We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; 1 alpha,25-dihydroxy-16-ene-23... more We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (Ro24-5531); and tamoxifen to inhibit the development of androgen-promoted carcinomas of the accessory sex organs of male Lobund-Wistar rats. Invasive carcinomas of the seminal vesicle (SV) and anterior prostate (AP) were induced in Lobund-Wistar rats with three different combinations of initiator [N-nitroso-N-methylurea (NMU)] and promoter [testosterone propionate (TP)]: (a) high-dose NMU (30 mg/kg) + high-dose TP (20 mg via implant every 2 months); (b) high-dose NMU + low-dose TP (10 mg implanted every 2 months); or (c) low-dose NMU (15 mg/kg) + low-dose TP. During the period of TP administration, rats were fed a diet supplemented with either N-(4-hydroxyphenyl)retinamide (1 or 2 mmol/kg diet), Ro24-5531 (1.25 or 2.5 nmol/kg diet), tamoxifen (0.5 or 5 mg/kg diet), or vehicle alone. After sacrifice at 8.5 or 11 months, the prostate-seminal vesicle complex from each rat was processed in toto and histologically staged as to the extent of tumor involvement. In animals given low-dose TP, all three agents were significantly effective at reducing the incidence of invasive carcinomas of the SV and, to a lesser degree, the AP. Of the three agents, tamoxifen given in high dose (5 mg/kg) had the strongest activity, reducing the occurrence of invasive SV carcinomas from 72-83% in controls to 6% (P = 0.0001) and the occurrence of invasive AP carcinomas from 50-72% to 18-22% (P < 0.05).
Over the last 30 years there have been dramatic changes in the manner in which we diagnose and ma... more Over the last 30 years there have been dramatic changes in the manner in which we diagnose and manage prostate cancer. With prostate cancer screening efforts there has been a shift towards smaller, more clinically localized tumors. Prostate cancers are often multifocal and display heterogeneity of grade and molecular features between tumor foci and even within individual tumors. Pathologic evaluation of tissue obtained by needle biopsy is necessary for diagnosis and to determine the extent and biologic aggressiveness of prostate cancer. However, random needle biopsy sampling protocols are limited by tumor sampling. Pathologic grading of prostate cancer remains one of the strongest predictors of tumor aggressiveness. There have been several refinements in prostate cancer grading using the Gleason grading system over the years due to shifts in grading practices among genitourinary pathologists. The advent of new molecular technologies may offer improved prognostication for cancers diagnosed by needle biopsy. Newer biopsy techniques such as template-guided mapping biopsies will improve tumor sampling to better account for tumor heterogeneity and multifocality. Maximizing the amount of information that can be gleaned from the biopsy is paramount in order to identify those patients that may be candidates for active surveillance or targeted focal therapy. Continued refinements in our ability to recognize the histologic and molecular features of cancer that contribute to its aggressiveness will ultimately improve the predictive accuracy of prostate biopsies.
The field of exploring potential biomarkers for prostate cancer prevention continues to expand ra... more The field of exploring potential biomarkers for prostate cancer prevention continues to expand rapidly. In addition to a limited scope of histologic alterations, mainly PIN, a growing array of promising technologies (eg, computer-assisted analysis), and molecules involved in cell-cycle regulations, angiogenesis, and structural and numerical chromosomal alterations are potential candidates for surrogate endpoint biomarkers for prevention trials. Before any these potential candidates are adopted, however, the technical, interpretational, and validation requirements must be satisfied. More important, it is crucial to demonstrate that modulation of the frequency of the biomarker decreases the rate of cancer development.
Although osteopontin (Opn) is a strong inhibitor of calcium oxalate crystallization in vitro, its... more Although osteopontin (Opn) is a strong inhibitor of calcium oxalate crystallization in vitro, its role in stone formation in vivo is unknown. We investigated the renal expression of Opn in normal, ethylene glycol (EG), and EG + ammonium chloride-treated rats. Male Sprague-Dawley rats were divided into three groups. Group 1 (N = 5) was the control. Animals in Group 2 (N = 6) received 4 weeks of treatment with 0.75% EG, and Group 3 animals (N = 6) were given 1 week of treatment with 0.75% EG and 1.0% NH4Cl. The kidneys were then examined for crystal deposition and Opn localization. In normal rats, staining for Opn was evident in the proximal tubules (PT; S3 &amp;amp;amp;amp;gt; S2 &amp;amp;amp;amp;gt; S1), distal tubules (DT), and the thick ascending limbs of Henle (TAL) and a few collecting ducts (CD). All rats in Group 3 had significant crystal deposition throughout their kidneys. In Group 2 rats, Opn staining increased in all segments of the PT, DT, and TAL. Staining in these tubular segments was even greater in Group 3 rats, including the CD and the papillary surface epithelium. In addition, Opn was present within all crystal deposits. Renal Opn expression in experimental urolithiasis becomes stronger and more diffuse as the severity of the lithiasis-inducing treatment increases. These results are consistent with the hypothesis that renal epithelial cells produce larger amounts of osteopontin to combat the development of kidney stones.
