Understanding the Enzyme (S)-Norcoclaurine Synthase Promiscuity to Aldehydes and Ketones.

The (S)-norcoclaurine synthase from Thalictrum flavum (TfNCS) stereoselectively catalyzes the Pictet-Spengler reaction between dopamine and 4-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. TfNCS can catalyze the Pictet-Spengler reaction with various aldehydes and ketones, leading to diverse tetrahydroisoquinolines. This substrate promiscuity positions TfNCS as a highly promising enzyme for synthesizing fine chemicals. Understanding carbonyl-containing substrates' structural and electronic signatures that influence TfNCS activity can help expand its applications in the synthesis of different compounds and aid in protein optimization strategies. In this study, we investigated the influence of the molecular properties of aldehydes and ketones on their reactivity in the TfNCS-catalyzed Pictet-Spengler reaction. Initially, we compiled a library of reactive and unreactive compounds from previous publications. We also performed enzymatic assays using nuclear magnetic resonance to identify some reactive and unreactive carbonyl compounds, which were then included in the library. Subsequently, we employed QSAR and DFT calculations to establish correlations between substrate-candidate structures and reactivity. Our findings highlight correlations of structural and stereoelectronic features, including the electrophilicity of the carbonyl group, to the reactivity of aldehydes and ketones toward the TfNCS-catalyzed Pictet-Spengler reaction. Interestingly, experimental data of seven compounds out of fifty-three did not correlate with the electrophilicity of the carbonyl group. For these seven compounds, we identified unfavorable interactions between them and the TfNCS. Our results demonstrate the applications of in silico techniques in understanding enzyme promiscuity and specificity, with a particular emphasis on machine learning methodologies, DFT electronic structure calculations, and molecular dynamic (MD) simulations.

Epicardial and pericoronary adipose tissue and coronary plaque burden in patients with Cushing's syndrome: a propensity score-matched study.

PURPOSE: To assess coronary inflammation by measuring the volume and density of the epicardial adipose tissue (EAT), perivascular fat attenuation index (FAI) and coronary plaque burden in patients with Cushing's syndrome (CS) based on coronary computed tomography angiography (CCTA). METHODS: This study included 29 patients with CS and 58 matched patients without CS who underwent CCTA. The EAT volume, EAT density, FAI and coronary plaque burden were measured. The high-risk plaque (HRP) was also evaluated. CS duration from diagnosis, 24-h urinary free cortisol (UFC), and abdominal visceral adipose tissue volume (VAT) of CS patients were recorded. RESULTS: The CS group had higher EAT volume (146.9 [115.4, 184.2] vs. 119.6 [69.0, 147.1] mL, P = 0.006), lower EAT density (- 78.79 ± 5.89 vs. - 75.98 ± 6.03 HU, P = 0.042), lower FAI (- 84.0 ± 8.92 vs. - 79.40 ± 10.04 HU, P = 0.038), higher total plaque volume (88.81 [36.26, 522.5] vs. 44.45 [0, 198.16] mL, P = 0.010) and more HRP plaques (7.3% vs. 1.8%, P = 0.026) than the controls. The multivariate analysis suggested that CS itself (ß [95% CI], 29.233 [10.436, 48.03], P = 0.014), CS duration (ß [95% CI], 0.176 [0.185, 4.242], P = 0.033), and UFC (ß [95% CI], 0.197 [1.803, 19.719], P = 0.019) were strongly associated with EAT volume but not EAT density, and EAT volume (ß [95% CI] - 0.037[- 0.058, - 0.016], P = 0.001) not CS was strongly associated with EAT density. EAT volume, FAI and plaque burden increased (all P < 0.05) in 6 CS patients with follow-up CCTA. The EAT volume had a moderate correlation with abdominal VAT volume (r = 0.526, P = 0.008) in CS patients. CONCLUSIONS: Patients with CS have higher EAT volume and coronary plaque burden but less inflammation as detected by EAT density and FAI. The EAT density is associated with EAT volume but not CS itself.

