The Sidney Kimmel Comprehensive Cancer Center

Baltimore, MD, United States

The Sidney Kimmel Comprehensive Cancer Center

Baltimore, MD, United States
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Xie Y.,University of Nebraska Medical Center | Murray-Stewart T.,The Sidney Kimmel Comprehensive Cancer Center | Wang Y.,University of Nebraska Medical Center | Yu F.,University of Nebraska Medical Center | And 4 more authors.
Journal of Controlled Release | Year: 2017

Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines. © 2016 Elsevier B.V.

Franco-Paredes C.,Phoebe Putney Memorial Hospital | Franco-Paredes C.,Hospital Infantil Of Mexico | Womack T.,Phoebe Putney Memorial Hospital | Bohlmeyer T.,Phoebe Putney Memorial Hospital | And 8 more authors.
The Lancet Infectious Diseases | Year: 2015

Cryptococcosis is a fungal disease caused by Cryptococcus neoformans and Cryptococcus gattii. By inhalation and subsequent pulmonary infection, it may disseminate to the CNS and cause meningitis or meningoencephalitis. Most cases occur in immunosuppressed hosts, including patients with HIV/AIDS, patients receiving immunosuppressing drugs, and solid organ transplant recipients. However, cryptococcosis also occurs in individuals with apparently healthy immune systems. A growing number of cases are caused by C gattii, with infections occurring in both immunosuppressed and immunocompetent individuals. In the majority of documented cases, treatment of C gattii infection of the CNS requires aggressive management of raised intracranial pressure along with standard antifungal therapy. Early cerebrospinal fluid evacuation is often needed through placement of a percutaneous lumbar drain or ventriculostomy. Furthermore, pharmacological immunosuppression with a high dose of dexamethasone is sometimes needed to ameliorate a persistently increased inflammatory response and to reduce intracranial pressure. In this Grand Round, we present the case of an otherwise healthy adolescent female patient, who, despite aggressive management, succumbed to C gattii meningoencephalitis. We also present a review of the existing literature and discuss optimum clinical management of meningoencephalitis caused by C gattii. © 2015 Elsevier Ltd.

Kelly R.J.,The Sidney Kimmel Comprehensive Cancer Center | Thomas A.,U.S. National Cancer Institute | Rajan A.,U.S. National Cancer Institute | Chun G.,U.S. National Cancer Institute | And 12 more authors.
Annals of Oncology | Year: 2013

Background: This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) andpaclitaxel (P). Patients and methods: Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m2) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m2 in combination with standard dosesof C (AUC6) and P (200 mg/m2) for six cycles. S was administered as a continuous intravenous infusion(CIVI) over 72 h in 21-day treatment cycles. Study end points included safety and toxic effect, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: Treatment with S was well tolerated, and toxic effects were mostly hematologicalin the phase II study. Two (11%) partial responses were observed with a median PFS of 5.7 months and median OS 16.1 months. Pharmacodynamic analysis did not demonstrate an association with response. Conclusion: The combination of S (10 mg/m2/day 72-h CIVI) administered with C and P every 3 weeks exhibited a favorable safety profile but failed to demonstrate an improvement in response rate in advanced NSCLC. Clinical trial number: NCT01100931. © The Author 2013.

Wilop S.,RWTH Aachen | van Gemmeren T.B.,RWTH Aachen | Lentjes M.H.F.M.,Maastricht University | van Engeland M.,Maastricht University | And 4 more authors.
Epigenetics | Year: 2011

The family of suppressor of cytokine signaling (SOCS) proteins negatively regulates cytokine signaling in different cellular pathways including interleukin-6 (IL-6). Since IL-6 plays an essential role in regulating growth and survival of multiple myeloma (MM) cells, methylation-associated dysregulation of SOCS3 may contribute to the malignant phenotype of MM cells. We used methylation-specific PCR (MSP) to assess the methylation status of the SOCS3 CpG island in 5 MM cell lines and 70 patient samples. Additional bisulfite sequencing and RNA expression analysis using reverse transcriptase polymerase chain reaction was performed in two cell lines. We identified aberrant SOCS3 methylation in 3/5 MM cell lines. Methylation of SOCS3 in cell lines was associated with transcriptional downregulation. Treatment of OPM-2 cells, which carry a methylated SOCS3 gene, with the demethylating agent 5-aza-2'-deoxycytidine restored SOCS3 expression in association with partial demethylation. In patient samples with malignant plasma cell disorders, SOCS3 was methylated in 5/70 (7.1%) cases, while there was no aberrant SOCS3 methylation in normal peripheral blood and non-malignant bone marrow cells. We found an association of SOCS3 methylation with extramedullary manifestations (p=0.03), plasma cell leukemia (P=0.003), elevated LDH (p=0.001), increased creatinine (p=0.01) and remarkably shortened survival (6.9 vs. 56.1 months, HR 5.9, p=0.0007). Our findings reveal a novel epigenetic event possibly implicated in the pathogenesis of MM and representing a potential prognostic biomarker. Epigenetic dysregulation of the SOCS3 gene may interfere with the cellular response to the complex cytokine network thus supporting survival and expansion of MM cells. © 2011 Landes Bioscience.

