Histological Findings in the Eyes of Abcc6 Knockout Rat Model of Pseudoxanthoma Elasticum.

Purpose: To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout. Methods: This experiment was conducted in four Abcc6-/- rats and compared with six wild-type Abcc6+/+ control rats. The animals underwent necropsy at 6 months of age. Histological examination of the eyes was performed. Results: Histological examination of eight eyes from four Abcc6-/- rats revealed multiple nodular foci of calcification in the uvea, sclera, and conjunctiva, focally in perivascular distribution, as well as linear and nodular calcification of Bruch's membrane. Calcific foci were not associated with inflammation in the knockout rats. There was no evidence of calcification in control eyes. Discussion: The Abcc6-/- rat model shows that PXE can affect multiple ocular tissues beyond the calcification in Bruch's membrane noted in human eyes. Nodular calcific foci probably correspond to comet lesions seen in patients with PXE. The presence of ectopic calcium without inflammation distinguishes it from inflammatory calcium deposition in atherosclerosis. Further studies are needed to determine why PXE does not cause inflammatory infiltration. Translational Relevance: The Abcc6-/- murine model may be suitable for studying ocular PXE pathophysiology and ectopic calcification and developing effective therapies.

Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification.

Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6-/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease.

High Expression of Microtubule-associated Protein TBCB Predicts Adverse Outcome and Immunosuppression in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with high heterogeneity and ill-fated outcome. Despite numerous advances in AML treatment, the prognosis remains poor for a significant proportion of patients. Consequently, it is necessary to accurately and comprehensively identify biomarkers as soon as possible to enhance the efficacy of diagnosis, prognosis and treatment of AML. In this study, we aimed to identify prognostic markers of AML by analyzing the cohorts from TCGA-LAML database and GEO microarray datasets. Interestingly, the transcriptional level of microtubule-associated protein TBCB in AML patients was noticeably increased when compared with normal individuals, and this was verified in two independent cohorts (GSE9476 and GSE13159) and with our AML patients. Furthermore, univariate and multivariate regression analysis revealed that high TBCB expression was an independent poor prognostic factor for AML. GO and GSEA enrichment analysis hinted that immune-related signaling pathways were enriched in up-regulated DEGs between two populations separated by the median expression level of TBCB. By constructing a protein-protein interaction network, we obtained six hub genes, all of which are immune-related molecules, and their expression levels were positively linked to that of TBCB. In addition, the high expression of three hub genes was significantly associated with a poor prognosis in AML. Moreover, we found that the tumor microenvironment in AML with high TBCB expression tended to be infiltrated by NK cells, especially CD56bright NK cells. The transcriptional levels of NK cell inhibitory receptors and their ligands were positively related to that of TBCB, and their high expression levels also predicted poor prognosis in AML. Notably, we found that the down-regulation of TBCB suppressed cell proliferation in AML cell lines by enhancing the apoptosis and cell cycle arrest. Finally, drug sensitivity prediction illustrated that cells with high TBCB expression were more responsive to ATRA and midostaurin but resistant to cytarabine, dasatinib, and imatinib. In conclusion, our findings shed light on the feasibility of TBCB as a potential predictor of poor outcome and to be an alternative target of treatment in AML.

Artificial intelligence in thyroid ultrasound.

Artificial intelligence (AI), particularly deep learning (DL) algorithms, has demonstrated remarkable progress in image-recognition tasks, enabling the automatic quantitative assessment of complex medical images with increased accuracy and efficiency. AI is widely used and is becoming increasingly popular in the field of ultrasound. The rising incidence of thyroid cancer and the workload of physicians have driven the need to utilize AI to efficiently process thyroid ultrasound images. Therefore, leveraging AI in thyroid cancer ultrasound screening and diagnosis cannot only help radiologists achieve more accurate and efficient imaging diagnosis but also reduce their workload. In this paper, we aim to present a comprehensive overview of the technical knowledge of AI with a focus on traditional machine learning (ML) algorithms and DL algorithms. We will also discuss their clinical applications in the ultrasound imaging of thyroid diseases, particularly in differentiating between benign and malignant nodules and predicting cervical lymph node metastasis in thyroid cancer. Finally, we will conclude that AI technology holds great promise for improving the accuracy of thyroid disease ultrasound diagnosis and discuss the potential prospects of AI in this field.