Diabetes and long duration leading to speech-, low/mid-, and high- frequency hearing loss: current evidence from the China National Health Survey 2023.

PURPOSE: To examine the effect of diabetes, duration of diabetes, and blood glucose on speech-, low/mid-, and high-frequency hearing loss. METHODS: In this cross-sectional study, 2821 participants aged 20-87 years in the China National Health Survey were included. Diabetes was defined as valid fasting blood glucose (FBG) of ≥ 7.0 mmol/L, a self-reported history of diabetes or the use of anti-diabetic medications. Speech-(500, 1000, 2000, and 4000 Hz), low/mid- (500, 1000 and 2000 Hz), and high-frequency (4000, 6000, and 8000 Hz) hearing loss was defined as pure tone average of responding frequencies > 20 dB HL in the better ear, respectively. RESULTS: In fully adjusted models, for speech-, low/mid-, and high-frequency hearing loss, compared with no diabetes, those with diabetes (OR[95%CI]: 1.44 [1.12, 1.86], 1.23 [0.94, 1.61], and 1.75 [1.28, 2.41], respectively) and with diabetes for > 5 years duration (OR[95%CI]: 1.63 [1.09, 2.42], and 1.63 [1.12, 2.36], 2.15 [1.25, 3.70], respectively) were at higher risk. High FBG level was associated with a higher risk of speech-, low/ mid-, and high-frequency hearing loss. And there were stronger associations between HL and diabetes, longer duration and higher in "healthier population" (no hypertension, no dyslipidemia and younger age). CONCLUSION: Diabetes, longer duration, and higher FBG level were independently associated with hearing loss for speech-, low/mid- and high-frequency hearing loss, particularly in higher frequency and "healthier population". Paying more attention to hearing loss in those populations could lower the burden of hearing loss.

A randomised controlled trial of dexmedetomidine for delirium in adults undergoing heart valve surgery.

Dexmedetomidine might reduce delirium after cardiac surgery. We allocated 326 participants to an infusion of dexmedetomidine at a rate of 0.6 µg kg-1 for 10 min and then at 0.4 µg.kg-1 .h-1 until the end of surgery; 326 control participants received comparable volumes of saline. We detected delirium in 98/652 (15%) participants during the first seven postoperative days: 47/326 after dexmedetomidine vs. 51/326 after placebo, p = 0.62, adjusted relative risk (95%CI) 0.86 (0.56-1.33), p = 0.51. Postoperative renal impairment (Kidney Disease Improving Global Outcomes stages 1, 2 and 3) was detected in 46, 9 and 2 participants after dexmedetomidine and 25, 7 and 4 control participants, p = 0.040. Intra-operative dexmedetomidine infusion did not reduce the incidence of delirium after cardiac valve surgery but might impair renal function.

[Review and perspective of clinical research involving chest tightness variant asthma in China].

Chest tightness variant asthma (CTVA) was first reported and named by Chinese scholars in 2013. It is a new clinical type of asthma characterized by chest tightness as the only or primary symptom, without typical asthma manifestations such as recurrent wheezing and shortness of breath, and without wheezing sounds heard during lung auscultation. The overall epidemiological data on CTVA is currently unavailable. Its pathogenesis is similar to that of typical asthma, involving eosinophilic airway inflammation. Due to the lack of typical clinical manifestations, insufficient knowledge of this disease in some clinicians and some other reasons, CTVA is susceptible to misdiagnosis or missed diagnosis. Currently, the diagnostic criteria for CTVA are: chest tightness as the only or primary symptom, without typical asthma symptoms and signs such as wheezing and shortness of breath, and with any one of the objective indicators of variable airflow limitation. Effective anti-asthma treatment is required, and other diseases that cause chest tightness, such as cardiovascular, digestive, nervous, muscular, and mental diseases should be excluded. CTVA treatment follows that of typical asthma, but the specific treatment duration is uncertain and may require long-term management. Traditional Chinese medicine has shown some therapeutic effects on CTVA. Most CTVA patients have a good prognosis after active anti-asthma treatment. This paper analyzes and summarizes the research of CTVA in China from 2013 and provides new perspectives for further exploration of CTVA.

