A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage.

Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and γ-irradiation. DNA damage induces BATF in a G-CSF/STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to γ-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.

Adiponectin suppresses stiffness-dependent, profibrotic activation of lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible respiratory disease with limited therapeutic options. A hallmark of IPF is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We performed an unbiased, next-generation sequencing (NGS) screen to identify signaling pathways involved in stiffness-dependent lung fibroblast activation. Adipocytokine signaling was downregulated in primary lung fibroblasts (PFs) cultured on stiff matrices. Re-activating adipocytokine signaling with adiponectin suppressed stiffness-dependent activation of human PFs. Adiponectin signaling depended on CDH13 expression and p38 mitogen-activated protein kinase gamma (p38MAPKγ) activation. CDH13 expression and p38MAPKγ activation were strongly reduced in lungs from IPF donors. Our data suggest that adiponectin-signaling via CDH13 and p38MAPKγ activation suppresses profibrotic activation of fibroblasts in the lung. Targeting of the adiponectin signaling cascade may provide therapeutic benefits in IPF.NEW & NOTEWORTHY A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We found that activation of the adipocytokine signaling pathway halts and reverses stiffness-induced, profibrotic fibroblast activation. Specific targeting of this signaling cascade may therefore provide therapeutic benefits in IPF.

Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis.

Lipid metabolism influences stem cell maintenance and differentiation but genetic factors that control these processes remain to be delineated. Here, we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout impairs differentiation of embryonic stem cells (ESCs), and knockdown of the planarian para-ortholog, Smed-exoc3, abrogates in vivo tissue homeostasis and regeneration-processes that are driven by somatic stem cells. When stimulated to differentiate, Tnfaip2-deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of vimentin (Vim)-a known inducer of LD formation. Smed-exoc3 depletion also causes a strong reduction of TAGs in planarians. The study shows that Tnfaip2 acts epistatically with and upstream of Vim in impairing cellular reprogramming. Supplementing palmitic acid (PA) and palmitoyl-L-carnitine (the mobilized form of PA) restores the differentiation capacity of Tnfaip2-deficient ESCs and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel role of Tnfaip2 and exoc3 in controlling lipid metabolism, which is essential for ESC differentiation and planarian organ maintenance.

Metadata Correction: Patient Empowerment During the COVID-19 Pandemic by Ensuring Safe and Fast Communication of Test Results: Implementation and Performance of a Tracking System.

[This corrects the article DOI: 10.2196/27348.].

Patient Empowerment During the COVID-19 Pandemic by Ensuring Safe and Fast Communication of Test Results: Implementation and Performance of a Tracking System.

BACKGROUND: Overcoming the COVID-19 crisis requires new ideas and strategies for online communication of personal medical information and patient empowerment. Rapid testing of a large number of subjects is essential for monitoring and delaying the spread of SARS-CoV-2 in order to mitigate the pandemic's consequences. People who do not know that they are infected may not stay in quarantine and, thus, risk infecting others. Unfortunately, the massive number of COVID-19 tests performed is challenging for both laboratories and the units that conduct throat swabs and communicate the results. OBJECTIVE: The goal of this study was to reduce the communication burden for health care professionals. We developed a secure and easy-to-use tracking system to report COVID-19 test results online that is simple to understand for the tested subjects as soon as these results become available. Instead of personal calls, the system updates the status and the results of the tests automatically. This aims to reduce the delay when informing testees about their results and, consequently, to slow down the virus spread. METHODS: The application in this study draws on an existing tracking tool. With this open-source and browser-based online tracking system, we aim to minimize the time required to inform the tested person and the testing units (eg, hospitals or the public health care system). The system can be integrated into the clinical workflow with very modest effort and avoids excessive load to telephone hotlines. RESULTS: The test statuses and results are published on a secured webpage, enabling regular status checks by patients; status checks are performed without the use of smartphones, which has some importance, as smartphone usage diminishes with age. Stress tests and statistics show the performance of our software. CTest is currently running at two university hospitals in Germany-University Hospital Ulm and University Hospital Tübingen-with thousands of tests being performed each week. Results show a mean number of 10 (SD 2.8) views per testee. CONCLUSIONS: CTest runs independently of existing infrastructures, aims at straightforward integration, and aims for the safe transmission of information. The system is easy to use for testees. QR (Quick Response) code links allow for quick access to the test results. The mean number of views per entry indicates a reduced amount of time for both health care professionals and testees. The system is quite generic and can be extended and adapted to other communication tasks.