Corrigendum: Association between diagnostic efficacy of acoustic radiation force impulse for benign and malignant thyroid nodules and the presence or absence of non-papillary thyroid cancer: A meta-analysis.

[This corrects the article DOI: 10.3389/fonc.2023.1007464.].

High-expression of the innate-immune related gene UNC93B1 predicts inferior outcomes in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with dismal prognosis. Identification of better biomarkers remained a priority to improve established stratification and guide therapeutic decisions. Therefore, we extracted the RNA sequence data and clinical characteristics of AML from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx) to identify the key factors for prognosis. We found UNC93B1 was highly expressed in AML patients and significantly linked to poor clinical features (p < 0.05). We further validated the high expression of UNC93B1 in another independent AML cohort from GEO datasets (p < 0.001) and performed quantitative PCR of patient samples to confirm the overexpression of UNC93B1 in AML (p < 0.005). Moreover, we discovered high level of UNC93B1 was an independent prognostic factor for poorer outcome both in univariate analysis and multivariate regression (p < 0.001). Then we built a nomogram model based on UNC93B1 expression, age, FAB subtype and cytogenetic risk, the concordance index of which for predicting overall survival was 0.729 (p < 0.001). Time-dependent ROC analysis for predicting survival outcome at different time points by UNC93B1 showed the cumulative 2-year survival rate was 43.7%, and 5-year survival rate was 21.9%. The differentially expressed genes (DEGs) between two groups divided by UNC93B1 expression level were enriched in innate immune signaling and metabolic process pathway. Protein-protein interaction (PPI) network indicated four hub genes (S100A9, CCR1, MRC1 and CD1C) interacted with UNC93B1, three of which were also significantly linked to inferior outcome. Furthermore, we discovered high UNC93B1 tended to be infiltrated by innate immune cells, including Macrophages, Dendritic cells, Neutrophils, Eosinophils, and NK CD56dim cells. We also found UNC93B1 had a significantly positive correlation with CD14, CD68 and almost all Toll-like receptors. Finally, we revealed negatively correlated expression of UNC93B1 and BCL2 in AML and conjectured that high-UNC93B1 monocytic AML is more resistant to venetoclax. And we found high MCL-1 expression compensated for BCL-2 loss, thus, we proposed MCL-1 inhibitor might overcome the resistance of venetoclax in AML. Altogether, our findings demonstrated the utility of UNC93B1 as a powerful poor prognostic predictor and alternative therapeutic target.

Association between diagnostic efficacy of acoustic radiation force impulse for benign and malignant thyroid nodules and the presence or absence of non-papillary thyroid cancer: A meta-analysis.

Purpose: The aim of this study was to investigate the diagnostic efficacy of Acoustic Radiation Force Impulse (ARFI) for benign and malignant thyroid nodules in the presence and absence of non-papillary thyroid cancer (NPTC) and to determine the cut-off values of Shear Wave Velocity (SWV) for the highest diagnostic efficacy of Virtual Touch Quantification (VTQ) and Virtual Touch Tissue Imaging and Quantification (VTIQ). Methods: The diagnostic accuracy of ARFI for benign and malignant thyroid nodules was assessed by pooling sensitivity, specificity and area under the curve (AUC) in each group in the presence and absence of both non-papillary thyroid glands, using histology and cytology as the gold standard. All included studies were divided into two groups according to VTQ and VTIQ, and each group was ranked according to the magnitude of the SWV cutoff value to determine the SWV cutoff interval with the highest diagnostic efficacy for VTQ and VTIQ. Results: A total of 57 studies were collected on the evaluation of ARFI for the diagnosis of benign and malignant thyroid nodules. The results showed that the presence of non-papillary thyroid carcinoma led to differences in the specificity of VTIQ for the identification of benign and malignant thyroid nodules, and the differences were statistically significant. In addition, the diagnostic efficacy of VTQ was best when the cutoff value of SWV was in the interval of 2.48-2.55 m/s, and the diagnostic efficacy of VTIQ was best when the cutoff value of SWV was in the interval of 3.01-3.15 m/s. Conclusion: VTQ and VTIQ have a high diagnostic value for benign and malignant thyroid nodules; however, when the malignant nodules in the study contain non-papillary thyroid carcinoma occupying the thyroid gland, the findings should be viewed in a comprehensive manner.

