46,XY disorders of sex development (DSD) present with diverse phenotypes and complicated genetic causes. Precise genetic diagnosis contributes to accurate management, and targeted next-generation ...sequencing (NGS) and whole-exome sequencing are powerful tools for investigating DSD. However, the prevalent variants resulting in 46,XY DSD remain unclear, especially those associated with mild forms, such as isolated hypospadias, inguinal cryptorchidism, and micropenis. From 2019 to 2021, 74 patients with 46,XY DSD (48 typical and 26 mild) from the First Affiliated Hospital of Sun Yat-sen University were enrolled in our cohort study for targeted NGS or whole-exome sequencing. Our targeted 46,XY DSD panel included 108 genes involved in disorders of gonadal development and differentiation, steroid hormone synthesis and activation, persistent Müllerian duct syndrome, idiopathic hypogonadotropic hypogonadism, syndromic disorder, and others. Variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign following the American College of Medical Genetics guidelines. As a result, 28 of 74 (37.8%) patients with pathogenic and/or likely pathogenic variants acquired genetic diagnoses. The Mild DSD patients acquired a diagnosis rate of 30.7%. We detected 44 variants in 28 DSD genes from 31 patients, including 33 novel and 11 reported variants. Heterozygous (65%) and missense (70.5%) variants were the most common. Variants associated with steroid hormone synthesis and activation were the main genetic causes of 46,XY DSD. In conclusion, 46,XY DSD manifests as a series of complicated polygenetic diseases. NGS reveals prevalent variants and improves the genetic diagnoses of 46,XY DSD, regardless of severity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recently, hypoglycemic drugs belonging to sodium-glucose cotransporter 2 inhibitors (SGLT2i) have generated significant interest due to their clear cardiovascular benefits for heart failure with ...preserved ejection fraction (HFpEF) since there are no effective drugs that may improve clinical outcomes for these patients over a prolonged period. But, the underlying mechanisms remain unclear, particularly its effects on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death during heart failure (HF). Here, with proteomics, we demonstrated that ferroptosis might be a key mechanism in a rat model of high-salt diet-induced HFpEF, characterized by iron overloading and lipid peroxidation, which was blocked following treatment with canagliflozin. Data are available via ProteomeXchange with identifier PXD029031. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4, glutathione peroxidase 4, ferritin heavy chain 1, transferrin receptor, Ferroportin 1, iron, glutathione, malondialdehyde, and 4-hydroxy-trans-2-nonenal. These findings highlight the fact that targeting ferroptosis may serve as a cardioprotective strategy for HFpEF prevention and suggest that canagliflozin may exert its cardiovascular benefits partly via its mitigation of ferroptosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Magnesium phosphate (MgP) has garnered growing interest in hard tissue replacement processes due to having similar biological characteristics to calcium phosphate (CaP). In this study, an MgP coating ...with the newberyite (MgHPO
·3H
O) was prepared on the surface of pure titanium (Ti) using the phosphate chemical conversion (PCC) method. The influence of reaction temperature on the phase composition, microstructure, and properties of coatings was systematically researched with the use of an X-ray diffractometer (XRD), a scanning electron microscope (SEM), a laser scanning confocal microscope (LSCM), a contact angle goniometer, and a tensile testing machine. The formation mechanism of MgP coating on Ti was also explored. In addition, the corrosion resistance of the coatings on Ti was researched by assessing the electrochemical behavior in 0.9% NaCl solution using an electrochemical workstation. The results showed that temperature did not obviously affect the phase composition of the MgP coatings, but affected the growth and nucleation of newberyite crystals. In addition, an increase in reaction temperature had a great impact on properties including surface roughness, thickness, bonding strength, and corrosion resistance. Higher reaction temperatures resulted in more continuous MgP, larger grain size, higher density, and better corrosion resistance.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
An extremely heavy rainfall cluster was observed over the middle reaches of the Yangtze River (MYR) in August 2021, breaking the historical record since 1981 and causing severe floods. The ...controlling circulation regime and possible predictability sources of the un-expected rainfall are still unclear, especially from a sub-seasonal perspective. Our results show that the successive heavy rainfall events in August 2021 had significant intraseasonal oscillations for 10–24 d and 30–60 d, and they were synergistically influenced by tropical and extra-tropical circulation regime. Above all, the East Asia–Pacific teleconnection pattern (EAP) turned into a negative phase in late July and maintained throughout August, providing favorable background conditions for the northward transport of tropical water vapor and the southward intrusion of cold air from mid-high latitudes. The 30–60-d oscillation of precipitation was dominated by the first mode of boreal summer intraseasonal oscillation (BSISO1, with 30–60-d period), which strengthened the tropical moisture transport, while the quasi-biweekly oscillation of the western Pacific subtropical high and the anomalous mid-latitude cyclone of EAP intensified the precipitation on the scale of 10–24 d. In addition, the second mode of BSISO (BSISO2, with 10–30-d period) may also intensify the 10–24-d precipitation in late August. The forecast leading time of the S2S models for the persistent heavy rainfall in August 2021 was basically 1–2 weeks, while the EAP and BSISO1 were revealed as the main predictable sources of the abnormal rainfall events. These results highlight the importance of superposition of different intraseasonal oscillations in forming the extreme rainfall event and demonstrate a potential chance to enhance the prediction skill of extreme event if the ensemble members in S2S models could be reasonably selected according to their performances on key predictability sources.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•TACE plus lenvatinib and cabozantinib was safe and effective for uHCC.•Adverse reactions were controllable and manageable.•High NLR and PLR predicted lower response and survival rates.•Low BMI was ...associated with improved survival and reduced death risk.•NLR, PLR, and BMI can guide personalized treatment and care.
