Radiation control by defects in dark-state resonant photonic lattices.

In this Letter, we present and explain novel radiation properties enabled by defects in resonant photonic lattices (PLs). Incorporating a defect breaks the lattice symmetry and generates radiation through the stimulation of leaky waveguide modes near the non-radiant bound (or dark) state spectral location. Analyzing a simple one-dimensional (1D) subwavelength membrane structure, we show that the defects produce local resonant modes that correspond to asymmetric guided-mode resonances (aGMRs) in spectra and near-field profiles. Without a defect, a symmetric lattice in the dark state is neutral, generating only background scattering. Incorporating a defect into the PL induces high reflection or transmission by robust local resonance radiation depending on the background radiation state at the bound state in the continuum (BIC) wavelengths. With the example of a lattice under normal incidence, we demonstrate defect-induced high reflection as well as high transmission. The methods and results reported here have significant potential to enable new modalities of radiation control in metamaterials and metasurfaces based on defects.

Cytoskeleton disruption by the metabolic inhibitor 3-bromopyruvate: implications in cancer therapy.

The small molecule 3-bromopyruvate (3BP), is an anticancer molecule that acts by hindering glycolysis and mitochondrial function leading to energy depletion and consequently, to cell death. In this work we have focused on understanding how the glycolytic inhibition affects cancer cell structural features. We showed that 3BP leads to a drastic decrease in the levels of ß-actin and α-tubulin followed by disorganization and shrinkage of the cytoskeleton in breast cancer cells. 3BP inhibits cell migration and colony formation independently of the activity of metalloproteinases. To disclose if these structural alterations occurred prior to 3BP toxic effect, non-toxic concentrations of 3BP were used and we could observe that 3BP was able to inhibit energy production and induce loss of ß-actin and α-tubulin proteins. This was accompanied with alterations in cytoskeleton organization and an increase in E-cadherin levels which may indicate a decrease in cancer cells aggressiveness. In this study we demonstrate that 3BP glycolytic inhibition of breast cancer cells is accompanied by cytoskeleton disruption and consequently loss of migration ability, suggesting that 3BP can potentially be explored for metastatic breast cancer therapy.

Analysis of local invasion and regional spread in malignant sublingual gland tumour: Implications for surgical planning.

Malignant tumours arising from the sublingual glands are very rare, and the extent and frequency of local invasion or regional spread in malignant sublingual gland tumour (MSLT) has not been fully studied due to the disease rarity. To provide comprehensive features of local and regional spread of MSLT, we reviewed 20 surgical cases for detailed pathological analyses among 26 cases diagnosed as having primary MSLT. Adenoid cystic carcinoma (ACC) was the most common pathological subtype, followed by mucoepidermoid carcinoma. Disease-free and overall survivals at 5 years were 76.1 % and 77.7 %, respectively. High-grade malignant tumours and grade 2-3 ACC accounted for 41.7 % and 85.7 %. Clinical and pathological extraparenchymal extensions were found in 34.6 % and 80.0 %, respectively. Tumour invasion to the lingual nerve and submandibular gland/ductal system were also detected in 40.0 % and 28.6 %. The incidences of lingual nerve invasion in ACC and ACC ≥4 cm were 30.8 % and 42.9 %. Regional nodal involvement occurred in seven of 26 cases, and all metastatic lymph nodes were found in neck levels Ib and IIa. In summary, a significant portion of MSLT cases consisted of high-grade tumours and grade 2-3 ACC; therefore local invasion into adjacent structures should be cautiously evaluated in cases of MSLT.

Melanoma of the Sinonasal Tract: Value of a Septate Pattern on Precontrast T1-Weighted MR Imaging.