Corrigendum: Ultrasound-based deep learning using the VGGNet model for the differentiation of benign and malignant thyroid nodules: A meta-analysis.

[This corrects the article DOI: 10.3389/fonc.2022.944859.].

Diagnostic value of multiple diagnostic methods for lymph node metastases of papillary thyroid carcinoma: A systematic review and meta-analysis.

Objective: This study compared the diagnostic value of various diagnostic methods for lymph node metastasis (LNM) of papillary thyroid carcinoma (PTC) through network meta-analysis. Methods: In this experiment, databases such as CNKI, Wanfang, PubMed, and Web of Science were retrieved according to the Cochrane database, Prisma, and NMAP command manual. A meta-analysis was performed using STATA 15.0, and the value of the surface under the cumulative ranking curve (SUCRA) was used to determine the most effective diagnostic method. Quality assessments were performed using the Cochrane Collaboration's risk of bias tool, and publication bias was assessed using Deeks' funnel plot. Results: A total of 38 articles with a total of 6285 patients were included. A total of 12 diagnostic methods were used to study patients with LNM of PTC. The results showed that 12 studies were direct comparisons and 8 studies were indirect comparisons. According to the comprehensive analysis of the area of SUCRA, US+CT(86.8) had the highest sensitivity, FNAC had the highest specificity (92.4) and true positive predictive value (89.4), and FNAC+FNA-Tg had higher negative predictive value (99.4) and accuracy (86.8). In the non-invasive method, US+CT had the highest sensitivity, and the sensitivity (SEN) was [OR=0.59, 95% confidence interval (CI): (0.30, 0.89]. Among the invasive methods, the combined application of FNAC+FNA-Tg had higher diagnostic performance. The sensitivity was [OR=0.62, 95% CI: (0.26, 0.98)], the specificity (SPE) was [OR=1.12, 95% CI: (0.59, 1.64)], the positive predictive value was [OR=0.98, 95% CI: (0.59, 1.37)], the negative predictive value was [OR=0.64, 95% CI (0.38, 0.90)], and the accuracy was [OR=0.71, 95% CI: (0.31, 1.12)]. Conclusion: In the non-invasive method, the combined application of US+CT had good diagnostic performance, and in the invasive method, the combined application of FNAC+FNA-Tg had high diagnostic performance, and the above two methods were recommended.

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.

ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.

Ultrasound-based deep learning using the VGGNet model for the differentiation of benign and malignant thyroid nodules: A meta-analysis.

Objective: The aim of this study was to evaluate the accuracy of deep learning using the convolutional neural network VGGNet model in distinguishing benign and malignant thyroid nodules based on ultrasound images. Methods: Relevant studies were selected from PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases, which used the deep learning-related convolutional neural network VGGNet model to classify benign and malignant thyroid nodules based on ultrasound images. Cytology and pathology were used as gold standards. Furthermore, reported eligibility and risk bias were assessed using the QUADAS-2 tool, and the diagnostic accuracy of deep learning VGGNet was analyzed with pooled sensitivity, pooled specificity, diagnostic odds ratio, and the area under the curve. Results: A total of 11 studies were included in this meta-analysis. The overall estimates of sensitivity and specificity were 0.87 [95% CI (0.83, 0.91)] and 0.85 [95% CI (0.79, 0.90)], respectively. The diagnostic odds ratio was 38.79 [95% CI (22.49, 66.91)]. The area under the curve was 0.93 [95% CI (0.90, 0.95)]. No obvious publication bias was found. Conclusion: Deep learning using the convolutional neural network VGGNet model based on ultrasound images performed good diagnostic efficacy in distinguishing benign and malignant thyroid nodules. Systematic Review Registration: https://www.crd.york.ac.nk/prospero, identifier CRD42022336701.