To be effective, a biorepository facility must have a well-defined organizational structure that ... more To be effective, a biorepository facility must have a well-defined organizational structure that encompasses all aspects of biospecimen management from specimen procurement and processing to data annotation, regulatory compliance, and distribution. The personnel represent the biggest asset for a well-functioning biorepository. The scope and type of biospecimens to be banked should be defined in order to establish infrastructure needs. The establishment of well-run biorepositories and its ability to address the needs of the scientific community is limited by significant funding challenges. Development of a business model that adequately incorporates capital investment and operating costs is essential for long-term sustainability.
The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV... more The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV-associated nephropathy (HIVAN), especially in the African American patient population. However, various patterns of glomerulonephritis (GN) are not uncommon, collectively accounting for nearly half of the renal biopsies performed in HIV patients. Most GNs that occur in HIV patients are immune complex mediated, often with concurrent infections such as hepatitis B or C. Fibrillary glomerulonephritis (FGN), a rare primary glomerular disease, has only been reported in 2 HIV patients, and both patients had concurrent hepatitis C (HCV) infection. Here we report a unique case of FGN with unusual ultrastructural morphology in an HIV-positive African American patient without concurrent HCV infection. The patient presented with nephrotic range proteinuria and renal insufficiency. A percutaneous kidney biopsy showed mesangial and segmental endocapillary proliferative GN with crescent formation. Immunofluorescence studies revealed IgG-, κ-, and C3-positive deposits in the mesangium and capillary loops. Electron microscopy demonstrated diagnostic features of FGN: randomly-arranged fibrillary deposits with a diameter of 15 - 30 nm. The deposits had an unusual distribution pattern of hump-like large deposits on the subepithelial aspect. Additionally, smaller deposits were also present in the mesangium. To our knowledge, this is the first reported case of FGN in an HIV patient without concurrent HCV infection. .
A 61-year-old female with end-stage renal disease who was undergoing hemodialysis presented with ... more A 61-year-old female with end-stage renal disease who was undergoing hemodialysis presented with an 8-week history of upper and lower extremity weakness associated with skin tightness and contractures. Physical examination, blood analysis, electromyogram and skin biopsy. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Methylprednisolone, thalidomide and physical therapy.
CN01-02 The Prostate Cancer Prevention Trial (PCPT), sponsored by the National Cancer Institute a... more CN01-02 The Prostate Cancer Prevention Trial (PCPT), sponsored by the National Cancer Institute and coordinated by the Southwest Oncology Group, was the first large-scale phase III chemoprevention trial for prostate cancer. The study randomized over 18,000 men to receive either finasteride (5 mg/day) or placebo and followed them with annual examinations and prostate-specific antigen (PSA) measurements. Biopsies of the prostate were obtained during the study if clinically indicated and also at the end of the study regardless of exam or PSA findings. The PCPT was designed to answer a single question: could finasteride, a selective type 1 5α-reductase inhibitor (5ARI), prevent the diagnosis of prostate cancer in men taking the drug versus placebo over a seven year period. In this aspect, the PCPT was a success. The study found a 24.8% reduction in the seven-year period-prevalence of prostate cancer in the finasteride group compared with placebo.1 However, the secondary findings of the ...
Cutaneous T‐cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary synd... more Cutaneous T‐cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30%, and none of these treatments are thought to be curative. C–C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4‐IL2 bispecific immunotoxin (CCR4‐IL2 IT) targeting both CCR4 and CD25. CCR4‐IL2 IT demonstrated superior efficacy against CCR4+CD25+CD30+ CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug‐enabling studies of CCR4–IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4‐IL2 IT versus the US Food and Drug Administration–approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4–IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4–IL2 IT and brentuximab was more effective than brentuximab or CCR4–IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4–IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment.