Influence of reagent lots and multiple measuring systems on estimating the coefficient of variation from quality control data; implications for uncertainty estimation and interpretation of QC results.

Background Clinical laboratories use internal quality control (QC) data to calculate standard deviation (SD) and coefficient of variation (CV) to estimate uncertainty of results and to interpret QC results. We examined the influence of different instruments, and QC and reagent lots on the CV calculated from QC data. Methods Results for BioRad Multiqual frozen liquid QC samples over a 2-year interval were partitioned by QC and reagent lots. The mean and CV were calculated for each partition for each of three Abbott Architect c8000 instruments for measuring serum alanine amino transferase (ALT), creatinine (enzymatic), glucose and sodium. Results CVs differed among partitions and instruments for two QC levels by 5.8- and 3.3-fold for ALT, by 4.7- and 2.1-fold for creatinine, by 2.0- and 2.6-fold for glucose, and by 2.1- and 2.0-fold for sodium. Pooled CVs for two QC levels varied among instruments by 1.78- and 1.11-fold for ALT, by 1.63- and 1.11-fold for creatinine, by 1.08- and 1.06-fold for glucose, and by 1.24- and 1.31-fold for sodium. Conclusions The CVs from QC data varied substantially among QC and reagent lots and for different identical specification instruments. The CV used to estimate uncertainty for a measurement result or as the basis for interpreting individual QC results must be derived over a sufficient time interval to obtain a pooled CV that represents "typical" performance of a measuring system. An estimate of uncertainty provided to users of laboratory results will itself have uncertainty that can influence medical decisions.

Social media processes in disasters: Implications of emergent technology use.

This article seeks to extend social science scholarship on social media technology use during disruptive events. Though social media's role in times of crisis has been previously studied, much of this work tends to focus on first-responders and relief organizations. However, social media use during disasters tends to be decentralized and this organizational structure can promote different types of messages to top-down information systems. Using 142,786 geo-tagged tweets collected before and after Hurricane Sandy's US landfall as a case study, this article seeks to explore shifts in social media behavior during disruptive events and highlights that though Sandy disrupted routine life within Twitter, users responded to the disaster by employing humor, sharing photos, and checking into locations. We conclude that social media use during disruptive events is complex and understanding these nuanced behaviors is important across the social sciences.

Early report on brain arousal regulation in manic vs depressive episodes in bipolar disorder.

OBJECTIVES: The arousal regulation model of affective disorders attributes an important role in the pathophysiology of affective disorders to dysregulation of brain arousal regulation. According to this model, sensation avoidance and withdrawal in depression and sensation seeking and hyperactivity in mania can be explained as auto-regulatory attempts to counteract a tonically high (depression) or unstable (mania) arousal. The aim of this study was to compare brain arousal regulation between manic and depressive bipolar patients and healthy controls. We hypothesized that currently depressed patients with bipolar disorder show hyperstable arousal regulation, while currently manic patients show unstable arousal regulation. METHODS: Twenty-eight patients with bipolar disorder received a 15-min resting electroencephalogram (EEG) during a depressive episode and 19 patients received the same during a manic/hypomanic episode. Twenty-eight healthy control subjects were matched for age and sex. The Vigilance Algorithm Leipzig (VIGALL), which classifies 1-s EEG segments as one of seven EEG-vigilance substages, was used to measure brain arousal regulation. RESULTS: Manic patients showed more unstable EEG-vigilance regulation as compared to the control sample (P = .004) and to patients with a depressive episode (P ≤ .001). Depressive patients had significantly higher mean vigilance levels (P = .045) than controls. CONCLUSIONS: A clear difference was found in the regulation of brain arousal of manic patients vs depressive patients and controls. These data suggest that brain arousal might depend on the current mood state, which would support the arousal regulation model of affective disorders.

