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Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2+/- mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2+/- osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2+/- mice resulted in increased severity of the Aga2+/- phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we demonstrate that cell surface BiP (cs-BiP) responds by increasing its levels in leukocytes. Neutrophiles show the highest levels of cs-BiP and respond by increasing their population, whereas alveolar macrophages increase their levels of cs-BiP. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.

Monogenic high bone mass (HBM) disorders are characterized by an increased amount of bone in general, or at specific sites in the skeleton. Here, we describe 59 HBM disorders with 50 known disease-causing genes from the literature, and we provide an overview of the signaling pathways and mechanisms involved in the pathogenesis of these disorders. Based on this, we classify the known HBM genes into HBM (sub)groups according to uniform Gene Ontology (GO) terminology. This classification system may aid in hypothesis generation, for both wet lab experimental design and clinical genetic screening strategies. We discuss how functional genomics can shape discovery of novel HBM genes and/or mechanisms in the future, through implementation of omics assessments in existing and future model systems. Finally, we address strategies to improve gene identification in unsolved HBM cases and highlight the importance for cross-laboratory collaborations encompassing multidisciplinary efforts to transfer knowledge generated at the bench to the clinic., peer-reviewed

The COMPASS-U tokamak (R = 0.894 m, a = 0.27 m, Bt = 5 T, Ip = 2 MA) is a new medium-size device with fully metallic plasma facing components, currently under construction at the Institute of Plasma Physics of the Czech Academy of Sciences in Prague. It features a unique combination of parameters, such as a high temperature of the tokamak walls up to 500 ◦C allowing a high recycling regime, a high magnetic field connected with a high plasma density above 1020 m -3 and with a high heat flux (perpendicular to divertor targets) density at the outer strikepoint up to 90 MW/m2 in attached conditions. These parameters of the device pose strict constraints and requirements on the design of individual diagnostic systems. Strategy and present status of the development of the diagnostic systems for COMPASS-U are provided. Plans for a diagnostic set for the first plasma are reviewed. The review of the diagnostics systems involves the high-temperature compatible slow (up to 20 kHz) and fast (up to several MHz) inductive and non-inductive magnetic sensors (including Thick Printed Copper coils and Hall sensors), the sub-millimetre interferometer with an unambiguous channel, Electron Cyclotron Emission, the interlock and overview cameras, high resolution Thomson scattering, radiation diagnostics (neutron diagnostics, soft and hard X-ray diagnostics, bolometers, impurity monitors, effective ion charge), probe diagnostics (including rail probes) and manipulators.

Follicular thyroid cancer (FTC) is a less common form of differentiated thyroid cancer. Liver metastasis of differentiated thyroid cancer frequently occurs in the late onset of the metastatic disease, are often unrescetable and noniodine avid, leading to a poor prognosis. A 69-year-old man with a 14-year history of multi-metastatic follicular thyroid cancer was treated iteratively with 131-Iodine allowing to maintain a stable disease. Upon a recent exponential increase of the thyroglobulin, a peritoneal mass and a voluminous hepatic metastasis were discovered, comorbidities and an insufficient future remnant liver function excluded liver surgical resection. The tumour board proposed a resection of the peritoneal mass followed by selective internal radiation therapy of the liver mass. Due to the already impaired liver function, personalized dosimetry allowed a safe treatment delivering low activity to the nontumoral liver followed by a clinical and imaging response of the liver mass at 3 months. At our knowledge, this is the first case of thyroid liver metastasis treated by selective internal radiation therapy. Keywords: Liver metastasis, Personalized dosimetry, Radioembolization, Thyroid Cancer

Background Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT. Methods Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4+ and CD8+ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups. Results Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4+ and CD8+ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3+ cells was observed in the peri-tumoral area in patients receiving + cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival. Conclusions SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

A 51-year-old male was found with bilateral thyroid nodules on ultrasonography neck imaging. The largest nodule, measuring 23 × 26 × 35 mm, was located in the left lobe and was classified as EU-TIRADS 4. Thyroid function tests were normal, as were serum levels of parathormone, Chromogranin A, carcinoembryonic antigen and calcitonin. The nodule was cold on thyroid scintigraphy. Fine-needle aspiration of the nodule did not demonstrate cellular atypia. High focal uptake was found on both 111In-DTPA-octreotide scintigraphy and 68Ga-DOTATATE PET/CT. Histopathological analysis showed a microfollicular adenoma without malignancy. Immunohistochemical staining did not suggest neuroendocrine neoplasia or C cell hyperplasia. However, high expression of somatostatin receptor 2 (SSTR2) was observed in the microfollicular adenoma compared to the surrounding healthy tissue, with predominant localization in the endothelial cells and at the secretory pole of the thyroid epithelial cells in contact with blood vessels. High focal thyroid uptake on 68Ga-DOTATATE PET/CT can be observed in benign thyroid nodules due to an overexpression of SSTR by endothelial cells. However, incidental focal thyroid uptake on SSTR imaging requires further investigations to rule out thyroid malignancy.

