Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.

Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend toward elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select proto-oncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders, but warrant caution for exposure of female germ cells.

Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice.

Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse Trpv4 gene. TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss. Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes. Symptomatic mutant mice exhibited focal disruptions of blood-spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure. Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice. Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non-cell autonomous manner by precipitating focal breakdown of the BSCB. Further, these data highlight the reversibility of TRPV4-mediated BSCB impairments and identify a potential therapeutic strategy for patients with TRPV4 mutations.

Somatostatin Receptor Gene Functions in Growth Regulation in Bivalve Scallop and Clam.

Bivalves hold an important role in marine aquaculture and the identification of growth-related genes in bivalves could contribute to a better understanding of the mechanism governing their growth, which may benefit high-yielding bivalve breeding. Somatostatin receptor (SSTR) is a conserved negative regulator of growth in vertebrates. Although SSTR genes have been identified in invertebrates, their involvement in growth regulation remains unclear. Here, we identified seven SSTRs (PySSTRs) in the Yesso scallop, Patinopecten yessoensis, which is an economically important bivalve cultured in East Asia. Among the three PySSTRs (PySSTR-1, -2, and -3) expressed in adult tissues, PySSTR-1 showed significantly lower expression in fast-growing scallops than in slow-growing scallops. Then, the function of this gene in growth regulation was evaluated in dwarf surf clams (Mulinia lateralis), a potential model bivalve cultured in the lab, via RNA interference (RNAi) through feeding the clams Escherichia coli containing plasmids expressing double-stranded RNAs (dsRNAs) targeting MlSSTR-1. Suppressing the expression of MlSSTR-1, the homolog of PySSTR-1 in M. lateralis, resulted in a significant increase in shell length, shell width, shell height, soft tissue weight, and muscle weight by 20%, 22%, 20%, 79%, and 92%, respectively. A transcriptome analysis indicated that the up-regulated genes after MlSSTR-1 expression inhibition were significantly enriched in the fat digestion and absorption pathway and the insulin pathway. In summary, we systemically identified the SSTR genes in P. yessoensis and revealed the growth-inhibitory role of SSTR-1 in bivalves. This study indicates the conserved function of somatostatin signaling in growth regulation, and ingesting dsRNA-expressing bacteria is a useful way to verify gene function in bivalves. SSTR-1 is a candidate target for gene editing in bivalves to promote growth and could be used in the breeding of fast-growing bivalves.

Prevalence and influencing factors of post-traumatic stress disorder among Chinese healthcare workers during the COVID-19 epidemic: a systematic review and meta-analysis.

Background: Post-traumatic stress disorder is an important psychological problem affecting the physical mental health of Chinese healthcare workers during the COVID-19 pandemic. Aims: To estimate the prevalence and influencing factors of post-traumatic stress disorder (PTSD) among Chinese healthcare workers during COVID-19. Methods: Search of Chinese and English literature in PubMed, EMbase, Web of Science, Medline, Elsevier, SpringerLink, China Biomedical Literature Database, CNKI, Wan-fang, and CQVIP for the period from December 2019 to August 2023. Stata 14.0 software was used for data analysis. The methodological quality of each study was scored, and data were extracted from the published reports. Pooled prevalence was estimated using the Random-effects model. Publication bias was evaluated using Egger's test and Begg's test. Results: Twenty-one studies included 11841 Chinese healthcare workers in this review. First, the overall prevalence of Post-traumatic stress disorder among Chinese healthcare workers during the COVID-19 epidemic was 29.2% (95% CI: 20.7% to 33.7%). Twelve factors included in the meta-analysis were found to be protective against PTSD among Chinese healthcare workers: female, nurse, married, front-line work, less work experience, family or friend diagnosed with COVID-19, history of chronic disease and fear of COVID-19. Conversely, outside Hubei, higher education, social support and psychological resilience are protective factors. Conclusion: These recent findings increase our understanding of the psychological status of Chinese healthcare workers and encourage that long-term monitoring and long-term interventions should be implemented to improve the mental health of Chinese healthcare workers in the aftermath of the COVID-19.

Prognostic nutritional index (PNI) and risk of non-alcoholic fatty liver disease and advanced liver fibrosis in US adults: Evidence from NHANES 2017-2020.

