Ultrastrong Electron-Phonon Coupling in Uranium-Organic Frameworks Leading to Inverse Luminescence Temperature Dependence.

Electron-phonon interactions, crucial in condensed matter, are rarely seen in Metal-Organic Frameworks (MOFs). Detecting these interactions typically involves analyzing luminescence in lanthanide- or actinide-based compounds. Prior studies on Ln- and Ac-based MOFs at high temperatures revealed additional peaks, but these were too faint for thorough analysis. In our research, we fabricated a high-quality, crystalline uranium-based MOF (KIT-U-1) thin film using a layer-by-layer method. Under UV light, this film showed two distinct "hot bands," indicating a strong electron-phonon interaction. At 77 K, these bands were absent, but at 300 K, a new emission band appeared with half the intensity of the main luminescence. Surprisingly, a second hot band emerged above 320 K, deviating from previous findings in rare-earth compounds. We conducted a detailed ab-initio analysis employing time-dependent density functional theory to understand this unusual behaviour and to identify the lattice vibration responsible for the strong electron-phonon coupling. The KIT-U-1 film's hot-band emission was then utilized to create a highly sensitive, single-compound optical thermometer. This underscores the potential of high-quality MOF thin films in exploiting the unique luminescence of lanthanides and actinides for advanced applications.

Primary Ovarian Pregnancy after Bilateral Tubal Sterilization.

Tubal sterilization is considered a permanent method of contraception because it is highly effective. However, pregnancy can still occur following a successful procedure and such pregnancies are likely to be ectopic. Primary ovarian pregnancy is one of the rarest forms of ectopic pregnancy having incidence of 1/7000-1/40,000 in live births and 0.5-3% of all ectopic gestations. In this paper, we report a rare case of ovarian pregnancy after tubal sterilization. All women who are offered this procedure should always be educated about its failure rate. And in women presenting with acute abdomen, a prior history of tubal sterilization doesn't preclude the possibility of ectopic pregnancy. Keywords: Contraception; ovarian pregnancy; tubal sterilization.

Clinical outcomes in patients with metastatic castrate-resistant prostate cancer treated with abiraterone with or without ongoing androgen deprivation therapy: A retrospective case-control study.

INTRODUCTION: Abiraterone and concurrent androgen deprivation therapy (ADT) are used in the treatment of patients with metastatic castration-resistant prostate cancer. Recently, it has been suggested that the use of abiraterone alone (without ADT) may have comparable efficacy to abiraterone with ongoing ADT. Here, we sought to assess the impact of ADT cessation in patients beginning abiraterone for castration-resistant prostate cancer. METHODS: We identified 39 patients at our institution who received abiraterone alone (with discontinuation of ADT) between 2011 and 2022. We then procured a comparable group of 39 patients (matched by age, Gleason score, and prostate-specific antigen [PSA] level) who received abiraterone with ongoing ADT during the same period. We assessed and compared clinical outcomes in the two groups (abiraterone-alone vs. abiraterone-ADT) with respect to PSA response rates, PSA progression-free survival, and overall survival. Results were adjusted using Cox proportional-hazards multivariable models. RESULTS: The median PSA before treatment initiation was 12.7 (range: 0.2-199) ng/mL in the abiraterone-alone group and 15.5 (range: 0.6-212) ng/mL in the abiraterone-ADT group. Use of abiraterone alone adequately suppressed testosterone levels in 35/37 (94.6%) patients. Patients receiving abiraterone alone had a median PSA reduction of 80.2% versus 79.5% in patients receiving abiraterone plus ADT. The median PSA progression-free survival in patients receiving abiraterone alone was 27.4 versus 25.8 months in patients receiving abiraterone plus ADT (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.65-1.71; p = 0.82). In addition, abiraterone alone was associated with an overall survival of 3.6 versus 3.1 years in patients receiving abiraterone plus ADT (HR 0.90; 95% CI 0.50-1.62; p = 0.72). There were no differences in PFS or OS between groups after performing Cox multivariable regression analyses. CONCLUSION: Use of abiraterone alone was associated with comparable clinical outcomes to patients who received abiraterone together with ADT. Further prospective studies are warranted to evaluate the impact of abiraterone alone on treatment outcomes and cost savings.