[Chest hemorrhage after left total pulmonary resection for secondary rifampin-resistant tuberculosis:a case report].

The patient had received five courses of anti-tuberculosis treatment for recurrent tuberculosis. The drug sensitivity test results of the first three courses showed drug-sensitive pulmonary tuberculosis, and the fourth diagnosis was rifampin-resistant tuberculosis (RR-TB), complicated by chronic obstructive pulmonary disease, type Ⅱ respiratory failure, pulmonary heart disease, and heart failure (grade Ⅲ). The patient stopped taking the anti-tuberculosis drugs on his own in the eighth month of receiving the resistant treatment. After admission, the symptoms improved temporarily after receiving oxygen therapy, anti-infection, and anti-tuberculosis treatment. Because of hemoptysis, the patient underwent arterial embolization by catheterization, but a large amount of hemoptysis occurred shortly thereafter. Emergency left total lung resection and gauze packing for hemostasis were performed. After surgery, the patient's vital signs were maintained with mechanical ventilation and vasopressors. Forty-eight hours after surgery, the gauze was removed, and the patient underwent tracheotomy, enteral nutrition, and anti-tuberculosis treatment. After discharge, the patient underwent rehabilitative exercise and anti-resistant tuberculosis therapy. The patient's condition remained stable for more than six months of follow-up.

Oral administration of Lactobacillus paracasei N1115 on neonatal mice prevents the intestinal inflammation in adulthood.

Colonization and development of gut microbiota during early life stage plays a key regulatory role in the establishment of the host-microbial relationship, which was conducive to progressing host immunity and maintaining health throughout the adulthood life span. This study was aimed to evaluate the protective effect from inflammatory bowel disease (IBD) in adulthood based on the early intervention of Lactobacillus paracasei N1115 (LP N1115). LP N1115 treatment was carried out during 2 weeks in postnatal mice. Then the dextran sodium sulphate (DSS)-induced colitis model mice were established in adulthood, and the status of intestinal tissues was detected. Results showed the decreased severity of intestinal tissue injury, cell apoptosis, and proinflammatory cytokines expression in DSS-induced model with LP N1115 early intervention. Therefore, the intake of LP N1115 in neonatal mice has played a long-term healthy role in the prevention of intestinal injury and inflammation in adulthood.

Genetic landscape of indolent and aggressive Kaposi sarcomas.

BACKGROUND: Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown. OBJECTIVES: To explore the tumour mutational burden in indolent and aggressive KS. METHODS: We performed whole-exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS. RESULTS: Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy-number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS. CONCLUSIONS: These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer.

Comparison of therapeutic efficacy and mechanism of paclitaxel alone or in combination with methotrexate in a collagen-induced arthritis rat model.

OBJECTIVE: To compare the therapeutic efficacy of paclitaxel (PTX) alone to its combination with methotrexate (MTX) on rheumatoid arthritis. METHODS: A collagen-induced arthritis (CIA) rat model was established by induction of type II collagen. Rats were divided into blank control group, CIA model group, MTX group 1 mg/kg, PTX 1.5 mg/kg, PTX 2.5 mg/kg, PTX 3.5 mg/kg, and MTX 1 mg/kg + PTX 3.5 mg/kg, with 10 rats per group. The inflammation of the ankle joint was analyzed by H&E staining and interleukin (IL)-1ß and IL­6 expression was detected by immunohistochemistry. TUNEL assay was performed to detect synovial tissue cell apoptosis after administration of PTX and MTX either alone or in combination. TLR4 and p­NF-κBp65 protein expression in synovial tissue and the changes of serum IL­1ß, IL­6, IL­12, MMP­3, and TNFα protein factors were detected by western blot and ELISA, respectively. RESULTS: PTX and MTX improved histopathological changes in CIA rats. Besides, the apoptosis rate of synovial tissue cells in the PTX 3.5 mg/kg group was more than that of the PTX + MTX group. Immunohistochemistry and western blot results indicated that PTX and MTX reduce the expression rate of IL­6 and IL­1ß and downregulate TLR4 and p­NF-κBp65 protein expression. Furthermore, TLR4 and p­NF-κBp65 reduced the concentration of MMP­3, IL­12, IL­6, IL1­ß, and TNFα. CONCLUSION: Both PTX and MTX exert significant suppression on rheumatoid arthritis, and the combined effect of the two drugs is weaker than that of PTX alone. Moreover, intraperitoneal injection of PTX 3.5 mg/kg every other day was the optimal dose observed in this study.