The objective of this study was to evaluate the effect and prognosis of transcatheter arterial chemoembolisation (TACE) combined with lenvatinib and cabozantinib in the treatment of advanced unresectable hepatocellular carcinoma (uHCC) and identify the predictors of prognosis related to cellular inflammation and body mass index (BMI). To the best of our knowledge, this is the first study to report the efficacy and prognosis of TACE combined with lenvatinib and cabozantinib in patients with uHCC and propose the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) as predictors of response and survival outcomes in this context.
The clinicopathologic data of 217 patients with advanced uHCC who underwent TACE combined with systemic therapy (lenvatinib mesylate + cabozantinib) in the Department of Hepatobiliary Surgery, Dazhou Central Hospital between October 2017 and February 2020 were collected retrospectively, and the relevant parameters were analysed and compared.
Univariate and multivariate logistic regression analyses showed that BMI, NLR, PLR and prothrombin time were independent factors for the objective response rate (ORR) of transformed therapy for uHCC (OR = 0.812 vs 1,290.68 vs 1.067 vs 0.626, 95 % CI: 0.719–0.897 vs 108.081–11,541.137 vs 1.037–1.099 vs 0.414–0.946, respectively, p < 0.05). The results showed that BMI, NLR and PLR had certain predictive values for the ORR in patients with liver cancer undergoing translational therapy (p < 0.05); the combined predictive effect of the three was the best, and the area under the curve (AUC) of BMI + NLR + PLR for predicting the ORR in patients with liver cancer undergoing translational therapy was 0.951 (95 % CI: 0.921, 0.964). A total of 181 patients experienced adverse reactions at different grades, including 104 cases at grade 1, 50 cases at grade 2, 22 cases at grade 3 and 5 cases at grade 4. There was a significant difference in overall survival (OS) between low- and high-NLR groups, low- and high-PLR groups and low- and high-BMI groups (χ2 = 9.644, 8.313 and 10.314, respectively, p < 0.05). There was a significant difference in progression-free survival (PFS) between the low- and high-NLR groups, the low- and high-PLR groups and the low- and high-BMI groups (χ2 = 8.965, 9.783 and 6.343, respectively, p < 0.05).
Transcatheter arterial chemoembolisation combined with lenvatinib and cabozantinib is safe and effective in the treatment of advanced uHCC, with controllable adverse reactions. High NLR and PLR and low BMI values before treatment were independent risk factors for the ORR. Body mass index, NLR and PLR predicted responses to triple switch therapy and survival outcomes in uHCC. Patients with pretreatment NLR ≥ 2.96 and PLR ≥ 184.41 had worse OS and PFS rates. Patients with pretreatment BMI ≥ 23 kg/m2 had improved OS and a reduced risk of death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. Nonspecific symptoms make the diagnosis elusive. In addition, locating ...the responsible tumor(s) is challenging. The aim of this study was to investigate the clinical management and outcomes of TIO.
The clinical features, diagnostic procedures, treatment, and outcomes of 12 patients were reviewed retrospectively.
The cohort comprised six men and six women (mean age 45.5 ± 9.9 years, range 23-61 years). The mean duration of disease was 3.7 ± 2.6 years. All patients manifested progressive bone pain, muscle weakness, and/or difficulty walking. Serum phosphorus concentrations were low in all patients (mean 0.42 ± 0.12 mmol/L). Technetium-99m octreotide scintigraphy was performed in 11 patients and showed lesions in the right distal femur, left femoral head, and right tibial plateau, respectively, in three patients. Magnetic resonance imaging (MRI) was negative for lesions in one patient. Two patients underwent biopsies that showed negative histopathology. Two patients, at 2 years and 8 months, respectively, after having negative technetium-99m octreotide studies, underwent
F-fluorodeoxyglucose positron emission tomography/computed tomography (CT), which revealed lesions in the sacrum and soft tissue of the left palm, respectively. One tumor was detected by CT and MRI. Overall, lesion sites were the head (two patients, 16.7%), thoracic and lumbar region (two, 16.7%), pelvis (three, 25%), lower limbs (four, 33.3%), and upper limbs (one, 8.3%). All patients underwent surgery, and histopathology showed phosphaturic mesenchymal tumors in each. Postoperatively, serum phosphorus concentrations normalized within 2-7 days in 11 patients. With follow-ups of 1-41 months, surgery was effective in 10 patients. One patient developed local recurrence and another had metastases.
