Outcome and etiology of fetal pleural effusion, fetal ascites and hydrops fetalis after fetal intervention: retrospective observational cohort from a single institution.

OBJECTIVES: Non-immune hydrops fetalis (NIHF) is the pathological accumulation of fluids in fetal compartments, without maternal isoimmunization. Fetal interventions (e.g. shunting, fetal paracentesis, fetal thoracocentesis, fetal pleurodesis) are used to alleviate fluid accumulations, but the outcome is uncertain because the underlying causes of NIHF vary. We aimed to explore the etiology and long-term outcome of NIHF after fetal intervention. METHODS: This was a retrospective review of fetuses with NIHF, defined by the presence of fetal ascites, pleural or pericardial effusion, skin edema or cystic hygroma, or a combination of these features, who underwent intervention at our institution during the period 2012-2021. Clinical surveillance, genetic analysis and viral infection screening were used to define the etiology. Chart reviews and telephone interviews were conducted to assess the long-term outcomes. RESULTS: In total, 55 fetuses were enrolled and 46 cases had final follow-up data after delivery. Etiology was identified in 33 cases, including four for which the underlying causes were not identified initially using small-gene-panel tests but which were later diagnosed with monogenic disorders by whole-exome sequencing (WES). Twenty-three cases with follow-up survived, having a follow-up period of 2-11 years at the time of writing, of which 17 were healthy. All 11 cases initially presenting as congenital chylothorax survived with favorable outcome. CONCLUSIONS: The etiologies of NIHF are heterogeneous, and the long-term (spanning 2-11 years) outcome of fetal intervention varies, according to the underlying etiology, with cases caused by congenital chylothorax having the best prognosis. Genome-wide tests, such as WES, may be helpful in determining the underlying condition in cases caused by a genetic disorder, and this may affect fetal therapy approaches in the future. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

First Report of Pseudomonas cichorii Causing Bacterial vein necrosis on Perilla plants [Perilla frutescens (L.) Britton.] in South Korea.

Perilla (Perilla frutescens L.) is the second most important upland crop and the third largest edible oil crop in Korea (Shin and Kim 1994). During a disease survey in Busan, Korea in September 2021, symptoms of vein necrosis were observed in perilla plants, with incidences of approximately 30% and 50% in two fields. Symptoms of spots on the perilla appeared as leaf dryness and spots with water-soaked blotches largely concentrated on the mid-veins of leaves. The lesions were initiated with water-soaked spots on the leaf or stem and gradually turned black or brown. Necrosis was also observed in the stems. A bacterium was isolated on Luria-Bertani (LB) agar from diseased leaf tissues that were surface-disinfected with 70% ethyl alcohol for 3-5 min and then washed with sterile water three times. Three pieces of sterilized leaf tissue (size: 0.5 × 0.5 cm) were mixed with 500 µL sterile water for 30 min, and then the suspension was serially diluted and spread on LB agar. Subsequently, isolates were cultivated on LB agar and King's Medium B agar (KMB) (Schaad et al. 2001), and they were predominantly cream-colored and circular bacterial colonies with undulated margins. The bacterial colonies on KMB displayed fluorescence under 365 nm UV light. The isolates were analyzed with the GEN III MicroPlate (Biolog, Hayward, CA, USA), and all isolates were identified as Pseudomonas cichorii, a devastating plant bacterium that damages a wide range of host plants worldwide, including in South Korea (Hikichi et al. 2013; Ramkumar et al. 2015). To identify the species of the bacterial pathogen, genomic DNA of four isolates (BS4922, BS4167, BS4345, and BS4560) was extracted, and the 16S rRNA gene and hrcRST gene were amplified with universal primers, 27F/1492R and Hcr1/Hcr2, and sequencing was then done (Patel et al. 2019). In the BLAST analysis, the 16S rRNA sequences (GenBank OM060656, OM275434, OM275435, OM275436) showed a 100% and 99% similarity to P. cichorii strains MAFF 302698 (AB724286) and P. cichorii strain Pc-Gd-4 (KU923373), respectively. Further, hrcRST gene sequences (GenBank OM143596, OM268864, OM268865, and OM268866) showed high similarity (>99%) with P. cichorii strain P16-51 (MG518230). A pathogenicity test of the four isolates was performed on 3 - 4 weeks old perilla plants by creating wounds with a needle on the lower leaves and stems, and then the plants were inoculated by spraying inoculum (108 CFU/ml). The plants that served as the negative control were wounded and sprayed with unsterilized water. The inoculated perilla plants were placed in a greenhouse at 28 ± 2oC , 80-85% relative humidity, and a natural photoperiod. The inoculation site began to show symptoms of water-soaked brown lesions. Disease symptoms such as leaf dryness, water-soaked blotches on the mid-vein of leaves, and necrosis on plant stems were observed in the inoculated plants 7-10 days after inoculation, whereas the plants of the negative control group did not show any symptoms. The bacteria were re-isolated from the diseased tissues of the plants, and DNA sequence analysis identified them as P. cichorii. Additionally, all isolates induced hypersensitivity reactions in tobacco and tomato leaves within 24 h after inoculation. To our knowledge, this is the first report of P. cichorii infecting perilla in South Korea. The findings in this study will provide the basic information for the development of diagnostic tools and management measures against P. cichorii in perilla.