Spin-orbit coupling corrections for the GFN-xTB method.

Spin-orbit coupling (SOC) is crucial for correct electronic structure analysis in molecules and materials, for example, in large molecular systems such as superatoms, for understanding the role of transition metals in enzymes, and when investigating the energy transfer processes in metal-organic frameworks. We extend the GFN-xTB method, popular to treat extended systems, by including SOC into the hamiltonian operator. We followed the same approach as previously reported for the density-functional tight-binding method and provide and validate the necessary parameters for all elements throughout the Periodic Table. The parameters have been obtained consistently from atomic SOC calculations using the density-functional theory. We tested them for reference structures where SOC is decisive, as in the transition metal containing heme moiety, chromophores in metal-organic frameworks, and in superatoms. Our parameterization paves the path for incorporation of SOC in the GFN-xTB based electronic structure calculations of computationally expensive molecular systems.

A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck.

PURPOSE: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. PATIENTS AND METHODS: This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment. RESULTS: 52 patients [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79). CONCLUSIONS: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

DFTB Parameters for the Periodic Table: Part III, Spin-Orbit Coupling.

Spin-orbit coupling (SOC) is crucially important for the correct description of the electronic structure and transport properties of inorganic semiconductors, and for assessing topological properties as in topological insulators. We present a consistent set of SOC parameters for the density-functional based tight-binding (DFTB) method covering the elements throughout the periodic table. The parameters are based on atomic SOC data calculated at the level of density-functional theory (DFT). We tested these parameters for representative systems with significant SOC, including transition metal dichalcogenide two-dimensional crystals, III-V bulk semiconductors, and topological insulators. Our parameterization opens the door for DFTB-based electronic structure and transport calculations of very large systems, such as twisted van der Waals heterostructures.

Immunoglobulin Restores Immune Responses to BTH1677 in Patients With Low Levels of Antibodies to Beta-glucan.

BACKGROUND: BTH1677 is a beta-glucan pathogen-associated molecular pattern (PAMP) being evaluated as a novel immunotherapy of cancer. We previously described that the presence of antibodies against beta-glucan (ABA) in serum is necessary for BTH1677 antitumoral activity. We hypothesized that infusion of immunoglobulin can reinstate responses to BTH1677 in individuals with low ABA levels. PATIENTS AND METHODS: We report two single-patient studies: one in a patient with metastatic colorectal cancer who received BTH1677, combined with tumor targeting antibody cetuximab; and a second in a patient with metastatic neuroendocrine tumor who received BTH1677 combined with immune checkpoint inhibitor pembrolizumab. RESULTS: The patients had low serum titers of ABA and low innate immune effector functionality induced by BTH1677. Addition of intravenous immunoglobulins restored innate immune activity of BTH1677 and induced clinically meaningful anti-tumoral activity, with long-term disease control. CONCLUSION: Infusion of immunoglobulin can restore activity of BTH1677 in individuals with low serum ABA level.

Nutrition Status and Health-Related Quality of Life Among Outpatients With Advanced Head and Neck Cancer.

This pilot study evaluated nutrition status and health-related quality of life (HRQOL) outcomes among outpatients with head and neck cancer (HNC). Data were collected from 19 patients (18 males, 1 female) during 3 time points: once before chemoradiotherapy (CRT) initiation and 1 and 3 months after CRT. Nutrition status was evaluated using the Scored Patient-Generated Subjective Global Assessment (PG-SGA). Malnutrition was defined as PG-SGA stage B (moderate/suspected malnutrition) or stage C (severely malnourished). HRQOL was assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its HNC-specific module (QLQ-H&N35). We found that well-nourished patients reported having fewer issues with pain, fatigue, appetite loss, chewing, sticky saliva, coughing, and social eating than those categorized as malnourished (P < .05). The association between the global quality-of-life score and PG-SGA score was statistically significant but weak in strength (r = -0.37, P = .012). Although PG-SGA identified 70% as either moderately or severely malnourished before treatment initiation, the mean body mass index was in the overweight category (29 ± 5 kg/m2 ). Compared with pretreatment, patients reported more severe problems with chewing, swallowing, sticky saliva, dry mouth, speech, social eating, and taste and smell sensations at 1-month follow-up, although issues with dry mouth persisted 3 months post treatment (P = .003). In conclusion, malnourished patients reported having worse HRQOL symptoms compared with well-nourished patients. Routine nutrition and psychosocial assessment through PG-SGA and EORTC tools might help identify patients in need of nutrition and psychosocial care.

