Exploration of the Minimum Necessary FVIII Level at Different Physical Activity Levels in Pediatric Patients with Hemophilia A

BACKGROUND: Physical activity can increase joint stability and reduce the risk of injury in hemophilia patients. There is limited clinical data on target trough FVIII levels during physical activity in hemophilia A patients. Hence, this study aimed to explore the target trough FVIII level required to avoid bleeding during different physical activities in hemophilia A patients. METHODS: Patients with severe or moderate hemophilia A, who underwent pharmacokinetics (PK) tests at our center were enrolled in this study. Physical activities and clinical information such as bleeding were recorded. The FVIII level during physical activity was calculated by the WAPPS-Hemo. RESULTS: A total of 105 patients were enrolled in this study. A total of 373 physical activities were recorded, of which 57.6% (215/373) was low-risk activities and the remaining 42.4% (158/373) was medium-risk activities. Most common physical activities were bicycling (59.0%), swimming (43.8%), running (48.6%), and jumping rope (41.0%). The FVIII trough level of low-risk physical activity was 3.8 IU/dl (AUC = 0.781, CONCLUSION: The minimum necessary FVIII level increased with higher risk physical activity, irrespective of arthropathy

Transpositional reactivation of the Dart transposon family in rice lines derived from introgressive hybridization with Zizania latifolia

<p>Abstract</p> <p>Background</p> <p>It is widely recognized that interspecific hybridization may induce "genome shock", and lead to genetic and epigenetic instabilities in the resultant hybrids and/or backcrossed introgressants. A prominent component involved in the genome shock is reactivation of cryptic transposable elements (TEs) in the hybrid genome, which is often associated with alteration in the elements' epigenetic modifications like cytosine DNA methylation. We have previously reported that introgressants derived from hybridization between <it>Oryza sativa </it>(rice) and <it>Zizania latifolia </it>manifested substantial methylation re-patterning and rampant mobilization of two TEs, a <it>copia </it>retrotransposon <it>Tos17 </it>and a MITE <it>mPing</it>. It was not known however whether other types of TEs had also been transpositionally reactivated in these introgressants, their relevance to alteration in cytosine methylation, and their impact on expression of adjacent cellular genes.</p> <p>Results</p> <p>We document in this study that the <it>Dart </it>TE family was transpositionally reactivated followed by stabilization in all three studied introgressants (RZ1, RZ2 and RZ35) derived from introgressive hybridization between rice (cv. Matsumae) and <it>Z. latifolia</it>, while the TEs remained quiescent in the recipient rice genome. Transposon-display (TD) and sequencing verified the element's mobility and mapped the excisions and re-insertions to the rice chromosomes. Methylation-sensitive Southern blotting showed that the <it>Dart </it>TEs were heavily methylated along their entire length, and moderate alteration in cytosine methylation patterns occurred in the introgressants relative to their rice parental line. Real-time qRT-PCR quantification on the relative transcript abundance of six single-copy genes flanking the newly excised or inserted <it>Dart</it>-related TE copies indicated that whereas marked difference in the expression of all four genes in both tissues (leaf and root) were detected between the introgressants and their rice parental line under both normal and various stress conditions, the difference showed little association with the presence or absence of the newly mobilized <it>Dart-</it>related TEs.</p> <p>Conclusion</p> <p>Introgressive hybridization has induced transpositional reactivation of the otherwise immobile <it>Dart</it>-related TEs in the parental rice line (cv. Matsumae), which was accompanied with a moderate alteration in the element's cytosine methylation. Significant difference in expression of the <it>Dart</it>-adjacent genes occurred between the introgressants and their rice parental line under both normal and various abiotic stress conditions, but the alteration in gene expression was not coupled with the TEs.</p

Corrigendum: Case Report: Durable response to immuno-chemotherapy in a case of ROS1 fusion-positive advanced lung adenocarcinoma: A case report

Immune checkpoint inhibitors (ICIs) have greatly transformed the treatment and improved the prognosis for patients with non-small cell lung cancer (NSCLC) without driver gene alterations. However, the effects of ICI combination therapy in ROS1 fusion-positive NSCLC remains unclear. Herein, we present a case with ROS1 fusion-positive NSCLC treated with ICI plus chemotherapy. The patient achieved a continuous partial response (PR) to ICI plus chemotherapy and a more than 35 months progression free survival. This case demonstrates that ICI plus chemotherapy is a promising option for patients with ROS1 fusion-positive NSCLC

Case report: The effect of second-line vebreltinib treatment on a patient with advanced NSCLC harboring the MET exon 14 skipping mutation after tepotinib treatment