Background and Objectives: Selection for surgery in patients with colorectal liver metastases (CRLM) remains inaccurate. We evaluated if CRLM baseline metabolic characteristics, assessed by [18]F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT), could predict postoperative outcomes. Methods: In a retrospective series of patients undergoing surgery for CRLM, we defined two groups: the long-term survival (LTS) and early relapse (ER) groups, where the postoperative recurrence-free survivals were ≥5 years or 4.3, defining low- and high-risk mCRS by scores of 0 to 2 and 3 to 6, respectively. Results: From a series of 450 patients operated for CRLM (mean follow-up of 58 months), we included for analysis 23 and 30 patients in the LTS and ER groups, respectively. Clinicopathologic parameters and CRS were similar in the LTS and ER groups. Median SUVmax/SUVmean(liver) ratios were higher in ER vs LTS patients (4.2 and 2.8, P =.008, respectively). mCRS was increased in ER patients (P =.024); 61% of LTS patients had low-risk mCRS and 73% of the ER patients had high-risk mCRS (P =.023). Conclusions: 18FDG-PET/CT characteristics combined with traditional CRS may represent a new tool to improve selection for surgery in patients with CRLM., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients’ characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome. Methods: This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox’s proportional hazards model. Results: Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29–5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14–4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50–5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05–3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31–5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08–5.11, p = 0.008 and HR = 2.92, 95%CI:1.01–8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23–5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome prediction above the clinical variables was the activity prescription method with HR of 2.26 (95%CI:1.09–4.70, p = 0.03). The average mean radiation dose to tumors was significantly higher with the partition-model (86Gy) versus BSA (38Gy). Conclusion: Radioembolization efficacy in patients with unresectable recurrent and/or chemorefractory IH-CCA strongly depends on the tumor radiation dose. Personalized activity prescription should be performed., SCOPUS: ar.j, info:eu-repo/semantics/published

Significance A properly functioning primary cilium is prerequisite for both normal development and aging of all ciliated organisms, including humans. In vertebrates, the signaling of Hedgehog family morphogens depends entirely on primary cilium. Recently, we reported that fibroblast growth factors (FGF) signaling interacts with that of Hedgehog, and that this is a consequence of FGF regulating length of the cilium and speed of processes that happen therein. In this report, we provide a molecular mechanism of such interaction, identifying intestinal cell kinase as a mediator of the FGF-induced changes in the ciliary morphology and function. This expands our understanding how FGF signaling regulates intracellular processes, and how aberrant FGF signaling contributes to diseases, such as achondroplasia and cancer., Vertebrate primary cilium is a Hedgehog signaling center but the extent of its involvement in other signaling systems is less well understood. This report delineates a mechanism by which fibroblast growth factor (FGF) controls primary cilia. Employing proteomic approaches to characterize proteins associated with the FGF-receptor, FGFR3, we identified the serine/threonine kinase intestinal cell kinase (ICK) as an FGFR interactor. ICK is involved in ciliogenesis and participates in control of ciliary length. FGF signaling partially abolished ICK’s kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. Activation of the FGF signaling pathway affected both primary cilia length and function in a manner consistent with cilia effects caused by inhibition of ICK activity. Moreover, knockdown and knockout of ICK rescued the FGF-mediated effect on cilia. We provide conclusive evidence that FGF signaling controls cilia via interaction with ICK.

Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF2, for its activity against FGFR3. In cultured rat chondrocytes or mouse embryonal tibia organ culture, RBM-007 rescued the proliferation arrest, degradation of cartilaginous extracellular matrix, premature senescence, and impaired hypertrophic differentiation induced by FGFR3 signaling. In cartilage xenografts derived from induced pluripotent stem cells from individuals with achondroplasia, RBM-007 rescued impaired chondrocyte differentiation and maturation. When delivered by subcutaneous injection, RBM-007 restored defective skeletal growth in a mouse model of achondroplasia. We thus demonstrate a ligand-trap concept of targeting the cartilage FGFR3 and delineate a potential therapeutic approach for achondroplasia and other FGFR3-related skeletal dysplasias.