FDG-PET/CT for Assessing the Response to Neoadjuvant Chemotherapy in Bladder Cancer Patients.

PURPOSE: To determine the accuracy of 18F-fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET/CT) scans in assessing the response to neoadjuvant chemotherapy (NAC) in patients with bladder cancer scheduled to undergo radical cystectomy (RC). PATIENTS AND METHODS: All patients treated at our center for muscle-invasive bladder cancer (MIBC) were counseled and offered NAC before RC. FDG-PET/CT scans were performed before the initiation of chemotherapy and after completion of the regimen. Patients with disease with complete response to NAC were those who had (pT0) or residual carcinoma-in-situ (pTis) on final pathology. Those who were downstaged from MIBC to non-MIBC were considered to have a chemosensitive tumor. We used percentage reduction in standardized maximum uptake value (SUVmax) from PET/CT scans as our measure to correlate with the final pathology after cystectomy. RESULTS: Thirty-seven patients with MIBC who underwent NAC followed by RC were included in the final analysis. FDG-PET/CT had 75% sensitivity (89.66% specificity) in identifying those with complete pathologic response with a 100% change in SUVmax, and 83% sensitivity (94% specificity) for the detection of chemosensitive tumors. CONCLUSION: FDG-PET/CT can help determine the response of primary tumor to NAC in patients with MIBC and thus can more accurately predict the prognosis of the patients, or potentially the appropriate time for cystectomy.

Malnutrition Identified by the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition Consensus Criteria and Other Bedside Tools Is Highly Prevalent in a Sample of Individuals Undergoing Treatment for Head and Neck Cancer.

BACKGROUND: Using the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (Academy/ASPEN) Consensus malnutrition definition, we estimated malnutrition prevalence in a sample of individuals with head and neck cancer (HNC) and compared it with the Patient-Generated Subjective Global Assessment (PG-SGA). We also investigated the utility of the 50-kHz phase angle (PA) and 200-kHz/5-kHz impedance ratio (IR) to identify malnutrition. MATERIALS AND METHODS: Nineteen individuals (18 males, 1 female) scheduled to undergo chemoradiotherapy were seen at 5 time points during and up to 3 months after treatment completion. Multiple-frequency bioelectrical impedance analysis, PG-SGA, nutrition-focused physical examination, anthropometry, dietary intake, and handgrip strength data were collected. RESULTS: Using the Consensus, 67% were found to be malnourished before treatment initiation; these criteria diagnosed malnutrition with overall good sensitivity (94%) and moderate specificity (43%) compared with PG-SGA. Over all pooled observations, "malnourished" (by Consensus but not PG-SGA category) had a lower mean PA (5.2 vs 5.9; P = .03) and higher IR (0.82 vs 0.79; P = .03) than "well-nourished" categorizations, although the clinical relevance of these findings is unclear. PA and IR were correlated with higher PG-SGA score (r = -0.35, r = 0.36; P < .01) and handgrip strength (r = 0.48, r = -0.47; P < .01). CONCLUSION: The Academy/ASPEN Consensus and the PG-SGA were in good agreement. It is unclear whether PA and IR can be used as surrogate markers of nutrition status or muscle loss.

Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients had minor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed. Dasatinib 70 mg twice daily does not have activity nor is it well tolerated in unselected patients with advanced stage, previously treated NSCLC.

The diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography and computed tomography in staging bladder cancer: a single-institution study and a systematic review with meta-analysis.