Glucocorticoid Receptor/HCN4 Channels Interaction in Spinal Dorsal Horn Participates in the Regulation of Neuropathic Pain after Peripheral Nerve Injury in Rats.

We studied the interaction between glucocorticoid receptor (GR) and HCN4 channels in the rat model of spared nerve injury (SNI) in Sprague-Dawley rats (n=124). The animals were randomly divided into 6 groups: sham-operated (SO; n=24), SNI (reference group; n=20), and 4 experimental SNI groups intrathecally treated with dexamethasone (DEX; GR agonist; n=20), RU38486 (GR antagonist; n=20), ZD7288 (HCN channels blocker; n=20), and ZD7288+DEX (n=20). The paw mechanical withdrawal threshold (PWT) was measured one day before surgery (SO group) and on days 1, 3, 7, 14, and 21 after surgery. Behavioral results showed that mechanical hyperalgesia appeared on day 1 after SNI, while PWT decreased gradually with time. The expression of GR and HCN4 channels in L4-L6 dorsal horn of the spinal cord was detected by Western blotting and immunohistochemistry. In the reference group, SNI significantly increased GR expression up to day 14 after surgery in comparison with the SO group. The expression of GR showed a tendency to increase in the DEX group (with the maximum expression on days 14 and 21), significantly increased in the RU38486 group (maximum on day 7). In the ZD7288 group, GR expression was lower than in the SNI group and did not change throughout the experiment, suggesting that ZD7288 could block the expression of GR. In the DEX group, the expression of HCN4 channels was significantly higher on day 1 after SNI, but there were no differences in this parameter between the RU38486 and ZD7288 groups. In the ZD7288+DEX group, the expression of HCN4 channels significantly increased on days 14 and 21 after SNI. Thus, GR and HCN4 have the same linkage in the formation of central sensitization after SNI, but antagonists have no significant effect on the improvement of pain behavior.

High-fat diet exacerbates periodontitis: is it because of dysbacteriosis or stem cell dysfunction?

Previous studies have shown that high-fat diet (HFD) may aggravate periodontitis, however the underlining mechanism remains to be further clarified. This study aims to explore whether HFD promotes periodontitis by inducing periodontal microbiota dysbiosis or stem cell dysfunction. A high-fat diet was given to four-week-old male Sprague-Dawley rats for 12 weeks. Periodontitis was induced during the latter 4 weeks. At the end of the 12th week, samples were collected after euthanasia. Maxillae were harvested for histological or microbial analysis. The microbial 16S rRNA gene sequencing was performed with the Illumina MiSeq platform. The data was analyzed through RDP Classifier against the SILVA database. The mandible molars were harvested for isolating periodontal ligament stem cells (PDLSCs). The protein level of p27, p21, and p16, which are negative regulators of the cell cycle, in PDLSCs were detected. Markers of osteogenic differentiation and pro-inflammatory mediators were detected by real-time polymerase chain reaction. Activation of pro-inflammatory signaling pathways was detected by Western blotting. We found that HFD significantly increased ligature-induced alveolar bone loss. HFD resulted in a less diverse periodontal microbiota, with increased proportions of Lactococcus, Bacillus, Alloprevotella, Carnobacterium, and Exiguobacterium and decreased proportion of Nitrospira. HFD increased the protein levels of p27, p16, and p21, and upregulated the expression of osteogenic biomarkers, IL-1ß and IL-10 with the ERK1/2 signaling pathway activated in PDLSCs.

