Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer.

Patient-derived organoids (PDOs) may facilitate treatment selection. This retrospective cohort study evaluated the feasibility and clinical benefit of using PDOs to guide personalized treatment in metastatic breast cancer (MBC). Patients diagnosed with MBC were recruited between January 2019 and August 2022. PDOs were established and the efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving organoid-guided treatment (OGT) were matched 1:2 by nearest neighbor propensity scores with patients receiving treatment of physician's choice (TPC). The primary outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Forty-six PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 78.4% (95% CI 64.9%-91.9%) in predicting clinical responses. Thirty-six OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs. 5.0 months; hazard ratio 0.53 [95% CI 0.33-0.85]; p = .01) and improved disease control (88.9% vs. 63.8%; odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis in hormone receptor-positive, human epidermal growth factor receptor 2-negative patients demonstrated differentially modulated pathways implicated in DNA repair and transcriptional regulation in those with reduced response to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in those with reduced response to palbociclib. Our study shows that PDO-based functional precision medicine is a feasible and effective strategy for MBC treatment optimization and customization.

The mechanisms of MicroRNA 21 in premature ovarian insufficiency mice with mesenchymal stem cells transplantation : The involved molecular and immunological mechanisms.

Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.

Organoid forming potential as complementary parameter for accurate evaluation of breast cancer neoadjuvant therapeutic efficacy.

BACKGROUND: 13-15% of breast cancer/BC patients diagnosed as pathological complete response/pCR after neoadjuvant systemic therapy/NST suffer from recurrence. This study aims to estimate the rationality of organoid forming potential/OFP for more accurate evaluation of NST efficacy. METHODS: OFPs of post-NST residual disease/RD were checked and compared with clinical approaches to estimate the recurrence risk. The phenotypes of organoids were classified via HE staining and ER, PR, HER2, Ki67 and CD133 immuno-labeling. The active growing organoids were subjected to drug sensitivity tests. RESULTS: Of 62 post-NST BC specimens, 24 were classified as OFP-I with long-term active organoid growth, 19 as OFP-II with stable organoid growth within 3 weeks, and 19 as OFP-III without organoid formation. Residual tumors were overall correlated with OFP grades (P < 0.001), while 3 of the 18 patients (16.67%) pathologically diagnosed as tumor-free (ypT0N0M0) showed tumor derived-organoid formation. The disease-free survival/DFS of OFP-I cases was worse than other two groups (Log-rank P < 0.05). Organoids of OFP-I/-II groups well maintained the biological features of their parental tumors and were resistant to the drugs used in NST. CONCLUSIONS: The OFP would be a complementary parameter to improve the evaluation accuracy of NST efficacy of breast cancers.

Trehalosemodulates OVRAS to improve oxidative stress and apoptosis in KGN cells and ovaries of PCOS mice.

The etiology of polycystic ovary syndrome (PCOS) is complex and variable, and there is no exact cause or good treatment method. Most of the methods of hormones are used to temporarily meet the needs of patients. Experimental evidence has shown that trehalose has, anti-apoptotic, anti-oxidative, glucose-lowering, and insulin resistance effects. However, whether trehalose has a therapeutic effect on PCOS is unknown. It has been reported that the ovarian renin-angiotensin system (OVRAS) is involved in the development of PCOS, but it has not been fully elucidated. This study aims to explore the effect of trehalose on PCOS and elucidate the related OVRAS mechanism. We first observed that body weight, estrous cycle, ovarian follicles at all levels, glucose tolerance, serum hormones, and insulin resistance were improved by trehalose treatment in the PCOS mouse model. Moreover, trehalose treatment also ameliorated ovarian oxidative stress and apoptosis in PCOS mice, as determined by TUNNEL apoptosis staining, total SOD in ovarian homogenate, and WB assay. OVRAS mainly involves two classic pathways, namely the ACE/AngII/AT1R/AT2R, and ACE2 / Ang1-7/ MASR, Which play different functions. In PCOS mouse ovaries, we found that ACE/AngII/AT1R was up-regulated and ACE2/Ang1-7/MASR and AT2R were down-regulated by PCR and WB experiments, However, trehalose treatment changed its direction. In addition, we also found that trehalose ameliorated DHEA-induced oxidative stress and apoptosis in KGN by PCR and WB experiments, mainly by down-regulating ACE/AngII/AT1R. Our study shows that trehalose improves symptoms of PCOS mainly by down-regulating ACE/AngII/AT1R, revealing a potential therapeutic target for PCOS.