Continuing perioperative estrogen therapy does not increase venous thromboembolic events in transgender patients: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study is to compare the risk of venous thromboembolic events (VTE) between patients suspending and continuing estrogen therapy perioperatively, in male to female gender-affirming surgery (vaginoplasty). MATERIALS AND METHODS: The authors conducted a systematic review and meta-analysis of existing research on male to female gender-affirming study, which compared the risk of VTE among the usage of estrogen perioperatively. RESULTS: A total of 209 studies were identified as potentially eligible among PubMed, Embase, and Cochrane library databases. Among the studies, 191 studies were excluded due to their abstract inappropriateness. Out of the remaining 18 studies, only 3 articles were eligible and were finally included. Meta-analysis was performed and showed odds ratio of 0.77 (95% CI: 0.04, 14.01). CONCLUSIONS: Perioperative estrogen therapy does not increase VTE risk on male to female gender-affirming surgery. Therefore, estrogen therapy may be continued perioperatively in vaginoplasty. More prospective studies are needed.

A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy.

BACKGROUND: Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear. PATIENTS AND METHODS: This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1 = 30%) for the BM cohort and overall survival (OS) (H1 = 5 months) for the LM cohort. RESULTS: The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months [95% confidence interval (CI) 5.0-16.6]; the median OS was 16.9 months [95% CI 7.9-not reached (NR)]. In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1-NR); the median PFS was 8.0 months (95% CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n = 18, P = 0.39) and LM (n = 17, P = 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P = 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2. CONCLUSION: Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

A QSAR model for predicting antidiabetic activity of dipeptidyl peptidase-IV inhibitors by enhanced binary gravitational search algorithm.

Time-varying binary gravitational search algorithm (TVBGSA) is proposed for predicting antidiabetic activity of 134 dipeptidyl peptidase-IV (DPP-IV) inhibitors. To improve the performance of the binary gravitational search algorithm (BGSA) method, we propose a dynamic time-varying transfer function. A new control parameter, µ , is added in the original transfer function as a time-varying variable. The TVBGSA-based model was internally and externally validated based on Qint2 , QLGO2 , QBoot2 , MSEtrain , Qext2 , MSEtest , Y-randomization test, and applicability domain evaluation. The validation results indicate that the proposed TVBGSA model is robust and not due to chance correlation. The descriptor selection and prediction performance of TVBGSA outperform BGSA method. TVBGSA shows higher Qint2 of 0.957, QLGO2 of 0.951, QBoot2 of 0.954, Qext2 of 0.938, and lower MSEtrain and MSEtest compared to obtained results by BGSA, indicating the best prediction performance of the proposed TVBGSA model. The results clearly reveal that the proposed TVBGSA method is useful for constructing reliable and robust QSARs for predicting antidiabetic activity of DPP-IV inhibitors prior to designing and experimental synthesizing of new DPP-IV inhibitors.

Anti-viral therapy is associated with improved survival but is underutilised in patients with hepatitis B virus-related hepatocellular carcinoma: real-world east and west experience.

BACKGROUND: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. METHODS: This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. RESULTS: Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001). CONCLUSIONS: Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed.

Systemic mastocytosis identified in two women developing fragility fractures during lactation.

Two women presenting with fragility fractures during lactation had bone mineral density (BMD) reduced more greatly than usually associated with lactation. The first woman was 29 years old with a BMD T-score of - 3.2 SD at the spine and- 2.0 SD at the femoral neck. The second woman was 35 years old with a BMD T-score of - 4.5 SD at the spine and - 2.8 SD at the femoral neck. Both women had increased cortical porosity and reduced trabecular density. Investigation identified an elevated serum tryptase, and marrow biopsy confirmed the diagnosis of mastocytosis. Lactation causes bone loss, but the occurrence of fractures in the setting of severe deficits in BMD and microstructural deterioration signals the need to consider additional causes of bone loss.

Diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI protocol for hepatocellular carcinoma screening.