PURPOSE: The purpose of this study was to assess the diagnostic accuracy of 18F-fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET-CT) to predict nodal metastases in patients with bladder cancer (BC) scheduled to undergo radical cystectomy (RC). METHODS: We retrospectively reviewed records of patients diagnosed with BC and scheduled to undergo RC at our center from January 2011 through February 2015, who also underwent FDG-PET-CT at the time of diagnosis. All patients underwent RC and an extended pelvic lymph node dissection as the reference standard. The primary endpoints were the sensitivity, specificity and overall accuracy of FDG-PET-CT in detecting lymph node metastasis. We also examined its accuracy in identifying distant metastasis. In addition, we conducted a protocol-driven systematic review and meta-analysis of accuracy of FDG-PET-CT for preoperative staging of BC, as compared to CT alone, as reported in individual studies. To assess the methodological quality of eligible studies, we used the QUADAS-2 tool (a revised tool for the Quality Assessment of Diagnostic Accuracy Studies) and pooled diagnostic accuracy measures using Meta-DiSc statistical software. RESULTS: For detecting nodal metastases in 78 patients, the sensitivity of FDG-PET-CT was 0.56 (95 % CI 0.29-0.80) and the specificity, 0.98 (95 % CI 0.91-1.00). Pooled sensitivity and specificity for detecting lymph node metastasis were 0.57 and 0.95, respectively. Positive likelihood ratio was 9.02. All lesions that were suspicious for distant metastasis were found to be positive on biopsy. CONCLUSION: FDG-PET-CT was more accurate than CT alone in staging BC in patients undergoing surgery. Standardization of FDG-PET-CT protocol and cost-effectiveness analysis are required before widespread implementation of this technology.

Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors.

OBJECTIVES: Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule stabilization inducing tumor and tumor endothelial cell apoptosis. The purpose of this study was to determine the optimal tolerated dose (OTD) of the combination of pazopanib and ixabepilone for the treatment of metastatic previously treated solid tumors. METHODS: Dose escalation started at 32 mg/m of ixabepilone and increased to 40 mg/m. Pazopanib was administered initially at 400 mg and escalated at 200 mg increments up to 800 mg. Pharmacokinetic analysis assessed effect of ixabepilone on pazopanib metabolism. Correlative studies evaluated changes in angiogenic cytokines. RESULTS: Thirty-one patients (20 male and 11 female; median age, 58 y) with ECOG PS of 0 or 1 were enrolled. Three patients had dose-limiting toxicities (fatigue and neutropenia) at dose level 2 (ixabepilone 40 mg/m and pazopanib 400 mg), and therefore the ixabepilone dose was decreased (32 mg/m) before escalating pazopanib to levels 3 and 4. One patient had a dose-limiting toxicity (thrombocytopenia) at dose level 4 (ixabepilone 32 mg/m and pazopanib 800 mg). Dose level 3 was determined to be the OTD (pazopanib 600 mg and ixabepilone 32 mg/m). The most common toxicities were cytopenias. A significant decrease in the level of sE-selectin was associated with improvement in progression free survival. CONCLUSIONS: The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.

Mutational Landscapes of Sequential Prostate Metastases and Matched Patient Derived Xenografts during Enzalutamide Therapy.

Developing patient derived models from individual tumors that capture the biological heterogeneity and mutation landscape in advanced prostate cancer is challenging, but essential for understanding tumor progression and delivery of personalized therapy in metastatic castrate resistant prostate cancer stage. To demonstrate the feasibility of developing patient derived xenograft models in this stage, we present a case study wherein xenografts were derived from cancer metastases in a patient progressing on androgen deprivation therapy and prior to initiating pre-chemotherapy enzalutamide treatment. Tissue biopsies from a metastatic rib lesion were obtained for sequencing before and after initiating enzalutamide treatment over a twelve-week period and also implanted subcutaneously as well as under the renal capsule in immuno-deficient mice. The genome and transcriptome landscapes of xenografts and the original patient tumor tissues were compared by performing whole exome and transcriptome sequencing of the metastatic tumor tissues and the xenografts at both time points. After comparing the somatic mutations, copy number variations, gene fusions and gene expression we found that the patient's genomic and transcriptomic alterations were preserved in the patient derived xenografts with high fidelity. These xenograft models provide an opportunity for predicting efficacy of existing and potentially novel drugs that is based on individual metastatic tumor expression signature and molecular pharmacology for delivery of precision medicine.