High Expression of DC-STAMP Gene Predicts Adverse Outcomes in AML.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy with poor prognosis. We explored the RNA sequence data and clinical information of AML patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database to search for the core molecule for prognosis. The DC-STAMP expression was significantly higher in AML patients, which was linked to old age, unfavorable cytogenetic risk, and death (all p < 0.05). Furthermore, it was revealed that high DC-STAMP expression was an independent unfavorable factor for overall survival (OS) by univariate analysis [hazard ratio (HR): 2.683; 95% confidence interval (CI): 1.723-4.178; p < 0.001] and multivariate analysis (HR: 1.733; 95% CI: 1.079-2.781; p = 0.023). The concordance index (C-index 0.734, 95% CI: 0.706-0.762), calibration curves, and decision curve analysis showed the certain predictive accuracy of a nomogram model based on multivariate analysis for OS. In addition, we found that the differentially expressed gene (DEG) enrichment pathways of high- and low-DC-STAMP expression group enrichment pathways were focused on channel activity and platelet alpha granule by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), while gene set enrichment analysis (GSEA) pathways were mainly involved in mTORC1 signaling and TNF-α signaling via the NF-kB pathway. Moreover, a protein-protein interaction (PPI) network demonstrated that DC-STAMP interacted with two hub genes (PPBP and PF4), which were highly regulated and associated with poor survival. Finally, high DC-STAMP expression showed a significantly positive correlation with four immune cell [NK CD56 (dim) cells, macrophages, cytotoxic cells, and CD8 (+) T cells] infiltration and high level of immune checkpoint genes (PDCD1, CD274, CTLA-4, and TIGIT). Therefore, our results suggest that high expression of DC-STAMP predicts adverse outcomes for AML patients.

INZ-701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6-/- mouse model of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ-701, a recombinant human ENPP1 protein, the principal PPi-generating enzyme, prevents ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ-701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ-701 at both doses increased steady-state plasma ENPP1 activity and PPi levels. In the 8-week treatment study, histopathologic examination and quantification of the calcium content in INZ-701-treated Abcc6-/- mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin-A. These results suggest that INZ-701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment.

Inhibition of the DNA Damage Response Attenuates Ectopic Calcification in Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is a heritable ectopic calcification disorder with multiorgan clinical manifestations. The gene at default, ABCC6, encodes an efflux transporter, ABCC6, which is a critical player regulating the homeostasis of inorganic pyrophosphate, a potent endogenous anticalcification factor. Previous studies suggested that systemic inorganic pyrophosphate deficiency is the major but not the exclusive cause of ectopic calcification in PXE. In this study, we show that the DNA damage response (DDR) and poly(ADP-ribose) (PAR) pathways are involved locally in PXE at sites of ectopic calcification. Genetic inhibition of PAR polymerase 1 gene PARP1, the predominant PAR-producing enzyme, showed a 54% reduction of calcification in the muzzle skin in Abcc6‒/‒Parp1‒/‒ mice, compared with that of age-matched Abcc6‒/‒Parp1+/+ littermates. Subsequently, oral administration of minocycline, an inhibitor of DDR/PAR signaling, resulted in an 86% reduction of calcification in the muzzle skin of Abcc6‒/‒ mice. Minocycline treatment also attenuated the DDR/PAR signaling and reduced the calcification of dermal fibroblasts derived from patients with PXE. The anticalcification effect of DDR/PAR inhibition was not accompanied by alterations in plasma inorganic pyrophosphate concentrations. These results suggest that local DDR/PAR signaling in calcification-prone tissues contributes to PXE pathogenesis and that its inhibition might provide a promising treatment strategy for ectopic calcification in PXE, a currently intractable disease.

Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification.

Pathologic soft tissue calcification can occur in both genetic and acquired clinical conditions, causing significant morbidity and mortality. Although the pathomechanisms of pathologic calcification are poorly understood, major progress has been made in recent years in defining the underlying genetic defects in Mendelian disorders of ectopic calcification. This review presents an overview of the pathophysiology of five monogenic disorders of pathologic calcification: pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to deficiency of CD73, ankylosis, and progeria. These hereditary disorders, caused by mutations in genes encoding ATP binding cassette subfamily C member 6, ectonucleotide pyrophosphatase/phosphodiesterase 1, CD73, progressive ankylosis protein, and lamin A/C proteins, respectively, are inorganic pyrophosphate (PPi) deficiency syndromes with reduced circulating levels of PPi, the principal physiologic inhibitor of calcium hydroxyapatite deposition in soft connective tissues. In addition to genetic diseases, PPi deficiency has been encountered in acquired clinical conditions accompanied by pathologic calcification. Because specific and effective treatments are lacking for pathologic calcification, the unifying finding of PPi deficiency suggests that PPi-targeted therapies may be beneficial to counteract pathologic soft tissue calcification in both genetic and acquired diseases.

The value of contrast-enhanced ultrasound for the diagnosis of metastatic cervical lymph nodes of papillary thyroid carcinoma: A systematic review and meta-analysis.

To investigate the diagnostic efficiency of contrast-enhanced ultrasound (CEUS) for the diagnosis of cervical lymph nodes metastasis (CLNM) of papillary thyroid carcinoma (PTC), eight available datasets of seven qualified articles before March 31, 2021 were included after a comprehensive search. Meta-analysis results showed that CEUS demonstrated acceptable diagnostic performance in the diagnosis of CLNM of PTC. Furthermore, meta-regression analysis was conducted to identify the reasons for heterogeneity and the results indicated that the criteria of CEUS for the diagnosis of CLNM in PTC need to be unified.

Functional Assessment of Missense Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder.

Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a transmembrane transporter, has a specialized efflux function in hepatocytes by contributing to plasma levels of inorganic pyrophosphate, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma inorganic pyrophosphate levels underlie the ectopic mineralization in pseudoxanthoma elasticum. In this study, we characterized the pathogenicity of three human ABCC6 missense variants using an adenovirus-mediated liver-specific ABCC6 transgene expression system in an Abcc6-/- mouse model of pseudoxanthoma elasticum. Variants p.L420V and p.R1064W were found benign because they had abundance and plasma membrane localization in hepatocytes similar to the wild-type human ABCC6 transgene, normalized plasma inorganic pyrophosphate levels, and prevented mineralization in the dermal sheath of vibrissae in muzzle skin, a phenotypic hallmark in the Abcc6-/- mice. In contrast, p.S400F was shown to be pathogenic because it failed to normalize plasma inorganic pyrophosphate levels and had no effect on ectopic mineralization despite its normal expression and proper localization in hepatocytes. These results showed that adenovirus-mediated hepatic ABCC6 expression in Abcc6-/- mice can provide a model system to effectively elucidate the multifaceted functional consequences of human ABCC6 missense variants identified in patients with pseudoxanthoma elasticum.

Inorganic pyrophosphate is reduced in patients with systemic sclerosis.

