CwJAZ4/9 negatively regulates jasmonate-mediated biosynthesis of terpenoids through interacting with CwMYC2 and confers salt tolerance in Curcuma wenyujin.

Plant JASMONATE ZIM-DOMAIN (JAZ) genes play crucial roles in regulating the biosynthesis of specialized metabolites and stressful responses. However, understanding of JAZs controlling these biological processes lags due to numerous JAZ copies. Here, we found that two leaf-specific CwJAZ4/9 genes from Curcuma wenyujin are strongly induced by methyl-jasmonate (MeJA) and negatively correlated with terpenoid biosynthesis. Yeast two-hybrid, luciferase complementation imaging and in vitro pull-down assays confirmed that CwJAZ4/9 proteins interact with CwMYC2 to form the CwJAZ4/9-CwMYC2 regulatory cascade. Furthermore, transgenic hairy roots showed that CwJAZ4/9 acts as repressors of MeJA-induced terpenoid biosynthesis by inhibiting the terpenoid pathway and jasmonate response, thus reducing terpenoid accumulation. In addition, we revealed that CwJAZ4/9 decreases salt sensitivity and sustains the growth of hairy roots under salt stress by suppressing the salt-mediated jasmonate responses. Transcriptome analysis for MeJA-mediated transgenic hairy root lines further confirmed that CwJAZ4/9 negatively regulates the terpenoid pathway genes and massively alters the expression of genes related to salt stress signaling and responses, and crosstalks of multiple phytohormones. Altogether, our results establish a genetic framework to understand how CwJAZ4/9 inhibits terpenoid biosynthesis and confers salt tolerance, which provides a potential strategy for producing high-value pharmaceutical terpenoids and improving resistant C. wenyujin varieties by a genetic approach.

CircHIPK3 regulates fatty acid metabolism through miR-637/FASN axis to promote esophageal squamous cell carcinoma.

The oncogenic role of circRNA in cancers including esophageal cancer (EC) has been well studied. However, whether and how circRNAs are involved in cancer cell metabolic processes remains largely unknown. Here, we reported that circRNA, circHIPK3, is highly expressed in ESCC cell lines and tissues. Knockdown of circHIPK3 significantly restrained cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, circHIPK3 was found to act as a ceRNA by sponging miR-637 to regulate FASN expression and fatty acid metabolism in ESCC cells. Anti-sense oligonucleotide (ASO) targeting circHIPK3 substantially inhibited ESCC both in vitro and in vivo. Therefore, these results uncover a modulatory axis constituting of circHIPK3/miR-637/FASN may be a potential biomarker and therapeutic target for ESCC in the clinic.

Gene coexpression networks allow the discovery of two strictosidine synthases underlying monoterpene indole alkaloid biosynthesis in Uncaria rhynchophylla.

Plant-derived monoterpene indole alkaloids (MIAs) from Uncaria rhynchophylla (UR) have huge medicinal properties in treating Alzheimer's disease, Parkinson's disease, and depression. Although many bioactive UR-MIA products have been isolated as drugs, their biosynthetic pathway remains largely unexplored. In this study, untargeted metabolome identified 79 MIA features in UR tissues (leaf, branch stem, hook stem, and stem), of which 30 MIAs were differentially accumulated among different tissues. Short time series expression analysis captured 58 pathway genes and 12 hub regulators responsible for UR-MIA biosynthesis and regulation, which were strong links with main UR-MIA features. Coexpression networks further pointed to two strictosidine synthases (UrSTR1/5) that were coregulated with multiple MIA-related genes and highly correlated with UR-MIA features (r > 0.7, P < 0.005). Both UrSTR1/5 catalyzed the formation of strictosidine with tryptamine and secologanin as substrates, highlighting the importance of key residues (UrSTR1: Glu309, Tyr155; UrSTR5: Glu295, Tyr141). Further, overexpression of UrSTR1/5 in UR hairy roots constitutively increased the biosynthesis of bioactive UR-MIAs (rhynchophylline, isorhynchophylline, corynoxeine, etc), whereas RNAi of UrSTR1/5 significantly decreased UR-MIA biosynthesis. Collectively, our work not only provides candidates for reconstituting the biosynthesis of bioactive UR-MIAs in heterologous hosts but also highlights a powerful strategy for mining natural product biosynthesis in medicinal plants.

Will male semen quality improve with environmental quality?