Objective: This study explored the potential association between the Prognostic Nutritional Index (PNI) and the incidence of non-alcoholic fatty liver disease (NAFLD) and advanced liver fibrosis (AF) in the adult population of the United States. Methods: Information on 6409 participants ≥18 years old was downloaded from the U.S. National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Multivariate analysis was combined with demographic factors to assess the relationships between PNI, NAFLD, and AF. A restricted cubic spline (RCS) was used to characterise the nonlinear association between the PNI and NAFLD and AF. Results: Patients without NAFLD had substantially lower mean values for parameters such as age, lymphocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), total cholesterol, triglycerides, HbA1c, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) than patients with NAFLD. Interestingly, non-NAFLD patients showed a pronounced increase in serum albumin levels compared to their NAFLD counterparts. In the subset without AF, there were discernibly lower measures of NLR, age, AST, ALT, γ-glutamyl transferase, triglycerides, neutrophil count, and body mass index (BMI) than in patients with AF. It was evident that those without AF had markedly elevated mean albumin and PNI levels in comparison to AF-affected individuals. In the comprehensive multivariable framework, a direct correlation was observed between PNI and NAFLD (adjusted odds ratio[aOR] = 1.07, 95% confidence interval [CI]: 1.05-1.09; p < 0.001), whereas PNI and AF were inversely correlated (aOR = 0.92; 95% CI: 0.88-0.96; p < 0.001). Within the RCS model, a swift ascendancy was noted in the relationship between the PNI and NAFLD, peaking at approximately 52. Conversely, a non-linear inverse association was observed between PNI and AF. Conclusion: Our analytical results indicate that elevated PNI levels are positively associated with an increased risk of NAFLD, but inversely related to the risk of AF. For robust validation of these observations, further research is required.

Giant Negative Photoresponse in van der Waals Graphene/AgBiP2Se6/Graphene Trilayer Heterostructures.

The positive photoconductive (PPC) effect is a well-established primary detection mechanism employed by photodetectors. In contrast, the negative photoconductive (NPC) effect is not extensively investigated thus far, and research on the NPC effect is still in its early stage. Herein, a quaternary van der Waals material, AgBiP2Se6 atomic layers, is discovered to achieve a giant NPC effect. Through experimental observations in a Graphene/AgBiP2Se6/ Graphene-based vertical photodetector, an irreversible conversion is identified from common PPC photoresponse to atypical NPC photoresponse. Notably, this device demonstrates an exceptionally high negative responsivity (R) of 4.9 × 105 A W-1, surpassing the previous records for NPC photodetectors. Additionally, it exhibits remarkable optoelectronic performances, including an external quantum efficiency of 1.3 × 108% and a detectivity (D) of 3.60 × 1012 Jones. The exceptionally high NPC photoresponse observed in this device can be attributed to the swift suppression of photogenerated free carriers at robust recombination centers situated at significant depths, induced by the elevated drain-source voltage bias. The remarkably high NPC photoresponse also positions AgBiP2Se6 as a promising 2D material for multifunctional optoelectronic devices and an excellent platform for systematic exploration of the NPC effect.

Bioinformatic Analysis of Key Biomarkers and Infiltrating Immune Cells in Nonalcoholic Fatty Liver Disease.