OBJECTIVE: The pathogenesis of calcinosis cutis, a disabling complication of SSc, is poorly understood and effective treatments are lacking. Inorganic pyrophosphate (PPi) is a key regulator of ectopic mineralization, and its deficiency has been implicated in ectopic mineralization disorders. We therefore sought to test the hypothesis that SSc may be associated with reduced circulating PPi, which might play a pathogenic role in calcinosis cutis. METHODS: Subjects with SSc and age-matched controls without SSc were recruited from the outpatient rheumatology clinics at Rutgers and Northwestern Universities (US cohort), and from the Universities of Szeged and Debrecen (Hungarian cohort). Calcinosis cutis was confirmed by direct palpation, by imaging or both. Plasma PPi levels were determined in platelet-free plasma using ATP sulfurylase to convert PPi into ATP in the presence of excess adenosine 5' phosphosulfate. RESULTS: Eighty-one patients with SSc (40 diffuse cutaneous, and 41 limited cutaneous SSc) in the US cohort and 45 patients with SSc (19 diffuse cutaneous and 26 limited cutaneous SSc) in the Hungarian cohort were enrolled. Calcinosis was frequently detected (40% of US and 46% of the Hungarian cohort). Plasma PPi levels were significantly reduced in both SSc cohorts with and without calcinosis (US: P = 0.003; Hungarian: P < 0.001). CONCLUSIONS: Circulating PPi are significantly reduced in SSc patients with or without calcinosis. Reduced PPi may be important in the pathophysiology of calcinosis and contribute to tissue damage with chronic SSc. Administering PPi may be a therapeutic strategy and larger clinical studies are planned to confirm our findings.

Diagnostic value of multiple ultrasound diagnostic techniques for axillary lymph node metastases in breast cancer: A systematic analysis and network meta-analysis.

Background: Early diagnosis of axillary lymph node metastasis is very important for the recurrence and prognosis of breast cancer. Currently, Lymph node biopsy is one of the important methods to detect lymph node metastasis in breast cancer, however, its invasiveness might bring complications to patients. Therefore, this study investigated the diagnostic performance of multiple ultrasound diagnostic methods for axillary lymph node metastasis of breast cancer. Materials and methods: In this study, we searched PubMed, Web of Science, CNKI and Wan Fang databases, conducted Bayesian network meta-analysis (NMA) on the studies that met the inclusion criteria, and evaluated the consistency of five different ultrasound imaging techniques in axillary lymph node metastasis of breast cancer. Funnel graph was used to evaluate whether it had publication bias. The diagnostic performance of each ultrasound imaging method was ranked using SUCRA. Results: A total of 22 papers were included, US+CEUS showed the highest SUCRA values in terms of sensitivity (SEN) (0.874), specificity (SPE) (0.911), positive predictive value (PPV) (0.972), negative predictive value (NPV) (0.872) and accuracy (ACC) (0.990). Conclusion: In axillary lymph node metastasis of breast cancer, the US+CEUS combined diagnostic method showed the highest SUCRA value among the five ultrasound diagnostic methods. This study provides a theoretical basis for preoperative noninvasive evaluation of axillary lymph node metastases in breast cancer patients and clinical treatment decisions. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022351977.

A novel homozygous missense variant in BTG4 causes zygotic cleavage failure and female infertility.

PURPOSE: "Zygotic cleavage failure" is an embryonic phenotype that causes female infertility and failure of in vitro fertilization and/or intracytoplasmic sperm injection. We aimed to identify pathogenic variants in a female infertility patient from a consanguineous family with the "zygotic cleavage failure" phenotype. METHODS: Whole-exome sequencing was performed in the affected patient; Sanger sequencing was used to confirm the identified variant. The functional effect of the identified variant was further investigated in HeLa cells. RESULTS: We identified a novel homozygous missense mutation in BTG4 (c.285G > C, p.W95C) in the affected individual. Co-immunoprecipitation in HeLa cells showed the complete loss of the interaction between the p.W95C BTG4 variant protein and CNOT7. CONCLUSION: This study confirms our previous research and expands the mutational spectrum of BTG4. Our findings complement the diagnostic genetic basis for "zygotic cleavage failure" patients and suggest that BTG4 may be a good target for future therapeutic strategies.