitary glands were collected for assessment of thyroid function by radioimmunoassays and for histology as well as gene and protein expression by quantitative PCR and immunoblotting respectively. Results: Keap1KD showed diffuse goiter that began to develop in early adult life and became highly prominent at the age of 12 months when the thyroids of Keap1KD were 6-fold heavier than WT. Histomorphometry assessment of thyroids showed that Keap1KD had ~3-fold larger follicle area and colloid compartment but no thyroid nodules or hyperplasia was detected. Keap1KD also showed primary hypothyroidism already in early adult life that was eventually well-compensated over time by increased TSH levels (at age of 12 months: WT TSH=47.7±9.1 mU/L, Keap1KD TSH=460±74 mU/L). This was also reflected in the pituitary gland of Keap1KD where Tshb mRNA was ~3-fold higher than WT. Despite a known stimulatory effect of Nrf2 on Tg gene transcription and Tg protein abundance, these measures were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, such as Duox1, Duoxa1, Duox2, Duoxa2, Tpo, Nis, Dio1, Dio2, Dehal1 mRNA levels, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L and S. Conclusions: Keap1KD mice showed age-dependent diffuse goiter and compensated hypothyroidism. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation. This study unravels novel roles of the druggable Keap1/Nrf2 pathway in thyroid function and economy. Subclinical hypothyroidism in Keap1KD mice may have broader implications regarding their use in metabolic research.

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<![CDATA[OR28-05 Approaching Indeterminate Thyroid Nodules in the Absence of Molecular Markers. “The BETH-TR Score”]]> https://www.researchpad.co/article/N87cb2358-9968-4663-9f02-0c229da487a8 Context: Given the lack of easy access to molecular markers, for indeterminate thyroid nodules (Bethesda (BETH) category III, IV), the clinician can either decide to get a second opinion from an expert high volume thyroid cytopatholgist, re-do the FNAC after a period of 3-6 months or send the patient for a diagnostic hemithyroidectomy. Reviewing the sonographic risk features is also one way of triaging these nodules. The ACR-TIRADS (TR) is an objective method of sonographic risk assessment and is superior to other forms of sonographic classification. Aim: We propose combining the scoring of TR category and BETH category (both expressed as numerical value and summated) and look at the score which could potentially guide the clinician in deciding whom to send for surgery. Settings and Design: Observational Prospective collection of consecutive patient data from Thyroid FNAC clinic. Statistical analysis used: The BETH categories were represented numerically and summated with the TR category. The categorical outcome variables of Benign and Malignant nodules and the summated score was analysed using Kruskal-Wallis test. Results: We analysed 450 FNAC data, out of which 403 were thyroid nodule aspirates. Out of these nodules, 96 of them underwent surgery and 64% of these nodules were malignant on final histopathology (Malignant=62 and Benign=34). The mean (sd) size of the benign nodules was 3.6 (2.2)cm compared to 2.8 (1.8)cm of the malignant nodules. After excluding those with BETH 1 (n=4), the mean BETH-TR score for benign nodules was 6(1.4) and malignant nodules 9.4(2.1) (p<0.0001). The BETH-TR score progressively increased from 7.3(0.92) in Follicular thyroid cancers (FTC) to 8.6(1.4) in Follicular variant Papillary thyroid cancer (FVPTC) to 10(1.3) in classic Papillary thyroid cancers (PTC). Among the indeterminate nodules (BETH III & IV; n=40), the BETH-TR score of benign nodules was 6.75(1) and malignant nodules was 7.5(0.72) (p value=0.01). A BETH-TR score >=7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases (Likelihood ratio 3.5; ROC area: 0.8841; CI 0.79-0.94). Conclusion: A combined sono-cytological BETH-TR score is one way to triage management of indeterminate thyroid nodules. A BETH-TR score >=7 gave a sensitivity of 92% specificity of 74% and correctly identified malignant nodules in 86% of cases.

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<![CDATA[From worms to fish to mice]]> https://www.researchpad.co/article/N38577ced-03dc-45b1-8b00-37d57a5512fc An multi-species approach can be used to identify small molecules with properties that might prove useful for the treatment of some neuromuscular diseases.

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<![CDATA[Encouraging cartilage production]]> https://www.researchpad.co/article/N964c4148-c45d-4588-a00d-7bc1bf088833 A long non-coding RNA called GRASLND is essential to help stem cells create stable cartilage.

