PAXIP1 and STAG2 converge to maintain 3D genome architecture and facilitate promoter/enhancer contacts to enable stress hormone-dependent transcription.

How steroid hormone receptors (SHRs) regulate transcriptional activity remains partly understood. Upon activation, SHRs bind the genome together with a co-regulator repertoire, crucial to induce gene expression. However, it remains unknown which components of the SHR-recruited co-regulator complex are essential to drive transcription following hormonal stimuli. Through a FACS-based genome-wide CRISPR screen, we functionally dissected the Glucocorticoid Receptor (GR) complex. We describe a functional cross-talk between PAXIP1 and the cohesin subunit STAG2, critical for regulation of gene expression by GR. Without altering the GR cistrome, PAXIP1 and STAG2 depletion alter the GR transcriptome, by impairing the recruitment of 3D-genome organization proteins to the GR complex. Importantly, we demonstrate that PAXIP1 is required for stability of cohesin on chromatin, its localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. In lung cancer, where GR acts as tumor suppressor, PAXIP1/STAG2 loss enhances GR-mediated tumor suppressor activity by modifying local chromatin interactions. All together, we introduce PAXIP1 and STAG2 as novel co-regulators of GR, required to maintain 3D-genome architecture and drive the GR transcriptional programme following hormonal stimuli.

Compartmentalization of androgen receptors at endogenous genes in living cells.

A wide range of nuclear proteins are involved in the spatio-temporal organization of the genome through diverse biological processes such as gene transcription and DNA replication. Upon stimulation by testosterone and translocation to the nucleus, multiple androgen receptors (ARs) accumulate in microscopically discernable foci which are irregularly distributed in the nucleus. Here, we investigated the formation and physical nature of these foci, by combining novel fluorescent labeling techniques to visualize a defined chromatin locus of AR-regulated genes-PTPRN2 or BANP-simultaneously with either AR foci or individual AR molecules. Quantitative colocalization analysis showed evidence of AR foci formation induced by R1881 at both PTPRN2 and BANP loci. Furthermore, single-particle tracking (SPT) revealed three distinct subdiffusive fractional Brownian motion (fBm) states: immobilized ARs were observed near the labeled genes likely as a consequence of DNA-binding, while the intermediate confined state showed a similar spatial behavior but with larger displacements, suggesting compartmentalization by liquid-liquid phase separation (LLPS), while freely mobile ARs were diffusing in the nuclear environment. All together, we show for the first time in living cells the presence of AR-regulated genes in AR foci.

Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer.

The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.

Laboratory evaluation in rheumatic diseases.

Autoantibodies can help clinicians to allow early detection of autoimmune diseases and their clinical manifestations, to determine effective monitoring of prognosis and the treatment response. From this point, they have a high impact in rheumatic disease management. When used carefully they allow rapid diagnosis and appropriate treatment. However, as they may be present in healthy population they may cause confusion for interpreting the situation. False positive test results may lead to wrong treatment and unnecessary anxiety for patients. Autoantibody positivity alone does not make a diagnosis. Similarly, the absence of autoantibodies alone does not exclude diagnosis. The success of the test is closely related to sensitivity, specificity and likelihood ratios. So, interpretation of these is very important for a proper laboratory evaluation. In conclusion, in spite of the remarkable advances in science and technology, a deeply investigated anamnesis and comprehensive physical examination still continue to be the best diagnostic method. The most correct approach is that clinicians apply laboratory tests to confirm or exclude preliminary diagnosis based on anamnesis and physical examination. This review will discuss these issues.

Effects of clinical reanalysis in dual energy X-ray absorptiometry reports.

OBJECTIVES: This study aims to assess poor positioning rates of patients during X-ray and the accuracy of the analysis. PATIENTS AND METHODS: In this study, we reanalyzed 323 dual energy X-ray absorptiometry (DXA) reports, by evaluating the scan images for proper patient positioning and scan analysis. We reviewed reports, according to a checklist prepared considering the proposals of Watts and The International Society for Clinical Densitometry official positions for 2013 (which were the same as in 2015). At least two remaining vertebrae were used to derive new bone mineral density and new T-scores. RESULTS: Positioning failures were found in 64.7% of the spine X-rays, 60.5% of the hip X-rays, and 83.9% of X-rays of both regions. A total of 112 (34.7%) spinal DXA images needed new T-score adjustments. T-scores and bone mineral density differed between the first reports and the clinician reanalysis (p<0.001). CONCLUSION: The error rate in DXA reports was higher than expected. Clinician analysis of DXA reports are important. To obtain a quality DXA report, all healthcare professionals should be trained and reminded about this topic.