LncRNA HOTAIR regulates autophagy and proliferation mechanisms in premature ovarian insufficiency through the miR-148b-3p/ATG14 axis.

Premature ovarian insufficiency (POI) is a serious disease significantly affecting the physical and mental health of women of reproductive age, not just impacting fertility outcomes. Ovarian damage due to chemotherapy remains a major cause of this condition. Recent studies have indicated the involvement of the long non-coding RNA HOTAIR in the progression of various diseases, showcasing important biological functions, yet its role in POI remains unclear. We conducted microarray dataset analysis and qRT-PCR experiments, demonstrating downregulation of HOTAIR expression in ovarian tissue and granulosa cells. Various functional experiments using plasmids overexpressing HOTAIR confirmed its promotion of cisplatin-induced granulosa cell autophagy and proliferation. Mechanistically, dual-luciferase assays showed that HOTAIR modulates ATG14 levels in POI by binding miR-148b-3p, thereby enhancing levels of autophagy and proliferation. In this study, we first explored the impact of miR-148b-3p on POI and found that overexpression of miR-148b-3p reversed the promotion of autophagy and proliferation induced by HOTAIR overexpression. The inhibitory effect of miR-148b-3p inhibitor on KGN cell autophagy and proliferation improvement could also be reversed by silencing ATG14. Overall, our findings indicate the promoting role of HOTAIR in POI and its potential as a biomarker for POI by modulating the miR-148b-3p/ATG14 axis to improve mechanisms of autophagy and proliferation in POI.

IGF2BP3-mediated regulation of GLS and GLUD1 gene expression promotes treg-induced immune escape in human cervical cancer.

This study aimed to investigate the impact of IGF2BP3, a well-known m6A modification-related protein, on the metabolic and immune microenvironment of human cervical cancer. Bioinformatics analysis was performed to analyze the expression of IGF2BP3 in various databases, and its findings were validated using human cervical cancer tissue microarrays. We conducted a study to investigate the impact of IGF2BP3 on glutamine metabolism in cervical cancer cells through the application of metabolomics and metabolic flow analysis. Additionally, we explored how cervical cancer cells promote immune escape by secreting glutamine-derived lactate in a 3D culture setting. To identify the specific targets of IGF2BP3 that influence glutamine metabolism in cervical cancer, we employed RIP-seq analysis. IGF2BP3 exhibited high expression levels in multiple cervical cancer datasets, and its expression was significantly associated with the prognosis of cervical cancer patients. In mixed 3D cell cultures of cervical cancer and T cells, IGF2BP3 was found to enhance glutamate and glutamine metabolism in cervical cancer cells by up regulating the expression of GLS and GLUD1 genes. Moreover, it influenced the differentiation of Treg cells by promoting lactate production and secretion in cervical cancer, leading to immune escape. Mechanistic analysis revealed that IGF2BP3 stabilized the mRNA of GLS and GLUD1 genes through m6A modification, thereby facilitating glutamate and glutamine metabolism in cervical cancer cells and regulating lactate production. Additionally, we investigated the correlation between GLS, GLUD1 protein expression, and IGF2BP3 expression in human cervical cancer through multicolor immunofluorescence staining. The relevance of IGF2BP3 in the context of Treg cell-associated immune escape in cervical cancer was also confirmed. IGF2BP3 exhibits high expression in human cervical cancer and plays a crucial role in stabilizing the mRNA of GLS and GLUD1 genes, key metabolic enzymes in glutamate and glutamine metabolism, through m6A modification. This process leads to immune escape in cervical cancer by promoting lactate production and secretion.

Impacts of the COVID-19 pandemic on Chinese assisted reproductive technology institutions and human sperm banks: reflections in the post-pandemic era.