BACKGROUND AND PURPOSE: Various tumors of the sinonasal tract can exhibit high signal intensity on T1WI. The purpose of this study was to determine the value of a septate pattern on precontrast T1WI for diagnosing sinonasal melanoma. MATERIALS AND METHODS: Retrospectively, 3 observers independently reviewed MR images of 31 histologically proved sinonasal melanomas with special attention to the presence or absence of a septate pattern on precontrast T1WI, defined as alternating hyperintense and hypointense striations on precontrast T1WI. For comparison, we evaluated the prevalence of a septate pattern on precontrast T1WI in 106 nonmelanomatous sinonasal malignant tumors with 16 different histologic types. We also tried to identify the histopathologic features responsible for the septate pattern on precontrast T1WI. RESULTS: Twenty-seven (87.1%) of 31 sinonasal melanomas showed hyperintense foci on T1WI, among which a septate pattern on precontrast T1WI was seen in 23 (74.2%), while 22 (20.8%) of 106 nonmelanomatous malignant tumors demonstrated hyperintense foci on T1WI, among which only 3 (2.8%) showed a septate pattern on precontrast T1WI. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a septate pattern on precontrast T1WI for the diagnosis of sinonasal melanoma were 74%, 97%, 88%, 93%, and 92%, respectively. Although limited due to the retrospective nature, 4 of 23 histologically reviewed sinonasal melanomas revealed an uneven distribution of melanin with alternating melanin and fibrous bands within the tumors. CONCLUSIONS: A septate pattern on precontrast T1WI might be an adjunctive imaging finding for the diagnosis of sinonasal melanoma. This might be attributed histologically to an uneven distribution of melanin and hemorrhage within the tumors.

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease.

BACKGROUND: Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. RESULTS: After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. CONCLUSIONS: Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.

The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside.

At the beginning of the twenty-first century, 3-bromopyruvate (3BP), a simple alkylating chemical compound was presented to the scientific community as a potent anticancer agent, able to cause rapid toxicity to cancer cells without bystander effects on normal tissues. The altered metabolism of cancers, an essential hallmark for their progression, also became their Achilles heel by facilitating 3BP's selective entry and specific targeting. Treatment with 3BP has been administered in several cancer type models both in vitro and in vivo, either alone or in combination with other anticancer therapeutic approaches. These studies clearly demonstrate 3BP's broad action against multiple cancer types. Clinical trials using 3BP are needed to further support its anticancer efficacy against multiple cancer types thus making it available to more than 30 million patients living with cancer worldwide. This review discusses current knowledge about 3BP related to cancer and discusses also the possibility of its use in future clinical applications as it relates to safety and treatment issues.

Prognostic relevance of pretransplant Deauville score on PET-CT and presence of EBV DNA in patients who underwent autologous stem cell transplantation for ENKTL.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) for extranodal natural killer/T-cell lymphoma (ENKTL) is a reasonable option for a subset of patients. The impact of response status, according to positron emission tomography/computed tomography (PET/CT) results and/or presence of circulating EBV DNA prior to ASCT, has not yet been established. We analyzed 27 ENKTL patients with pre-ASCT circulating EBV DNA who had undergone pre-ASCT PET/CT between 2009 and 2014. We classified patients into two groups based on the result of pretransplantation assessment: a favorable risk group (pretransplant five-point Deauville score (DS) of 1-2 based on PET/CT and no detectable EBV DNA) and an unfavorable risk group (DS 1-2 with detectable EBV DNA, DS 3-5 with or without detectable EBV DNA). After a median follow-up of 37 months, overall survival and PFS were significantly different between the two groups (median OS: not reached for favorable risk group vs 7.0 months for unfavorable risk group, P=0.017; median PFS: 16.0 vs 5.0 months, P=0.019). Multivariate analysis revealed that pre-ASCT DS and EBV DNA was the only independent prognostic factor considering stage, IPI and NKPI. Precise assessment of the status of disease before transplantation may provide more benefit from ASCT to ENKTL patients.

A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas.