We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; 1 alpha,25-dihydroxy-16-ene-23... more We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (Ro24-5531); and tamoxifen to inhibit the development of androgen-promoted carcinomas of the accessory sex organs of male Lobund-Wistar rats. Invasive carcinomas of the seminal vesicle (SV) and anterior prostate (AP) were induced in Lobund-Wistar rats with three different combinations of initiator [N-nitroso-N-methylurea (NMU)] and promoter [testosterone propionate (TP)]: (a) high-dose NMU (30 mg/kg) + high-dose TP (20 mg via implant every 2 months); (b) high-dose NMU + low-dose TP (10 mg implanted every 2 months); or (c) low-dose NMU (15 mg/kg) + low-dose TP. During the period of TP administration, rats were fed a diet supplemented with either N-(4-hydroxyphenyl)retinamide (1 or 2 mmol/kg diet), Ro24-5531 (1.25 or 2.5 nmol/kg diet), tamoxifen (0.5 or 5 mg/kg diet), or vehicle alone. After sacrifice at 8.5 or 11 months, the prostate-seminal vesicle complex from each rat was processed in toto and histologically staged as to the extent of tumor involvement. In animals given low-dose TP, all three agents were significantly effective at reducing the incidence of invasive carcinomas of the SV and, to a lesser degree, the AP. Of the three agents, tamoxifen given in high dose (5 mg/kg) had the strongest activity, reducing the occurrence of invasive SV carcinomas from 72-83% in controls to 6% (P = 0.0001) and the occurrence of invasive AP carcinomas from 50-72% to 18-22% (P < 0.05).
Over the last 30 years there have been dramatic changes in the manner in which we diagnose and ma... more Over the last 30 years there have been dramatic changes in the manner in which we diagnose and manage prostate cancer. With prostate cancer screening efforts there has been a shift towards smaller, more clinically localized tumors. Prostate cancers are often multifocal and display heterogeneity of grade and molecular features between tumor foci and even within individual tumors. Pathologic evaluation of tissue obtained by needle biopsy is necessary for diagnosis and to determine the extent and biologic aggressiveness of prostate cancer. However, random needle biopsy sampling protocols are limited by tumor sampling. Pathologic grading of prostate cancer remains one of the strongest predictors of tumor aggressiveness. There have been several refinements in prostate cancer grading using the Gleason grading system over the years due to shifts in grading practices among genitourinary pathologists. The advent of new molecular technologies may offer improved prognostication for cancers diagnosed by needle biopsy. Newer biopsy techniques such as template-guided mapping biopsies will improve tumor sampling to better account for tumor heterogeneity and multifocality. Maximizing the amount of information that can be gleaned from the biopsy is paramount in order to identify those patients that may be candidates for active surveillance or targeted focal therapy. Continued refinements in our ability to recognize the histologic and molecular features of cancer that contribute to its aggressiveness will ultimately improve the predictive accuracy of prostate biopsies.
The field of exploring potential biomarkers for prostate cancer prevention continues to expand ra... more The field of exploring potential biomarkers for prostate cancer prevention continues to expand rapidly. In addition to a limited scope of histologic alterations, mainly PIN, a growing array of promising technologies (eg, computer-assisted analysis), and molecules involved in cell-cycle regulations, angiogenesis, and structural and numerical chromosomal alterations are potential candidates for surrogate endpoint biomarkers for prevention trials. Before any these potential candidates are adopted, however, the technical, interpretational, and validation requirements must be satisfied. More important, it is crucial to demonstrate that modulation of the frequency of the biomarker decreases the rate of cancer development.
Although osteopontin (Opn) is a strong inhibitor of calcium oxalate crystallization in vitro, its... more Although osteopontin (Opn) is a strong inhibitor of calcium oxalate crystallization in vitro, its role in stone formation in vivo is unknown. We investigated the renal expression of Opn in normal, ethylene glycol (EG), and EG + ammonium chloride-treated rats. Male Sprague-Dawley rats were divided into three groups. Group 1 (N = 5) was the control. Animals in Group 2 (N = 6) received 4 weeks of treatment with 0.75% EG, and Group 3 animals (N = 6) were given 1 week of treatment with 0.75% EG and 1.0% NH4Cl. The kidneys were then examined for crystal deposition and Opn localization. In normal rats, staining for Opn was evident in the proximal tubules (PT; S3 &amp;amp;amp;amp;gt; S2 &amp;amp;amp;amp;gt; S1), distal tubules (DT), and the thick ascending limbs of Henle (TAL) and a few collecting ducts (CD). All rats in Group 3 had significant crystal deposition throughout their kidneys. In Group 2 rats, Opn staining increased in all segments of the PT, DT, and TAL. Staining in these tubular segments was even greater in Group 3 rats, including the CD and the papillary surface epithelium. In addition, Opn was present within all crystal deposits. Renal Opn expression in experimental urolithiasis becomes stronger and more diffuse as the severity of the lithiasis-inducing treatment increases. These results are consistent with the hypothesis that renal epithelial cells produce larger amounts of osteopontin to combat the development of kidney stones.