Challenges of managing elderly men with prostate cancer.

The incidence of prostate cancer increases with age. Current evidence suggests that prostate cancer is under treated in patients aged ≥70 years, despite evidence of efficacy and acceptable toxicity. Radical cystectomy and definitive radiotherapy are often denied owing to fears of post-operative complications and radiotherapy-associated gastrointestinal and genitourinary toxicity. However, modern radical prostatectomy techniques provide excellent clinical outcomes with low perioperative morbidity. Moreover, volume-restricted intensity-modulated radiation therapy is a significant improvement over previous 2D conformal radiotherapy with similar efficacy and lower toxicity. Androgen-deprivation therapy is also under-prescribed among the elderly, owing to concerns of increases in cardiac deaths and osteoporosis acceleration. However, prospective trials have not identified any increase in cardiovascular mortality among elderly men receiving androgen-deprivation therapy compared to age-matched controls. Most patients on androgen deprivation eventually progress to a castration-resistant state. At this stage, the disease still responds to newer agents that target the androgen pathway and to chemotherapy. Among the elderly, chemotherapy is under-prescribed even though it has been demonstrated to be palliative and improve survival. We describe the trends in prostate cancer management in the elderly and the importance of assessing comorbidity status, tumour characteristics, and health status, including a complete geriatric evaluation, before making treatment recommendations.

Randomized phase II study of IL-2 with or without an allogeneic large multivalent immunogen vaccine for the treatment of stage IV melanoma.

OBJECTIVE: To evaluate the activity of interleukin-2 (IL-2) in combination with allogeneic large multivalent immunogen (LMI) vaccine, prepared by immobilizing SK23-CD80 melanoma cell line plasma membrane on 5-µm-diameter silica beads, in patients with melanoma. METHODS: Twenty-one patients with metastatic melanoma were randomly assigned to an IL-2 alone control group or an IL-2 plus LMI vaccine treatment group. The primary objective was to evaluate the progression-free survival (PFS) of each group. Secondary clinical objectives included median overall survival (OS) and 1- and 2-year rates of OS. RESULTS: Treatment was very well tolerated. Median PFS was no different between the treatment arm (2.20 mo) and control arm (1.95 mo). Median OS was also similar for the treatment arm (11.89 mo) and control arm (9.97 mo). CONCLUSIONS: This study failed to demonstrate that allogeneic LMI vaccine and low-dose IL-2 improved survival in patients with melanoma as compared with low-dose IL-2 alone.

Adjuvant radiotherapy for synchronous bilateral testicular seminoma: a case report and a review of the pertinent literature.

Few cases of synchronous bilateral stage I seminomas have been reported in the world literature. We present a case of bilateral synchronous testicular seminoma, the current literature on the management of stage I seminoma, and the implications for radiotherapy. A forty-year-old man presented with synchronous bilateral classical seminomas, both stage IA. After undergoing bilateral inguinal orchiectomy, he received adjuvant external beam radiotherapy, with a standard paraaortic field. After 18 months of followup, he remains well, without evidence of recurrence. Bilateral germ cell tumors (BGCTs) are reported consistently at a low rate. Bilateral radical inguinal orchiectomy is standard of care, yet some groups have proposed an organ preservation approach. Of the reported cases of bilateral stage I synchronous GCT, with concordant seminoma histology, most of them were treated with bilateral orchiectomy and adjuvant radiotherapy. Although morbidity associated with radiotherapy directed at the abdomen is not negligible, adjuvant paraaortic radiotherapy remains safe and well-tolerated treatment regime. Bilateral synchronous stage I seminoma of the testes is rare. Organ preservation remains investigational. Chemotherapy is probably a reasonable option. We propose that patients with bilateral stage I synchronous GCT, with concordant seminoma histology, should be managed with bilateral orchiectomy, followed by paraaortic radiotherapy.

Anastrozole Use in Early Stage Breast Cancer of Post-Menopausal Women.