Elevated lactate dehydrogenase - A red herring in the diagnosis of a sclerosing stromal tumor: A case report.

Sclerosing stromal tumors are a rare type of ovarian tumor in the category of sex cord stromal tumors, which arise from the ovarian connective tissue. This report concerns a case of a sclerosing stromal tumor in a 19-year-old nulliparous woman who presented with the chief complaints of menstrual irregularities and dyspareunia. Preoperative imaging revealed a complex right adnexal mass with blood flow and without associated ascites. Tumor markers were all normal except lactate dehydrogenase, which was elevated. The elevated lactate dehydrogenase, in combination with patient age and menstrual irregularities, initially misdirected the clinicians toward suspicion for dysgerminoma or other malignant germ cell tumor of the ovary. Clinicians should beware of excluding the diagnosis of sex cord stromal tumor on the differential in a young person with an adnexal mass and elevated lactate dehydrogenase.

A novel gelatinized barium sulfate injection method for assessment of bronchoalveolar lavage parameters.

INTRODUCTION: Bronchoalveolar lavage (BAL) is frequently used in pulmonary medicine though it requires further optimization. Practical obstacles such as patient safety and procedural limitation have to date precluded large, controlled trials aimed at standardization of BAL procedure. Indeed, BAL guidelines are based on observational data. Innovative research methods are necessary to advance the clinical practice of BAL. METHODS: In our study, we evaluated the effect of injecting a gelatinized barium solution into different lobes and segments of cadaveric lungs. As the technique requires an irreversible injection into lung airspaces, it is not suitable for in vivo purposes. We measured the volume returned from BAL as well as the distribution of BAL injection via dissection. Segmental anatomic orientation was compared to a radiologist's impression of plain film radiographs taken of injected lungs. RESULTS: Mean injected volume distributions were greatest in the upper lobes and lowest in the lower lobes; mean ratios of injected volume distribution to lung lobe volume also followed this trend. Cannulated bronchi orders favored lower branches in the upper lobe and higher branches in the lower lobes. Segmental anatomy varied by the lung lobe injected and was most varied in the lower lobes. CONCLUSION: This novel gelatinized-barium injection technique provides a minimally complex method to yield clinically meaningful feedback on the performance of BAL. The technique is also adaptable to study of procedural parameters in the context of variable lung anatomies and pathologies.

Venetoclax resistance in acute lymphoblastic leukemia is characterized by increased mitochondrial activity and can be overcome by co-targeting oxidative phosphorylation.

Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Accordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using Oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.

In Vivo Optical Clearing of Mammalian Brain.

Established methods for imaging the living mammalian brain have, to date, taken optical properties of the tissue as fixed; we here demonstrate that it is possible to modify the optical properties of the brain itself to significantly enhance at-depth imaging while preserving native physiology. Using a small amount of any of several biocompatible materials to raise the refractive index of solutions superfusing the brain prior to imaging, we could increase several-fold the signals from the deepest cells normally visible and, under both one-photon and two-photon imaging, visualize cells previously too dim to see. The enhancement was observed for both anatomical and functional fluorescent reporters across a broad range of emission wavelengths. Importantly, visual tuning properties of cortical neurons in awake mice, and electrophysiological properties of neurons assessed ex vivo, were not altered by this procedure.

Bilateral Virchow nodes: an unusual finding of pulmonary small-cell neuroendocrine carcinoma metastasis.