OBJECTIVE: The COVID-19 pandemic has been the most serious public health emergency encountered in modern assisted reproductive technology (ART) development. In order to identify lessons learned, this study reviews the effect of the pandemic on ART institutions and human sperm banks in China, and summarizes the experiences and reflections of Chinese scholars post-pandemic era. METHODS: This review is based on multiple consensus statements on the COVID-19 pandemic issued by Chinese experts as well as current national regulations and principles in ART institutions and human sperm banks to document the current situation of ART services in China, describe the impact of the pandemic on these services, and offer Chinese reflections on worrying issues in the post-pandemic era. RESULTS: China reached one million ART cycles in 2016, and there are currently 540 ART medical institutions and 27 human sperm banks, with 540 licensed for AIH, 91 for AID, 415 for conventional IVF and ICSI and 85 for PGT. Of these, only 4 institutions carry out 10,000 cycles or more annually, and the proportion of institutions with less than 1,000 cycles has reached 66%, which means that a considerable number of ART institutions are still not saturated. As a consequence of the COVID-19 pandemic, 63.6% of ART providers and 95.5% of human sperm banks suspended operations. By the end of May 2020, China, as an early country affected by the pandemic achieved a national resumption rate of ART medical services of 99.2% and that of human sperm banks of 100.0%. Reports from the first and largest human sperm bank in China showed that qualification, semen concentration and sperm viability rates measured at primary screening have significantly decreased post-pandemic. Much like in other countries, Chinese experts developed a consensus on prevention and control measures during the pandemic. In principle, all ART activities should be suspended during acute phases of infection spread. Chinese scholars highlight that attention should be paid to young patients with fertility requirements during and after COVID-19, and emphasize the importance of fertility evaluation and clinical intervention. In addition, couples should be reminded that during ART treatment, disinfectants should not be used excessively to minimize risks of damaging the reproductive system, gametes and zygotes. At the same time, timely and reasonable guidance for tackling negative emotions from stress response is needed to provide reassurance and to avoid irrational fear and excessive stress. Seminal parameters should be re-examined 2 months after SARS-CoV-2 vaccination, and ART treatments recommenced if no abnormalities are detected. CONCLUSIONS: Given the growing frequency of outbreaks of global infectious diseases in recent years, ART institutions and human sperm banks should pay attention to improving their prevention and control capabilities. To a certain extent, decisions and measures adopted in China during COVID-19 pandemic are worthy of recognition and acceptance. Chinese scholars have discussed, proactively responded to and understand the key issues surrounding ART development during the pandemic with the aim of contributing to the substantial progress and healthy development of ART services in the world.

Altered local RAS in the liver increased the risk of NAFLD in male mouse offspring produced by in vitro fertilization.

BACKGROUND: Assisted reproductive technology (ART) is associated with an increased risk of adverse metabolic health in offspring, and these findings have been demonstrated in animal models without parental infertility issues. However, it is unclear what changes lead to abnormal metabolism. The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. Thus, we focused on the local RAS of the liver, which is the central organ for glucose and lipid metabolism in offspring conceived by in vitro fertilization (IVF), and studied the role of local liver RAS in metabolic diseases. METHODS: Male C57BL/6 mouse offspring obtained by natural pregnancy and IVF were fed a standard chow diet or a high-fat diet (HFD) from 4 weeks of age through 16 weeks of age. We assessed glucose and lipid metabolism, hepatic histopathology, and the gene and protein expression of key RAS components. In addition, the blocker losartan was used from 4 weeks of age through 16 weeks of age to investigate the regulatory mechanisms of abnormal local RAS on metabolic activity in the IVF offspring liver. RESULTS: The growth trajectories of IVF offspring body and liver weights were different from those of naturally pregnant offspring. Impaired glucose tolerance (IGT) and insulin resistance (IR) occurred in IVF-conceived male offspring. After continuous HFD feeding, male offspring in the IVF group underwent earlier and more severe IR. Furthermore, there was a trend of lipid accumulation in the livers of chow-fed IVF offspring. Hepatic steatosis was also more serious in the IVF offspring after HFD treatment. Type 1 receptor (AT1R), which is the primary receptor mediating the action of angiotensin (Ang) II, has been confirmed to be upregulated in IVF offspring livers. Losartan reduced or even eliminated most of the significant differences between the IVF and NC groups after HFD consumption. CONCLUSIONS: The upregulation of AT1R expression in the liver increased the activity of the local RAS, resulting in abnormal glucose and lipid metabolism and lipid accumulation in the liver, significantly increasing the risk of nonalcoholic fatty liver disease (NAFLD) in IVF offspring.

