Overexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment.

Expression of the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which MALAT1 promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress MALAT1/Malat1 in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. Malat1 overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of MALAT1/Malat1 enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. Ccl2 up-regulation was the result of increased global chromatin accessibility upon Malat1 overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of Malat1 overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.

Predicting Overall Survival for Patients with Malignant Mesothelioma Following Radiotherapy via Interpretable Machine Learning.

PURPOSE/OBJECTIVES: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based on dosimetric metrics as well as patient characteristics. MATERIALS/METHODS: Sixty MPM (37 right, 23 left) patients treated on a Tomotherapy unit between 2013 and 2018 were retrospectively analyzed. All patients received 45 Gy (25 fractions). The multivariable Cox regression (Cox PH) model and Survival Support Vector Machine (sSVM) were applied to build predictive models of overall survival (OS) based on clinical, dosimetric, and combined variables. RESULTS: Significant differences in dosimetric endpoints for critical structures, i.e., the lung, heart, liver, kidney, and stomach, were observed according to target laterality. The OS was found to be insignificantly different (p = 0.18) between MPM patients who tested left- and right-sided, with 1-year OS of 77.3% and 75.0%, respectively. With Cox PH regression, considering dosimetric variables for right-sided patients alone, an increase in PTV_Min, Total_Lung_PTV_Mean, Contra_Lung_Volume, Contra_Lung_V20, Esophagus_Mean, and Heart_Volume had a greater hazard to all-cause death, while an increase in Total_Lung_PTV_V20, Contra_Lung_V5, and Esophagus_Max had a lower hazard to all-cause death. Considering clinical variables alone, males and increases in N stage had greater hazard to all-cause death; considering both clinical and dosimetric variables, increases in N stage, PTV_Mean, PTV_Min, and esophagus_Mean had greater hazard to all-cause death, while increases in T stage and Heart_V30 had lower hazard to all-cause-death. In terms of C-index, the Cox PH model and sSVM performed similarly and fairly well when considering clinical and dosimetric variables independently or jointly. CONCLUSIONS: Clinical and dosimetric variables may predict the overall survival of mesothelioma patients, which could guide personalized treatment planning towards a better treatment response. The identified predictors and their impact on survival offered additional value for translational application in clinical practice.

HER2Δ16 Engages ENPP1 to Promote an Immune-Cold Microenvironment in Breast Cancer.

The tumor-immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER2Δ16, an oncogenic splice variant of the HER2, has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and associates with a poor clinical outcome in breast cancer. To understand how HER2 variants modulated the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2Δ16 in the mammary epithelium. We found that HER2∆16 tumors were immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of Enpp1 in aggressive HER2+ breast cancer. Knockdown of Enpp1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth, which correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent Enpp1 activation associates with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.

Tislelizumab in Patients with Previously Treated Advanced Hepatocellular Carcinoma (RATIONALE-208): A Multicenter, Non-Randomized, Open-Label, Phase 2 Trial.

Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC. Methods: The multiregional phase 2 study RATIONALE-208 examined single-agent tislelizumab (200 mg intravenously every 3 weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by the Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab. Results: Between April 9, 2018, and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% (n = 32/249; 95% confidence interval [CI], 9-18), including five complete and 27 partial responses. The number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8-20]; two or more prior lines, 13% [95% CI, 7-20]). Median duration of response was not reached. The disease control rate was 53%, and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment. Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC.

Overexpressed Malat1 Drives Metastasis through Inflammatory Reprogramming of Lung Adenocarcinoma Microenvironment.

Metastasis is the main cause of cancer deaths but the molecular events leading to metastatic dissemination remain incompletely understood. Despite reports linking aberrant expression of long noncoding RNAs (lncRNAs) with increased metastatic incidence , in vivo evidence establishing driver roles for lncRNAs in metastatic progression is lacking. Here, we report that overexpression of the metastasis-associated lncRNA Malat1 (metastasis-associated lung adenocarcinoma transcript 1) in the autochthonous K-ras/p53 mouse model of lung adenocarcinoma (LUAD) is sufficient to drive cancer progression and metastatic dissemination. We show that increased expression of endogenous Malat1 RNA cooperates with p53 loss to promote widespread LUAD progression to a poorly differentiated, invasive, and metastatic disease. Mechanistically, we observe that Malat1 overexpression leads to the inappropriate transcription and paracrine secretion of the inflammatory cytokine, Ccl2, to augment the mobility of tumor and stromal cells in vitro and to trigger inflammatory responses in the tumor microenvironment in vivo . Notably, Ccl2 blockade fully reverses cellular and organismal phenotypes of Malat1 overexpression. We propose that Malat1 overexpression in advanced tumors activates Ccl2 signaling to reprogram the tumor microenvironment to an inflammatory and pro-metastatic state.