Wenzhou has improved its environmental quality because of comprehensive environmental remediation; nevertheless, the semen quality of infertile males remains unclear. This study determined whether better environmental quality improved semen quality in this region. We recorded semen quality data from 22 962 infertile males from January 2014 to November 2019 at the Center for Reproductive Health of The First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China). Patients were predominantly 30-35 years old (33.1%) and workers (82.0%), with high school education or lower (77.6%); more than a half of the patients (52.6%) were Wenzhou household registration; and most patients (77.5%) had abnormal semen quality. Patients who were older than 40 years and workers, and those with Wenzhou household registration, had significantly worse semen quality (all P < 0.05). From 2014 to 2019, progressive sperm motility, total sperm motility, and semen volume showed increasing linear trends in all patients (P = 0.021, 0.030, and 0.005, respectively), yet normal sperm morphology showed a linearly decreasing trend (P = 0.046). Sensitivity analyses for subgroups yielded similar results. In conclusion, the improvement of environmental quality and better function of the accessory glands are associated with progressive sperm motility, total sperm motility, and semen volume. Normal sperm morphology is influenced by occupational exposures and personal lifestyle and does not improve with environmental quality.

Development of a multi-recombinase polymerase amplification assay for rapid identification of COVID-19, influenza A and B.

The coronavirus disease 2019 (COVID-19) pandemic caused extensive loss of life worldwide. Further, the COVID-19 and influenza mix-infection had caused great distress to the diagnosis of the disease. To control illness progression and limit viral spread within the population, a real-time reverse-transcription PCR (RT-PCR) assay for early diagnosis of COVID-19 was developed, but detection was time-consuming (4-6 h). To improve the diagnosis of COVID-19 and influenza, we herein developed a recombinase polymerase amplification (RPA) method for simple and rapid amplification of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 and Influenza A (H1N1, H3N2) and B (influenza B). Genes encoding the matrix protein (M) for H1N1, and the hemagglutinin (HA) for H3N2, and the polymerase A (PA) for Influenza B, and the nucleocapsid protein (N), the RNA-dependent-RNA polymerase (RdRP) in the open reading frame 1ab (ORF1ab) region, and the envelope protein (E) for SARS-CoV-2 were selected, and specific primers were designed. We validated our method using SARS-CoV-2, H1N1, H3N2 and influenza B plasmid standards and RNA samples extracted from COVID-19 and Influenza A/B (RT-PCR-verified) positive patients. The method could detect SARS-CoV-2 plasmid standard DNA quantitatively between 102 and 105 copies/ml with a log linearity of 0.99 in 22 min. And this method also be very effective in simultaneous detection of H1N1, H3N2 and influenza B. Clinical validation of 100 cases revealed a sensitivity of 100% for differentiating COVID-19 patients from healthy controls when the specificity was set at 90%. These results demonstrate that this nucleic acid testing method is advantageous compared with traditional PCR and other isothermal nucleic acid amplification methods in terms of time and portability. This method could potentially be used for detection of SARS-CoV-2, H1N1, H3N2 and influenza B, and adapted for point-of-care (POC) detection of a broad range of infectious pathogens in resource-limited settings.

[The mediating effect of coping style between illness perception and fear of cancer recurrence in patients undergoing radical prostatectomy].

OBJECTIVE: To explore the mediating effect of coping style between illness perception and fear of cancer recurrence in patients undergoing radical prostatectomy. METHODS: A questionnaire survey was carried out in 254 eligible patients who underwent radical prostatectomy in the urology department of two comprehensive tertiary hospitals in Wenzhou City from June 2022 to December 2022. The questionnaires include the general data questionnaire, brief illness perception questionnaire (BIPQ), Medical Coping Modes Questionnaire (MCMQ) and Fear of Progression Questionnaire-Short Form (FoP-Q-SF). A structural equation model was used to analyze the mediating effect of coping style between illness perception and fear of cancer recurrence. RESULTS: The score of fear of cancer recurrence in prostate cancer patients is (30.08 ± 10.11). Illness perception, avoidance, and surrender coping styles could forward prediction fear of cancer recurrence (P=0.001, P=0.019, P=0.001); facing coping styles can negatively predict fear of cancer recurrence (P=0.001). Coping style played a part of the mediating role between illness perception and fear of cancer recurrence, and the mediating effect is 0.150，which accounted for 47.62% of the total effect. CONCLUSION: Coping style is a mediator between illness perception and fear of cancer recurrence in patients undergoing radical prostatectomy. Doctors and nurses should reduce patients' negative perception, guide them to adopt positive coping strategies, and thereby reduce their fear of cancer recurrence.