Isolation and identification of high-yielding alkaline phosphatase strain: a novel mutagenesis technique and optimization of fermentation conditions.

Isolating and screening enzyme-producing strains from microorganisms and the commercial production of ALPs from microorganisms are of increasing interest. In this work, isolation and identification of high-yielding alkaline phosphatase strain were carried out using atmospheric and room temperature plasma mutagenesis (ARTP) for optimization of fermentation conditions. A strain of alkaline phosphatase-producing bacteria was screened from soil and identified by 16S rRNA gene sequencing as Bacillus amyloliquefaciens and named S-1. This strain had an alkaline phosphatase activity of 2594.73 U/L. Later, mutagenesis breeding of the alkaline phosphatase-producing S-1 strain was conducted using (ARTP), from which a higher alkaline phosphatase-producing positive mutant strain S-52 was screened. A central combination of five factors, including corn starch, yeast extract, metal ions, fermentation temperature and inoculum ratio, was then used to influence the activity of alkaline phosphatase. Results from the response surface methodology showed that the maximum enzyme activity of alkaline phosphatase was 12,110.6 U/L at corn starch, yeast extract and magnesium ions concentrations of 17.48 g/L, 18.052 g/L and 0.744 g/L, respectively; fermentation temperature of 37.192 °C; and inoculation ratio of 5.59%. This study is important for further exploring ARTP mutagenesis in B. amyloliquefaciens and the commercialization of ALPs.

Association of maternal risk factors with fetal aneuploidy and the accuracy of prenatal aneuploidy screening: a correlation analysis based on 12,186 karyotype reports.

BACKGROUND: NIPT is becoming increasingly important as its use becomes more widespread in China. More details are urgently needed on the correlation between maternal risk factors and fetal aneuploidy, and how these factors affect the accuracy of prenatal aneuploidy screening. METHODS: Information on the pregnant women was collected, including maternal age, gestational age, specific medical history and results of prenatal aneuploidy screening. Additionally, the OR, validity and predictive value were also calculated. RESULTS: A total of 12,186 analysable karyotype reports were collected with 372 (3.05%) fetal aneuploidies, including 161 (1.32%) T21, 81 (0.66%) T18, 41 (0.34%) T13 and 89 (0.73%) SCAs. The OR was highest for maternal age less than 20 years (6.65), followed by over 40 years (3.59) and 35-39 years (2.48). T13 (16.95) and T18 (9.40) were more frequent in the over-40 group (P < 0.01); T13 (3.62/5.76) and SCAs (2.49/3.95) in the 35-39 group (P < 0.01). Cases with a history of fetal malformation had the highest OR (35.94), followed by RSA (13.08): the former was more likely to have T13 (50.65) (P < 0.01) and the latter more likely to have T18 (20.50) (P < 0.01). The sensitivity of primary screening was 73.24% and the NPV was 98.23%. The TPR for NIPT was 100.00% and the respective PPVs for T21, T18, T13 and SCAs were 89.92, 69.77, 53.49 and 43.24%, respectively. The accuracy of NIPT increased with increasing gestational age (0.81). In contrast, the accuracy of NIPT decreased with maternal age (1.12) and IVF-ET history (4.15). CONCLUSIONS: ①Pregnant patients with maternal age below 20 years had higher risk of aneuploidy, especially in T13; ②A history of fetal malformations is more risky than RSA, with the former more likely to have T13 and the latter more likely to have T18; ③Primary screening essentially achieves the goal of identifying a normal karyotype, and NIPT can accurately screen for fetal aneuploidy; ④A number of maternal risk factors may influence the accuracy of NIPT diagnosis, including older age, premature testing, or a history of IVF-ET. In conclusion, this study provides a reliable theoretical basis for optimizing prenatal aneuploidy screening strategies and improving population quality.