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<![CDATA[Driving polar growth]]> https://www.researchpad.co/article/Nb5f2fb1c-910a-4289-9d7a-1266ceac5116 Profiling the phenotype of 200,000 mutants revealed a new cofactor that may help a group of rod-shaped bacteria elongate and grow.

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<![CDATA[Some research advances of immune mechanism during infection in China]]> https://www.researchpad.co/article/N8ef9314a-b0e9-43ff-a96b-25f54b62f377 ]]> <![CDATA[Exerting an influence on evolution]]> https://www.researchpad.co/article/Nf511f50e-6267-4881-ac0e-704373321200

Experiments on mice have shown that developmental processes are influencing the generation of phenotypic variation in a way that shapes evolution.

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<![CDATA[Taking a close look at a large-pore channel]]> https://www.researchpad.co/article/Ne1f3b2bd-883f-41cc-b649-888e9e881f84

The structure of pannexin 1, a channel protein with a large pore, has been determined for the first time.

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<![CDATA[An adaptable defense]]> https://www.researchpad.co/article/Ncf24e325-dced-47b7-a6c8-7133e3262303

The response of bacteria to the threat posed by phages depends on their local environment.

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<![CDATA[Finding sense in the context]]> https://www.researchpad.co/article/N950796ad-a816-4ab6-a8d0-a9d44ecfe049

Ribosomal profiling has shed new light on how ribosomes can ignore stop codons in messenger RNA.

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<![CDATA[How the brain represents mass]]> https://www.researchpad.co/article/Nf8e33965-f11b-4655-96a0-b6e5a79142d3

New fMRI experiments and machine learning are helping to identify how the mass of objects is processed in the brain.

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<![CDATA[Shaping the genome of plants]]> https://www.researchpad.co/article/N242446ca-b9d4-4ad5-9a55-f360cb5be552

Fertilization of an egg cell by more than one sperm cell can produce viable progeny in a flowering plant.

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<![CDATA[Metabolism makes and mends the heart]]> https://www.researchpad.co/article/N8bb10d5b-5bff-4d84-bb72-5dc0b09e0f37

Experiments in zebrafish have shed new light on the relationship between development and regeneration in the heart.

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<![CDATA[Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis and agranulocytosis in a patient with Graves’ disease]]> https://www.researchpad.co/article/Nc8394a54-eced-44c4-b2fb-979b720a9e0b

Summary

This case is the first to describe a patient who experienced concomitant agranulocytosis and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis as an adverse effect of propylthiouracil treatment for Graves’ disease. A 42-year-old female with Graves’ disease presented to the emergency department (ED) with a 2-week history of fevers, night sweats, transient lower limb rash, arthralgia, myalgia and fatigue. She had been taking propylthiouracil for 18 months prior to presentation. On admission, agranulocytosis was evident with a neutrophil count of 0.36 × 109/L and immediately propylthiouracil was stopped. There was no evidence of active infection and the patient was treated with broad-spectrum antibodies and one dose of granulocyte colony-stimulation factor, resulting in a satisfactory response. On further investigation, ANCAs were positive with dual positivity for proteinase 3 and myeloperoxidase. There was no evidence of end-organ damage secondary to vasculitis, and the patient’s constitutional symptoms resolved completely on discontinuation of the drug precluding the need for immunosuppressive therapy.

Learning points:

  • Continued vigilance and patient education regarding the risk of antithyroid drug-induced agranulocytosis is vital throughout the course of treatment.

  • ANCA-associated vasculitis is a rare adverse effect of antithyroid drug use.

  • Timely discontinuation of the offending drug is vital in reducing end-organ damage and the need for immunosuppressive therapy in drug-induced ANCA-associated vasculitis.

  • Similarities in the pathogenesis of agranulocytosis and drug-induced ANCA-associated vasculitis may offer insight into an improved understanding of vasculitis and agranulocytosis.

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<![CDATA[Searching for solutions to the missing heritability problem]]> https://www.researchpad.co/article/Nacf42950-277c-4436-94d5-8925ac2a766d

Rare genetic variants in yeast explain a large amount of phenotypic variation in a complex trait like growth.