[Seminal vesicoscopy in the treatment of seminal abnormalities associated with ejaculatory duct obstruction：Advances in studies].

Obstructive azoospermia is a kind of common clinical disease, which often happens in epididymis, vas deferens and ejaculatory duct obstruction and accounts for male infertility. Azoospermia, which is caused by obstruction of the ejaculatory duct, is relatively rare. but the development of endoscopic technology now allows the disease to be resolved by surgery. In the past, transurethral resection of ejaculatory duct (TURED) has been used to treat patients with ejaculatory duct obstruction and azoosperm-free disease. But with the further study of TURED operation in recent years, as well as in patients with postoperative follow-up results showed that the urine - tube reflux and retrograde ejaculation ejaculation the incidence of iatrogenic injury is higherduring the TURED.therefore, in recent years, some experts committed to seeking a less damage and better effect of the surgical method. With the continuous development of endoscopic technology, seminal vesiculoscopy has come into being, which also creates conditions for further understanding the structure and function of the seminal vesicle and distal seminal duct, accurate diagnosis and minimally invasive treatment of the currently discovered diseases. In this article, we summarized the semen abnormalities associated with seminal vesiculoscopy in the treatment of ejaculatory duct obstruction, and also reviewed the surgical methods, clinical application and research progress of seminal vesiculoscopy.

Changes in metabolism modulate induced by viroid infection in the orchid Dendrobium officinale.

Dendrobium officinale is an important traditional Chinese medicinal herb, and the stem tissue is the main medicinal that is harvested from D. officinale. Recently, the first viroid was identified from D. officinale in China, and it has been named Dendrobium viroid (DVd). Whether DVd interferes with metabolic pathways in dendrobium plants and affects the medicinal value of the host is unknown. In this study, metabolomics data from stem tissues supported by transcriptome studies were used to investigate how metabolism modulate of D. officinale is altered by DVd infection. Our results show that metabolism of D. officinale is reprogrammed in many ways during DVd infection, and this is reflected by significant changes in the levels of flavonoids, alkaloids, and phenolic acids. Furthermore, we found that DVd infection significantly decreased the accumulation of flavonoids and alkaloid metabolites in infected stems, and the decreases in these metabolites appears to affect the medicinal components of the infected plants, weakening the host antiviral immune response as well. Conversely, phenolic acids occupy a larger proportion of the up-regulated metabolites from DVd infection in comparison with the mock-inoculated control, and the increase in the total phenolic acids may reflect the activation of the pathogen defense response in D. officinale. Taken together, our results provide an interesting overview and give a better understanding of the relationship between metabolism and DVd infection in the orchid D. officinale.

Prognostic Value of Site-Specific Metastases and Therapeutic Roles of Surgery and Chemotherapy for Patients With Metastatic Renal Pelvis Cancer: A SEER Based Study.

BACKGROUND AND AIMS: There is a lack of research on metastatic renal pelvis cell carcinoma in the current literature. In this study, we aimed to detect distant metastatic patterns in renal pelvis cell carcinoma, and illustrated the affection of different metastatic sites, surgery to primary site and chemotherapy on prognosis outcomes in patients with diverse conditions. METHODS: We collected data between 2010 and 2015 from the Surveillance, Epidemiology and End Results database. Kaplan-Meier analysis with log-rank test was used for survival comparisons. Multivariate Cox regression model was employed to analyze the effect of distant metastatic sites on overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 424 patients were included in the analysis, the median follow-up time was 5 months (interquartile range (IQR): 2-12) and 391 deaths (92.2%) in all patients were recorded. Among them, 192 (45.3%), 153 (36.1%), 137 (32.3%) and 127 (30.0%) patients were diagnosed with lung, bone, liver and brain metastases, respectively, while only 12 (2.8%) patients had brain metastases. The bi-organ, tri-organ and tetra-organ metastatic pattern was found in 135 (31.8%), 32 (7.5%) and 11 (2.6%) patients, respectively. The multivariate Cox analyses showed that distant lymph nodes (DL) metastases was not an independent prognostic factor for both OS and CSS (OS: Hazard ratios (HR) = 1.1, 95% CI = 0.8-1.4, P = 0.622; CSS: HR = 1.0, 95% CI = 0.8-1.3, P = 0.906). Besides, there was no significant difference of survival in patients with T3-T4 stage (OS: HR = 0.8, 95% CI = 0.5-1.2, P = 0.296; CSS: HR = 0.8, 95% CI = 0.5-1.2, P = 0.224), N2-3 stage (OS: HR = 0.8, 95% CI = 0.5-1.3, P = 0.351; CSS: HR = 0.7, 95% CI = 0.4-1.2, P = 0.259) and multi-organ metastases (OS: HR = 0.8, 95% CI = 0.5-1.3, P = 0.359; CSS: HR = 0.7, 95% CI = 0.4-1.2, P = 0.179) between surgery to primary site group and no-surgery to primary site group. CONCLUSION: we described the metastatic patterns of mRPCC and the prognosis outcomes of DL metastases, surgery to primary site and chemotherapy. Our findings provide more information for clinical therapeutic intervention and translational study designs.