Cardiac Arrest during Interventional Radiology Procedures: A 7-Year Single-Center Retrospective Study.

An intervention radiology (IR) unit collected cardiac arrest data between January 2014 and July 2020. Of 344,600 procedures, there were 23 cardiac arrest patients (0.0067%). The patient data was compared to a representative sample (N = 400) of the IR unit to evaluate the incidence and factors associated with cardiac arrest during IR procedures. Age, procedure urgency, American Society of Anesthesiologists (ASA) physical status, procedure type, and underlying medical conditions were identified as valuable predictors of a patient's susceptibility to cardiac arrest during an IR procedure. The proportion of pediatrics was higher for cardiac arrest patients, and most required immediate procedures. The distribution of high ASA physical status (III or greater) was skewed compared to that of the non-cardiac arrest patients. Vascular procedures were associated with higher risk than non-vascular procedures. The patients who underwent non-transarterial chemoembolization arterial procedures demonstrated relative risks of 4.4 and 11.7 for cardiac arrest compared to biliary procedures and percutaneous catheter drainage, respectively. In addition, the six patients (26.1%) who died before discharge all underwent vascular procedures. Relative to patients with acute kidney injury, patients with malignancy, hypertension, and diabetes mellitus demonstrated relative risks of 3.3, 3.4, and 4.8 for cardiac arrest, respectively.

Longitudinal complications associated with PEG: Rate and severity of 30-day and 1-year complications experienced by patients after primary PEG insertion.

BACKGROUND AND AIMS: Percutaneous Endoscopic Gastrostomy (PEG) feeding is utilised in patients with exceptionally poor oral intake but is associated with both short and long-term complications. This study reviews longitudinal PEG complications and compares key subgroups. METHODS: Single-centre retrospective observational study of all patients receiving PEG insertion between January 2016 and December 2018. RESULTS: 306 patients met the inclusion criteria. The mean age at insertion was 67 years. The majority were cared for in their own home (80.4%) by themselves or family (74.9%). 127 PEG tubes were inserted for dysphagia and 165 prophylactically prior to treatment for head and neck cancer. In the first 30 days 16.7% experienced a complication. The most frequently reported was peristomal pain (9.2%). In the first year, 35.6% experienced at least one complication, 12.4% two complications and 6.6% three complications and 6.5% required inpatient treatment for their complication. The most common was pain (14.4%) followed by site weeping, site infection and external overgranulation. Patients with dysphagia took longer to develop complications, had fewer complications and took longer to require management by members of the secondary care team than those with head and neck cancer. Discounting peristomal pain, there was no difference in total complications between patients caring for themselves when compared to those receiving professional input. CONCLUSION: One third of patients will experience a complication related to their PEG tube over 1 year, but the majority are managed in an outpatient setting. This study has implications for planning support services and consenting and counselling patients pre-PEG-insertion.

Survey of nurses' knowledge and practice regarding medication administration using enteral tubes.

AIM AND OBJECTIVES: To identify the practice variation of the individual practitioners in medications' formulation modification for patients using enteral feeding tubing and to support health practitioners involved in this process. BACKGROUND: Blockage of enteral tubes is a common problem that can sometimes be resolved but may require replacement of the tube. Medications are a common culprit. DESIGN: A survey of 73 registered nurses' practices around medication administration via enteral feeding tubes. METHODS: A questionnaire study was undertaken within a district general hospital across a broad variety of wards to explore nurses' experiences of medication administration via enteral tubes. The study is reported in accordance with the squire 2.0 guidelines from the EQUATOR network. RESULTS: Seventy-three nurses responded. Twenty-six per cent reported never checking about drug modification for administration via a tube, 12% check every time and 61% when unsure about a new drug. The volume of fluid flushes administered after medication ranged from 7.5-150 ml. Seventy-one per cent of participants reported stopping feed when medications are required, varying from 1-60 min. Sixty per cent had experienced a blocked tube and 52% the tube being removed for these reasons. The clinical nurse specialist was the commonest first point of call to help. Staff named 15 medications as the most problematic to administer, lactulose and omeprazole were the top two. CONCLUSIONS: Practice varies significantly amongst nurses around medication administration. Theoretically, this may contribute to blocked tubes and excessive fluid administration to some patients. Barriers to medication administration were thematically grouped into: time, difficulty modifying medication, medication interactions and knowledge. Areas identified to support staff include training, devices to crush medications, medication suitability, multidisciplinary approach to streamline care and quick reference guides. RELEVANCE TO CLINICAL PRACTICE: Health professionals may use these results to reduce and ultimately avoid problems with administering medications through feeding tubes. Organisations may use these results to develop their local practice pathways for prescribing, dispensing and training around administration of medications through enteral tubes. In a community setting, this paper may improve the awareness of patients, caregivers and prescribers of the possible implications of tubing blockages.