Prevalence and Genotype Distribution of Hepatitis C Virus from 1,668 Individuals of Sichuan Area in China.

BACKGROUND: Hepatitis C virus (HCV) is one of the main causes of liver fibrosis, chronic hepatitis, and liver cirrhosis. The aim of this study is to determine the prevalence of HCV, age-dependent prevalence and genotypes distribution in a large number of clinical samples in Sichuan area of China. METHODS: In the past five years from 2014 to 2018, a total number of 4,508 individuals received the serum HCV-RNA analysis in the Sichuan Provincial People's Hospital. Viral nucleic acid was extracted from the serum samples and amplified using COBAS AmpliPre/COBAS TaqMan Detection Platform. Five HCV genotypes (1b, 2a, 3a, 3b, and 6a) of serum samples from 469 HCV positive individuals collected from 2016 to 2018 were analyzed using the PCR-fluorescence probe technique. RESULTS: A total of 1,668 individuals had positive results by high precision HCV-RNA quantitative technique, corresponding to a crude prevalence of 37.0% (95% confidence interval: 33.6 - 40.3%). The majority of HCV positive individuals were aged over 41 years, accounting for 80.7% (1,346/1,668, CI: 72.3 - 87.1%). Among the nine age groups, the 41 - 50-year age group had the highest HCV prevalence of 29.8% (497/1,668, CI: 25.6 - 32.3%). Of the 469 HCV-RNA positive serum samples collected in 2016 - 2018, genotype 1b was the most frequent type found in 357 individuals, corresponding to a prevalence of 76.1% (CI: 72.3 - 80.0%). CONCLUSIONS: Positive rates of HCV in the years of 2014 to 2018 showed a downward trend year by year, of which a majority of positive cases were aged over 41 years. HCV was distributed with multi-genotype features while genotype 1b yielded a very high prevalence in the Sichuan area. The results have potential for prevention and treatment of HCV infection, as well as epidemiological research.

Clinical and radiological characteristics of COVID-19: a multicentre, retrospective, observational study.

BACKGROUND: Multicentre cohort investigations of patients with coronavirus disease 2019 (COVID-19) have been limited. We investigated the clinical and chest computed tomography characteristics of patients with COVID-19 at the peak of the epidemic from multiple centres in China. METHODS: We retrospectively analysed the epidemiologic, clinical, laboratory, and radiological characteristics of 189 patients with confirmed COVID-19 who were admitted to seven hospitals in four Chinese provinces from 18 January 2020 to 3 February 2020. RESULTS: The mean patient age was 44 years and 52.9% were men; 186/189 had ≥1 co-existing medical condition. Fever, cough, fatigue, myalgia, diarrhoea, and headache were common symptoms at onset; hypertension was the most common co-morbidity. Common clinical signs included dyspnoea, hypoxia, leukopenia, lymphocytopenia, and neutropenia; most lesions exhibited subpleural distribution. The most common radiological manifestation was mixed ground-glass opacity with consolidation (mGGO-C); most patients had grid-like shadows and some showed paving stones. Patients with hypertension, dyspnoea, or hypoxia exhibited more severe lobe involvement and diffusely distributed lesions. Patients in severely affected areas exhibited higher body temperature; more fatigue and dyspnoea; and more manifestations of multiple lesions, lobe involvement, and mGGO-C. During the Wuhan lockdown period, cough, nausea, and dyspnoea were alleviated in patients with newly confirmed COVID-19; lobe involvement was also improved. CONCLUSIONS: Among patients with COVID-19 hospitalised at the peak of the epidemic in China, fever, cough, and dyspnoea were the main symptoms at initial diagnosis, accompanied by lymphocytopenia and hypoxaemia. Patients with severe disease showed more severe lobe involvement and diffuse pulmonary lesion distribution.