Vander Griend D.J.,The Sidney Kimmel Comprehensive Cancer Center | Vander Griend D.J.,The Brady Urological Institute | Litvinov I.V.,The Sidney Kimmel Comprehensive Cancer Center | Litvinov I.V.,Johns Hopkins Hospital | And 3 more authors.
International Journal of Biological Sciences | Year: 2014

In normal prostate, androgen-dependent androgen receptor (AR) signaling within prostate stromal cells induces their secretion of paracrine factors, termed "andromedins" which stimulate growth of the epithelial cells. The present studies demonstrate that androgen-dependent andromedin-driven growth stimulation is counter-balanced by androgen-induced AR signaling within normal adult prostate epithelial cells resulting in terminal G0 growth arrest coupled with terminal differentiation into ΔNp63-negative, PSA-expressing secretory luminal cells. This cell autonomous AR-driven terminal differentiation requires DNA-binding of the AR protein, is associated with decreases in c-Myc m-RNA and protein, are coupled with increases in p21, p27, and SKP-2 protein expression, and does not require functional p53. These changes result in down-regulation of Cyclin D1 protein and RB phosphoryation. shRNA knockdown documents that neither RB, p21, p27 alone or in combination are required for such AR-induced G0 growth arrest. Transgenic expression of a constitutive vector to prevent c-Myc down-regulation overrides AR-mediated growth arrest in normal prostate epithelial cells, which documents that AR-induced c-Myc down-regulation is critical in terminal growth arrest of normal prostate epithelial cells. In contrast, in prostate cancer cells, androgen-induced AR signaling paradoxically up-regulates c-Myc expression and stimulates growth as documented by inhibition of both of these responses following exposure to the AR antagonist, bicalutamide. These data document that AR signaling is converted from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells during prostatic carcinogenesis and that this conversion involves a gain of function for regulation of c-Myc expression. © Ivyspring International Publisher.

Wu D.,University of Louisville | Erwin D.,Management Information Services Inc. | Rosner G.L.,The Sidney Kimmel Comprehensive Cancer Center
Lung Cancer | Year: 2011

We investigate screening sensitivity, transition probability and sojourn time in lung cancer screening for male heavy smokers using the Mayo Lung Project data. We also estimate the lead time distribution, its property, and the projected effect of taking regular chest X-rays for lung cancer detection. Methods: We apply the statistical method developed by Wu et al. [1] using the Mayo Lung Project (MLP) data, to make Bayesian inference for the screening test sensitivity, the age-dependent transition probability from disease-free to preclinical state, and the sojourn time distribution, for male heavy smokers in a periodic screening program. We then apply the statistical method developed by Wu et al. [2] using the Bayesian posterior samples from the MLP data to make inference for the lead time, the time of diagnosis advanced by screening for male heavy smokers. The lead time is distributed as a mixture of a point mass at zero and a piecewise continuous distribution, which corresponds to the probability of no-early-detection, and the probability distribution of the early diagnosis time. We present estimates of these two measures for male heavy smokers by simulations. Results: The posterior sensitivity is almost symmetric, with posterior mean 0.89, and posterior median 0.91; the 95% highest posterior density (HPD) interval is (0.72, 0.98). The posterior mean sojourn time is 2.24 years, with a posterior median of 2.20 years for male heavy smokers. The 95% HPD interval for the mean sojourn time is (1.57, 3.35) years. The age-dependent transition probability is not a monotone function of age; it has a single maximum at age 68. The mean lead time increases as the screening time interval decreases. The standard error of the lead time also increases as the screening time interval decreases. Conclusion: Although the mean sojourn time for male heavy smokers is longer than expected, the predictive estimation of the lead time is much shorter. This may provide policy makers important information on the effectiveness of the chest X-rays and sputum cytology in lung cancer early detection. © 2010.

Sfanos K.S.,The Sidney Kimmel Comprehensive Cancer Center | de Marzo A.M.,The Sidney Kimmel Comprehensive Cancer Center | de Marzo A.M.,Johns Hopkins University
Histopathology | Year: 2012

Chronic inflammation is now known to contribute to several forms of human cancer, with an estimated 20% of adult cancers attributable to chronic inflammatory conditions caused by infectious agents, chronic non-infectious inflammatory diseases and/or other environmental factors. Indeed, chronic inflammation is now regarded as an 'enabling characteristic' of human cancer. The aim of this review is to summarize the current literature on the evidence for a role for chronic inflammation in prostate cancer aetiology, with a specific focus on recent advances regarding the following: (i) potential stimuli for prostatic inflammation; (ii) prostate cancer immunobiology; (iii) inflammatory pathways and cytokines in prostate cancer risk and development; (iv) proliferative inflammatory atrophy (PIA) as a risk factor lesion to prostate cancer development; and (v) the role of nutritional or other anti-inflammatory compounds in reducing prostate cancer risk. © 2011 Blackwell Publishing Limited.