A Simple and Noninvasive DOSY NMR Method for Droplet Size Measurement of Intact Oil-In-Water Emulsion Drug Products.

In a typical oil-in-water emulsion drug product, oil droplets with varied sizes are dispersed in a water phase and stabilized by surfactant molecules. The size and polydispersity of oil droplets are critical quality attributes of the emulsion drug product that can potentially affect drug bioavailability. More critically, to ensure accuracy in characterization of the finished drug product, analytical methods should introduce minimal physical perturbation (e.g., temperature variation or dilution) before the analysis. The classical methods of dynamic light scattering or electron microscopy can be used but they generally require sample dilution or harsh preparation conditions, respectively. By contrast, the size distribution of emulsion formulations can be assessed with a simple and noninvasive solution nuclear magnetic resonance method, namely, two-dimensional Diffusion Ordered SpectroscopY. The two-dimensional Diffusion Ordered SpectroscopY method probed signal decay of methyl resonances from oil and sorbate molecules and was applied to 3 types of U.S.-marketed emulsion drug products, that is, difluprednate, cyclosporine, and propofol, yielding measured droplet sizes of 40-280 nm in diameter. The high precision of ±6 nm of the new nuclear magnetic resonance method allows analytical differentiation of lot-to-lot and brand-to-brand droplet size differences in emulsion drug products, critical for drug-quality development, control, and surveillance.

Lymphomatoid papulosis presenting as a rash in a patient with HIV infection.

A 43-year-old Malaysian man with well-controlled HIV infection on combination antiretroviral therapy presented with a six-week history of a widespread rash. The patient was otherwise well but was developing new lesions on a daily basis. Referral to Dermatology instigated punch biopsies, which revealed a diagnosis of lymphomatoid papulosis type A. This case highlights the importance of swift referral, especially in cases of spontaneous regression of symptoms, in order to obtain the correct diagnosis. In most patients, this condition tends to be chronic, with its chronicity and benign clinical course setting it apart from cutaneous anaplastic T-cell lymphoma and Hodgkin's disease, which are major entities in the histological differential diagnosis.

Cancer prevention by targeting angiogenesis.

Healthy individuals can harbour microscopic tumours and dysplastic foci in different organs in an undetectable and asymptomatic state for many years. These lesions do not progress in the absence of angiogenesis or inflammation. Targeting both processes before clinical manifestation can prevent tumour growth and progression. Angioprevention is a chemoprevention approach that interrupts the formation of new blood vessels when tumour cell foci are in an indolent state. Many efficacious chemopreventive drugs function by preventing angiogenesis in the tumour microenvironment. Blocking the vascularization of incipient tumours should maintain a dormancy state such that neoplasia or cancer exist without disease. The current limitations of antiangiogenic cancer therapy may well be related to the use of antiangiogenic agents too late in the disease course. In this Review, we suggest mechanisms and strategies for using antiangiogenesis agents in a safe, preventive clinical angioprevention setting, proposing different levels of clinical angioprevention according to risk, and indicate potential drugs to be employed at these levels. Finally, angioprevention may go well beyond cancer in the prevention of a range of chronic disorders where angiogenesis is crucial, including different forms of inflammatory or autoimmune diseases, ocular disorders, and neurodegeneration.

Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation.

BACKGROUND: Development of anticancer drugs is challenging. Indeed, much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity. We have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin. In this study, we investigated the delivery and treatment efficiency of PEG surface-modified lipid nanoparticles as a carrier platform. METHODS: We encapsulated antitumor drugs into PEG-modified lipid nanoparticles and these were characterized by size, zeta potential, and encapsulation efficiency. The delivery efficiency into tumor tissue was evaluated using a biodistribution study. To evaluate antitumor efficacy, gold porphyrin or camptothecin (a DNA topoisomerase I inhibitor) were encapsulated and compared using an in vivo neuroblastoma (N2A) model. RESULTS: We showed that drug encapsulation into PEG-modified lipid nanoparticles enhanced the preferential uptake in tumor tissue. Furthermore, higher tumor killing efficiency was observed in response to treatment with PEG-modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin. The in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity. Surface modification of lipophilic nanoparticles with PEG increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity. CONCLUSION: This specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy.