An enlarged left-sided supraclavicular node is a signal node for cancer metastasis. In such a case, the enlarged lymph node is often referred to as a Virchow node. The left-sided nature of the node is due to the drainage of the thoracic duct. So, the enlargement of a Virchow node is typically associated with malignancies, including gastrointestinal, pulmonary, and genitourinary carcinomas, in addition to lymphomas. This report documents a particularly unusual finding: bilateral Virchow nodes, representing metastasis of small-cell neuroendocrine carcinoma.

One year of COVID-19 pandemic: what we Radiologists have learned about imaging. / Ein Jahr COVID-19-Pandemie: Was wir Radiologen über die Bildgebung gelernt haben.

BACKGROUND: Since its outbreak in December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has infected more than 151 million people worldwide. More than 3.1 million have died from Coronavirus Disease 2019 (COVID-19), the illness caused by SARS-CoV-2. The virus affects mainly the upper respiratory tract and the lungs causing pneumonias of varying severity. Moreover, via direct and indirect pathogenetic mechanisms, SARS-CoV-2 may lead to a variety of extrapulmonary as well as vascular manifestations. METHODS: Based on a systematic literature search via PubMed, original research articles, meta-analyses, reviews, and case reports representing the current scientific knowledge regarding diagnostic imaging of COVID-19 were selected. Focusing on the imaging appearance of pulmonary and extrapulmonary manifestations as well as indications for imaging, these data were summarized in the present review article and correlated with basic pathophysiologic mechanisms. RESULTS AND CONCLUSION: Typical signs of COVID-19 pneumonia are multifocal, mostly bilateral, rounded, polycyclic or geographic ground-glass opacities and/or consolidations with mainly peripheral distribution. In severe cases, peribronchovascular lung zones are affected as well. Other typical signs are the "crazy paving" pattern and the halo and reversed halo (the latter two being less common). Venous thromboembolism (and pulmonary embolism in particular) is the most frequent vascular complication of COVID-19. However, arterial thromboembolic events like ischemic strokes, myocardial infarctions, and systemic arterial emboli also occur at higher rates. The most frequent extrapulmonary organ manifestations of COVID-19 affect the central nervous system, the heart, the hepatobiliary system, and the gastrointestinal tract. Usually, they can be visualized in imaging studies as well. The most important imaging modality for COVID-19 is chest CT. Its main purpose is not to make the primary diagnosis, but to differentiate COVID-19 from other (pulmonary) pathologies, to estimate disease severity, and to detect concomitant diseases and complications. KEY POINTS: · Typical signs of COVID-19 pneumonia are multifocal, mostly peripheral ground-glass opacities/consolidations.. · Imaging facilitates differential diagnosis, estimation of disease severity, and detection of complications.. · Venous thromboembolism (especially pulmonary embolism) is the predominant vascular complication of COVID-19.. · Arterial thromboembolism (e. g., ischemic strokes, myocardial infarctions) occurs more frequently as well.. · The most common extrapulmonary manifestations affect the brain, heart, hepatobiliary system, and gastrointestinal system.. CITATION FORMAT: · Gross A, Albrecht T. One year of COVID-19 pandemic: what we Radiologists have learned about imaging. Fortschr Röntgenstr 2022; 194: 141 - 151.

Liesegang rings in the setting of end-stage renal disease.

Introduction: Liesegang rings are acellular, lamellar, concentric rings of organic or inorganic material naturally formed in both biologic and environmental systems. Description in human tissue is scarce. Liesegang rings have exclusively been identified in association with pathologic disease processes and thus are not typically considered in differential diagnosis. They are usually described with cystic or inflammatory lesions. Histologically, Liesegang rings show features that are also seen in sections of parasitic ova, larvae, psammoma bodies, and by radiology as calcifications in cystic diseases of the breast and kidney. Case presentation: We noted at autopsy of a 59-year-old diabetic woman multiple black "stones" in the renal medulla. Microscopic examination demonstrated these to contain Liesegang rings. Conclusion: Liesegang rings formation should be considered in the differential diagnosis of atypical appearing deposits in the kidneys and other tissues. They may play a role in the pathogenesis of kidney stones.