Tanner E.J.,The Sidney Kimmel Comprehensive Cancer Center | Chi D.S.,Sloan Kettering Cancer Center | Eisenhauer E.L.,Sloan Kettering Cancer Center | Diaz-Montes T.P.,The Sidney Kimmel Comprehensive Cancer Center | And 3 more authors.
Gynecologic Oncology | Year: 2010

Objective: To compare the survival impact of diagnosing recurrent disease by routine surveillance testing versus clinical symptomatology in patients with recurrent epithelial ovarian cancer (EOC) who have achieved a complete response following primary therapy. Methods: We identified all patients who underwent primary surgery for EOC at two institutions between 1/1997 and 12/2004 and were diagnosed with recurrent disease following a complete clinical response to primary chemotherapy. Survival and post-recurrence management were compared between asymptomatic patients in which recurrent disease was diagnosed at a scheduled visit by routine surveillance testing and symptomatic patients in which recurrent disease was diagnosed based on clinical symptomatology at an unscheduled office visit or hospitalization. Results: Of the 121 patients that met inclusion criteria, 22 (18.2%) were diagnosed with a symptomatic recurrence. Median primary PFS was similar for asymptomatic and symptomatic patients (24.8 versus 22.6 months, P = 0.36); however, post-recurrence survival was significantly greater in asymptomatic patients (45.0 versus 29.4 months, P = 0.006). Secondary cytoreductive surgery (SCRS) was attempted equally in both groups (41% versus 32%, P = NS); however, optimal residual disease (≤5mm) was more often achieved in asymptomatic patients (90% versus 57%, P = 0.053). On multivariate analysis, detection of asymptomatic recurrence was a significant and independent predictor of improved overall survival (P = 0.001). Median OS was significantly greater for asymptomatic patients (71.9 versus 50.7 months, P = 0.004). Conclusions: In patients with platinum-sensitive EOC, detection of asymptomatic recurrences by routine surveillance testing was associated with a high likelihood of optimal SCRS in operative candidates and extended overall survival. © 2010.

Zachariah A.,Government of Kerala | Zong J.-C.,The Sidney Kimmel Comprehensive Cancer Center | Long S.Y.,The Sidney Kimmel Comprehensive Cancer Center | Latimer E.M.,National Elephant Herpesvirus Laboratory | And 3 more authors.
Journal of Wildlife Diseases | Year: 2013

Up to 65% of deaths of young Asian elephants (Elephas maximus) between 3 mo and 15 yr of age in Europe and North America over the past 20 yr have been attributed to hemorrhagic disease associated with a novel DNA virus called elephant endotheliotropic herpesvirus (EEHV). To evaluate the potential role of EEHV in suspected cases of a similar lethal acute hemorrhagic disease occurring in southern India, we studied pathologic tissue samples collected from field necropsies. Nine cases among both orphaned camp and wild Asian elephants were identified by diagnostic PCR. These were subjected to detailed gene subtype DNA sequencing at multiple PCR loci, which revealed seven distinct strains of EEHV1A and one of EEHV1B. Two orphan calves that died within 3 days of one another at the same training camp had identical EEHV1A DNA sequences, indicating a common epidemiologic source. However, the high level of EEHV1 subtype genetic diversity found among the other Indian strains matches that among over 30 EEHV1 strains that have been evaluated from Europe and North America. These results argue against the previous suggestions that this is just a disease of captive elephants and that the EEHV1 virus has crossed recently from African elephant (Loxodonta africana) hosts to Asian elephants. Instead, both the virus and the disease are evidently widespread in Asia and, despite the disease severity, Asian elephants appear to be the ancient endogenous hosts of both EEHV1A and EEHV1B. © Wildlife Disease Association 2013.

Pu J.J.,The Sidney Kimmel Comprehensive Cancer Center
BMJ case reports | Year: 2011

Gallbladder carcinosarcoma is a rare gastrointestinal tract malignant tumour, which contains both epithelial cancer component and mesenchymal sarcoma component. Because of its unique anatomic location and unspecific medical presentation, preoperative diagnosis is difficult. The prognosis of gallbladder carcinoma is poor with median survival time of 5.5 months. T- and N-staging system has no role in cancer prognostic stratification. Currently, we still have limited experience in managing this form of notorious cancer. Surgical resection is the common practice in treating gallbladder carcinoma though recurrence rate is high (80%). Here, we report a 59-year-old female with new diagnosed gallbladder carcinosarcoma. She was found to have a carcinosarcoma masse at gallbladder extending into proximal bile ducts with no metastatic lesion. She underwent a radical cholangiocholecystocholedochectomy and Roux-en-Y hepatocholangioduodenostomy. Postsurgery, she received six cycles of adjuvant chemotherapy consisting of oxaliplatin and 5-fluorouracil. She maintains in complete remission 6 months after adjuvant chemotherapy.

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