A genomic and epigenomic atlas of prostate cancer in Asian populations.

Prostate cancer is the second most common cancer in men worldwide1. Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients2,3. However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.

Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy.

Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

Overexpression of YTHDC2 contributes to the progression of prostate cancer and predicts poor outcomes in patients with prostate cancer.

YTH domain-containing protein 2 (YTHDC2), a member of N6-methyladenosine (m6A) readers, has been reported to be closely associated with multiple cancer types. However, very little is known about the YTHDC2 gene and its involvement in prostate cancer. YTHDC2 protein expression level was analyzed and correlated to clinical outcomes in prostate cancer patients who underwent prostatectomy in Guizhou Provincial People's Hospital. The YTHDC2 expression level was also detected in prostate cancer cell lines and an immortalized prostate epithelial cell line BPH-1 and RWPE1 by quantitative real-time reverse transcription polymerase chain reaction. Furthermore, we established stable cell lines (DU145 and PC-3) transfected with either empty vector or the full-length YTHDC2 gene and conducted cell function assays in vitro. Fisher's exact test and Pearson χ2 test were employed, Kaplan-Meier method was used for the survival analysis. Of 32 patient samples who enrolled in this study, YTHDC2 was significantly upregulated in prostate cancer (PCa) patients with higher Gleason scores and serum prostate-specific antigen levels. YTHDC2 expression was significantly elevated in all PCa cell lines compared to BPH-1 and RWPE1 (all p < 0.05). Functionally, the enforced expression of YTHDC2 markedly promoted cell growth, migration, and invasion efficacies in prostate cancer cells. Our data indicate that YTHDC2 upregulation may be potentially associated with the prognosis of prostate cancer patients.

3,4-benzopyrene aggravates myocardial ischemia-reperfusion injury-induced pyroptosis through inhibition of autophagy-dependent NLRP3 degradation.

Polycyclic aromatic hydrocarbons (PAHs) are produced during combustion of organic matter, such as during cigarette smoking, and they exist widely in the environment. Exposure to 3,4-benzo[a]pyrene (BaP), as the most widely studied PAHs, relates to many cardiovascular diseases. However, the underlying mechanism of its involvement remains largely unclear. In this study, we developed a myocardial ischemia-reperfusion (I/R) injury mouse model and an oxygen and glucose deprivation-reoxygenation H9C2 cell model to evaluate the effect of BaP in I/R injury. After BaP exposure, the expression of autophagy-related proteins, the abundance of NLRP3 inflammasomes, and the degree of pyroptosis were measured. Our results show that BaP aggravates myocardial pyroptosis in a autophagy-dependent manner. In addition, we found that BaP activates the p53-BNIP3 pathway via the aryl hydrocarbon receptor to decrease autophagosome clearance. Our findings present new insights into the mechanisms underlying cardiotoxicity and reveal that the p53-BNIP3 pathway, which is involved in autophagy regulation, is a potential therapeutic target for BaP-induced myocardial I/R injury. Because PAHs are omnipresent in daily life, the toxic effects of these harmful substances should not be underestimated.

Combining UBR5 and CD163+ tumor-associated macrophages better predicts prognosis of clear cell renal cell carcinoma patients.

PURPOSE: Identification of reliable postoperative indicators for accurately evaluating prognosis of clear cell renal cell carcinoma (ccRCC) patients remains an important clinical issue. This study determined the prognostic value of UBR5 expression in ccRCC patients by combining with CD163+ tumor-associated macrophages (TAMs) and the established clinical parameters. METHODS: The expression of UBR5 was analyzed in ccRCC patients from TCGA databases. A total of 310 ccRCC patients were randomly divided into the training and validation cohorts at a 3:2 or 1:1 ratio, and immunohistochemistry (IHC) and statistical analyses were performed to examine the prognostic value of UBR5 and CD163+ TAMs. RESULTS: UBR5 expression was commonly downregulated in human ccRCC specimens, which was associated with TNM stage, SSIGN, WHO/ISUP Grading and poor prognosis of ccRCC patients. In addition, UBR5 expression was negatively correlated with CD163 expression (a TAM marker) in ccRCC tissues, and combining expressions of UBR5 and CD163 better predicted worse overall survival and progression-free survival of ccRCC patients. Even after multivariable adjustment, UBR5, CD163, TNM stage and SSIGN appeared to be independent risk factors. By time-dependent c-index analysis, the integration of intratumoral UBR5 and CD163 achieved higher c-index value than UBR5, CD163, TNM stage or SSIGN alone in predicting ccRCC patients' prognosis. Moreover, the incorporation of both UBR5 and CD163 into the clinical indicators TNM stage or SSIGN exhibited highest c-index value. CONCLUSIONS: Integrating intratumoral UBR5 and CD163+ TAMs with the current clinical parameters achieves better accuracy in predicting ccRCC patients' postoperative prognosis.

Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma.

BACKGROUND: Although many intratumoral biomarkers have been reported to predict clear cell renal cell carcinoma (ccRCC) patient prognosis, combining intratumoral and clinical indicators could predict ccRCC prognosis more accurately than any of these markers alone. This study mainly examined the prognostic value of HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 1 (HECW1) expression in ccRCC patients in combination with established clinical indicators. METHODS: The expression level of HECW1 was screened out by data-independent acquisition mass spectrometry (DIA-MS) and analyzed in ccRCC patients from the The Cancer Genome Atlas (TCGA) database and our cohort. A total of 300 ccRCC patients were stochastically divided into a training cohort and a validation cohort, and real-time PCR, immunohistochemistry (IHC) and statistical analyses were employed to examine the prognostic value of HECW1 in ccRCC patients. RESULTS: The expression level of HECW1 usually decreased in human ccRCC specimens relative to control specimens in TCGA (p < 0.001). DIA-MS, Real-time PCR, and IHC analyses also showed that the majority of ccRCCs harbored decreased HECW1 expression compared with that in normal adjacent tissues (p < 0.001). Additionally, HECW1 expression was reduced in ccRCC cell lines compared with the normal renal cell line HK-2 (p < 0.001). Moreover, lower HECW1 expression was found in ccRCC patients with a higher tumor node metastasis (TNM) stage, bone metastasis, or first-line targeted drug resistance (p < 0.001). Low HECW1 expression indicated higher TNM stage, SSIGN (Stage, Size, Grade, and Necrosis) score and WHO/ISUP grade and poor prognosis in ccRCC patients (p < 0.05). Even after multivariable adjustment, HECW1, TNM stage, and SSIGN score served as independent risk factors. The c-index analysis showed that integrating intratumoral HECW1 expression into TNM stage or SSIGN score resulted in a higher c-index value than these indicators alone for predicting ccRCC patient prognosis. CONCLUSION: HECW1 is a novel prognostic biomarker and therapeutic target in ccRCC, and integrating intratumoral HECW1 expression with established clinical indicators yields higher accuracy in assessing the postoperative prognosis of ccRCC patients.

Clinical outcomes of 168 Chinese patients after local surgery for bone metastases arising from advanced renal cell carcinoma.

BACKGROUND: The effectiveness of local surgery for bone metastases (BM) arising from renal cell carcinoma (RCC) remains uncertain. Herein, the authors performed what to the best of their knowledge is the first investigation of the outcomes of Chinese patients with RCC and BM. METHODS: Data were collected for 168 patients with RCC and BM who were treated at Changzheng Hospital in Shanghai, China, between March 2009 and December 2018. All patients underwent local surgery for BM arising from RCC. Overall survival (OS) was defined as the interval between the date of local surgery and death or last follow-up and was estimated using the Kaplan-Meier method. Univariate and multivariable Cox proportional hazards analyses were used to identify significant prognostic factors. RESULTS: The median OS in the study cohort was 43 months (range, 0-113 months). The 1-year, 3-year, and 5-year survival rates after surgery were 77.4%, 55.9%, and 31.8%, respectively. Univariate analyses demonstrated significant survival differences associated with sex (P = .003), the number of preoperative metastatic sites (BM alone or BM with concomitant metastasis; P < .001), and the number of BM (single or multiple; P = .008). OS also did not appear to differ regardless of whether the patients received postsurgical targeted therapy. Multivariable Cox regression demonstrated that the following characteristics were independent predictors of OS: the number of preoperative metastatic sites, International Metastatic Renal Cell Carcinoma Database Consortium risk score, and Memorial Sloan Kettering Cancer Center score. CONCLUSIONS: Careful patient selection for local surgery is of paramount importance. The prognoses of patients in the Memorial Sloan Kettering Cancer Center-based and International Metastatic Renal Cell Carcinoma Database Consortium-based poor-risk groups were much worse than those of the intermediate-risk groups. In current clinical practice, "stratified treatment" can be performed according to these criteria.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

