Chemoproteomic Profiling Reveals that Anticancer Natural Product Dankastatin†B Covalently Targets Mitochondrial VDAC3.

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strain Gymnascella dankaliensis have been reported to possess significant anticancer activity but their mode of action is unknown. These members possess electrophilic functional groups that can might undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine reactivity of the most potent of these alkaloids, dankastatin B, by using activity-based protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion-selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hypersensitivity to dankastatin B-mediated antiproliferative effects in breast cancer cells, thus indicating that VDAC3 was at least partially involved in the anticancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlights the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Outcomes of Next-Day Versus Non-next-Day Colonoscopy After an Initial Inadequate Bowel Preparation.

BACKGROUND: Inadequate bowel preparation is the most common cause of failed colonoscopy, and repeat failure occurs in more than 20 % of follow-up attempts. Limited data suggest that next-day follow-up may reduce the risk for repeat inadequate preparation. OBJECTIVE: Evaluate differences in prep quality with next-day follow-up after initial inadequate preparation. DESIGN: Retrospective study. SETTING: Academic center. PATIENTS: Outpatient screening and surveillance colonoscopies between 7/2002 and 6/2007. INTERVENTION: Comparison of next-day versus any other day ("non-next-day") repeat colonoscopy outcomes. MAIN OUTCOME MEASUREMENTS: Aronchick scale, polyp and adenoma detection rates. RESULTS: Of 20,798 initial colonoscopies, 857 (4.1 %) had inadequate preparation. 460 (54 %) were lost to follow-up. One hundred and fourteen (13 %) had next-day and 283 (33 %) had non-next-day colonoscopy with mean follow-up of 8.8 months. On follow-up examination, 29.8 % of next-day and 23.3 % of non-next-day colonoscopies had inadequate bowel preparation (p = 0.48). The adenoma detection rate for the next-day group improved from 3.5 to 38.6 % on follow-up, compared to 20.5 and 36.8 % in the non-next-day group. There was no significant difference between groups in detection of total adenoma (p = 0.73) or advanced adenomas (p = 0.20) on follow-up examinations. LIMITATIONS: Retrospective design, differences in baseline colonoscopy characteristics. CONCLUSION: The results confirm the need for repeat examination after a colonoscopy with inadequate bowel prep, as there was substantial increase in adenoma detection on follow-up. There were no differences in outcomes between next-day versus non-next-day colonoscopy. These data support repeating after inadequate colonoscopy within 1 year as convenient for patient and physician.

Chemoproteomic Profiling Reveals that Anti-Cancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3.

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strain Gymnascella dankaliensis have been reported to possess significant anti-cancer activity but their mode of action is unknown. These members possess electrophilic functional groups that may undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine-reactivity of the most potent of these alkaloids, dankastatin B, using activitybased protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hyper-sensitivity to dankastatin B-mediated anti-proliferative effects in breast cancer cells indicating that VDAC3 was at least partially involved in the anti-cancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlight the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey.

CONTEXT: Patients often combine prescription medications with herbal and dietary substances (herein referred to as herbal medicines). A variety of potential adverse herb-drug interactions exist based on the pharmacological properties of herbal and prescription medications. OBJECTIVE: To determine the incidence of potential and observed adverse herb-drug interactions in patients using herbal medicines with prescription medications. DESIGN: Consecutive patients were questioned about their use of herbal medicines in 6 outpatient clinics. Patients reporting use of these products provided a list of their prescription medications, which were reviewed for any potential adverse herb-drug interactions using a comprehensive natural medicine database. Any potential adverse herb-drug interactions prompted a review of the patient's chart for evidence of an observed adverse herb-drug interaction. MAIN OUTCOME MEASURE: The rate of potential and observed adverse herb-drug interactions. RESULTS: Eight hundred four patients were surveyed, and 122 (15%) used herbal medicines. Eighty-five potential adverse herb-drug interactions were found in 49 patients (40% of herbal medicine users). Twelve possible adverse herb-drug interactions in 8 patients (7% of herbal medicine users) were observed. In all 12 cases, the severity scores were rated as mild, including 8 cases of hypoglycemia in diabetics taking nopal (prickly pear cactus). CONCLUSIONS: A substantial number of potential adverse herb-drug interactions were detected and a small number of adverse herb-drug interactions observed, particularly in diabetics taking nopal. Screening for herbal medicine usage in 804 patients did not uncover any serious adverse interactions with prescription medications.

Closure of a Chronic, Non-Healing Tracheoesophageal Fistula With a New Over-the-Scope Clip.

Tracheoesophageal fistulas can arise from both benign and malignant conditions, and often present clinically as increased secretions, coughing with or without hypoxia after swallowing, and recurrent aspiration pneumonia. We describe a tracheoesophageal fistula in a post-chemotherapy lymphoma patient that was closed with use of an over-the-scope Aponos clip.

Complete clinical response of metastatic hepatocellular carcinoma to sorafenib in a patient with hemochromatosis: a case report.

Hepatocellular carcinoma is rare, but increasing in prevalence in the United States. Recent studies have shown that sorafenib, a multikinase inhibitor, can reduce tumor progression in patients with this cancer. However, complete remission has not been observed. We report a case of a 78-year old patient with unresectable metastatic hepatocellular carcinoma who had a rapid and complete clinical response following therapy with sorafenib for six months. No evidence of disease recurrence has been noted for 6 months after discontinuation of therapy.