A Modified Arthroscopic Outside-in Shoulder Release Approach for Severe Shoulder Stiffness.

OBJECTIVE: Arthroscopic release is effective for patients with shoulder stiffness, but the traditional inside-out procedure cannot effectively alleviate the mobility of some severe stiff shoulder and even cause itrogenic injuries sometimes. The aim of this study is to evaluate the clinical efficacy and advantages of a modified outside-in shoulder release approach for severe shoulder stiffness. METHODS: Included in this retrospective study were 15 patients (five male and 10 female) with severe shoulder stiffness who underwent modified outside-in shoulder release surgery at our hospital between June 2019 and March 2021. Of them, 10 patients had a primary frozen shoulder and five had secondary shoulder stiffness, involving the right shoulder in six cases and the left shoulder in nine cases. The mean age of the 15 patients was 56.7 (34-69) years. The patients were instructed to exercise passively from second-day post-operation and enhance the rehabilitation exercise gradually. All patients received a range of motion (ROM) examination before and after surgery. The American Shoulder and Elbow Surgeon's Score (ASES), Constant Score (CS), and Visual Analog Scale (VAS) score for pain were recorded. All data were tested by normal distribution first and then by paired T test, otherwise by Wilcoxon rank sum test. RESULTS: The mean follow-up period was 18.2 (12-33) months. Compared with the preoperative value, the mean ASES score at the final follow-up improved from 38.4 ± 7.37 to 88.13 ± 6.33 points; the mean CS score from 43.27 ± 6.71 to 78.74 ± 6.93 points; the mean VAS score from 5.07 ± 1.03 to 0.81 ± 0.83 points; forward flexion from 81.93° ± 11.45° to 156.73° ± 9.12°; abduction from 65.93° ± 16.82° to 144.80° ± 8.83°; neutral external rotation from 13.53° ± 10.38° to 51.20° ± 4.77°; internal rotation from the buttock to waist (L3), all showing a significant difference (P < 0.0001). No serious complication was observed in any patient during the postoperative follow-up periods. CONCLUSION: The present study has demonstrated that the modified arthroscopic outside-in shoulder release approach can improve ROM of patients and alleviate pain effectively, proving it to be an appropriate surgical option for the treatment of severe shoulder stiffness.

Construction of a ceRNA-based lncRNA-mRNA network to identify functional lncRNAs in premature ovarian insufficiency.

Premature ovarian insufficiency, characterized by ovarian infertility and low fertility, has become a significant problem in developed countries due to its propensity for late delivery. It has been described that the vital role of lncRNA in the development and progression of POI. The aim of this work was to create a POI-based lncRNA-mRNA network (POILMN) to recognize key lncRNAs. Overall, differently expressed mRNAs (DEGs) and differently expressed lncRNAs (DELs) were achieved by using the AnnoProbe and limma R packages. POI-based lncRNA-mRNA network (POILMN) construction was carried out using the tinyarray R package and hypergeometric distribution. To identify key lncRNAs, we used CentiScaPe plug-in Cytoscape as a screening tool. In total, 244 differentially expressed lncRNAs (DELs) and 288 differentially expressed mRNAs (DEGs) were obtained in this study. Also, 177 lncRNA/mRNA pairs (including 39 lncRNAs and 86 mRNAs) were selected using the hypergeometric test. Finally, we identified four lncRNA (HCP5, NUTM2A-AS1, GABPB1-IT1, and SMIM25) intersections by topological analysis between two centralities (degree and betweenness), and we explored their subnetwork GO and KEGG pathway enrichment analysis. Here, we have provided strong evidence for a relationship with apoptosis, DNA repair damage, and energy metabolism terms and pathways in the key lncRNAs in our POI-based lncRNA-mRNA network. In addition, we evaluated the localization information of genes related to POI and found that genes were more distributed on chromosomes 15, 16, 17, and 19. However, more experiments are needed to confirm the functional significance of such predicted lncRNA/mRNA. In conclusion, our study identified four long non-coding RNA molecules that may be relevant to the progress of premature ovarian insufficiency.