Two new species of Hypostomus suckermouth-armoured catfishes (Teleostei: Loricariidae) from central Brazil.

This study describes two new endemic Hypostomus species from central Brazil, which were previously identified as genetically distinct lineages in a recent genomic study that recommended their testing and potential description based on morphological data. A machine learning classification procedure (random forest) was used to investigate morphological variation and identify putatively diagnostic characters for these candidate species and revealed that each is morphologically distinct. The new species Hypostomus cafuringa is characterized by small size, dark spots under a light background, deeper caudal peduncle and shorter first ray of the pectoral fin and base of the dorsal fin when compared to congeneric species from the region. H. cafuringa is known from the headwaters of the Maranhão River, upper Tocantins River basin, Distrito Federal, Brazil. The second new species, Hypostomus crulsi, is characterized by dark spots under a light background, absence of plates along the abdomen region, shorter first ray of the pelvic fin, shorter first ray of the pectoral fin and smaller body size. H. crulsi is known from the headwaters of the São Bartolomeu River, upper Paraná River basin, Distrito Federal, Brazil. The rapid conversion of natural habitats for agricultural development and the isolation of protected areas represent a serious threat to the continued existence of these two newly described endemic species, which warrant conservation assessment.

MicroRNA-4443 regulates monocyte activation by targeting tumor necrosis factor receptor associated factor 4 in stroke-induced immunosuppression.

BACKGROUND AND PURPOSE: MicroRNAs (miRNAs) have been demonstrated to play crucial roles in the early stage of acute ischaemic stroke (AIS). The purpose of this study was to investigate the expression patterns of miRNAs in peripheral blood mononuclear cells (PBMCs) from AIS patients and further explore related molecular mechanisms in stroke-induced immunodeficiency syndrome (SIDS). METHODS: The miRNA expression patterns of PBMCs were detected by miRNA microarray and validated by quantitative real-time polymerase chain reaction (qRT-PCR) in AIS patients and healthy controls. Bioinformatics methods and luciferase reporter assays were used to detect the downstream target genes. Following stimulation with lipopolysaccharide and interleukin-4, the expression of miR-4443, tumor necrosis factor receptor associated factor 4 (TRAF4) and the nuclear factor kappa B (NF-κB) pathway were evaluated. Furthermore, transfection with miR-4443 mimic or inhibitor in the monocytes was carried out to gain insight into the mechanisms in SIDS. RESULTS: Interleukin-10 in AIS patients was significantly higher than that of healthy controls. The miRNA microarray analysis and qRTPCR validation showed that only miR-4443 was upregulated expressed in PBMCs from AIS patients, especially in monocytes. miR-4443 was shown to directly interact with the 3' untranslated regions of TRAF4, resulting in suppression of TRAF4 protein expression. Furthermore, the expression of miR-4443 and TRAF4 was regulated by stimulation with lipopolysaccharide or interleukin-4. Additionally, overexpression of miR-4443 suppressed the TRAF4/Iκα/NF-κB signaling pathway to activate the expression of anti-inflammatory cytokines in monocytes. CONCLUSIONS: The increased expression of miR-4443 induced monocyte dysfunction by targeting TRAF4, which may function as a crucial mediator in SIDS.

Silencing LncRNA LINC01305 inhibits epithelial mesenchymal transition in lung cancer cells by regulating TNXB-mediated PI3K/Akt signaling pathway.