Context: The liver is both the largest metabolic and the largest immune organ and is closely related to the mechanisms of disease development. Clarifying the immune environment of the NAFLD liver to determine its interactions with biomarkers would be beneficial in exploring the mechanisms of disease development. Objective: The study aimed to identify biomarkers and immune cells associated with nonalcoholic fatty liver disease (NAFLD) and to analyze the correlation between key genes and immune cells in NAFLD, to improve the understanding of the mechanisms underlying NAFLD and provide potential therapeutic targets. Design: The research team performed a genetic study. Setting: The study took place at Qingdao, Shandong Province, China. Outcome Measures: The research team: (1) obtained the NAFLD-related datasets GSE63067, GSE48452, and GSE89632 from the Gene Expression Omnibus (GEO) database; (2) analyzed immune-cell infiltrates using single-sample gene set enrichment analysis (ssGSEA) to determine the hub immune cells; (3) selected the differentially expressed genes (DEGs) between the NAFLD and normal samples and screened them to identify the hub genes; (4) evaluated the efficiency of the hub genes using receiver operating characteristic (ROC) curves; and (5) analyzed the correlations between hub genes and immune cells. Results: The research team: (1) found 28 differential immune cells; (2) identified monocytes as the hub immune cells; (3) identified 55 DEGs; (4) comparing the top 10 genes, identified five hub genes: S100 calcium binding proteins A12 (S100A12), S100A9, S100A8, selectin L (SELL), and sex hormone binding globulin (SHBG); (5) for all five, the area under the ROC curve (AUC) was greater than 0.6-training set: AUCSA00A12 = 0.699, AUCSELL = 0.743, AUCS100A9 = 0.735, AUCSHBG = 0.752, and AUCS100A8 = 0.703; and validation set: AUCSA00A12 = 0.852, AUCSELL = 0.905, AUCS100A9 = 0.819, AUCSHBG = 0.830, and AUCS100A8 = 0.822; (6) negatively correlated SHBG with immune cells (P > .05, r=-0.09); and (7) positively correlated S100A12, S100A9, S100A8, and SELL with immune cells-rS100A8 = 0.40, rS100A9 = 0.50, rS100A12 = 0.38, and rSELL = 0.42, respectively. Conclusions: Based on bioinformatic analyses, the progression of NAFLD may involve monocytes through promotion of liver inflammation. The hub genes S100A12, S100A9, S100A8, SELL, and SHBG are potential biomarkers that may be useful as diagnostic tools or therapeutic targets for NAFLD.

An effective method for establishing a regeneration and genetic transformation system for Actinidia arguta.

The all-red A. arguta (Actinidia arguta) is an anthocyanin-rich and excellent hardy fruit. Many studies have focused on the green-fleshed A. arguta, and fewer studies have been conducted on the all-red A. arguta. Here we reported a regeneration and Agrobacterium-mediated transformation protocol by using leaves of all-red A. arguta as explants. Aseptic seedling leaves of A. arguta were used as callus-inducing materials. MS medium supplemented with 0.3 mg·L-1 2,4-D and 1.0 mg·L-1 BA was the optimal medium for callus induction of leaves, and medium supplemented with 3 mg·L-1 tZ and 0.5 mg·L-1 IAA was optimal for adventitious shoot regeneration. The best proliferation medium for adventitious buds was MS + 1.0 mg·L-1 BA + 0.3 mg·L-1 NAA. The best rooting medium was 1/2MS + 0.7 mg·L-1 IBA with a 100% rooting rate. For the red flesh hardy kiwi variety 'Purpurna Saduwa' (A. arguta var. purpurea), leaves are receptors for Agrobacterium (EHA105)-mediated transformation. The orthogonal experiment was used for the optimization of each genetic transformation parameter and the genetic transformation of the leaves was 21% under optimal conditions. Our study provides technical parameters for applying genetic resources and molecular breeding of kiwifruit with red flesh.

Comparison of the probability of four anticonvulsant mood stabilizers to facilitate polycystic ovary syndrome in women with epilepsies or bipolar disorder-A systematic review and meta-analysis.

Background: Patients treated with anticonvulsant mood stabilizers have a higher incidence of polycystic ovary syndrome (PCOS). However, there is no comparison between different anticonvulsant mood stabilizers. The purpose of this study was to systematically evaluate the prevalence of PCOS in women taking anticonvulsant mood stabilizers and compare the probability of PCOS caused by different anticonvulsant mood stabilizers. Methods: Five databases, namely PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials, were searched for literature on anticonvulsant mood stabilizers and PCOS published up to October 28, 2022. This meta-analysis was performed using Revman 5.4, Stata 14.0, and R4.1.0, and effect size pooling was performed in fixed- or random-effects models based on the results of I2 and Q-test, and the surface under the cumulative ranking curve (SUCRA) was used for analysis to assess the cumulative probability of drug-induced PCOS. Publication bias was assessed by funnel plot Egger's test and meta regression. Results: Twenty studies with a total of 1,524 patients were included in a single-arm analysis, which showed a combined effect size (95% CI) of 0.21 (0.15-0.28) for PCOS in patients taking anticonvulsant mood stabilizers. Nine controlled studies, including 500 patients taking medication and 457 healthy controls, were included in a meta-analysis, which showed OR = 3.23 and 95% CI = 2.19-4.76 for PCOS in women taking anticonvulsant mood stabilizers. Sixteen studies with a total of 1416 patients were included in a network meta-analysis involving four drugs, valproate (VPA), carbamazepine (CBZ), oxcarbazepine (OXC), and lamotrigine (LTG), and the results of the network meta-analysis showed that VPA (OR = 6.86, 95% CI = 2.92-24.07), CBZ (OR = 3.28, 95% CI = 0.99-12.64), OXC (OR = 4.30, 95% CI = 0.40-49.49), and LTG (OR = 1.99, 95% CI = 0.16-10.30), with cumulative probabilities ranked as VPA (90.1%), OXC (63.9%), CBZ (50.1%), and LTG (44.0%). Conclusion: The incidence of PCOS was higher in female patients treated with anticonvulsant mood stabilizers than in the healthy population, with VPA having the highest likelihood of causing PCOS. The most recommended medication when considering PCOS factors is LTG. Systematic review registration: identifier: CRD42022380927.