Tumor angiogenesis as a target for dietary cancer prevention.

Between 2000 and 2050, the number of new cancer patients diagnosed annually is expected to double, with an accompanying increase in treatment costs of more than $80 billion over just the next decade. Efficacious strategies for cancer prevention will therefore be vital for improving patients' quality of life and reducing healthcare costs. Judah Folkman first proposed antiangiogenesis as a strategy for preventing dormant microtumors from progressing to invasive cancer. Although antiangiogenic drugs are now available for many advanced malignancies (colorectal, lung, breast, kidney, liver, brain, thyroid, neuroendocrine, multiple myeloma, myelodysplastic syndrome), cost and toxicity considerations preclude their broad use for cancer prevention. Potent antiangiogenic molecules have now been identified in dietary sources, suggesting that a rationally designed antiangiogenic diet could provide a safe, widely available, and novel strategy for preventing cancer. This paper presents the scientific, epidemiologic, and clinical evidence supporting the role of an antiangiogenic diet for cancer prevention.

Priming with a combination of proangiogenic growth factors enhances wound healing in streptozotocin-induced diabetes in mice.

BACKGROUND: Numerous proangiogenic growth factors have been shown to improve impaired wound healing. This study evaluated the effects of subcutaneous pretreatment with a combination of proangiogenic growth factors on wound closure, mechanical properties, vessel density, and morphology. METHODS: Thirty-six Balb/c mice with streptozotocin-induced diabetes were divided into 3 groups. A mixture of VEGF (35.0 µg), bFGF (2.5 µg), and PDGF (3.5 µg) was administered subcutaneously 3, 5, and 7 days prior to wounding in the first group, whereas the second group received three doses of 3.5 µg PDGF. Wound sizes were assessed daily and the repaired tissues were harvested 7 days after wound closure. RESULTS: Complete closure (≥95% healing of initial wound area) was reached in all proangiogenic pretreated animals by day 17, whereas the PDGF monotherapy group needed up to 20 days for complete closure. By the time of tissue harvesting on day 24, complete closure was not reached in all control animals. Punch biopsy material revealed 1.6-fold higher vessel densities in the proangiogenic combination-pretreated group than in the controls. CONCLUSIONS: Proangiogenic priming revealed several significant effects on diabetic wound healing: faster time to closure, a higher vessel density, and improved functional outcome.

Priming with a combination of proangiogenic growth factors improves wound healing in normoglycemic mice.

Growth factors and/or angiogenic factors are supposed to improve wound healing. The aim of our study was to evaluate the effects of subcutaneous pretreatment with combinatory proangiogenic factors on wound closure, mechanical properties, vessel density and morphology. Twenty-eight Balb/c mice were divided equally into two groups. A mixture of VEGF (35.0 µg), bFGF (2.5 µg) and PDGF (3.5 µg) was administered subcutaneously 3, 5 and 7 days to 14 mice before full thickness skin punch biopsy wounding, whereas 14 control animals received three injections of 0.2 ml saline solution. Wound sizes were assessed daily and the repaired tissues were harvested 7 days after complete wound closure. Complete closure (≥ 95% healing of initial wound area) was reached in all proangiogenic pretreated animals on day 10, whereas controls needed 13 days for complete closure. Tensile strengths were nearly twofold higher compared to the controls (p ≤ 0.01). The punch biopsy material revealed 4.2-fold higher vessel densities in the proangiogenic pretreated group. On day 17, the vessel densities in the proangiogenic pretreated wounds were also 3.2-fold higher compared to the untreated controls. No significant differences were seen in the collagen ratio. Pretreatment with proangiogenic factors revealed several significant effects on wound healing: faster time to closure, a higher vessel density and a better functional outcome. These results suggest a beneficial effect of pretreatment with combinatory growth factors in mouse skin wounds without impaired wound healing. This might be exploited in further investigations in diabetic healing as a therapeutic approach for elective surgery.

Impact of combinatory growth factor application on rabbit Achilles tendon injury with operative versus conservative treatment: a pilot study.