BACKGROUND: Everolimus, an oral mTOR inhibitor, has single-agent activity against relapsed lymphomas. Thus, we carried out a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma (PTCL) based on our phase I study results. PATIENTS AND METHODS: Participants (n = 30) received CHOP with 5 mg everolimus per day from day 1 to 14 every 21 days for a total of six cycles. The primary end point was the overall response rate (ORR), which included complete response (CR) and partial response (PR) to this regimen. Immunohistochemistry was used to evaluate the expression of phosphatase and tensin homology (PTEN) and phosphorylated S6 kinase (pS6K) as a response. RESULTS: The objective response rate was 90% with CR (n = 17) and PR (n = 10). The CR rate was different among subtypes; angioimmunoblastic T-cell lymphoma (AITL, n = 3) had a CR whereas PTCL-not-otherwise specified and ALK-negative anaplastic large-cell lymphoma (ALCL) patients showed 63% (12/19) and 29% (2/7) of CR rate, respectively. This difference in CR rate among subtypes was associated with PTEN loss because PTEN loss was not seen in AITL but 33% of ALCL patients. The most common toxicity was hematological, with 80% of patients experiencing at least one event of grade 3/4 neutropenia, and 60% of patients had grade 3/4 thrombocytopenia. CONCLUSION: The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN.

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin.

BACKGROUND: Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL). PATIENTS AND METHODS: We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity. RESULTS: A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study. CONCLUSIONS: Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.

EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity?

BACKGROUND: Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults. PATIENTS AND METHODS: We analyzed patients with de novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731). RESULTS: A total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83-4.47; P < 0.001], but not in the young group (HR 1.17; 95% CI 0.35-3.89; P = 0.801). CONCLUSION: A substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and 'EBV-positive DLBCL in young adults' needs to be considered as a clinically distinct disease entity. ClinicalTrials.gov: NCT02060435.

Relevance of hepatoduodenal ligament lymph nodes in resectional surgery for gastric cancer.

BACKGROUND: Hepatoduodenal lymph node (HDLN) positivity is considered distant metastasis in gastric cancer according to the seventh American Joint Committee on Cancer (AJCC) classification. In contrast, the International Union Against Cancer seventh edition and the Japanese Gastric Cancer Association both consider HDLN as a regional lymph node that can be included in the context of a curative resection. The purpose of this study was to determine whether there was justification for considering HDLN involvement as a distant metastasis for which resectional surgery could not have survival benefit. METHODS: This study enrolled consecutive patients with gastric cancer having D2 or greater resections, with removal and pathological assessment of the HDLN, between 1989 and 2009. The pathological stage of all patients was determined based on the seventh AJCC criteria, with HDLN included as a regional lymph node. RESULTS: A total of 1872 patients had their HDLN removed, of whom 68 had a metastatic lymph node in the hepatoduodenal ligament. The 5-year survival rate of these 68 patients was 30 per cent, compared with 47·7 per cent for those with stage III (P < 0·001) and 9·8 per cent for those with stage IV (P = 0·007) HDLN-negative tumours. The 5-year survival rate of 41 patients with HDLN metastasis and no evidence of distant metastasis at any other site was significantly higher than that among 120 patients with stage IV disease without HDLN metastasis (P < 0·001), whereas 5-year survival did not differ between the 41 patients with stage I-III disease with HDLN metastasis and 568 patients with stage III tumours without HDLN metastasis (P = 0·184). HDLN metastasis was not a significant factor for survival in multivariable analysis. CONCLUSION: It is inappropriate to include the HDLN in the distant metastatic lymph node group in gastric cancer. The seventh AJCC criteria for node grouping should be revised.

The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases.

BACKGROUND: Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. PATIENTS AND METHODS: To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. RESULTS: The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. CONCLUSION: DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.

Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype.