TMPRSS2:ERG fusion gene occurs less frequently in Chinese patients with prostate cancer.

Prostate cancer is the commonest male malignancy in the Western world, but its morbidity is much lower in China. The principal aim of this study was to evaluate the frequency of TMPRSS2:ERG fusion in Chinese prostate cancer patients using immunohistochemistry and reverse transcription polymerase chain (RT-PCR). In addition, we compared the ERG protein expression with TMPRSS2:ERG fusion gene. The relationship between ERG expression and clinicopathologic features was also examined. Samples from patients who underwent radical prostatectomies in Changhai Hospital (Shanghai, China) were collected and stored in ethically approved tissue banks. One hundred seventy-four prostate cancer tissue samples and 10 normal tissues were marked on standard hematoxylin-eosin (HE) sections, punched out of the paraffin blocks and inserted into a recipient block using tissue arrayer instruments. Immunohistochemistry and RT-PCR were employed to detect TMPRSS2:ERG fusion gene. ERG was highly expressed in the nuclei of endothelial cells of vessels and weak cytoplasmic staining was occasionally observed. ERG positive staining was present in 14.9 % (26/174) of the tumor samples in microarray. All benign prostate samples were found to be negative. RT-PCR results revealed that 11.1 % (15/135) were TMPRSS2:ERG fusion positive. Altogether, there was a good agreement of ERG immunostaining with the presence of TMPRSS2:ERG. However, no correlation was observed between ERG expression and age, Gleason score, stage, surgical margin, and seminal vesicle involvement in Chinese patients. In the present study, we identified a high correlation between ERG expression and ERG TMPRSS2:ERG, with 100 % sensitivity and 88.9 % specificity. The expression level of ERG was unrelated to the age, Gleason score, stage, surgical margin, and seminal vesicle involvement. Therefore, the association between ERG expression and prostate cancer based on Chinese population should be further investigated in the future.

MicroRNA-410-5p as a potential serum biomarker for the diagnosis of prostate cancer.

BACKGROUND: Prostate cancer (PCa) remains to be a diagnostic challenge due to its variable presentation and the lack of reliable diagnosis tool. MicroRNAs (miRNAs) regulate gene in extensive range of pathophysiologic processes. Plasma miRNAs are ideal biomarkers in heart failure, diabetes and other disease. However, using circulating miRNAs as biomarkers for the diagnosis of PCa is still unknown. METHODS: 149 PCa patients, 57 healthy controls, and 121 non-cancer patients (benign prostatic hyperplasia and other urinary diseases) were enrolled in this study. The reverse transcription of miRNA and SYBR-Green-based double standards curve miRNA quantitative polymerase chain reactions (qPCR) were used to evaluate the dysregulated miR-410-5p. Receiver operator characteristic (ROC) curve analysis was used to evaluate the diagnostic accuracy of miR-410-5p identified as the alternative biomarker. RESULTS: Circulating miRNA-410-5p (miR-410-5p) level was significantly higher in the PCa patients than in healthy controls or non-cancer patients. ROC curve analysis showed that plasma miR-410-5p was a specific diagnostic biomarker of PCa with an area under curve(AUC) of 0.8097 (95 % confidence interval, 0.7371-0.8823; P < 0.001). CONCLUSIONS: The serum miR-410-5p level is a potential biomarker for the diagnosis of PCa.

Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma.

BACKGROUND: Previous study showed that mitochondrial ND6 (mitND6) gene missense mutation resulted in NADH dehydrogenase deficiency and was associated with tumor metastasis in several mouse tumor cell lines. In the present study, we investigated the possible role of mitND6 gene nonsense and missense mutations in the metastasis of human lung adenocarcinoma. METHODS: The presence of mitND6 gene mutations was screened by DNA sequencing of tumor tissues from 87 primary lung adenocarcinoma patients and the correlation of the mutations with the clinical features was analyzed. In addition, we constructed cytoplasmic hybrid cells with denucleared primary lung adenocarcinoma cell as the mitochondria donor and mitochondria depleted lung adenocarcinoma A549 cell as the nuclear donor. Using these cells, we studied the effects of mitND6 gene nonsense and missense mutations on cell migration and invasion through wounding healing and matrigel-coated transwell assay. The effects of mitND6 gene mutations on NADH dehydrogenase activity and ROS production were analyzed by spectrophotometry and flow cytometry. RESULTS: mitND6 gene nonsense and missense mutations were detected in 11 of 87 lung adenocarcinoma specimens and was correlated with the clinical features including age, pathological grade, tumor stage, lymph node metastasis and survival rate. Moreover, A549 cell containing mitND6 gene nonsense and missense mutation exhibited significantly lower activity of NADH dehydrogenase, higher level of ROS, higher capacity of cell migration and invasion, and higher pAKT and pERK1/ERK2 expression level than cells with the wild type mitND6 gene. In addition, NADH dehydrogenase inhibitor rotenone was found to significantly promote the migration and invasion of A549 cells. CONCLUSIONS: Our data suggest that mitND6 gene nonsense and missense mutation might promote cell migration and invasion in lung adenocarcinoma, probably by NADH dehydrogenase deficiency induced over-production of ROS.

Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma.

OBJECTIVE: Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis. DESIGN: We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided. RESULTS: Five signatures were selected to construct a subnetwork. The expression of GRB2, PTPN11, ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71). CONCLUSIONS: Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis.

miR-663 induces castration-resistant prostate cancer transformation and predicts clinical recurrence.

Castration-resistant prostate cancer (CRPC) and its treatment are challenging issues in prostate cancer management. Here, we report that miR-663 is upregulated in CRPC tissues. Overexpression of miR-663 in prostate LNCaP cells promotes cell proliferation and invasion, neuroendocrine differentiation, and reduction in dihydrotestosterone-induced upregulation of prostate-specific antigen expression. Furthermore, results of in situ hybridization show that miR-663 expression is correlated with Gleason score and TNM stage and is an independent prognostic predictor of clinical recurrence. Together, these findings suggest that miR-663 is a potential oncomiR for CRPC and may serve as a tumor biomarker for the early diagnosis of CRPC.

Phlorizin, a novel caloric restriction mimetic, stimulates hypoxia and protects cardiomyocytes through activating autophagy via modulating the Hif-1α/Bnip3 axis in sepsis-induced myocardial dysfunction.