Background and Objectives The histological growth pattern (HGP) represents a strong prognostic factor in patients undergoing surgery for colorectal liver metastases (CRLM). We evaluated whether the combination of HGP with clinico-metabolic parameters could improve its prognostic value. Methods In a series of 108 patients undergoing resection of CRLM, the HGP of CRLM was scored according to international guidelines. Baseline clinico-metabolic clinical status was evaluated using a metabolic-Clinical Risk Score (mCRS), combining traditional Memorial Sloan Kettering-CRS parameters with the tumor-to-liver glucose uptake ratio as measured with (18)Fluorodeoxyglucose/positron emission tomography. Results In patients with desmoplastic HGP (DHGP) CRLM (20% of all patients), 5- and 10-years overall survival (OS) and disease free survival (DFS) were 66% and 43% and 37% and 24.5%, as compared with 35% and 21% and 11% and 11% in the non-DHGP group (p = 0.07 and 0.054). Among DHGP patients, those with a low-risk mCRS had improved postoperative outcomes, 5- and 10-years OS and DFS reaching 83.3% and 62.5% and 50% and 33%, as compared with 18% and 0% and 0% and 0% in high-risk mCRS patients (p = 0.007 and 0.003). In contrast, mCRS did not influence postoperative survivals in non-DHGP patients. Conclusions Combining the clinico-metabolic characteristics with the HGP may improve prognostication in patients undergoing surgery for CRLM.

Recent advances in semiconductor and packaging technologies have accelerated the miniaturization of portable sensing devices including visible-domain cameras, IR cameras, and millimeter-wave (mmWave) radars. Simultaneously, image and sensor data processing capabilities based on Systems-on-Chip (SoCs) have evolved as well to the extent toward the goal of implementing learning-based automatic recognition capabilities. This paper discusses the challenges and opportunities associated with the vertical sensors-to-software integration of portable systems capable of performing multi-spectral imaging, where data from different portions of the EM spectrum is captured, processed, and displayed simultaneously. An example hardware implementation, multi-spectral image data, and potential applications are discussed

Background Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders, yet the consequences of an abnormal ECM on cellular communication remains less well understood Methods Clinical and radiographic examinations defined the phenotype in this unappreciated bent bone skeletal disorder. Exome analysis identified the genetic alteration, confirmed by Sanger sequencing. Quantitative PCR, western blot analyses, immunohistochemistry, luciferase assay for WNT signaling were employed to determine RNA, proteins levels and localization, and dissect out the underlying cell signaling abnormalities. Migration and wound healing assays examined cell migration properties. Findings This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin-mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered β1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling. Interpretation This newly described mechanism revealed a LAMA5-β1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. Funding Supported by NIH awards R01 AR066124, R01 DE019567, R01 HD070394, and U54HG006493, and Czech Republic grants INTER-ACTION LTAUSA19030, V18-08-00567 and GA19-20123S.

Background The relationship between the mean absorbed dose delivered to the tumour and the outcome in liver metastases from colorectal cancer patients treated with radioembolization has already been presented in several studies. The optimization of the personalized therapeutic activity to be administered is still an open challenge. In this context, how well the 99mTc-MAA SPECT/CT predicts the absorbed dose delivered by radioembolization is essential. This work aimed to analyse the differences between predictive 99mTc-MAA-SPECT/CT and post-treatment 90Y-microsphere PET/CT dosimetry at different levels. Dose heterogeneity was compared voxel-to-voxel using the quality-volume histograms, subsequently used to demonstrate how it could be used to identify potential clinical parameters that are responsible for quantitative discrepancies between predictive and post-treatment dosimetry. Results We analysed 130 lesions delineated in twenty-six patients. Dose-volume histograms were computed from predictive and post-treatment dosimetry for all volumes: individual lesion, whole tumoural liver (TL) and non-tumoural liver (NTL). For all dose-volume histograms, the following indices were extracted: D90, D70, D50, Dmean and D20. The results showed mostly no statistical differences between predictive and post-treatment dosimetries across all volumes and for all indices. Notably, the analysis showed no difference in terms of Dmean, confirming the results from previous studies. Quality factors representing the spread of the quality-volume histogram (QVH) curve around 0 (ideal QF = 0) were determined for lesions, TL and NTL. QVHs were classified into good (QF < 0.18), acceptable (0.18 ≤ QF < 0.3) and poor (QF ≥ 0.3) correspondence. For lesions and TL, dose- and quality-volume histograms are mostly concordant: 69% of lesions had a QF within good/acceptable categories (40% good) and 65% of TL had a QF within good/acceptable categories (23% good). For NTL, the results showed mixed results with 48% QF within the poor concordance category. Finally, it was demonstrated how QVH analysis could be used to define the parameters that predict the significant differences between predictive and post-treatment dose distributions. Conclusion It was shown that the use of the QVH is feasible in assessing the predictive value of 99mTc-MAA SPECT/CT dosimetry and in estimating the absorbed dose delivered to liver metastases from colorectal cancer via 90Y-microspheres. QVH analyses could be used in combination with DVH to enhance the predictive value of 99mTc-MAA SPECT/CT dosimetry and to assist personalized activity prescription.