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<![CDATA[Fatty liver formation in fulminant type 1 diabetes]]> https://www.researchpad.co/article/5c6863f3d5eed0c484023c9f

Summary

A 32-year-old woman presented with 3days of epigastric pain and was admitted to our hospital (day 3 of disease). We diagnosed acute pancreatitis based on epigastric abdominal pain, hyperamylasemia, and an inflammatory reaction of withdrawn blood, pancreatic enlargement, and so on. Her condition improved with treatment; however, on day 8, she had decreased level of consciousness. Laboratory results led to a diagnosis of fulminant type 1 diabetes mellitus (FT1DM) with concomitant diabetic ketoacidosis. Insulin therapy improved her blood glucose levels as well as her symptoms. Fatty liver with liver dysfunction was observed on day 14, which improved by day 24. Blood levels of free fatty acids (FFAs) increased rapidly from 440μEq/L (normal range: 140–850μEq/L) on day 4 to 2097μEq/L on days 7–8 (onset of FT1DM) and subsequently decreased to 246μEq/L at the onset of fatty liver. The rapid decrease in insulin at the onset of FT1DM likely freed fatty acids derived from triglycerides in peripheral adipocytes into the bloodstream. Insulin therapy rapidly transferred FFAs from the periphery to the liver. In addition, insulin promotes the de novo synthesis of triglycerides in the liver, using newly acquired FFAs as substrates. At the same time, inhibitory effects of insulin on VLDL secretion outside of the liver promote the accumulation of triglycerides in the liver, leading to fatty liver. We describe the process by which liver dysfunction and severe fatty liver occurs after the onset of FT1DM, from the perspective of disturbed fatty acid metabolism.

Learning points

  • FT1DM is rare but should be considered in patients with pancreatitis and a decreased level of consciousness.

  • Fatty liver should be considered in patients with FT1DM when liver dysfunction is observed.

  • Insulin is involved in mechanisms that promote fatty liver formation.

  • Pathophysiological changes in fatty acid metabolism may provide clues on lipid metabolism in the early phases of FT1DM.

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<![CDATA[Physaliphorous cells]]> https://www.researchpad.co/article/5c48f84dd5eed0c4841f7b7f ]]> <![CDATA[Climate change can affect crop pollination in unexpected ways]]> https://www.researchpad.co/article/5c0832c6d5eed0c484f97f1b ]]> <![CDATA[OR28-03 Drug Repurposing Identifies Inhibitors of the Proteostasis Network to Augment Radioiodine Uptake in Combinatorial Approaches Targeting Thyroid Cancer]]> https://www.researchpad.co/article/Na41dbd79-642b-43a4-8149-dd36c6e45464 2 SD above mean. Categorisation of these revealed a high proportion of drugs that modulate the proteostasis network (19/48; ~40%), including key processes in protein homeostasis such as endoplasmic reticulum-associated protein degradation (ERAD) and autophagy. Secondary screening validated the activity of proteostasis modulators in enhancing iodide uptake after ranking 73 leading compounds based on their pharmacologic (AUC, EMAX and EC50) and specificity of response (NIS+ve vs NIS-ve YFP-thyroid cells) at ten different drug doses (0.1 to 50 μM). Of importance, several repurposed drugs (e.g. ebastine, Prestwick N, Prestwick C and clotrimazole) in combination with the HDAC inhibitor vorinostat induced a robust enhancement in RAI uptake in thyroid cancer cells (TPC-1 and 8505C NIS+ve cells, up to 11-fold vs DMSO, P<0.001), which was significantly greater than using vorinostat alone (up to 3-fold, P<0.01). For clotrimazole, we designed 7 new chemical derivatives, 3 of which showed enhanced aqueous solubility and retained the ability to significantly enhance RAI uptake. TaqMan RT-PCR revealed that, in contrast to vorinostat, our repurposed drugs failed to alter NIS mRNA expression, highlighting post-transcriptional mechanisms. Critically, 11 repurposed drugs induced significant gains in RAI uptake in human primary thyroid cells (up to 4.1-fold; P<0.05), the most physiological setting for NIS function. In conclusion, we performed high-throughput screening and identified proteostasis modulators, as well as other repurposed drugs, that markedly enhance radioiodine uptake. Further clinical investigation of these drugs might offer new combinatorial approaches, especially with existing therapies, to improve the treatment of thyroid cancer. ]]>