Influencing factors of medication adherence in schizophrenic patients: a meta-analysis.

Medication adherence of schizophrenic patients is a growing public health problem. We conducted a meta-analysis on the influencing factors of medication compliance in schizophrenic patients. We searched PubMed, Embase, Cochrane Library, and Web Of Science for relevant articles published up to December 22, 2022. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess influencing factors. Egger's test, funnel plot, the trim and fill method, and meta-regression analysis were used to assess publication bias. A total of 20 articles were included in the analysis. Twenty influencing factors were divided into seven categories: drug factors (OR = 1.96, 95% CI: 1.48-2.59), problem behavior (OR = 1.77, 95% CI: 1.43-2.19), income and quality of life (OR = 1.23, 95% CI: 1.08-1.39), personal characteristics (OR = 1.21, 95% CI: 1.14-1.30), disease factors (OR = 1.14, 95% CI: 1.98-1.21), support level (OR = 0.54, 95% CI: 0.42-0.70), and positive attitude and behavior (OR = 0.52, 95% CI: 0.45-0.62). This meta-analysis found that drug factors, disease factors, problem behavior, low income and quality of life, and factors related to personal characteristics appear to be risk factors for medication adherence in people with schizophrenia. And support level, positive attitude and behavior appear to be protective factors.

Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation.

Intercellular communication between axons and Schwann cells is critical for attaining the complex morphological steps necessary for axon maturation. In the early onset motor neuron disease spinal muscular atrophy (SMA), many motor axons are not ensheathed by Schwann cells nor grow sufficiently in radial diameter to become myelinated. These developmentally arrested motor axons are dysfunctional and vulnerable to rapid degeneration, limiting efficacy of current SMA therapeutics. We hypothesized that accelerating SMA motor axon maturation would improve their function and reduce disease features. A principle regulator of peripheral axon development is neuregulin 1 type III (NRG1-III). Expressed on axon surfaces, it interacts with Schwann cell receptors to mediate axon ensheathment and myelination. We examined NRG1 mRNA and protein expression levels in human and mouse SMA tissues and observed reduced expression in SMA spinal cord and in ventral, but not dorsal root axons. To determine the impact of neuronal NRG1-III overexpression on SMA motor axon development, we bred NRG1-III overexpressing mice to SMA∆7 mice. Neonatally, elevated NRG1-III expression increased SMA ventral root size as well as axon segregation, diameter, and myelination resulting in improved motor axon conduction velocities. NRG1-III was not able to prevent distal axonal degeneration nor improve axon electrophysiology, motor behavior, or survival of older mice. Together these findings demonstrate that early SMA motor axon developmental impairments can be ameliorated by a molecular strategy independent of SMN replacement providing hope for future SMA combinatorial therapeutic approaches.

LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice.

BACKGROUND: Amino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood. METHODS: To investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an ApcMin/+ background (LAT1fl/fl; vil-cre; ApcMin/+), which were subject to analysis; organoids derived from those mice were also analyzed. RESULTS: This study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of ApcMin/+ mice. Organoids derived from LAT1-deleted ApcMin/+ intestinal crypts displayed fewer spherical organoids with reduced Wnt/ß-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production. CONCLUSIONS: LAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.