Transurethral seminal vesiculoscopy for intractable hematospermia: experience from 144 patients.

PURPOSE: to describe the methodology of transurethral seminal vesiculoscopy and the anatomy of the area of the verumontanum, and to determine the safety of this procedure, especially in terms of postoperative complications. METHODS: This retrospective observational study enrolled 144 patients with intractable hematospermia from May 2011 and August 2019. A 4.5/6.5-Fr vesiculoscope was inserted into the seminal vesicle to deal with the positive findings. The solution of quinolones was used to rinse each seminal vesicle. RESULTS: In this study, Transurethral seminal vesiculoscopy was successfully performed in 139 patients (96.53%). Hematospermia was alleviated or disappeared in 116 (80.56%) patients by less than half a year after surgery. Common intraoperative manifestations were hemorrhage, stones, utricle polyps and cysts. The surgical approach in our study were categorized into four types, including 24 (16.7%), 73 (50.7%), 42 (29.2%), and 5 (3.5%) cases in Type A (natural opening of the ejaculatory duct), B (trans-duct fenestration), C (trans-utricle fenestration), and D (not founded), respectively. Sexual function change was recorded in 12 patients of 111 patients, all by the method of trans-utricle fenestration, including 8 (7.21%), 3 (2.70%), and 1 (0.90%) patients in shorter intravaginal ejaculatory latency time, worse erection hardness and loss of orgasm, respectively. CONCLUSION: Transurethral seminal vesiculoscopy is an effective and safe procedure for the management of hematospermia. The anatomy of the distal seminal tract should be understood more deeply and Wu'method (uncover-curtain method) needs to be promoted to verify its universality and safety. Besides, the complications of the function dysfunction should be discussed in the future in multi-center clinical trials.

Analysis of semen quality of 38 905 infertile male patients during 2008-2016 in Wenzhou, China.

This study analyzed the trend in semen quality of infertile male patients in Wenzhou, China, based on the data obtained from 38 905 patients during 2008-2016 in The First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China). The results showed that only 24.9% of the patients had normal semen quality. For the semen quality of infertile male patients, that of the workers and 40-year-olds was significantly worse than the other occupational and age groups. For all the infertile patients, low semen volume, asthenozoospermia, and teratozoospermia accounted for 8.4%, 50.5%, and 54.1%, respectively. During 2008-2016, the annual mean percentage of fast forward motile spermatozoa, percentage of total forward motile spermatozoa, and percentage of spermatozoa with normal morphology decreased linearly with slopes of -2.11, -2.59, and -0.70, respectively. The proportion of patients with asthenozoospermia and multi-abnormal spermatozoa increased during 2008-2016 with slopes of 4.70 and 4.87, respectively, while for low semen volume, it decreased with a slope of -0.47 in the same time period. The proportion of patients with teratozoospermia increased from 2008 to 2011 and from 2011 to 2016 with slopes of 17.10 and 2.09, respectively. In general, the deteriorating trend of semen quality of infertile male patients in Wenzhou was obvious. Future efforts should be made to reveal the adverse influences on semen quality, such as occupational exposure, environmental quality, and living habits. Furthermore, more pervasive reproduction health education is necessary.

[Influence of testicular microlithiasis on male fertility: An update].

With the increasing awareness of men's health, more and more clinical studies are reported on the relationship of testicular microlithiasis (TM) with male infertility. TM is a relatively rare disease characterized by multiple microcalcifications (<3 mm) in the seminiferous tubules of the testis. This review summarizes the findings in the studies of the diagnosis, epidemiology, correlation with male fertility, treatment, and follow-up of TM in recent years. Many researches show that TM has a certain correlation with the decline of male fertility, which, however, is not identically agreed on at home and abroad. As for the treatment of TM complicated with male infertility, there is still a lack of effective and reliable drugs and strategies and a need for many basic and clinical studies.

