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Experimental measurements of two-dimensional (2D) dose rate distributions in proton pencil beam scanning (PBS) FLASH radiation therapy (RT) are currently lacking. In this study, we characterize a newly designed 2D strip-segmented ionization chamber array (SICA) with high spatial and temporal resolution and demonstrate its applications in a modern proton PBS delivery system at both conventional and ultrahigh dose rates.A dedicated research beamline of the Varian ProBeam system was employed to deliver a 250-MeV proton PBS beam with nozzle currents up to 215 nA. In the research and clinical beamlines, the spatial, temporal, and dosimetric performances of the SICA were characterized and compared with measurements using parallel-plate ion chambers (IBA PPC05 and PTW Advanced Markus chamber), a 2D scintillator camera (IBA Lynx), Gafchromic films (EBT-XD), and a Faraday cup. A novel reconstruction approach was proposed to enable the measurement of 2D dose and dose rate distributions using such a strip-type detector.The SICA demonstrated a position accuracy of 0.12 ± 0.02 mm at a 20-kHz sampling rate (50 μs per event) and a linearity of RThe newly designed SICA demonstrated excellent spatial, temporal, and dosimetric performances and is well suited for commissioning, quality assurance, and a wide range of clinical applications in proton PBS clinical and FLASH-RT.

Background Previous reports have been inconsistent about the associations between amyotrophic lateral sclerosis (ALS) and psychiatric disorders. More importantly, it needs to be elucidated whether these associations are causal or confounded. Objective We aimed to determine the presence of cause-effect relationships between ALS and four psychiatric disorders (schizophrenia; bipolar disorder; anxiety, nerves, tension or depression disorders (ADD); and neuroticism) using a bidirectional Mendelian randomization (BDMR) analysis based on gene associations. Methods First, we extracted genome-wide association studies (GWAS) summaries for the four psychiatric disorders and ALS from the Integrative Epidemiology Unit (IEU) and the Psychiatric Genomics Consortium (PGC) GWAS database. We then identified single-nucleotide polymorphisms (SNPs) that are strongly associated with exposure, are independent of confounders, and are related to exposure-outcome, as instrumental variables (IVs) for Mendelian randomization (MR) analyses. In the MR analysis, the cause-effect relationships were analyzed using psychiatric disorders as the exposure variable and ALS as the outcome, with six methods (primary inverse-variance weighted (IVW), MR-Egger, weighted median estimator, simple mode, weighted mode, and robust adjusted profile score (RAPS)analyses). Moreover, the results were subjected to sensitivity analyses, namely, IVW and MR-Egger analyses (for potential heterogeneity and horizontal pleiotropy) and MR leave-one-out analysis (to determine whether one SNP drove the causal signal). Finally, reverse MR analyses were conducted using ALS as the exposure variable and four psychiatric disorders as outcome variables; sensitivity was assessed. Results After extracting the GWAS summaries, we established IVs, including 147, 13, 37, and 105 SNPs for schizophrenia, bipolar disorder, ADD, and neuroticism, respectively. Subsequently, the MR analyses conducted using the six methods revealed no cause-effect relationships of the four psychiatric disorders with ALS. Moreover, we set up six SNPs as IVs for ALS in reverse MR analyses. Finally, no statistically significant cause-effect relationship of ALS with the four psychiatric disorders was found. These associations were robust as shown by the sensitivity analyses. Conclusions BDMR analyses revealed no significant genetic evidence for a cause-effect relationship between ALS and four psychiatric disorders.

Purpose: To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer. Patients and Methods: Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors. Results: In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo. Conclusion: The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer.The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

Cleidocranial dysplasia (CCD) is a rare, autosomal dominant hereditary disorder characterized by skeletal malformations and dental abnormalities. The purpose of this study was to explore the functional role of a novel mutation in the pathogenesis of CCD. Genomic DNA was extracted from peripheral blood mononuclear cells collected from family members of a Chinese patient with CCD. An analysis of their RUNX Family Transcription Factor 2 (RUNX2) gene sequences was performed by PCR amplification and Sanger sequencing. The function of the mutant RUNX2 was studied by bioinformatics, real-time PCR, western blotting, and subcellular localization analysis. Sanger sequencing identified a novel single-base deletion (NM_001024630.4:c.132delG;NP_001019801.3: Val45Trpfs

Face verification can be regarded as a two-class fine-grained visual-recognition problem. Enhancing the feature's discriminative power is one of the key problems to improve its performance. Metric-learning technology is often applied to address this need while achieving a good tradeoff between underfitting, and overfitting plays a vital role in metric learning. Hence, we propose a novel ensemble cascade metric-learning (ECML) mechanism. In particular, hierarchical metric learning is executed in a cascade way to alleviate underfitting. Meanwhile, at each learning level, the features are split into nonoverlapping groups. Then, metric learning is executed among the feature groups in the ensemble manner to resist overfitting. Considering the feature distribution characteristics of faces, a robust Mahalanobis metric-learning method (RMML) with a closed-form solution is additionally proposed. It can avoid the computation failure issue on an inverse matrix faced by some well-known metric-learning approaches (e.g., KISSME). Embedding RMML into the proposed ECML mechanism, our metric-learning paradigm (EC-RMML) can run in the one-pass learning manner. The experimental results demonstrate that EC-RMML is superior to state-of-the-art metric-learning methods for face verification. The proposed ECML mechanism is also applicable to other metric-learning approaches.

