Nuclear morphometry and molecular biomarkers of actinic keratosis, sun-damaged, and nonexposed skin.

Computer-assisted image analysis is useful for quantifying the histologic and molecular changes of sun-induced squamous cell carcinoma progression. We used the CAS 200 image analysis system to measure nuclear morphometric parameters, p53 expression, and proliferation markers in actinic keratosis (AK), sun-exposed, and normal skin in 51 patients. Nuclear morphometry revealed significant increases in nuclear absorbance, irregularity of nuclear shape, and nuclear size in AK compared with normal and sun-damaged skin. These parameters showed significantly greater variability in AK nuclei. Argyrophyllic nucleolar organizer area and number were also significantly greater in AK compared with sun-damaged skin and normal skin. Ki67 and p53 expressions were both increased in sun-damaged skin relative to normal and greater still in AK. These data are evidence that sun damage induces proliferation and p53 abnormalities before the appearance of nuclear abnormalities and their associated DNA instability. Following these changes during a skin cancer chemopreventative trial can then help assess the efficacy of the agent and help determine where in the progression of neoplastic changes it exerts its biological effects.     

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.     

Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus

Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study investigated the metabolism of the tobacco carcinogens N'- nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples from China than the USA. All microsomal samples activated NDMA. However, most of the microsomal samples did not activate NNK. Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formation of NNN-derived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic- metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.      

Intraperitoneal pretarget radioimmunotherapy with CC49 fusion protein.

PURPOSE: This study examined a pretarget radioimmunotherapy strategy for treatment of an i.p. tumor model (LS174T). EXPERIMENTAL DESIGN: The strategy used regional administration (i.p.) of a novel targeting molecule composed of four CC49 anti-tumor-associated glycoprotein 72 (TAG-72) single-chain antibodies linked to streptavidin as a fusion protein (CC49 fusion protein); 24 hours later, a synthetic clearing agent was administered i.v. to produce hepatic clearance of unbound CC49 fusion protein/synthetic clearing agent complexes. Four hours later, a low molecular weight radiolabeled reagent composed of biotin conjugated to the chelating agent 7,10-tetra-azacyclododecane-N,N',N',N'-tetraacetic acid (DOTA) complexed with (111)In-, (90)Y-, or (177)Lu-DOTA-biotin was injected. RESULTS: Radiolocalization to tumor sites was superior with i.p. administration of radiolabeled DOTA-biotin as compared with i.v. administration. Imaging and biodistribution studies showed excellent tumor localization of radioactivity with (111)In- or (177)Lu-DOTA-biotin. Tumor localization of (111)In-DOTA-biotin was 43% ID/g and 44% ID/g at 4 and 24 hours with the highest normal tissue localization in the kidney with 6% ID/g at 48 and 72 hours. Therapy studies with (90)Y-DOTA-biotin at doses of 400 to 600 microCi or (177)Lu-DOTA-biotin at doses of 600 to 800 microCi produced significant prolongation of survival compared with controls (P = 0.03 and P < 0.01). CONCLUSIONS: Pretarget radioimmunotherapy using regional administration of CC49 fusion protein and i.p. (90)Y- or (177)Lu-DOTA-biotin represents a successful therapeutic strategy in the LS174T i.p. tumor model and this strategy may be applicable to human trials in patients with i.p. ovarian cancer.     

Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome.

PURPOSE: To establish the feasibility of capecitabine with concurrent radiotherapy (XRT) in patients with locally advanced (LA) pancreatic cancer and evaluate the effect of XRT on thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and tumor necrosis factor-alpha (TNF-alpha). PATIENTS AND METHODS: Fifteen patients with LA pancreatic cancer received three-dimensional conformal XRT to a dose of 50.4 Gy with capecitabine at escalating doses from 600 to 1,250 mg/m2 bid (Monday through Friday). Following chemo-XRT, stable and responding patients were treated with capecitabine 2,000 mg/m2 orally bid for 14 days every 21 days. Tumor specimens were procured with endoscopic ultrasound-guided fine-needle aspiration 1 week before and 2 weeks after chemo-XRT to evaluate TP, DPD, and TNF-alpha mRNA levels. RESULTS: Dose-limiting grade 3 diarrhea was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 with XRT. Three patients (20%) achieved partial response. Mean percent difference in TP pre- and post-XRT was 119.2% (P = .1934). There was no significant differences in mean TNF-alpha, or DPD levels pre- and post-XRT (P = .1934 and .4922, respectively). TP and TNF-alpha levels were not significantly correlated both at pre- and post-XRT (P = .670 and P < .154, respectively). Median value of TP:DPD ratios at baseline was 2.65 (range, 0.36 to 11.08). No association between TP:DPD ratio and efficacy of capecitabine or severity of toxicities was identified. CONCLUSION: The recommended dose for phase II evaluation is capecitabine 800 mg/m2 bid (Monday through Friday) with concurrent XRT. This approach offers an easy alternative to intravenous fluorouracil as a radiosensitizer in these patients. Role of TP and TP:DPD ratio warrants further investigation in a larger clinical trial.     

