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Whether from environmental and occupational hazards or from topical pharmaceuticals, the human skin comes into contact with various chemicals every day. In vivo experiments not only require large investments of both time and money, but in vivo experiments can also be unethical due to the need to intentionally or incidentally expose humans or animals to toxic chemicals. Comparatively, in vitro experiments offer ethical and financial advantages when combined with the opportunity to selectively choose chemicals for experimentation. With in vivo experimentation being so infeasible, many scientists have chosen to make their in vitro data available publicly. Using these data, a detailed database containing 73 chemicals was created with a robust set of descriptors to be used in connection with mathematical modeling to predict diffusion, permeability, and partition coefficients. This resulting database is tailored to be easily used in various coding languages., (© 2024. The Author(s).)

Dermal uptake is an important and complex exposure route for a wide range of chemicals. Dermal exposure can occur due to occupational settings, pharmaceutical applications, environmental contamination, or consumer product use. The large range of both chemicals and scenarios of interest makes it difficult to perform generalizable experiments, creating a need for a generic model to simulate various scenarios. In this study, a model consisting of a series of four well-mixed compartments, representing the source solution (vehicle), stratum corneum, viable tissue, and receptor fluid, was developed for predicting dermal absorption. The model considers experimental conditions including small applied doses as well as evaporation of the vehicle and chemical. To evaluate the model assumptions, we compare model predictions for a set of 26 chemicals to finite dose in-vitro experiments from a single laboratory using steady-state permeability coefficient and equilibrium partition coefficient data derived from in-vitro experiments of infinite dose exposures to these same chemicals from a different laboratory. We find that the model accurately predicts, to within an order of magnitude, total absorption after 24 h for 19 of these chemicals. In combination with key information on experimental conditions, the model is generalizable and can advance efficient assessment of dermal exposure for chemical risk assessment., Competing Interests: Declaration of competing interest This manuscript is being submitted exclusively to Chemosphere and this research and the results have not been published previously, and if accepted this paper will not be published elsewhere. None of the authors have financial and personal relationships with other people or organizations that could inappropriately influence our work. All authors have approved this manuscript in its submitted version. The research and manuscript have been reviewed, cleared, and approved by U.S. Environmental Protection Agency. Daniel A. Vallero, Ph.D. Corresponding Author., (Published by Elsevier Ltd.)

Purpose: The nuclear transcription factor nuclear factor-kappa B (NF kappa B) and its inhibitor, I kappa B, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NF kappa B transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NF kappa B has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NF kappa B immunoreactivity in prostate adenocarcinomas (PACs)., Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NF kappa B and I kappa B alpha (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence., Results: Forty-nine percent of PACs overexpressed cytoplasmic NF kappa B, and 63% showed decreased I kappa B expression. Cytoplasmic NF kappa B overexpression correlated with advanced tumor stage (P = 0.048), aneuploidy (P = 0.022), and biochemical disease recurrence (P = 0.001). When we compared the means for the NF kappa B-positive and -negative subgroups, NF kappa B overexpression correlated with preoperative serum prostate-specific antigen (P = 0.04) and DNA index (P = 0.05). Fifteen percent of PACs expressed nuclear NF kappa B, which correlated with high tumor grade (P = 0.001) and advanced stage (P = 0.05). Decreased I kappa B alpha expression correlated with high tumor grade (P = 0.015). On multivariate analysis, tumor stage (P = 0.043) and NF kappa B overexpression (P = 0.006) were independent predictors of biochemical recurrence., Conclusion: These results support a role for NF kappa B pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NF kappa B blockade in decreasing the rate of disease relapse.