Investigation of Nerve Conduction Studies of Carpal Tunnel Syndrome Cases With Different Risk Factors: An Electrodiagnostic Study.

PURPOSE: The aim of this study was to determine whether there are electrodiagnostic differences between carpal tunnel syndrome (CTS) patients with diabetes mellitus, CTS + hypothyroidism (HT), CTS + fibromyalgia syndrome, CTS + rheumatoid arthritis (RA), and idiopathic CTS cases, by comparing nerve conduction studies. METHODS: This research examined electrophysiologic studies of 47 untreated HT + CTS, 47 diabetes mellitus + CTS, 49 RA + CTS, 52 fibromyalgia syndrome + CTS, 50 idiopathic CTS cases, and a healthy control group of 50 individuals (a total of 293 patients and 433 hands with CTS). RESULTS: There were no significant differences between the groups in terms of sex and age. There was no significant difference between the CTS groups-in terms of numbers-with mild, moderate, and severe CTS. When the CTS groups were compared with the control group, in all CTS groups on both left and right hands, there was a significant prolongation in median motor latency and median sensory latency (in the 3rd finger); also a significant decrease in median sensory velocity in the 3rd finger. In diabetes mellitus, HT, and RA groups, the median motor amplitudes in both hands were significantly decreased compared with the idiopathic group. There was a moderate significant negative correlation between disease duration and median motor amplitudes (of both right and left sides) in RA (right; P = 0.028, r = 0.761, left; P = 0.041, r = 0.694) and HT groups (right; P = 0.035, r = 0.637, left; P = 0.049, r = 0.697). CONCLUSIONS: Electrodiagnostic results showed both demyelinating injury and axonal damage in diabetes mellitus, HT, and RA patients with CTS, in these patients during treatment for CTS. Early treatment planning should include the risk factor diseases.

Comparing the efficacy of exercise, internal and external shoe modification in pes planus: A clinical and pedobarographic study.

Pes planus is a condition that can cause pain along the innerfoot due to the absence or abnormal depression of the longitudinal arch. There are few studies available that compare therapy modalities used in these patients. In our study, those treated with conservative therapies - internal and external shoe modifications and pes planus exercises - were compared clinically and pedobarographyically. 60 pes planus patients were included in the study. In the first group; internal modification was performed by placing a medial longitudinal arch support inside the shoe. In the second group, external shoe modification was performed using the Thomas heel. In the third group of patients however, only an exercise program was executed. The patients' foot pain levels, functional asssessment, satisfaction and quality of life were recorded. Pedobarography was used in measuring both static and dynamic plantar pressure. Assessments were carried out at baseline and at the end of the first and third months respectively where intra- and inter- group comparisons were performed. Each group was composed of 20 subjects. While improvement in terms of foot pain, foot function index and quality of life was observed in all the study groups (p< 0.05), the most improvement was observed in the group of patients treated with internal modification (p< 0.016). This was followed by the external modification and the exercise groups respectively. No difference was observed between the internal and external modification groups in terms of patient satisfaction. Cross-sectionally; clinical assessments, pedobarographic analysis were correlated. The changes observed after static and dynamic pedobarographic studies were not significantly different between the study groups. At the end of the study it was observed that internal modification yielded the most significant clinical improvement. In the literature, there are limited publications comparing the conservative treatments with each other. In this study we aimed to compare the conservative treatments for flatfoot.

[A case of painful legs and moving toes syndrome treated with gabapentin]. / Gabapentin tedavisine belirgin yanit alinan agrili ayaklar ve hareketli parmaklar sendromu.

A 58-year-old woman was evaluated following complaints of pain in both lower extremities and brief involuntary movements in her toes, which had begun 2 years prior. No signs were present beyond a curling, flexion/extension, abduction/adduction movement in the toes of both lower extremities, voluntarily stoppable during neurologic examination. During investigation into etiology, lumbar vertebrae MRI revealed a posterior annular protrusion causing partial compression of the dural sac and neural elements by the L3-4 and L4-5 discs. Semirhythmic repetitious movements were detected on electromyography performed on right extensor digitorum brevis (EDB) muscle with 200 mV and 1 Hz frequency. Patient was put on a gradually increased dose of gabapentin, starting at 1200 mg/day. A brief regression in pain and involuntary movements in feet and toes was observed. GABAergic agents are very effective treatment of painful legs and moving toes syndrome. The present clinically and electrophysiologically diagnosed case was considered worth reporting, as painful legs and moving toes syndrome is a very rare condition.