The majority of breast cancers express the estrogen receptor and depend on estradiol (E2) for their growth. Hormonal therapy aims at depriving estrogen signaling either by using selective estrogen receptor modulators (SERM)-that interfere with the binding of E2 to its receptor (ER)-or aromatase inhibitors (AI)-that block the aromatase-dependent synthesis of E2. While SERMs are recommended for both pre- and post-menopausal patients, AIs are indicated only for post-menopausal patients. For the past 20 years, the SERM tamoxifen has been considered the "gold standard" for the treatment of hormone receptor positive breast cancers. However, tamoxifen's role is now challenged by third generation AIs, such as anastrozole, which exhibit greater efficacy in the adjuvant setting in several recently reported trials. This review will focus on anastrozole's mechanism of action, dosing, pharmacology, pharmacokinetics, and clinical applications. It will briefly discuss the clinical trials that determined anastrozole's efficacy in the treatment of advanced breast cancer (ABC) and in the neoadjuvant setting. Finally, it will present the clinical trials that established anastrozole as a frontline agent in the treatment of post-menopausal women with hormone receptor positive early breast cancer.

Metabolites of the carcinogen 2-amino-alpha-carboline formed in male Sprague-Dawley rats in vivo and in rat hepatocyte and human HepG2 cell incubates.

2-amino-alpha-carboline (AaC, 2-amino-9H-pyrido[2,3-b]indole) is a genotoxic carcinogen produced by cooking of protein-containing foods and combustion of biomaterial. Humans are chronically exposed to low levels of AaC through foods (grilled or pan-fried meats), drinking water, and smoke inhalation (cigarette/wood smoke, diesel exhaust). We report herein 17 metabolites of AaC formed in vivo in male Sprague-Dawley rats (from bile, urine, and plasma) and in situ in rat hepatocytes and human HepG2 liver tumor cells. We confirmed several expected sites of AaC metabolism, but also observed novel metabolites. The novel metabolites include extensive N-acetylated AaC conjugates, multiple N-glucuronides, and at least one additional site of aromatic ring hydroxylation. The abundance of N-acetylated metabolites is noteworthy because this metabolic pathway is generally unrecognized for HAAs. Also noteworthy are metabolites that were not detected, i.e., no direct AaC N-sulfonation to form the sulfamate. These results, combined with earlier publications on the reactive (DNA adduct forming) metabolites of AaC, indicate that both bioactivation and detoxification of AaC share the same metabolic pathways--namely, oxidation, acetylation, and sulfonation. This may be an important factor attenuating the risk of carcinogenesis from AaC exposure; increased potential for bioactivation could be balanced by increased potential for detoxification.

Room air entrainment during beta-agonist delivery with heliox.

Studies of the efficacy of heliox in patients with severe asthma have shown mixed results. Among the factors that are responsible for variable outcomes, the failure of heliox delivery systems to prevent room air entrainment (RAE) during beta-agonist delivery is probably the most critical. While keeping the rotameter flow rate (FR) of heliox mixed 70:30 to a nebulizer at 10 L/min, the FR of heliox from a second gas source to a T-connector (TC) was increased during the delivery of the beta-agonist with a conventional T-nebulizer delivery system (TNDS). A negative peak inspiratory flow (pneumotachometer reading) or a helium concentration of < 70% (quadralizer reading) were indicators of RAE. RAE was tested during spontaneous tidal breathing and acute asthma. A rotameter FR of 10 L/m to the nebulizer with no flow from a second gas source to a TC (conventional TNDS) resulted in a significant drop in helium concentration during tidal breathing (46.2%) and acute asthma (27.5%) due to RAE. This degree of helium dilution can negate the beneficial effects of heliox to lung mechanics almost completely. A rotameter FR of 10 L/m each to a nebulizer and a TC resulted in a helium concentration 69.8% during tidal breathing (no RAE), but 49% (significant RAE) during asthma events. A rotameter FR of 15 L/m (pressure regulator setting, 100 lbs per square inch) to a TC, while maintaining a rotameter FR of 10 L/m to a nebulizer prevented RAE during asthma (helium concentration, 69.9%). Conventional TNDS may be used to deliver the beta-agonist with heliox during asthma without RAE.