[Biosafety in andrology laboratories during the outbreak of COVID-19].

The novel coronavirus disease 2019 (COVID-19) broke out in December 2019 and has been rapidly escalating throughout the world. Clinical findings show that the patients with either symptomatic or asymptomatic COVID-19 can be a potential source of infection. Although respiratory droplets and close contact are considered to be the main routes of transmission, there is the possibility of aerosol transmission in a relatively closed environment. The nucleic acid of the novel coronavirus can be detected in nasopharyngeal swabs, sputum and other lower respiratory tract secretions, blood, feces, urine and so on, but whether it exists in the semen has not been confirmed. It is reported that the novel coronavirus may affect the testis that highly expresses angiotensin-converting enzyme 2 (ACE2) and theoretically the semen is a possible carrier of the virus considering the fact that it is discharged from the same channel as the urine. Andrology laboratorians are exposed to most of the specimens above, including semen, and some open operations in the laboratory increase the risk of aerosol generation. Therefore, corresponding protective procedures are necessitated in andrology laboratories to reduce the risk of infection during the outbreak of COVID-19. Based on the knowledge and experience available as regards the pandemic and the characteristics of the work in the andrology laboratory, we summarize some biosafety points for andrology laboratorians to attend to during the outbreak of COVID-19.

[Application of transurethral seminal vesiculoscopy in uroandrology].

With the continuous improvement of living conditions, increasing attention is being drawn to the genitourinary health of males, which has boomed the development of uroandrology in recent years. Refractory hemospermia, infertility, and perineal pain are commonly seen in some male patients, and mainly relied on medical imaging for diagnosis in the past, which, however, has a high pseudopositive rate and cannot give an etiological explanation. Patients with these diseases often adopt conservative treatments such as medication and physiotherapy, often with poor prognosis, and those suffering frequent recurrence used to be treated by transurethral resection, laparoscopic surgery or open surgery, which are now rarely employed due to their high rate of postoperative complications, slow recovery, and easy recurrence. In recent years, transurethral seminal vesiculoscopy has gained a wide application in the diagnosis and treatment of the above-mentioned uroandrological diseases and shown its advantages of high clinical effectiveness and low incidence of complications. The review updates on the indications, methods, skills and clinical application of transurethral seminal vesiculoscopy.

Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer.

BACKGROUND: Programmed death ligand 1 (PD-L1) immunotherapy remains poorly efficacious in colorectal cancer (CRC). The recepteur d'origine nantais (RON) receptor tyrosine kinase plays an important role in regulating tumor immunity. AIM: To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC. METHODS: Gene expression data from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot. RESULTS: In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment (P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells. CONCLUSION: RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.

U-shaped relationship of age at diagnosis and cancer-specific mortality in primary urachal adenocarcinoma: a cohort study.

BACKGROUND: To examine the association between age at diagnosis and cancer-specific mortality (CSM) in primary urachal adenocarcinoma. METHODS: The data was obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results program (SEER). A total of 393 patients were included in the study. Smooth curve fitting and two-piecewise Cox proportional hazards models were used to identify the nonlinearity between the age at initial diagnosis and cancer-specific survival rate. Survival time between different groups was compared using Kaplan-Meier survival curves and the log-rank test. RESULTS: Using smooth curve fitting we found that the relationship between age at diagnosis and cancer-specific survival takes on a U-shaped curve. The inflection point that we identified for the age at initial diagnosis was 60 years. The log-likelihood ratio test (P<0.05) indicated that the two-piecewise Cox regression model was more appropriate for fitting the correlation of age at diagnosis and CSM. The two-piecewise Cox regression model showed that when the age was <60 years, reduced risk of CSM was significantly associated with increased age (HR: 0.95, P=0.0002). Conversely, when age was >60 years, increased risk of CSM was significantly associated with increased age (HR: 1.05, P=0.0499). CONCLUSIONS: In summary, our study suggested that the relationship between age at diagnosis and cancer-specific survival is nonlinear, and takes on a U-shaped curve. Both younger and older age at initial diagnosis age were associated with increased CSM.

Dendrobium viroid, a new monocot-infecting apscaviroid.