BACKGROUND: Sepsis is a systemic inflammatory syndrome that can lead to multiple organ dysfunction and life-threatening complications. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to be present in half of patients with septic shock, increasing their mortality rate to 70-90%. The pathogenesis of SIMD is complex, and no specific clinical treatment has yet been developed. Caloric restriction mimetics (CRM), compounds that simulate the biochemical and functional properties of CR, can improve cardiovascular injury by activating autophagy. This study investigated the effect of a new type of CRM which can induce hypoxia, the SGLT nonspecific inhibitor phlorizin on SIMD. MATERIALS AND METHODS: In vivo, phlorizin was administered at 1 mg/kg/day intragastrically for 28 days. In vitro, AC16 was treated with 120 µM phlorizin for 48 h. Echocardiography was used to assess cardiac function. Myocardial injury markers were detected in serum and cell supernatant. Western blotting was employed to detect changed proteins associated with apoptosis and autophagy. Immunofluorescence, immunohistochemistry, co-immunoprecipitation, molecular docking, and other methods were also used to illustrate cellular changes. RESULTS: In vivo, phlorizin significantly improved the survival rate and cardiac function after sepsis injury, reduced markers of myocardial injury, inhibited myocardial apoptosis and oxidative stress, and promoted autophagy. In vitro, phlorizin alleviated the apoptosis of AC16, as well as inhibited oxidative stress and apoptotic enzyme activity. Phlorizin acts on autophagy at multiple sites through low energy (activation of AMPK) and hypoxia (release of Beclin-1 by Hif-1α/Bnip3 axis), promoting the formation and degradation of autophagosomes. CONCLUSION: We indicated for the first time that phlorizin could inhibit glucose uptake via GLUT-1 and conforms to the metabolic characteristics of CRM, it can induce the hypoxic transcriptional paradigm. In addition, it inhibits apoptosis and improves SIMD by promoting autophagy generation and unobstructing autophagy flux. Moreover, it affects autophagy by releasing Beclin-1 through the Hif-1α/Bnip3 axis.

Papillary renal neoplasm with reverse polarity: an observational study of histology, immunophenotypes, and molecular variation.

Background: Papillary renal neoplasm with reverse polarity (PRNRP) is a novel entity with unique clinicopathological characteristics, and only a small number of patients with PRNRP have been described. Methods: We retrospectively analyzed the data for nine patients with PRNRP and evaluated differences in the clinical, histomorphological, immunohistochemical, and molecular features; prognosis; and differential diagnosis of PRNRP from other renal tumors with papillary structure. Results: There were six males and three females aged 36 to 74 years (mean: 62.33 years; median: 68 years). All the tumors were solitary and ranged from 1 to 3.7 cm (mean: 2.17 cm; median: 2 cm), with three and six tumors arose in the left and right renal tract, respectively. Pathologically, PRNRP is a small, well-circumscribed neoplasm with predominant papillary formations. The lining epithelium is composed of a monolayer of cuboidal to low-columnar cells with low-grade nuclei arranged against the apical pole of the tumor cells. Edema, mucinous degeneration, and hyaline degeneration are found in the fibrovascular cores. Foamy macrophages, psammoma bodies, hemosiderin deposition, and infiltrative tumor boundaries were present in some patients. Immunohistochemically, all tumors showed diffuse positive staining for GATA3. Sanger sequencing confirmed the presence of KRAS mutation in seven patients. All patients had a good prognosis after surgery and were relapse free. Positive staining for GATA3 and negative staining for vimentin were the most significant markers for differentiating PRNRP from other renal tumors with analogous structure. Conclusions: These findings suggested that PRNRP is a distinctive subtype of renal tumor with specific pathological features and indolent behaviors that should be distinguished from other renal tumors, especially papillary renal cell carcinoma. A monolayer of tumor cells with an inverted nuclear pattern, positive staining for GATA3, and KRAS mutation are essential for pathological diagnosis. Owing to its satisfactory prognosis, the surveillance and follow-up of patients with PRNRP should be additionally formulated.

Efficacy of ceftazidime-avibactam in the treatment of carbapenem-resistant Klebsiella pneumoniae infections: Focus on solid organ transplantation recipients.