Identification of GPC3 mutation and upregulation in a multidrug resistant osteosarcoma and its spheroids as therapeutic target.

BACKGROUND: Drug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance. METHODS: To identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated. RESULTS: NGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 µM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 µg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%). CONCLUSION: This study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.

18F-PSMA-1007 Uptake in Pulmonary Lymphangitic Carcinomatosis Metastasis From Prostate Cancer.

ABSTRACT: A 55-year-old man with cough, bone pain, and cervical lymphadenopathy underwent both 18F-FDG and 18F-PSMA-1007 PET/CT scans with clinical suspicion of malignant disease. Compared with 18F-FDG PET/CT, 18F-PSMA PET/CT showed intense tracer uptake in the prostate gland, lungs, osteogenic lesions, and multiple lymph nodes. Interestingly, we also found the high tracer concentration of pulmonary lymphangitic carcinomatosis, a very rare form of prostate cancer metastasis to the lung, on 18F-PSMA-1007 PET/CT images.

The C-terminal domain of the type III secretion chaperone HpaB contributes to dissociation of chaperone-effector complex in Xanthomonas campestris pv. campestris.

Many animal and plant pathogenic bacteria employ a type three secretion system (T3SS) to deliver type three effector proteins (T3Es) into host cells. Efficient secretion of many T3Es in the plant pathogen Xanthomonas campestris pv. campestris (Xcc) relies on the global chaperone HpaB. However, how the domain of HpaB itself affects effector translocation/secretion is poorly understood. Here, we used genetic and biochemical approaches to identify a novel domain at the C-terminal end of HpaB (amino acid residues 137-160) that contributes to virulence and hypersensitive response (HR). Both in vitro secretion assay and in planta translocation assay showed that the secretion and translocation of T3E proteins depend on the C-terminal region of HpaB. Deletion of the C-terminal region of HpaB did not affect binding to T3Es, self-association or interaction with T3SS components. However, the deletion of C-terminal region sharply reduced the mounts of free T3Es liberated from the complex of HpaB with the T3Es, a reaction catalyzed in an ATP-dependent manner by the T3SS-associated ATPase HrcN. Our findings demonstrate the C-terminal domain of HpaB contributes to disassembly of chaperone-effector complex and reveal a potential molecular mechanism underpinning the involvement of HpaB in secretion of T3Es in Xcc.

Efficacy of combined treatment with mechanical circulation support devices and immunomodulation therapy for patients with fulminant myocarditis / 中华心血管病杂志

Objective: To summarize the efficacy of combined treatment strategy of mechanical circulation support devices and immunomodulation therapy for patients with fulminant myocarditis. Method: We retrospectively analyzed the clinical data and outcomes of 37 fulminant myocarditis patients complicating cardiogenic shock, who were hospitalized from October 2017 to December 2019 in our department. Patients received guideline therapy according to "Chinese expert consensus statement on clinical diagnosis and treatment of fulminant myocarditis in adults"issued by Chinese Society of Cardiology of Chinese Medical Association. Patients were divided into IABP group (n=19), ECMO group (n=5) and IABP+ECMO group (n=13) according to different mechanical circulation support regimen. The treatment effectiveness among various groups were compared. The major endpoint was in-hospital mortality. The duration and outcome of mechanical circulation support were also analyzed. Furthermore, relationships between baseline data, proportion of different treatments (including medicine treatment, temporary pacemaker and continuous renal replacement treatment, immunomodulation therapy) and clinical outcome were analyzed. Results: The age of the 37 patients in the cohort was (37.4±17.0) years, and there were 22 male among them. Immunomodulation therapy included glucocorticoid (methylprednisolone) and intravenous immunoglobin. At admission, blood pressure was (70.21±17.37)mmHg(1 mmHg=0.133 kPa),heart rate was(100±30)beat/minutes,there were 10 cases of Ⅲ° atrioventricular block and all received temporary pacemaker implantation, 12 cases of ventricular tachycardia and fibrillation,1 patient received temporary pacemaker implantation due to electronic storm, peak cardiac troponin I level was (18.61±9.55)μg/L, peak B type natriuretic peptide level was 1 670(518,3 410)ng/L,left ventricular ejection fraction (LVEF) was(32.3±10.4)%. Thirty-four out of the 37 patients survived and 3 patients died. Hospital duration was (22.7±8.2)days, LVEF was (50.1±10.5)% at discharge. Lactic acid level was significantly higher in IABP+ECMO group than in IABP group and ECMO group(P<0.001 or =0.005),LVEF was significantly lower in IABP+ECMO group than in IABP group(P=0.004),the proportion of ventilator usage was higher in IABO+ECMO group than in IABP group (P<0.05). Survival rate was similar among the three groups. Conclusion: Comprehensive treatment regimen with combined mechanical circulation support and immunomodulation therapy as the core strategies is effective in the treatment of fulminant myocarditis complicated with cardiogenic shock.