Context: Dysregulated cell proliferation caused by inhibitors of programmed cell death (apoptosis) contributes to tumor progression and spread. Aberrant expression of Bcl-2, the most notable inhibitor of apoptosis, has been well characterized in several human malignancies. Recent studies have described a novel apoptosis inhibitor, survivin, in human carcinomas, although its exact role remains to be characterized., Objective: The purpose of this study was to evaluate the immunohistochemical expression of Bcl-2 and survivin proteins in prostate cancer and to correlate the results with clinicopathologic variables., Design: Formalin-fixed, paraffin-embedded tissue sections from 138 cases of prostatic adenocarcinomas (PACs) were immunostained by an automated method using specific antibodies against survivin and Bcl-2. Staining was semiquantitatively scored based on both intensity and distribution, and results were correlated with morphologic and prognostic variables., Results: Of the 138 PACs tested, 113 (82%) expressed survivin. We found no correlation between survivin expression and prognostic variables, including grade, stage, DNA content (ploidy), and recurrence. Bcl-2 expression was positive in 95 (69%) of these 138 cases and correlated with nondiploid DNA content. Fourteen (50%) of 28 nondiploid PACs expressed Bcl-2, compared to 17 (25%) of 68 diploid tumors (P =.02). A trend for association of Bcl-2 expression with tumor stage was noted as follows: 21 (39%) of 54 advanced-stage PACs expressed Bcl-2, in comparison with 20 (24%) of 84 low-stage tumors (P =.07). On univariate analysis, 25 (48%) of the 52 PACs that recurred expressed Bcl-2, as compared with 16 (19%) of the 86 nonrecurrent PACs (P <.001). No correlation was noted between survivin and Bcl-2 expression., Conclusion: Survivin is expressed in a majority of PACs and is not a prognosis-related marker, but may be a potential target for apoptosis-based therapy. Overexpression of Bcl-2 correlates with other prognostic variables and predicts disease recurrence of PACs. These data also suggest that survivin and Bcl-2 may regulate cell proliferation and cell death through different mechanisms.

Purpose: The restricted expression of the surface glycoprotein prostrate-specific membrane antigen (PSMA) to normal prostate tissue, primary and metastatic prostate cancer (PCa), and the neovasculature of various nonprostatic epithelial malignancies has enabled targeting strategies for PCa treatment using anti-PSMA antibodies., Experimental Design: Using prostatectomy specimens, immunohistochemical staining for PSMA (7E11 antibody) was performed on formalin-fixed paraffin-embedded sections of 136 cases of PCa. Cytoplasmic immunoreactivity was scored for intensity and distribution, and results were correlated with tumor grade, pathological stage, DNA ploidy status (Feulgen spectroscopy), and disease recurrence. PSMA mRNA expression in selected primary tumors and metastatic lesions was also detected using in situ hybridization and autoradiography., Results: Generally, PCa cells expressed relatively increased levels of PSMA as compared with benign elements. Among the PCa cases, increased (high) PSMA expression correlated with tumor grade (P = 0.030), pathological stage (P = 0.029), aneuploidy (P = 0.010), and biochemical recurrence (P = 0.001). The mean serum prostate-specific antigen level of 18.28 ng/ml at the time of diagnosis for the PSMA-overexpressing tumors was significantly greater than the mean serum prostate-specific antigen of 9.10 ng/ml for the non-PMSA-overexpressing group (P = 0.006). On multivariate analysis, pathological stage (P = 0.018) and PSMA expression (P = 0.002) were independent predictors of biochemical recurrence. PSMA protein overexpression in high-grade primary PCa tumors and metastatic lesions also correlated with increased PSMA mRNA expression levels using in situ hybridization and autoradiography., Conclusions: This study demonstrates for the first time that overexpression of PSMA in primary PCa correlates with other adverse traditional prognostic factors and independently predicts disease outcome.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading the structural support network for normal and malignant cells, promoting neoplastic cell invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) maintain connective tissue integrity by modulating MMP activity. Formalin-fixed paraffin-embedded tissue sections from 138 prostatic adenocarcinomas (PACs) were immunostained by a combined automated/manual method using monoclonal antibodies against MMP2 and TIMP2. Immunoreactivity was semiquantitatively scored based on stain intensity and distribution, and results were correlated with Gleason grade, pathologic stage, ploidy status, and disease recurrence. One hundred five of 138 (76%) and 113/138 (82%) PACs expressed MMP2 and TIMP2, respectively. Co-expression was observed in 94/138 (68%) of PACs (P =.01), correlated with advanced tumor stage (P =.05), and tended to be associated with disease recurrent cases (P =.07). TIMP2 expression individually correlated with advanced tumor stage (P =.04) and reached near significance with disease recurrence (P =.06). MMP2 expression was also more frequent in recurrent PACs, although this value did not reach statistical significance (P =.07). However, on multivariate analysis, only pathologic stage (P =.009) and ploidy status (P =.03) independently predicted disease recurrence. In conclusion, MMP2 and TIMP2 are co-expressed in a majority of PACs and correlate with prognostic variables. Interestingly, contrary to the previously documented anti-tumor effects of TIMPs, TIMP2 expression appears to have a tumor-promoting role in PACs and warrants further investigation.