The aim of this study was to investigate whether LINC01305 can regulate TNXB-mediated phosphatidilinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and therefore affect epithelial mesenchymal transition in lung cancer cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect LINC01305 level in 52 non-small cell lung cancer (NSCLC) tissues and paracancerous normal lung tissues, and the relationship between LINC01305 expression and clinical pathological parameters of these subjects was analyzed. After LINC01305 was knocked down in PC9 cell and overexpressed in A549 cells, qRT-PCR was used to verify the transfection efficiency, and nuclear fractionation technique, cell counting kit-8 (CCK-8), plate cloning assay and Transwell test were used to detect the effect of LINC01305 on cell viability. LINC01305 had an obviously higher expression in NSCLC tissues, and the expression in lung cancer patients with tumor size >3 cm was higher than those with tumor ≤3 cm. LINC01305 expression in tumor tissues in T3-T4 stage was obviously higher than those in T1-T2 stage, and the overall survival rate of lung cancer patients with high expression of LINC01305 was lower than those with low expression. Moreover, clinical analysis revealed that LINC01305 level was related to tumor size, TNM stage and lymph node metastasis of patients with lung cancer, but not related to age or gender. Silencing LINC01305 can inhibit the epithelial mesenchymal transition-induced transformation of lung cancer cells through regulating TNXB-mediated PI3K/Akt signaling pathway, which in turn affects the progression of lung cancer.

Breast cancer recurrence risk prediction using whole-lesion histogram analysis with diffusion kurtosis imaging.

AIM: To explore the role of whole-lesion histogram analysis on diffusion kurtosis imaging (DKI) for predicting breast cancer 21-gene expression profiles and recurrence scores (RSs). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. Seventy-two patients with breast cancer, who underwent genomic testing and DKI (b values: 0-2,800 s/mm2) were enrolled. Patients were divided into low-, intermediate-, and high-RS groups based on their genomic testing results. Diffusivity (D), kurtosis (K), total apparent diffusion coefficient (Total ADC), and ADC0-700 histogram parameters were calculated. Student's t-test, Wilcoxon signed-rank test, Jonckheere-Terpstra test, receiver operating characteristic curves, and Spearman's correlation were used for the statistical analysis. RESULTS: Total ADC mean/30%/50%/70%, D mean/50%, K mean/30%/50%/70% showed significant differences among the low-, intermediate-, and high-RS groups (p ≤ 0.001, respectively). K50% had the strongest correlation with RSs (correlation coefficient, CC: 0.55). Furthermore, K50% was also correlated with the expression of gene PR, BCL2 and CEGP1 (CC: 0.45, -0.41, -0.41). CONCLUSIONS: Whole-lesion histogram analysis of DKI parameters can be a useful tool for RS prediction of breast cancer. K50% was found to be the most promising parameter for RS prediction.

KLF8 promotes cancer stem cell-like phenotypes in osteosarcoma through miR-429-SOX2 signaling.

Krüppel-like factor 8 (KLF8) regulates critical gene transcription associated with different types of cancer. A novel paradigm in tumor biology suggests that the initiation and progression of osteosarcoma (OS) are driven by osteosarcoma stem cell-like cells (OSCs), but the role and underlying mechanisms of KLF8 in OSCs are poorly elucidated. In this study, an obviously increased level of KLF8 is shown in 9 out of 10 primary OS tissues and is associated with the poor progression-free interval. Significantly, KLF8 expression in CD133+ OSCs is higher than that in CD133- counterparts. By knocking down KLF8 in CD133+ OSCs, we show that si-KLF8-OSCs can hardly form compact spheres. In the meantime, infection with si-KLF8 in CD133+ OSCs results in the downregulation of OCT4 and SOX2; increased adriamycin (ADM) sensitivity; and decreased tumorigenic potential in vivo. Mechanisms study demonstrates that KLF8 directly binds the miR-429 promoter region and regulates its expression transcriptionally. Furthermore, we indicate that miR-429 directly targets SOX2 to mediate cancer stem cell-like features in CD133+ OSCs. In the clinic, miR-429 levels are negatively associated with KLF8 levels in OS, suggesting that an elevated KLF8/miR-429 ratio may have clinical value as a predictive biomarker. In conclusion, targeting the KLF8-miR-429-SOX2 signaling pathway may provide an effective therapeutic approach to suppress the initiation and progression of OS.

[The perioperative safety of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei].