Association between bone marrow fluorodeoxyglucose uptake and recurrence after curative surgical resection in patients with T1-2N0M0 lung adenocarcinoma: a retrospective cohort study.

BACKGROUND: Evidence regarding the relationship between fluorodeoxyglucose (FDG) uptake in the bone marrow of patients with lung adenocarcinoma and prognosis is limited. This study aimed to identify whether bone marrow FDG uptake is a risk factor for recurrence in patients after curative surgical resection of T1-2N0M0 lung adenocarcinoma. METHODS: From January 2012 to December 2016, we retrospectively enrolled 195 pT1-2N0M0 lung adenocarcinoma patients who underwent both preoperative FDG positron emission tomography/computed tomography (PET/CT) and surgical resection from the lung adenocarcinoma database maintained by the PET/CT department at our hospital. After surgical resection, patients were followed up mainly through regular outpatient examinations. The maximum standardized uptake value (SUVmax) of the primary tumor, the mean FDG uptake of bone marrow (BM SUV), bone marrow-liver uptake ratio (BLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured from the pretreatment FDG PET/CT images. Multi-adjusted Cox proportional hazards models were built to evaluate the independent prognostic value of BLR in predicting recurrence-free survival (RFS). A restricted cubic spline regression model was conducted to provide more precise estimates and examine the shape of the associations between BLR and the risk of recurrence. RESULTS: The follow-up results showed that 30 of the 195 patients (15.4%) had tumor recurrence. Compared with non-recurrent patients, the primary tumor size in recurrent patients was larger, and the SUVmax, TLG, and serum C-reactive protein (CRP) levels were higher. Univariate analysis showed that BLR, tumor size, SUVmax, TLG, and CRP were significantly correlated with postoperative tumor recurrence. After adjustment for conventional confounding factors, the hazard ratio of BLR was 5.01 (95% CI, 1.32, 18.98) for the highest tertile of BLR compared with the lowest tertile. The multi-adjusted spline regression showed that BLR had a linear relationship with log relative risk (RR) for recurrence when BLR was lower than 0.7. Over this level, the effect stabilized, suggesting a saturation effect for BLR at a level of approximately 0.7 at recurrence. CONCLUSIONS: BLR was an independent risk factor for predicting RFS in T1-2N0M0 lung adenocarcinoma patients after curative surgical resection. BLR can be used as a biomarker for evaluating the risk of lung cancer recurrence.

A comprehensive validation of the novel 8th edition of American Joint Committee on Cancer staging manual for the long-term survivals of patients with non-functional pancreatic neuroendocrine neoplasms.