In this review, a series of relatively well-documented ancillary biomarkers and emerging molecular assays are evaluated for their relative ability to predict prognosis in prostate cancer. Prognostic factors that have achieved widespread use and classified as Category I by the College of American Pathologists Solid Tumor Prognostic Factor Consensus Conference are compared with newer tests that are beginning to be used in clinical practice (Category II) and emerging molecular-based assays that have yet to be widely validated in the published literature or clinical trials (Category III).

Unlabelled: Postoperative ileus is a concern among surgical patients. Epidural anesthesia and analgesia with local anesthetics can decrease the duration of ileus. Significant systemic absorption of local anesthesia occurs during epidural use. In this study, we examined whether many of the beneficial effects on bowel function seen with epidural lidocaine are also present when the drug is given parenterally. Forty patients undergoing radical retropubic prostatectomy were studied with one half of the patients receiving a lidocaine bolus (1.5 mg/kg) and infusion (3 mg/min, unless weight <70 kg, then 2 mg/min); the other half received a saline infusion. A blind observer recorded the patient's daily pain score, the time the patient first experienced flatulence and had the first bowel movement, and the total use of analgesics. Lidocaine-treated patients first experienced flatulence in a significantly shorter time (P < 0.01) than control patients. Lidocaine patients' hospital stay was also significantly shorter (P < 0.05); on average, they spent 1.1 fewer days in the hospital. I.V. lidocaine initiated before anesthesia and continued 1 h postoperatively significantly sped up the return of bowel function. Lidocaine patients were also more comfortable postoperatively. Many of the bowel function benefits attributed to epidural lidocaine are also present when the drug is administered parenterally. Additionally, the length of hospital stay was reduced in lidocaine-treated patients., Implications: This study prospectively examined whether I.V. lidocaine could affect the return of bowel function after radical prostate surgery. Lidocaine-treated patients had shorter hospital stays, less pain, and faster return of bowel function. In this population, lidocaine infusion can be a useful adjunct in anesthetic management.

Transforming growth factor alpha-Pseudomonas exotoxin-40 (TP40) is a hybrid fusion protein that selectively binds to cancer cells that express the epidermal growth factor receptor. TP40 is then internalized and kills these cells by virtue of its Pseudomonas exotoxin-derived domains. We studied the safety and short-term antitumor activity of intravesical TP40 in 43 patients with refractory superficial bladder cancer. These patients had resected Ta/T1 disease (n = 19), visible Ta or T1 lesions (n = 11), or carcinoma in situ (n = 13). Patients were treated with increasing dose levels of TP40 at 0.15, 0.3, 0.6, 1.2, 2.4, 4.8, or 9.6 mg/week for 6 weeks and evaluated by comparing pretreatment and posttreatment cystoscopic examinations, cytology, and histopathology. All TP40 doses were well tolerated. No evidence of antitumor activity was seen in any of the patients with Ta or T1 lesions. However, 8 of 9 patients with evaluable carcinoma in situ were judged by histopathology of multiple biopsy specimens to exhibit clinical improvement following TP40 therapy. In most of these responsive patients, cystoscopic examination supported the histopathological findings, although cytology of urine and bladder washings persistently demonstrated malignant cells. Therefore, TP40 appears to be a well-tolerated biological agent that may prove to have utility in treating carcinoma in situ of the bladder.

DNA ploidy analysis of five renal oncocytomas, six pure oncocytic-granular renal cell carcinomas, 15 pure clear cell renal carcinomas, and two cases of mixed oncocytic-granular and clear cell heterogenous renal cell carcinomas were determined on Feulgen-stained paraffin sections using the (CAS-200 image Analyzer). All five renal oncocytomas were diploid, as were six oncocytic-granular renal cell carcinomas. Three of the 15 clear renal cell carcinomas were aneuploid. In one heterogeneous renal cell carcinoma, the oncocytic-granular foci were diploid and the clear cell focus was aneuploid. The other heterogeneous renal cell carcinoma was uniformly diploid. In 21 renal cell carcinomas, one of 14 stage I tumors was aneuploid, all four stages II and III tumors were diploid, and two of three stage IV cases were aneuploid. All stages I, II, and III patients were free of disease 3 to 48 months after surgery. All three stage IV cases were dead of their disease within 36 months of surgery. We conclude that DNA analysis by image cytometry best identifies the heterogeneity of ploidy patterns in mixed cell type carcinomas, generally correlates with the stage of disease, and may be of value in predicting overall prognosis of renal epithelial neoplasms. DNA analysis by image cytometry, however, did not reveal significant differences between oncocytic granular cell carcinoma and oncocytoma, since both lesions were generally diploid. The distinction between the two tumors is best made on morphologic grounds.