Acute Achilles tendon (AT) rupture is a common injury with a comparatively high complication rate. Presently, surgical treatments compete with nonoperative treatment modalities. The aim of this study was to elucidate the possible beneficial effects of short-term combinatory application of growth factors on tendon healing during operative or conservative treatment. In this controlled laboratory study, the left ATs of 40 adult New Zealand White rabbits were transected and either sutured or treated conservatively. Half of the animals from each treatment modality group repetitively received a mixture of VEGF165, bFGF, and rPDGF which was administered peritendineally. The left legs were immobilized with external fixateurs for 6 weeks. The ATs were harvested 3 months after intervention. Tensile strength tests revealed no significant differences between operative and conservative treatments. Compared to the normal right ATs, 60% of the average breaking strength was reached 3 months after surgery. Growth factor application did not result in significant improvements. Only a tendency towards higher blood vessel densities was noted in the groups treated with the factors. Collagen type I/III ratios also displayed no significant differences. This study indicates that there is no difference in the biomechanical outcome of conservative versus operative AT rupture treatment and only a marginal impact of short-term combinatory growth and angiogenesis factor application.

Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case.

BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date. OBSERVATIONS: An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions). CONCLUSIONS: Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti-tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.

Cloning and developmental expression of kinesin superfamily7 (kif7) in the brackish medaka (Oryzias melastigma), a close relative of the Japanese medaka (Oryzias latipes).

kif7 is a member of the kinesin superfamily members which are molecular motor proteins that move along microtubules in a highly regulated manner through ATP hydrolysis. In this paper, we report on the cloning of the Oryziasmelastigmakif7 (omkif7) using primers designed according to the Japanese medaka (Oryziaslatipes) database. The cloned omkif7 has an open reading frame of 3762bp and is deduced to encode a polypeptide of 1254 amino acids that possesses the putative ATP-binding and microtubule-binding motifs in its motor domain at the N-terminal region. We characterized the cloned omkif7 by comparison with the zebrafish kif7. Both omkif7 and zebrafish kif7 are shown to be expressed in all embryonic stages and adult tissues examined with higher expression level in the testis and ovary. Whole-mount in situ hybridization revealed that the expression of omkif7 is ubiquitous during the early stages of embryonic development, but became more restrictive and localized to the brain, fin bud and eye at later development. This study suggested that the brackish O.melastigma can serve as a good seawater model organism for developmental studies by utilizing the resources developed from its close relative of the Japanese medaka.

Antiangiogenesis in the treatment of skin cancer.

Angiogenesis is the formation of new capillary blood vessels from existing vasculature. Cancers are dependent upon angiogenesis for their growth. Inhibition of angiogenesis can slow, halt, or regress tumors. Angiogenesis inhibition is now validated for the treatment of cancer using a variety of approved biologic, small molecule, multitargeting, and immunomodulatory agents. In the skin, strategies to inhibit angiogenesis-signaling pathways include blockade of COX-2, m-TOR, sonic hedgehog, growth factor receptor activation, and activation of Toll-like receptors (TLR). The agent with the most clinical experience as a topical antiangiogenic therapy is imiquimod. Imiquimod is a TLR agonist, with immune response modifying properties that also stimulates antiangiogenic cytokines, downregulates the expression of proangiogenic factors, upregulates the expression of endogenous inhibitors, and induces endothelial cell apoptosis. By titrating its dosing for angiogenesis inhibitory activity and not for gross inflammation, imiquimod can be applied in an efficacious and well-tolerated fashion to treat skin cancer.

Choriogenin mRNA as a sensitive molecular biomarker for estrogenic chemicals in developing brackish medaka (Oryzias melastigma).

Teleost choriogenins, precursors of the inner layer subunits of the egg envelope, are regarded as sensitive biomarkers for estrogenic pollutants. In this study, two full-length cDNAs, omChgH and omChgL, which encode the choriogenin H and L forms, respectively, were isolated from a brackish medaka, Oryzias melastigma. 17beta-Estradiol (E2; 10 microg/L)-dependent expression of omChgH and omChgL was observed starting at embryonic stage 34 and restricted exclusively to the liver. In hatchlings, E2 induction of omChgH was stronger than that of omChgL. Static exposure of adult fish to E2 (0, 1, 10, 100, and 500 ng/L), 17alpha-ethinylestradiol (EE2; 0, 1, 10, 100 and 500 ng/L), 4-nonylphenol (NP; 0, 1, 10, 100, and 200 microg/L), and bisphenol A (BPA; 0, 1, 10, 100, and 200 microg/L) in artificial seawater for 7 days resulted in dose-dependent induction of both genes in the liver. In the male livers, the sensitivity of omChgH to these estrogenic compounds was higher than that of omChgL; the lowest-observed-effect concentrations (LOECs) of E2, EE2, NP, and BPA on omChgH were 10 ng/L, 10 ng/L, 100 microg/L and 100 microg/L, respectively, and on omChgL were 100 ng/L, 100 ng/L, 100 microg/L, and 200 microg/L, respectively. All these suggest that omChgH can be used as a highly sensitive biomarker for monitoring estrogenic chemicals in the marine environment.