AIM: To evaluate the diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI (AMRI) in cirrhotic and chronic hepatitis B (CHB) patients for hepatocellular carcinoma (HCC) screening. MATERIALS AND METHODS: Seventy-nine consecutive patients at risk for HCC due to cirrhosis and/or CHB were included in this retrospective study. For each patient, the first gadoxetate disodium-enhanced MRI between 2008 through 2014 was analysed. Two independent readers read an anonymised abbreviated image set comprising axial T1-weighted (W) images with fat saturation in the hepatobiliary phase, 20 minutes or more after gadoxetate injection, and axial T2W single-shot fast spin echo images. Each observation >10 mm was scored as negative or suspicious for HCC. Inter-reader agreement was assessed. A composite reference standard was used to determine the per-lesion diagnostic performance for each reader. RESULTS: Inter-reader agreement was substantial (κ = 0.75). The final reference standard showed 27 HCCs in 13 patients (median 21 mm, range 11-100 mm). The two readers each correctly scored 23 as suspicious for HCC (sensitivity = 85.2%), scored a total of 27 and 32 observations as suspicious for HCC (positive predictive value [PPV] = 85.2% and 71.9%), and scored 83 and 78 observations or complete examinations as negative for HCC (negative predictive value [NPV] = 95.2% and 94.9%). CONCLUSIONS: The AMRI protocol provides higher per-lesion sensitivity and NPV than reported values for ultrasound, the current recommended technique for screening, and similar per-lesion sensitivity and PPV to reported values for complete dynamic contrast-enhanced MRI.

Assessment of impact of urbanisation on background radiation exposure and human health risk estimation in Kuala Lumpur, Malaysia.

Kuala Lumpur has been undergoing rapid urbanisation process, mainly in infrastructure development. The opening of new township and residential in former tin mining areas, particularly in the heavy mineral- or tin-bearing alluvial soil in Kuala Lumpur, is a contentious subject in land-use regulation. Construction practices, i.e. reclamation and dredging in these areas are potential to enhance the radioactivity levels of soil and subsequently, increase the existing background gamma radiation levels. This situation is worsened with the utilisation of tin tailings as construction materials apart from unavoidable soil pollutions due to naturally occurring radioactive materials in construction materials, e.g. granitic aggregate, cement and red clay brick. This study was conducted to assess the urbanisation impacts on background gamma radiation in Kuala Lumpur. The study found that the mean value of measured dose rate was 251±6nGyh-1 (156-392nGyh-1) and 4 times higher than the world average value. High radioactivity levels of 238U (95±12Bqkg-1), 232Th (191±23Bqkg-1,) and 40K (727±130Bqkg-1) in soil were identified as the major source of high radiation exposure. Based on statistical ANOVA, t-test, and analyses of cumulative probability distribution, this study has statistically verified the dose enhancements in the background radiation. The effective dose was estimated to be 0.31±0.01mSvy-1 per man. The recommended ICRP reference level (1-20mSvy-1) is applicable to the involved existing exposure situation in this study. The estimated effective dose in this study is lower than the ICRP reference level and too low to cause deterministic radiation effects. Nevertheless based on estimations of lifetime radiation exposure risks, this study found that there was small probability for individual in Kuala Lumpur being diagnosed with cancer and dying of cancer.

Predictors of general discomfort, limitations in activities of daily living and intention of a second donation in unrelated hematopoietic stem cell donation.

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0-10) and donor's intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30-39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

BRCA1 positively regulates FOXO3 expression by restricting FOXO3 gene methylation and epigenetic silencing through targeting EZH2 in breast cancer.

BRCA1 mutation or depletion correlates with basal-like phenotype and poor prognosis in breast cancer but the underlying reason remains elusive. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with downregulation of the expression of the pleiotropic tumour suppressor FOXO3. Knockdown of BRCA1 by small interfering RNA (siRNA) resulted in downregulation of FOXO3 expression in the BRCA1-competent MCF-7, whereas expression of BRCA1 restored FOXO3 expression in BRCA1-defective HCC70 and MDA-MB-468 cells, suggesting a role of BRCA1 in the control of FOXO3 expression. Treatment of HCC70 and MDA-MB-468 cells with either the DNA methylation inhibitor 5-aza-2'-deoxycitydine, the N-methyltransferase enhancer of zeste homologue 2 (EZH2) inhibitor GSK126 or EZH2 siRNA induced FOXO3 mRNA and protein expression, but had no effect on the BRCA1-competent MCF-7 cells. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNMT1/3a/b and histone H3 lysine 27 trimethylation (H3K27me3) are recruited to the endogenous FOXO3 promoter, further advocating that these proteins interact to modulate FOXO3 methylation and expression. In addition, ChIP results also revealed that BRCA1 depletion promoted the recruitment of the DNA methyltransferases DNMT1/3a/3b and the enrichment of the EZH2-mediated transcriptional repressive epigenetic marks H3K27me3 on the FOXO3 promoter. Methylated DNA immunoprecipitation assays also confirmed increased CpG methylation of the FOXO3 gene on BRCA1 depletion. Analysis of the global gene methylation profiles of a cohort of 33 familial breast tumours revealed that FOXO3 promoter methylation is significantly associated with BRCA1 mutation. Furthermore, immunohistochemistry further suggested that FOXO3 expression was significantly associated with BRCA1 status in EZH2-positive breast cancer. Consistently, high FOXO3 and EZH2 mRNA levels were significantly associated with good and poor prognosis in breast cancer, respectively. Together, these data suggest that BRCA1 can prevent and reverse FOXO3 suppression via inhibiting EZH2 and, consequently, its ability to recruit the transcriptional repressive H3K27me3 histone marks and the DNA methylases DNMT1/3a/3b, to induce DNA methylation and gene silencing on the FOXO3 promoter.