In this multicentre study, we examined 60 cases of Type II enteropathy-associated T-cell lymphoma (EATL) from the Asia-Pacific region by histological review, immunohistochemistry and molecular techniques. Patients were mostly adult males (median age: 58 years, male:female 2.6:1), presenting with abdominal pain (60%), intestinal perforation (40%) and weight loss (28%). None had a history of coeliac disease and the median survival was only 7 months. Histologically, these tumours could be divided into (i) central tumour zone comprising a monotonous population of neoplastic lymphocytes, (ii) peripheral zone featuring stunted villi and morphologically atypical lymphocytes showing epitheliotropism, and (iii) distant mucosa with normal villous architecture and cytologically normal intra-epithelial lymphocytes (IELs). Characterized by extensive nuclear expression of Megakaryocyte-associated tyrosine kinase (MATK) (87%) and usually a CD8(+)CD56(+) (88%) cytotoxic phenotype, there was frequent aberrant expression of CD20 (24%). T-cell receptor (TCR) expression was silent or not evaluable in 40% but of the remainder, there was predominant expression of TCRαß over TCRγδ (1.6:1). In keeping with the normal ratio of IEL subsets, CD8(+) cases showed predominant CD8αα homodimer expression (77%), regardless of TCR lineage. These tumours constitute a distinct entity from classical EATL, and the pathology may reflect tumour progression from IEL precursors, remnants of which are often seen in the distant mucosa.

Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis.

BACKGROUND: Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. PATIENTS AND METHODS: This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. RESULTS: Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1-2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. CONCLUSION: In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

The relaxant effect of ginseng saponin on the bladder and prostatic urethra: an in vitro and in vivo study.

AIM: To assess the effects of ginseng saponin on relaxation of the bladder and prostatic urethra and to determine its mechanism of action. MATERIALS AND METHODS: For the in vitro study, prostatic urethra muscle strips were harvested from 18 male New Zealand rabbits. The strips were mounted in organ baths and connected to force displacement transducers. After stabilization, maximal tissue contractions were obtained by the application of phenylepinephrine to the urethra strips, and a dose-response curve for ginseng saponin was constructed (10(-6)-10(-2)M). After pretreatment of urethra strips with N-nitro-L-arginine methyl ester (L-NAME), another dose-response curve for ginseng saponin was constructed. For the in vivo study, we used adult male Sprague-Dawley rats divided into three groups [control, partial bladder outlet obstruction (PBOO) and saponin-fed groups], and we monitored the vesical pressure (P(ves)) and urethral perfusion pressure (UPP). RESULTS: The ginseng saponin induced a significant dose-dependent relaxant effect on the prostatic urethra strips. A significant relaxant effect of ginseng saponin was observed from 10(-3)M, and ginseng saponin significantly relaxed urethra strips by 50.2 ± 20.26% at 10(-2)M. The relaxant effect was partially inhibited with L-NAME pretreatment. In the in vivo study, the change in UPP between baseline and relaxation was significantly higher in the saponin group than in the control or PBOO group (p < 0.001). The saponin group showed a significantly lower baseline P(ves) than the PBOO group. CONCLUSIONS: We observed a significant relaxation effect of ginseng saponin on the bladder and prostatic urethra in both in vitro and in vivo studies. The mechanism by which ginseng saponin induces relaxation appears to involve the nitric oxide/nitric oxide synthase pathway.

A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.

The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly.

Silencing of the GnRH type 1 receptor blocks the antiproliferative effect of the GnRH agonist, leuprolide, on the androgen-independent prostate cancer cell line DU145.

This study investigated the mechanism of action of a gonadotropin-releasing hormone (GnRH) agonist, leuprolide, on proliferation of the hormone-refractory prostate cancer cell line DU145, transfected with short hairpin RNA (shRNA), to reduce expression of the GNRHR1 gene (which encodes the GnRH type 1 receptor). DU145 cell proliferation in the presence of leuprolide (10(-9) and 10(-7) M) or control medium was measured before and after GnRHR1 knockdown. Reverse transcription-polymerase chain reaction and Western blot analysis were used to measure the degree of GNRHR1 silencing. DU145 cells treated with leuprolide (10(-9) and 10(-7) M) showed significant growth inhibition compared with control-treated DU145 cells. Transfection with GNRHR1 -shRNA significantly decreased GNRHR1 expression at 48 h. DU145 cells transfected with silencing GNRHR1 -shRNA showed normal growth patterns; however, there was no significant inhibition of proliferation of DU145 cells transfected with GNRHR1 -shRNA compared with cells transfected with control-shRNA in response to leuprolide. These data demonstrated that the antiproliferative effect of leuprolide was mediated by the GnRHR1.