INTRODUCTION: Ceftazidime-avibactam (CAZ-AVI) is a new option to treat KPC- and OXA-48 carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. However, clinical evidence is limited regarding its use in treating CRKP infections, especially in solid organ transplantation (SOT) recipients. In this study, we assessed the efficacy of CAZ-AVI in treating CRKP infections in both the general population and the SOT recipients in comparison with other antibiotic regimens. METHODS: This is a single-centre retrospective cohort study of patients admitted between January 1, 2018 and June 30, 2021 with the diagnosis of CRKP infections receiving either CAZ-AVI or other regimens ≥ 72 hours and clinical outcomes were analysed. RESULTS: Of 200 patients with CRKP infections, 67 received CAZ-AVI, 133 received other regimens, and 50 were SOT recipients. In the SOT cohort, 30 patients received CAZ-AVI, and 20 received other regimens. The overall 30-day mortality was 38% in the SOT cohort. Compared with patients receiving other regimens, CAZ-AVI therapy resulted in lower 30-day mortality (23.3% vs. 60%, P = 0.014) and 90-day mortality (35.7% vs. 86.7%, P = 0.003), higher clinical cure (93.3% vs. 40%, P < 0.001) and microbiological clearance. Similar promising results of CAZ-AVI were also shown in the whole population cohort. Moreover, clinical outcomes of SOT recipients receiving CAZ-AVI were not inferior to those without SOT. CONCLUSIONS: CAZ-AVI therapy was associated with better clinical outcomes in CRKP infections in both the general population and SOT recipients. Considering the limitations of the present study, well-conducted RCTs are still warranted to confirm these findings.

Retinal structural thicknesses reflect clinically relevant microstructural white matter abnormalities in neuromyelitis optica spectrum disorders.

BACKGROUND: Thinning of retinal thickness seen on optical coherence tomography (OCT) is frequent in patients with neuromyelitis optica spectrum disorder (NMOSD). We explored the association between OCT metrics, MRI measurements and clinical outcomes in NMOSD. METHODS: 44 NMOSD and 60 controls underwent OCT and MR imaging. Mean peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell complex (GCC) thicknesses were measured. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) was used to measure the white matter microstructural integrity. In NMOSD patients, Expanded Disability Status Scale (EDSS) was used to quantify disability. Visual acuity (VA) was also performed for all participants. RESULTS: pRNFL thickness was positively associated with mean diffusivity in left posterior thalamic radiation (pp = 0.010) and axial kurtosis in inferior cerebellar peduncle (p = 0.023). Similarly, GCC thickness in NMOSD patients was positively associated with fractional anisotropy in right superior longitudinal fascicules (p = 0. 041) and axial kurtosis of left cerebellar peduncle (p = 0.011). CONCLUSIONS: In NMOSD, pRNFL and GCC reflect integrity of clinically relevant white matter structures underlying the value of OCT metrics as markers of neuronaxonal loss and disability.

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS: NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS: Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score ≥ 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P = .011), especially for those who received 5-fluorouracil-based chemotherapy (P = .016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLUSIONS: High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-3445.. © 2013 American Cancer Society.

Establishment and characterization of clear cell renal cell carcinoma cell lines with different metastatic potential from Chinese patients.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) cell lines with distinct metastatic potential are essential to study the mechanism of ccRCC metastasis. However, none of them originated from Chinese. METHODS: Primary cell cultures were performed using a primary tumor of a 49-year-old male ccRCC patient and a metastatic tumor of a 62-year-old male patient who had received nephrectomy to excise primary ccRCC 10 years ago. Cell growth, microstructure, cytogenetics, cytometry, expression of metastasis-associated molecules, tumorigenesis and metastasis were subsequently characterized. RESULTS: Two successive cell lines named NRCC from the primary ccRCC and MRCC from the metastatic ccRCC were established, respectively. Compared to NRCC, MRCC exhibited stronger anchorage-independent growth and invasion potentials and contained more glycogen granules in the cytoplasm. Gains of chromosomes and some translocations were the major chromosomal aberrations in both cell strains. CD24 expression was more frequent in MRCC than in NRCC and the same was true for CD56. The transcriptional levels of TNFα, IL-6, VEGF, HIF2α, MMP2, and RhoC were significantly higher in MRCC than in NRCC. Cytosolic IκBα protein was more degraded in MRCC than in NRCC following TNFα treatment. Both cell lines had strong tumorigenicity in athymic nude mice. However, MRCC had strong potential in generating metastasis to lung and hemorrhagic ascites than NRCC following orthotopic transplantations. CONCLUSIONS: Cancer cells isolated from metastatic ccRCC have more malignant and metastatic potential than those from the primary tumor from the patients who shared the similar race background. Establishment of MRCC and NRCC may provide suitable models with which to investigate molecular mechanisms of ccRCC metastasis.