Three-dimensional isotropic fast spin-echo MR lymphangiography of T1-weighted and intermediate-weighted pulse sequences in patients with lymphoedema.

AIM: To evaluate the feasibility of magnetic resonance (MR) lymphangiography acquired using three-dimensional (3D) isotropic T1-weighted fast spin-echo (FSE) and 3D isotropic intermediate-weighted FSE sequences, as the new method of MR lymphangiography, and to compare the results of these two methods in patients with lymphoedema. MATERIALS AND METHODS: Thirty-three extremities of 27 patients with primary or secondary lymphoedema and who had undergone radionuclide lymphoscintigraphy and MR lymphangiography with 3D isotropic T1-weighted FSE and 3D isotropic intermediate-weighted FSE were included in the study. The results of both imaging techniques were independently reviewed by two readers in consensus who rated the lymphatic drainage pattern, the quality of the depiction of lymphatic vessels and lymph nodes, and the level of lymph vessel enhancement. The assessment scores of each imaging sequence were compared using the Wilcoxon signed-rank test. The results were expressed as means with standard deviations. RESULTS: More lymphatic vessels were visualised on T1-weighted FSE than on intermediate-weighted FSE (p<0.001). As more lymphatic vessels were detected on T1-weighted FSE, the per-extremity grade of the lymphatic drainage pattern was higher (p=0.046) and the visible levels of lymph-vessel enhancement were also significantly higher (p=0.004) on the T1-weighted FSE sequence, whereas the conspicuity of lymph nodes was superior on intermediate-weighted FSE (p=0.004). CONCLUSION: MR lymphangiography using the 3D FSE pulse sequence is a feasible and noticeable new technique of MR lymphangiography. Between the two applicable protocols used, T1-weighted FSE provided better information regarding lymphatic vessels and their drainage, whereas intermediate-weighted FSE has the advantage of depicting lymph nodes in lymphoedematous extremities.

Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis.

Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner.

Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. The role of Sirtuin 1 (SIRT1) in hepatic I/R injury remains elusive. Using human and mouse livers, we investigated the effects of I/R on hepatocellular SIRT1. SIRT1 expression was significantly decreased after I/R. Genetic overexpression or pharmacological activation of SIRT1 markedly suppressed defective autophagy, onset of the mitochondrial permeability transition, and hepatocyte death after I/R, whereas SIRT1-null hepatocytes exhibited increased sensitivity to I/R injury. Biochemical approaches revealed that SIRT1 interacts with mitofusin-2 (MFN2). Furthermore, MFN2, but not MFN1, was deacetylated by SIRT1. Moreover, SIRT1 overexpression substantially increased autophagy in wild-type cells, but not in MFN2-deficient cells. Thus, our results demonstrate that the loss of SIRT1 causes a sequential chain of defective autophagy, mitochondrial dysfunction, and hepatocyte death after I/R.

Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data.

Glioblastoma (GBM) is a common and malignant tumor with a poor prognosis. Glioblastoma stem cells (GSCs) have been reported to be involved in tumorigenesis, tumor maintenance and therapeutic resistance. Thus, to discover novel candidate therapeutic drugs for anti-GBM and anti-GSCs is an urgent need. We hypothesized that if treatment with a drug could reverse, at least in part, the gene expression signature of GBM and GSCs, this drug may have the potential to inhibit pathways essential in the formation of GBM and thereby treat GBM. Here, we collected 356 GBM gene signatures from public databases and queried the Connectivity Map. We systematically evaluated the in vitro antitumor effects of 79 drugs in GBM cell lines. Of the drugs screened, thioridazine was selected for further characterization because it has potent anti-GBM and anti-GSCs properties. When investigating the mechanisms underlying the cytocidal effects of thioridazine, we found that thioridazine induces autophagy in GBM cell lines, and upregulates AMPK activity. Moreover, LC3-II was upregulated in U87MG sphere cells treated with thioridazine. In addition, thioridazine suppressed GBM tumorigenesis and induced autophagy in vivo. We not only repurposed the antipsychotic drug thioridazine as a potent anti-GBM and anti-GSCs agent, but also provided a new strategy to search for drugs with anticancer and anticancer stem cell properties.