Objective: This study was to investigate the perioperative safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei (PMP), and analyze the risk factors of serious adverse events (SAEs). Methods: The occurrences of perioperative SAEs were retrospectively analyzed in 254 PMP patients treated with CRS plus HIPEC. Univariate and multivariate analysis were performed to identify independent risk factors. Results: Among the 272 CRS plus HIPEC procedures for 254 PMP patients, a total of 93 (34.2%) perioperative SAEs occurred, including 26 in infection, 22 in digestive system, 17 in respiratory system, 15 in cardiovascular system, 8 in hematological system, and 4 in urinary system. In terms of severity, the vast majority was grade Ⅲ with 76 cases, followed by grade Ⅳ with 13 cases and grade Ⅴ with 4 cases. Univariate analysis revealed 3 risk factors of perioperative SAEs: HIPEC regimen (P=0.020), intraoperative red blood cell transfusion volume (P=0.004), and intraoperative blood loss volume (P=0.002). Multivariate analysis by logistic regression model analysis revealed that intraoperative red blood cell transfusion volume was an independent risk factor for perioperative SAEs (OR=1.160, P=0.001). Conclusion: In conclusion, the perioperative safety of CRS plus HIPEC was acceptable. Moreover, intraoperative blood loss volume and red blood cell transfusion volume are expected to be reduced in order to prevent SAEs for PMP patients.

[Clinical evaluation of tumor-stroma ratio in pseudomyxoma peritonei from the appendix].

OBJECTIVE: To evaluate the effect of tumor-stroma ratio (TSR) on disease progression and prognosis of pseudomyxoma peritonei (PMP) from the appendix. METHODS: The study included 30 PMP patients with complete individual patient data, who underwent cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in Beijing Shijitan Hospital. Image-Pro Plus was used to quantitatively analyze the proportion of tumor and stromal areas in hematoxylin-eosin staining pathological images, from which TSR was derived. Correlation studies were conducted to evaluate the relationships between TSR and clinicopathological features, immunohistochemical characteristics, and prognosis of PMP. RESULTS: Among 30 PMP patients, there were 16 males (53.3%) and 14 females (46.7%), with the mean age of (54.9±2.3) years. There were 15 cases (50.0%) of low-grade mucinous carcinoma peritonei (LMCP) and high-grade mucinous carcinoma peritonei (HMCP), respectively, with vascular tumor emboli occurring in 4 cases (13.3%), nerve invasion occurring in 3 cases (10.0%), and lymphatic metastasis occurring in 4 cases (13.3%). The median peritoneal cancer index (PCI) score was 36 (range: 3-39). The median TSR was 8% (range: 2%-24%), with TSR≤10% in 19 cases (63.3%) and TSR>10% in 11 cases (36.7%). Immunohistochemistry showed that 16 cases (53.3%) had Ki67 label index ≤ 50% and 14 cases (46.7%) > 50%. The mutation rate of p53 was 56.7% and the loss rate of MMR protein was 11.8%. In addition, the expression rates of MUC2, MUC5AC, CDX2, CK7, and CK20 were 66.7%, 100.0%, 82.6%, 56.0%, and 92.3%, respectively. There were significant correlations between TSR and histopathological types, nerve invasion, Ki67 label index, and p53 mutation (P<0.05 for all). At the end of the last follow-up, 21 patients (70.0%) died and 9 patients (30.0%) survived, including 6 patients survived with tumor. The median overall survival (OS) was 12.7 months (95%CI: 10.4-11.5 months), and the 1-, 2-, and 3-year survival rates were 60.5%, 32.3%, and 27.7%, respectively. The median OS was 19.4 months (95%CI: 3.0-35.9 months) in the TSR≤10% group, versus 12.6 months (95%CI: 0.7-24.5 months) in the TSR>10% group (χ2=3.996, P=0.046). CONCLUSION: TSR is correlated with histopathological types, tumor proliferation, invasion behaviors and prognosis of PMP, thus could be a new prognostic indicator for PMP.