Rationale: Renal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD) can originate from any nephron segments, including proximal tubules (PT), the loop of Henle (LOH), distal tubules (DT), and collecting ducts (CD). Previous studies mostly used limited cell markers and failed to identify cells negative for these markers. Therefore, the cell composition and origin of ADPKD cyst are still unclear, and mechanisms of cystogenesis of different origins await further exploration. Methods: We performed single-cell RNA sequencing for the normal kidney tissue and seven cysts derived from superficial or deep layers of the polycystic kidney from an ADPKD patient. Results: Twelve cell types were identified and analyzed. We found that a renal cyst could be derived either from CD or both PT and LOH. Gene set variation analysis (GSVA) showed that epithelial mesenchymal transition (EMT), TNFA signaling via the NFKB pathways, and xenobiotic metabolism were significantly activated in PT-derived cyst epithelial cells while robust expression of genes involved in G2M Checkpoint, mTORC1 signaling, E2F Targets, MYC Targets V1, MYC Targets V2 were observed in CD-derived cells. Conclusion: Our results revealed that a single cyst could originate from CD or both PT and LOH, suggesting heterogeneity of polycystic composition and origin. Furthermore, cyst epithelial cells with different origins have different gene set activation.

To investigate the clinical significance of miRNA-146, OX-LDL and ROS in patients with primary ovarian insufficiency (POI).100 patients with POI were prospectively collected and 100 women with normal ovarian function were randomly selected as control group. Serum miRNA-146 expression level was detected by qRT-PCR and serum OX-LDL and ROS expression levels were detected by ELISA. Ovarian granulosa cells of mouse were transfected with miRNA-146 mimics or inhibitors, and then treated with OX-LDL. Cell viability, colony forming ability, apoptosis rate and toll like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) of pathway proteins were evaluated respectively.Compared with control group, the expression level of miRNA-146 in POI group was significantly lower, the expression level of OX-LDL and ROS were significantly higher, and the ovarian volume and peak systolic blood flow velocity of ovarian artery were significantly decreased in POI group. Upregulation of miRNA-146 expression had a protective effect on OX-LDL injured ovarian granulosa cells, as evidenced by increased ovarian granulosa cell viability and colony number, reduced apoptosis, and downregulation of TLR4/NF-κB expression.miRNA-146 can target downstream TLR4/NF-κB signaling pathway affects oxidative stress and inflammatory response of POI induced by OX-LDL and ROS, and is expected to become a biomarker for early prediction of POI and a new target for treatment.

Twins with Duchenne muscular dystrophy (DMD) have been widely studied. We report the first rare case of monozygotic triplets with DMD who shared consistent phenotypes, including delayed motor and language milestones, muscle wasting and weakness, joint contracture, and lumbar lordosis. Muscle magnetic resonance imaging and biopsy revealed the similar muscle injury characteristics and dystrophin absence. Short tandem repeat analysis confirmed monozygosity. A de novo mutation (exon 49-52 deletion) was found in the triplets but not in their mother. Treatment included prednisone, idebenone, and rehabilitation management. At the 2-year follow-up, motor function had deteriorated, and muscle fatty infiltration was more extensive and severe. Our case offers a unique opportunity for genetic and therapeutic research. Furthermore, it highlights the critical role of genetic factors in DMD phenotypes and provides a potential choice for treatment observations.

Purpose: This study was designed to identify the underlying molecular genetic cause of idiopathic hypogonadotropic hypogonadism (IHH) in a nonconsanguineous Chinese family. Methods: All the family members underwent medical history evaluation, physical examination, and laboratory studies. Whole-exome sequencing and RNA sequencing was performed on 2 affected siblings and unaffected parents. All candidate variants were confirmed in all family members by Sanger sequencing and silico function prediction. Results: The proband and his twin brother were diagnosed with IHH, and an autosomal recessive mode of inheritance was identified. Whole-exome sequencing identified the compound heterozygous variants c.9230G>A (p.Arg3077Gln) and c.12883G>A (p.Val4295Met) in DNAH5 in both affected siblings. Sanger sequencing verified that c.9230G>A in DNAH5 was from the unaffected mother and c.12883G>A was from the unaffected father. In addition, we found heterozygous mutations in BBS2 (c.1705delC, p.Gln569fs) and NR5A1 (c.460G>A, p.Ala154Thr) in the siblings, which were from their father.Conclusion: Compound heterozygous variants in DNAH5 were identified in the affected siblings, and were predicted to be pathogenic by silico analysis. This is the first report that suggests variants in DNAH5 are relevant to the pathogenesis of IHH. This study expands the variant spectrum of genes associated with IHH.