Record-High Work-Function p-Type CuBiP2 Se6 Atomic Layers for High-Photoresponse van der Waals Vertical Heterostructure Phototransistor.

The notable lack of intrinsic p-type 2D layered semiconductors has hindered the engineering of 2D devices for complementary metal oxide semiconductors (CMOSs). Herein, a novel quaternary intrinsic p-type 2D semiconductor, CuBiP2 Se6 atomic layers, is introduced into the 2D family. The semiconductor displays a high work function of 5.26 eV, a moderate hole mobility of 1.72 cm2 V-1 s-1 , and an ultrahigh on/off current exceeding 106 at room temperature. To date, 5.26 eV is the highest work-function recorded in p-type 2D materials, indicating the ultrastable p-type behavior of CuBiP2 Se6 . Additionally, a multilayer graphene/CuBiP2 Se6 /multilayer graphene (MLG/CBPS/MLG)-based fully vertical van der Waals heterostructure phototransistor is designed and fabricated. This device exhibits outstanding optoelectronic performance with a responsivity (R) of 4.9 × 104 A W-1 , an external quantum efficiency (EQE) of 1.5 × 107 %, a detectivity (D) of 1.14 × 1013 Jones, and a broad working wavelength (400-1100 nm), respectively. This is comparable to state-of-the-art 2D devices. Such excellent performance is attributed to the ultrashort transmit length and nondestructive/defect-free contacts. This leads to faster response speed and eliminates Fermi-level pinning effects. Moreover, ultrahigh responsivity and detectivity endow the device with applaudable imaging sensing capability. These results make CuBiP2 Se6 an ideal p-type candidate material for next-generation CMOSs logic devices.

Relationship Between Self-Acceptance and Intention to Stay at Work Among Clinical Nurses in China: A Cross-Sectional Online Survey.

Background: During the pandemic and with the growing shortage of nurses, the problem of how to retain existing nurses was of paramount importance. However, there is limited evidence on the relationship between nurses' self-acceptance and intention to stay. Objectives: This study aimed to investigate the factors influencing nurses' intention to stay at work, and explore the relationship between self-acceptance and their intention to stay. Methods: Convenience sampling was conducted to select nurses who worked in a clinical environment during June 2020, in hospitals in Shandong Province, China. Self-designed basic information and two questionnaires, namely, the "self-acceptance questionnaire" and "intention to stay" were adopted. Mean, median, related analysis, and regression analysis were adopted to describe the relationship of self-acceptance and intention to stay on part of Chinese nurses. Results: A total of 1,015 clinical nurses participated in the survey. The mean score of intention to stay among participants was 22.00. The multiple regression analysis revealed various factors, such as age, family support the work, interest in work, job suitability, type of employment, professional level, weekly working hours, working department and self-acceptance influenced the nurse's intention to stay (ß range from -1.506 to 2.249). Conclusion: Our findings identified several factors that are significantly related to and impact the level of intention to stay among clinical nurses.

Dual-Energy Computed Tomography For Differentiation Between Osteoblastic Metastases and Bone Islands.

Objective: The objective of our study was to evaluate the utility of Rho/Z on dual-energy computed tomography (DECT) for the differentiation of osteoblastic metastases (OBMs) from bone islands (BIs). Methods: DECT images of 110 patients with malignancies were collected. The effective atomic number (Z), electron density (Rho), dual energy index (DEI), and regular CT (rCT) values were measured by two observers. Independent-sample t-test was used to compare these values between OBMs and BIs. The diagnostic performance was assessed by receiver operating characteristic (ROC) analysis and the cutoff values were evaluated according to ROC curves. Results: A total of 205 OBMs and 120 BIs were included. The mean values of Z, Rho, DEI, and rCT of OBMs were significantly lower than those of BIs, whereas the standard deviation values were higher than those of BIs (all p ≤ 0.05). ROC analysis showed that 11.86 was the optimal cutoff value for Z, rendering an area under the ROC curve (AUC) of 0.91, with a sensitivity of 91.2% and a specificity of 82.5%. Conclusion: DECT can provide quantitative values of Z, Rho, and DEI and has good performance in differentiating between OBMs and BIs.

Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy: A Double-Blind, Placebo-Controlled, Phase 2 Randomized Clinical Trial.

Importance: Safe and effective prophylactic therapies for radiation-induced dermatitis (RID) remain an unmet need. Objective: To determine if epigallocatechin-3-gallate (EGCG) solution reduces the incidence of RID in patients undergoing radiotherapy after breast cancer surgery. Design, Setting, and Participants: This phase 2 double-blind, placebo-controlled randomized clinical trial enrolled 180 patients with breast cancer receiving postoperative radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China, between November 2014 and June 2019. Data analysis was performed from September 2019 to January 2020. Interventions: Participants were randomly assigned (2:1) to receive either EGCG solution (660 µmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion. Main Outcomes and Measures: The primary end point was incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety. Results: A total of 180 eligible patients were enrolled, of whom 165 (EGCG, n = 111; placebo, n = 54) were evaluable for efficacy (median [range] age, 46 [26-67] years). The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Furthermore, symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]). Conclusions and Relevance: In this randomized clinical trial, prophylactic use of EGCG solution significantly reduced the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It has the potential to become a new choice of skin care for patients receiving radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02580279.

Effect of stocking density on performance, meat quality and cecal bacterial communities of yellow feather broilers.

Totally, 315 42-day-old male Xueshan chickens were allocated into 3 caging densities, 14, 21 and 28 birds/m2. Each treatment was represented by 5 replicates. The body weight (BW), slaughter performance, meat quality, behavioral assessment, and the cecal microorganisms were detected at the market age. The results showed that the BW of broilers in the low- and medium-density groups was significantly higher (p < 0.05) than that of the high-density group from the age of 10 weeks. Only the feather quality of the broilers in the low-density group improved significantly (p < 0.05) compared with those of the other two groups. And, the abdominal fat percentage and the fat content of thigh muscle of broilers in the low- and medium-density groups were higher (p < 0.05) than those in the high-density group. No significant difference (p > 0.05) was noted in the other traits. The abundance of some microbial like Akkermansiaceae, Lactobacillaceae and Faecalibacterium may be correlated with the BW and fat content of broilers. The findings of this study suggest that increasing the stocking density decreased the final BW, fat content and the feather quality, whereas no evidence was found that stocking density caused changes in other parameters.

GPR43 Suppresses Intestinal Tumor Growth by Modification of the Mammalian Target of Rapamycin Complex 1 Activity in ApcMin/+ Mice.

OBJECTIVE: G protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using ApcMin/+, a murine model of intestinal tumors. MATERIALS AND METHODS: Using GPR43-/- ApcMin/+ and GPR43+/- ApcMin/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways. RESULTS: Our results revealed that GPR43 deficiency resulted in increased tumor numbers in ApcMin/+ mice. Ki67 was highly expressed in GPR43-/- mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088). CONCLUSION: Collectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway.

Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets.

Numerous pediatric neurogenetic diseases may be optimally treated by in utero gene therapy (IUGT); but advancing such treatments requires animal models that recapitulate developmental physiology relevant to humans. One disease that could benefit from IUGT is the autosomal recessive motor neuron disease spinal muscular atrophy (SMA). Current SMA gene-targeting therapeutics are more efficacious when delivered shortly after birth, however postnatal treatment is rarely curative in severely affected patients. IUGT may provide benefit for SMA patients. In previous studies, we developed a large animal porcine model of SMA using AAV9 to deliver a short hairpin RNA (shRNA) directed at porcine survival motor neuron gene (Smn) mRNA on postnatal day 5. Here, we aimed to model developmental features of SMA in fetal piglets and to demonstrate the feasibility of prenatal gene therapy by delivering AAV9-shSmn in utero. Saline (sham), AAV9-GFP, or AAV9-shSmn was injected under direct ultrasound guidance between gestational ages 77-110 days. We developed an ultrasound-guided technique to deliver virus under direct visualization to mimic the clinic setting. Saline injection was tolerated and resulted in viable, healthy piglets. Litter rejection occurred within seven days of AAV9 injection for all other rounds. Our real-world experience of in utero viral delivery followed by AAV9-related fetal rejection suggests that the domestic sow may not be a viable model system for preclinical in utero AAV9 gene therapy studies.