Locating tumors responsible for tumor-induced osteomalacia is often challenging. Although complete tumor resection confers a good prognosis in most patients, surveillance for recurrence and metastasis is necessary. Before surgery or when surgery is not indicated, oral phosphate can alleviate symptoms and metabolic imbalance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cracks easily generate in concrete at early age owing to the shrinkage deformation. CaO-based expansion agent (CEA) and superabsorbent polymers (SAP) have been extensively used for the mitigation of ...concrete shrinkage. The macroscopic properties of concrete are highly determined by the microstructure. In this study, the influence of CEA and SAP addition on the pore structure evolution of cement paste under different curing temperatures was evaluated via low-field nuclear magnetic resonance spectroscopy. Test results indicated that, in cement paste, a higher CEA content led to a higher porosity and a larger most probable pore diameter (MPPD). Meanwhile, SAP addition increased the porosity and MPPD of CEA cement paste at early age but decreased them after 7 d, and a higher SAP content always brought a higher porosity and MPPD. Furthermore, the addition of SAP led to a lower porosity and MPPD of CEA cement paste than that of plain cement paste after 14 d. Moreover, the porosity and MPPD of CEA cement paste decreased first and subsequently increased as the curing temperature raised.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains ...poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from Kras
;Trp53
; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.
As an endemic freshwater crab group in China, the phylogenetic relationships within Sinopotamon are still controversial because of the limited taxon samples. In this study, the complete mitogenomes ...of Sinopotamon chishuiense with 17,311 bp and the nearly complete mitogenomes of S. wushanense with 16,785 bp were firstly sequenced and analyzed. Compared with other reported mitogenomes of Potamidae, some novel patterns of gene rearrangement were detected in these two Sinopotamon mitogenomes, which could be illuminated by the mechanisms of tandem duplication‐random loss, recombination, and translocation. Phylogenetic analyses showed the nonmonophyly of the Sinopotamon and a sister group relationship with Tenuilapotamon. These crabs from the eastern and southern of the Yangtze River basin were more closely related while other crabs form the plateau areas formed a separate clade. Divergence time indicated that the Sinopotamon and its sister group Tenuilapotamon diverged from other potamiscine freshwater crabs approximately 42.65 Mya, which belongs to the recent main uplifts period of the Tibetan Plateau in the Late Miocene. Combined with the similar evolutionary rates and relatively stable habitat altitude of these Sinopotamon species, these results implied that the ecological environment may be relatively stable during the speciation. Overall, our study yielded worthy perceptions for the evolutionary and taxonomic relationship of Sinopotamon and will help to better clarify the gene rearrangement events of the invertebrate mitogenome and lay the foundation for further phylogenetic study of Sinopotamon. Overall, our study yielded valuable insights into the evolutionary history and taxonomic relationship of Sinopotamon and these results will help to better explain the gene rearrangement events of the invertebrate mitogenome and lay the foundation for further phylogenetic study of Sinopotamon.
Overall, our study yielded valuable insights into the evolutionary history and taxonomic relationship of Sinopotamon and these results will help to better explain the gene rearrangement events of the invertebrate mitogenome and lay the foundation for further phylogenetic study of Sinopotamon.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Record-breaking numbers of Northeast China cold vortex (NCCV) occurred during the late spring (April–May) of 2021, which provided favorable background for more severe convection weather (such as ...hailstorm and tornado) happened and struck Jiangsu and Hubei provinces, China, causing heavy casualties and property losses. To better understand the possible causes of extremely abnormal NCCV activities, the external forcing and dynamical analysis was conducted. The results show that the extreme NCCV activity is regulated by the preceding sea surface temperature (SST) anomalies in the tropical Pacific, the snow conditions over the Tibetan Plateau, and the wave-mean flow interaction over the Eurasian continent. During the preceding autumn and winter in 2020, a moderate La Niña event occurred over the tropical Pacific, which triggered the Pacific–North America teleconnection pattern (PNA) like wave train and further dispersed the Rossby wave energy downstream along the mid-latitude westerly jet, forming a zonal wave train over the Eurasian continent. Moreover, the second minimum snow depth was recorded over the southeastern Tibetan Plateau during the boreal winter of 2020/2021, which induced a concurrent local anomalous anticyclone and a cyclone over northeast Asia in the following spring. Finally, the anomalous circulation is capable of achieving energy from the mean state through barotropic energy conversion and strengthening the downstream wave train accordingly. This study highlights the joint impacts of external forcings and internal atmospheric processes on the NCCV activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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