TCDD and PCBs inhibit breast cancer cell proliferation in vitro

The effects on cell proliferation of arylhydrocarbon receptor (AhR) agonists in estrogen-responsive T47D and ZR-75-1 cells were investigated. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the non-ortho-substituted polychlorinated biphenyl (PCB) congeners, PCB 77, PCB 81, PCB 126, and PCB 169 each inhibited 17β-estradiol (E₂)-stimulated cell proliferation in a dose–responsive manner. In the absence of added E₂, TCDD, PCB 77, PCB 81, and PCB 169 had no significant effect on cell proliferation, while PCB 126 at high concentrations caused slight elevations. The order of effective inhibition of E₂-stimulated cell proliferation by the PCB congeners was: PCB 81>PCB 126PCB 169>PCB 77. In the comparative literature, mammalian TEFs for these congeners toxic potency are in the order: PCB 126>PCB 169>PCB 81PCB 77 [Organohalogen Compd. 34 (1997) 237]. Our results thus show an unexpected different pattern for the inhibitory effects of PCBs congeners on E₂-mediated cell proliferation.     

Photochemistry of aqueous pyruvic acid

The study of organic chemistry in atmospheric aerosols and cloud formation is of interest in predictions of air quality and climate change. It is now known that aqueous phase chemistry is important in the formation of secondary organic aerosols. Here, the photoreactivity of pyruvic acid (PA; CH₃COCOOH) is investigated in aqueous environments characteristic of atmospheric aerosols. PA is currently used as a proxy for α-dicarbonyls in atmospheric models and is abundant in both the gas phase and the aqueous phase (atmospheric aerosols, fog, and clouds) in the atmosphere. The photoreactivity of PA in these phases, however, is very different, thus prompting the need for a mechanistic understanding of its reactivity in different environments. Although the decarboxylation of aqueous phase PA through UV excitation has been studied for many years, its mechanism and products remain controversial. In this work, photolysis of aqueous PA is shown to produce acetoin (CH₃CHOHCOCH₃), lactic acid (CH₃CHOHCOOH), acetic acid (CH₃COOH), and oligomers, illustrating the progression from a three-carbon molecule to four-carbon and even six-carbon molecules through direct photolysis. These products are detected using vibrational and electronic spectroscopy, NMR, and MS, and a reaction mechanism is presented accounting for all products detected. The relevance of sunlight-initiated PA chemistry in aqueous environments is then discussed in the context of processes occurring on atmospheric aerosols.     

Salivary secretion in health and disease

Saliva is a complex fluid produced by 3 pairs of major salivary glands and by hundreds of minor salivary glands. It comprises a large variety of constituents and physicochemical properties, which are important for the maintenance of oral health. Saliva not only protects the teeth and the oropharyngeal mucosa, it also facilitates articulation of speech, and is imperative for mastication and swallowing. Furthermore, saliva plays an important role in maintaining a balanced microbiota. Thus, the multiple functions provided by saliva are essential for proper protection and functioning of the body as a whole and for the general health. A large number of diseases and medications can affect salivary secretion through different mechanisms, leading to salivary gland dysfunction and associated oral problems, including xerostomia, dental caries and fungal infections. The first part of this review article provides an updated insight into our understanding of salivary gland structure, the neural regulation of salivary gland secretion, the mechanisms underlying the formation of saliva, the various functions of saliva and factors that influence salivary secretion under normal physiological conditions. The second part focuses on how various diseases and medical treatment including commonly prescribed medications and cancer therapies can affect salivary gland structure and function. We also provide a brief insight into how to diagnose salivary gland dysfunction.     

Therapeutic plasma exchange in neuromyelitis optica: A case series

Neuromyelitis optica (NMO) is a relapsing inflammatory disease of the central nervous system that predominantly affects the spinal cord and optic nerves. The clinical hallmark of the disease is a step‐wise deterioration of visual and spinal cord function. This study reviews patients with steroid resistant relapsing NMO presenting for therapeutic plasma exchange (TPE) at our institution from December 2005 to December 2012. A total of five patients were treated with single volume TPE. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist) with the patient and Transfusion Medicine physician's final assessment of response made at the time of the last TPE in the series and the treating neurologist's assessment of response made at the time of the next neurological exam after the last TPE. A total of 17 TPE series were performed with the average course of therapy being three series (ranged 1–5) with five TPE (ranged 3–7) per series. All patients demonstrated improvement with each series of TPE and all procedures were well tolerated with only transient and well‐described reactions all of which were successfully resolved with minor or no sequelae. J. Clin. Apheresis 29:171–177, 2014. © 2013 Wiley Periodicals, Inc.     

Adverse Side Effects of Psychotropic Medication and Challenging Behavior: Pilot Work Assessing Impact

Psychotropic medications are often prescribed to reduce challenging behavior in individuals with intellectual and developmental disabilities (IDD). Functional analyses (FAs) have demonstrated utility in assessing medication impact on behavior; however, the impact of adverse side effects (ASE) on challenging behavior is under-assessed. The purpose of this study was to develop a methodology, similar to FAs, to explore potential medication ASE impact on challenging behavior in seven individuals with IDD. Results revealed response rate differences in designed ASE conditions for most participants. Outcomes support further development and use of this methodology to assess the presence and impact of ASEs.