Viroids are small circular RNA molecules which have been found to infect many dicot species. Only coconut cadang-cadang viroid and coconut tinangaja viroid have been reported so far to infect a monocot (coconut). Data mining in silico has proven an efficient approach to identify new viruses/viroids, and a systematic screen of public transcriptomic data revealed a 648 nucleotides (nt) sequence potentially representing a novel viroid-like RNA in a transcriptome shotgun assembly from Dendrobium officinale. This sequence contained two central conserved regions (CCRs) characteristic of members of the genus Apscaviroid, indicating that the viroid-like RNA is 324 nt in length. The infectivity of dimeric RNA transcripts generated by in vitro transcription of a synthetic cDNA, was demonstrated by directly injecting into the stems of young Dendrobium officinale plants. The presence of this novel viroid, tentatively designated as Dendrobium viroid (DVd), in the inoculated plants was confirmed by 2D-PAGE together with northern hybridization. DVd is predicted to have a rod-like secondary structure containing a CCR and a terminal conserved region (TCR), and phylogenetic analysis shows that it groups with the known members of the genus Apscaviroid. It is most closely related to citrus viroid V (56% nt identity). A field survey revealed a low DVd incidence (0.96%) in Dendrobium species in China. To our best knowledge, DVd is the only viroid known to infect orchids and the third one from monocotyledonous plants.

RON and MET Co-overexpression Are Significant Pathological Characteristics of Poor Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment. MATERIALS AND METHODS: We analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model. RESULTS: Patients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060. CONCLUSION: RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

Adding radiotherapy based on chemotherapy can improve cancer-specific survival in N3 penile cancer: a SEER-based study.

BACKGROUND: Controversial effectiveness of chemotherapy and still poor prognosis prompt us to find better treatment options. This study targeted at investigating whether adding radiotherapy based on chemotherapy can effectively improve the prognosis of patients, especially for advanced penile cancer. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results database (SEER*Stat software V.8.3.5; USA; Accession numbers: 13693-Nov2015 and lh8N79l2), and the survival curves were conducted using the Kaplan-Meier method. Univariate and multivariate cox regression models were performed in order to determine the hazard ratios (HRs) with 95% confidence intervals (CIs) for penile cancer-specific survival (PCSS). Subgroup analysis via multivariate Cox models were conducted to discovery the different effect in population with different features. RESULTS: The median follow-up time was 25 months, the 2-year PCSS was 52.98% in the chemoradiotherapy group and 55.81% in the chemotherapy group. In multivariate analysis of all patients, combined chemoradiotherapy was not associated with PCSS (HR =0.90, 95% CI: 0.63-1.29, P=0.572). In subgroup analysis, chemoradiotherapy improved the PCSS in N3 patients compared to these patients without therapy of radiotherapy (HR =0.54, 95% CI: 0.30-0.98, P=0.043). CONCLUSIONS: Our study demonstrated a significant correlation of chemoradiotherapy with improved cancer-specific survival of penile cancer (PeCa) in N3 patients. Prospective international multicenter studies are necessary in order to improve prognosis for patients with advanced penile cancer.

Development and validation of a nomogram to predict survival in patients with metastatic testicular germ cell tumors.

BACKGROUND: To develop a nomogram to predict cancer-specific survival (CSS) in patients with metastatic testicular germ cell tumors (mTGCTs). METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression models were used to identify factors associated with CSS. Survival times between different groups were compared using Kaplan-Meier survival curves and the log-rank test. A nomogram visualization model was established using the R language to predict survival rates. Harrell's concordance index (C-index), the area under the receiver operating characteristic curve (AUC) and calibration plots were used to assess the performance of the model. RESULTS: We analyzed the data of 949 patients. The median follow-up time was 32 months (range 0 to 83 months), and 224 (23.60%) patients died before the last follow-up, of whom 193 (20.33%) died of mTGCTs. The site of distant metastases was an independent prognostic factor for CSS. Compared to patients without involvement of the corresponding organ, patients with bone, brain, liver, and lung involvement had worse CSS. We also found that age, histological type, surgery, radiation therapy, chemotherapy, metastatic site and insurance status affected the CSS of patients with mTGCTs. We used these prognostic factors to construct our nomogram. Harrell's C-index for CSS was 0.739. The AUC and calibration plots indicated good performance of the nomogram. CONCLUSIONS: A nomogram for predicting CSS in patients with mTGCTs has been developed, which can help patients and clinicians accurately predict mortality risk and recommend personalized treatment modalities.