Graphical abstract

Additional file 2: Supplementary material 2. Relationship between dose and weighting factors.

Additional file 1: Supplementary material 1. Image acquisition and reconstruction parameters.

Background The aim of this work was to confirm that post-selective internal radiation therapy (SIRT) 90Y-PET/CT-based dosimetry correlates with lesion metabolic response and to determine its correlation with overall survival (OS) in liver-only metastases from colorectal cancer (mCRC) patients treated with SIRT. Twenty-four mCRC patients underwent pre/post-SIRT FDG-PET/CT and post-SIRT 90Y-PET/CT. Lesions delineated on pre/post-SIRT FDG-PET/CT were classified as non-metabolic responders (total lesion glycolysis (TLG)-decrease < 15%) and high-metabolic responders (TLG-decrease ≥ 50%). Lesion delineations were projected on the anatomically registered 90Y-PET/CT. Voxel-based 3D dosimetrywas performed on the 90Y-PET/CT and lesions’ mean absorbed dose (Dmean) was measured. The coefficient of correlation between Dmean and TLG-decrease was calculated. The ability of lesion Dmean to predict non-metabolic response and high-metabolic response was tested and two cutoff values (Dmean-under-treated and Dmean-well-treated) were determined using ROC analysis. Patients were dichotomised in the “treated” group (all the lesions received a Dmean > Dmean-under-treated) and in the “under-treated” group (at least one lesion received a Dmean < Dmean-under-treated). Kaplan-Meier product limit method was used to describe OS curves. Results Fifty-seven evaluable mCRC lesions were included. The coefficient of correlation between Dmean and TLG-decrease was 0.82. Two lesion Dmean cutoffs of 39 Gy (sensitivity 80%, specificity 95%, predictive-positive-value 86% and negative-predictive-value 92%) and 60 Gy (sensitivity 70%, specificity 95%, predictive positive-value 96% and negative-predictive-value 63%) were defined to predict non-metabolic response and high-metabolic response respectively. Patients with all lesions Dmean> 39 Gy had a significantly longer OS (13 months) than patients with at least one lesion Dmean < 39 Gy (OS = 5 months) (p = 0.012;hazard-ratio, 2.6 (95% CI 0.98–7.00)). Conclusions In chemorefractory mCRC patients treated with SIRT, lesion Dmean determined on post-SIRT 90Y-PET/CT correlates with metabolic response and higher lesion Dmean is associated with prolonged OS.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. It involves anatomical abnormalities that change the normal flow of blood through the heart resulting in low oxygenation. Although not all of the underlying causes of TOF are completely understood, the disease has been associated with varying genetic etiologies including chromosomal abnormalities and Mendelian disorders, but can also occur as an isolated defect. In this report, we describe a familial case of TOF associated with a 1.8 Mb deletion of chromosome 10p11. Among the three genes in the region one is Neuropilin1 (NRP1), a membrane co-receptor of VEGF that modulates vasculogenesis. Hemizygous levels of NRP1 resulted in a reduced expression at the transcriptional and protein levels in patient-derived cells. Reduction of NRP1 also lead to decreased function of its activity as a co-receptor in intermolecular VEGF signaling. These findings support that diminished levels of NRP1 contribute to the development of TOF, likely through its function in mediating VEGF signal and vasculogenesis.