Functional Genomic Screening in Human Pluripotent Stem Cells Reveals New Roadblocks in Early Pancreatic Endoderm Formation.

Human pluripotent stem cells, with their ability to proliferate indefinitely and to differentiate into virtually all cell types of the human body, provide a novel resource to study human development and to implement relevant disease models. Here, we employed a human pancreatic differentiation platform complemented with an shRNA screen in human pluripotent stem cells (PSCs) to identify potential drivers of early endoderm and pancreatic development. Deep sequencing followed by abundancy ranking pinpointed six top hit genes potentially associated with either improved or impaired endodermal differentiation, which were selected for functional validation in CRISPR-Cas9 mediated knockout (KO) lines. Upon endoderm differentiation (DE), particularly the loss of SLC22A1 and DSC2 led to impaired differentiation efficiency into CXCR4/KIT-positive DE cells. qPCR analysis also revealed changes in differentiation markers CXCR4, FOXA2, SOX17, and GATA6. Further differentiation of PSCs to the pancreatic progenitor (PP) stage resulted in a decreased proportion of PDX1/NKX6-1-positive cells in SLC22A1 KO lines, and in DSC2 KO lines when differentiated under specific culture conditions. Taken together, our study reveals novel genes with potential roles in early endodermal development.

Breast carcinoma metastasising to the gastric wall and the peritoneum: what physicians need to know.

Breast cancer is the most common cancer among women in the USA and rarely metastasises to the gastric wall. We present a case of a 69-year-old woman with medical history of stage II-B breast cancer who presented with epigastric abdominal pain and black tarry stools. CT scan of the abdomen showed moderate gastric wall thickening and ascites. The patient underwent an esophagogastroduodenoscopy (EGD) with endoscopic ultrasound (EUS) for a fine-needle biopsy, which was negative for malignancy. Based on her presentation, we kept a high index of suspicion for peritoneal carcinomatosis and malignancy. The patient underwent laparoscopic wedge resection of the gastric wall with biopsies of gastric wall and peritoneum. Both biopsies confirmed the diagnosis of metastatic invasive lobular breast carcinoma. Our case highlights the importance of diagnostic laparoscopy and EUS in the setting of negative EGD biopsy results with a high suspicion of breast cancer metastasis to gastric wall.

Neuroendocrine Neoplasm of the Breast Presenting as a Liver Metastasis: A Rare Diagnostic Challenge.

We present a case of a 58-year-old female who presented initially to an outside institution with abdominal pain and was diagnosed on liver biopsy with a well-differentiated neuroendocrine tumor of an unknown primary source. She was referred to our academic institution for a second opinion after disease progression on the initial chemotherapy regimen. Through additional evaluation, diagnostics, and multi-disciplinary tumor board discussion she was diagnosed with metastases from a well-differentiated neuroendocrine neoplasm of the breast (NENB). Consequently, her treatment plan was modified leading to significant clinical and radiological improvement.

Robotic resection of a fibroepithelial polyp arising in the setting of nephrolithiasis.

Though rare, fibroepithelial polyps of the ureter consistently present with symptoms such as flank discomfort and may lead to renal failure. This often affects young adults and characteristically arises in the proximal ureter. The pathogenesis is unclear. Flank pain is the most common presenting symptom, which may create diagnostic confusion. Indeed, resection provides lasting relief which otherwise may elude patients who receive other treatments. Resection modality may be selected on a patient-by-patient basis. Here we present a case in which flank pain, and historical episodes of abdominal pain, were resolved by excision of a fibroepithelial polyp by a robotic assisted laparoscopic approach.