To be effective, a biorepository facility must have a well-defined organizational structure that ... more To be effective, a biorepository facility must have a well-defined organizational structure that encompasses all aspects of biospecimen management from specimen procurement and processing to data annotation, regulatory compliance, and distribution. The personnel represent the biggest asset for a well-functioning biorepository. The scope and type of biospecimens to be banked should be defined in order to establish infrastructure needs. The establishment of well-run biorepositories and its ability to address the needs of the scientific community is limited by significant funding challenges. Development of a business model that adequately incorporates capital investment and operating costs is essential for long-term sustainability.
The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV... more The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV-associated nephropathy (HIVAN), especially in the African American patient population. However, various patterns of glomerulonephritis (GN) are not uncommon, collectively accounting for nearly half of the renal biopsies performed in HIV patients. Most GNs that occur in HIV patients are immune complex mediated, often with concurrent infections such as hepatitis B or C. Fibrillary glomerulonephritis (FGN), a rare primary glomerular disease, has only been reported in 2 HIV patients, and both patients had concurrent hepatitis C (HCV) infection. Here we report a unique case of FGN with unusual ultrastructural morphology in an HIV-positive African American patient without concurrent HCV infection. The patient presented with nephrotic range proteinuria and renal insufficiency. A percutaneous kidney biopsy showed mesangial and segmental endocapillary proliferative GN with crescent formation. Immunofluorescence studies revealed IgG-, κ-, and C3-positive deposits in the mesangium and capillary loops. Electron microscopy demonstrated diagnostic features of FGN: randomly-arranged fibrillary deposits with a diameter of 15 - 30 nm. The deposits had an unusual distribution pattern of hump-like large deposits on the subepithelial aspect. Additionally, smaller deposits were also present in the mesangium. To our knowledge, this is the first reported case of FGN in an HIV patient without concurrent HCV infection. .
A 61-year-old female with end-stage renal disease who was undergoing hemodialysis presented with ... more A 61-year-old female with end-stage renal disease who was undergoing hemodialysis presented with an 8-week history of upper and lower extremity weakness associated with skin tightness and contractures. Physical examination, blood analysis, electromyogram and skin biopsy. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Methylprednisolone, thalidomide and physical therapy.
CN01-02 The Prostate Cancer Prevention Trial (PCPT), sponsored by the National Cancer Institute a... more CN01-02 The Prostate Cancer Prevention Trial (PCPT), sponsored by the National Cancer Institute and coordinated by the Southwest Oncology Group, was the first large-scale phase III chemoprevention trial for prostate cancer. The study randomized over 18,000 men to receive either finasteride (5 mg/day) or placebo and followed them with annual examinations and prostate-specific antigen (PSA) measurements. Biopsies of the prostate were obtained during the study if clinically indicated and also at the end of the study regardless of exam or PSA findings. The PCPT was designed to answer a single question: could finasteride, a selective type 1 5α-reductase inhibitor (5ARI), prevent the diagnosis of prostate cancer in men taking the drug versus placebo over a seven year period. In this aspect, the PCPT was a success. The study found a 24.8% reduction in the seven-year period-prevalence of prostate cancer in the finasteride group compared with placebo.1 However, the secondary findings of the ...
Cutaneous T‐cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary synd... more Cutaneous T‐cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30%, and none of these treatments are thought to be curative. C–C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4‐IL2 bispecific immunotoxin (CCR4‐IL2 IT) targeting both CCR4 and CD25. CCR4‐IL2 IT demonstrated superior efficacy against CCR4+CD25+CD30+ CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug‐enabling studies of CCR4–IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4‐IL2 IT versus the US Food and Drug Administration–approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4–IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4–IL2 IT and brentuximab was more effective than brentuximab or CCR4–IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4–IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment.
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