Histologically, the World Health Organization has classified pancreatic neuroendocrine neoplasms (p-NENs) into well-differentiated pancreatic neuroendocrine tumors (G1/G2 p-NETs) and poorly-differentiated pancreatic neuroendocrine carcinoma (G3 p-NECs) based on tumor mitotic counts and Ki-67 index. Recently, the 8th edition of American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging manual has incorporated some major changes in 2017 that the TNM staging system for p-NENs should only be applied to well-differentiated G1/G2 p-NETs, while poorly-differentiated G3 p-NECs be classified according to the new system for pancreatic exocrine adenocarcinomas. However, this new manual for p-NENs has seldom been evaluated.Data of patients with both G1/G2 and G3 non-functional p-NENs (NF-p-NENs) from our institution was retrospectively collected and analyzed using 2 new AJCC 8th staging systems. We also made survival comparisons between the 8th and 7th edition system separately for different subgroups.For G1/G2 NF-p-NETs, there were 52 patients classified in AJCC 8th edition stage I, 40 in stage II, 41 in stage III and 19 in stage IV. As for G3 NF-p-NECs, 17, 19, 24, and 18 patients were respectively defined from AJCC 8th edition stage I to stage IV. In terms of the AJCC 7th staging system, the 230 patients with NF-p-NENs were totally distributed from stage I to stage IV (94, 63, 36, 37, respectively). For the survival analysis of both G1/G2 NF-p-NETs and G3 NF-p-NECs, the AJCC 7th edition system failed to discriminate the survival differences when compared stage III with stage II or stage IV (P > .05), while the 8th edition ones could perfectly allocate patients into 4 statistically different groups (P < .05). The HCIs of AJCC 8th stage for G1/G2 NF-p-NETs [HCI=0.658, 95% confidence interval (CI)=0.602-0.741] and stage for G3 NF-p-NECs (HCI=0.704, 95% CI=0.595-0.813) was both statistically larger than those of AJCC 7th stage for different grading NF-p-NENs [(HCI=0.578, 95% CI=0.557-0.649; P=.031), (HCI=0.546, 95% CI=0.531-0.636; P = .019); respectively], indicating a more accurate predictive ability for the survivals of NF-p-NENs.Our data suggested the 2 new AJCC 8th staging systems were superior to its 7th edition for patients with both G1/G2 NF-p-NETs and G3 NF-p-NECs.

The value of 18F-PSMA-1007 PET/CT in identifying non-metastatic high-risk prostate cancer.

BACKGROUND: Clinical management decisions on prostate cancer (PCa) are often based on a determination of risk. 68Ga-prostate-specific membrane antigen (PSMA)-11-positron emission tomography (PET)/computer tomography (CT) is an attractive modality to assess biochemical recurrence of PCa, detect metastatic disease and stage of primary PCa, making it a promising strategy for risk stratification. However, due to some limitation of 68Ga-PSMA-11 the development of alternative tracers is of high interest. In this study, we aimed to investigate the value of 18F-PSMA-1007 in identifying non-metastatic high-risk PCa. METHODS: A total of 101 patients with primary non-metastatic PCa who underwent 18F-PSMA-1007 PET/CT were retrospectively analyzed. According to the European Association of Urology guidelines on PCa, patients were classified into intermediate-risk (IR) group or high-risk (HR) group. The maximum standardized uptake values (SUVmax) of the primary prostate tumor were measured on PET/CT images. The diagnostic performance of PET/CT for IR and HR PCa was calculated, and the relationship between the SUVmax of primary prostate tumor, prostate-specific antigen (PSA) level and Gleason score (GS) was analyzed. RESULTS: Of all 101 patients, 49 patients were classified into IR group and 52 patients were classified into HR group. There was a significant positive correlation between PSA level/GS and SUVmax (r = 0.561, r = 0.496, P < 0.001, respectively). Tumors with GS 6 and 7a showed significantly lower 18F-PSMA-1007 uptake compared to patients with GS 8 and 9 (P < 0.01). SUVmax in patients of HR was significantly higher than those of IR (median SUVmax: 16.85 vs 7.80; P < 0.001). In receiver operating characteristic curve analysis, the optimal cutoff value of the SUVmax for identifying high-risk PCa was set as 9.05 (area under the curve: 0.829; sensitivity: 90.4%; specificity: 65.3%). CONCLUSION: 18F-PSMA-1007 PET/CT showed the powerful diagnosis efficacy for high-risk PCa, which can be used as an objective imaging reference index for clinical reference.