BackgroundHighly selective type Ib mesenchymal–epithelial transition gene (MET) tyrosine kinase inhibitors (TKIs) are the standard-of-care (SOC) therapy for previously untreated non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. However, there are rare reports describing effective regimens for patients who fail SOC without identifying resistant mutations or tissue transformation.Case reportWe report the first case of a 74-year-old woman with lung adenocarcinoma (cT1cNxM0) harboring METex14 splice region mutation, which was identified by a next-generation sequencing (NGS)-based assay. The patient was administered two treatments, including first-line tepotinib and second-line vebreltinib. The patient achieved progression-free survival (PFS) of 7.6 months, and then disease progression of tepotinib was observed. A re-biopsy was performed for NGS, which revealed the same mutations as before, with no new gene mutations detected. The woman received subsequent vebreltinib therapy and experienced durable clinical benefits. In the first 6.8 months, chest computed tomography demonstrated stable disease. Then, she achieved partial response (PR). The durable PR lasted for more than 13 months, and the PFS is currently over 20 months, exceeding the prior treatment.ConclusionThis case highlights the importance of considering re-biopsy and reanalysis of genetic profiles in NSCLC patients harboring METex14 skipping mutations after progressive disease in MET TKI treatment. This raises the possibility that vebreltinib may have long-term survival benefits for patients without mutations conferring resistance (funded by Beijing Pearl Biotechnology Co., Ltd; ClinicalTrials.gov number, NCT04258033)

Associations between Urinary Phthalate Metabolites and Serum Anti-Müller Hormone Levels in U.S. Men Based on National Health and Nutrition Examination Survey 2003–2004

Anti-Müller hormone (AMH) plays an important role in reproductive development and has a wide potential clinical application value. Phthalates have been widely found in human living environment and have negative effects on human reproduction. This study aimed to explore the relationship between urinary phthalate metabolites and serum AMH level in the general male population. Cross-sectional analyses were performed with a population of 489 men aged more than 12 years who participated in National Health and Nutrition Examination Survey (NHANES) 2003–2004 by Centers for Disease Control and Prevention, the United States. NHANES public data (demographic and socioeconomic information, examinations, and laboratory tests) were analyzed using Kruskal-Wallis test, Wilcoxon test and multivariable regression. Results showed that the urine concentration of mono (3-carboxypropyl) phthalate (MCPP) of 12–20 age group was significantly positively correlated with serum AMH concentration in the model without any covariates (p &lt; 0.05). In the 60-year-old group, the monomethyl phthalate (MEP), mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) concentrations were significantly correlated with serum AMH concentrations in models both with and without covariates (all p &lt; 0.05). It could be concluded that exposure to phthalates might have negative effects on AMH level, especially in seniors. AMH could be used as a marker of exposure to phthalates in aged males. How exposure to phthalates affected AMH level and what the potential long-term health consequences of their relationship are needs more investigation

Ample Evidence: Dehydroepiandrosterone (DHEA) Conversion into Activated Steroid Hormones Occurs in Adrenal and Ovary in Female Rat.

Dehydroepiandrosterone (DHEA) is important for human health, especially for women. All estrogens and practically half of androgens are synthesized from DHEA in peripheral tissues. However, the mechanism and exact target tissues of DHEA biotransformation in the female are not fully clear. The present study showed that maximal content of androstenedione (AD) and testosterone (T) were observed at 3h after DHEA administration in female rats, which was 264% and 8000% above the control, respectively. Estradiol (E2) content significantly increased at 6h after DHEA administration, which was 113% higher than that in control group. Gavage with DHEA could significantly reduce 3β-hydroxysteroid dehydrogenase (3β-HSD) mRNA level at 3-12h and 17β-hydroxysteroid dehydrogenase (17β-HSD) mRNA level at 12h in ovary, while increasing aromatase mRNA levels at 6, 24, and 48 h. It is interesting that administration of DHEA caused a significant increase of 17β-HSD, 3β-HSD and aromatase mRNA levels in adrenal. The AD and T contents also markedly increased by 537% and 2737% after DHEA administration in ovariectomised rats, in company with a significant increase in 17β-HSD and 3β-HSD mRNA levels and decreased aromatase mRNA level in adrenal. However, DHEA administration did not restore the decreased E2, estrone (E1), and progesterone (P) caused by the removal of the ovaries in females. These results clearly illustrated that exogenous DHEA is preferentially converted into androgens in adrenal, while its conversion to estrogens mainly happens in the ovary through steroidogenic enzyme in female rats