Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched-chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes. The cytosolic branched-chain aminotransferase (BCATc) that is commonly overexpressed in cancer cells, was down-regulated in chondrosarcoma (SW1353) in contrast with osteosarcoma (143B) cells that expressed both BCATc and its mitochondrial isoform BCATm. Treating SW1353 cells with gabapentin, a selective inhibitor of BCATc, further revealed that these cells failed to respond to gabapentin. Application of the structural analog of leucine, N-acetyl-leucine amide (NALA) to disrupt leucine uptake, indicated that all bone sarcoma cells used leucine to support their energy metabolism and biosynthetic demands. This was evident from the increased activity of the energy sensor AMP-activated protein kinase (AMPK), down-regulation of complex 1 of the mammalian target of rapamycin (mTORC1), and reduced cell viability in response to NALA. The observed changes were most profound in the 143B cells, which appeared highly dependent on cytosolic and mitochondrial BCAA metabolism. This study thus demonstrates that bone sarcomas rely on leucine and BCAA metabolism for energy and growth; however, the differential expression of BCAA enzymes and the presence of other carbon sources may dictate how efficiently these cancer cells take advantage of BCAA metabolism.
Figure 1. Biopsy of bronchial mucosa showing dense infiltration of eosinophils beneath the bronchial epithelium (greater than 50 per high power field). The granular pink cells are the eosinophils, largely on the left-hand side of the image (400X magnification, H&E stain).
Figure 1. Kaplan-Meier curve showing 30-day mortality for ALD related admissions pre-COVID (red) compared to Pandemic (blue).
Methods: We utilized the SEER Census Tract-level Socioeconomic Status and Rurality Database from 2006-2018 to calculate incidence rates (IR) and incidence rate ratios (IRR) of EOGC among Hispanic and non-Hispanic persons by census tract rural-urban location, age, year, and stage of disease. We estimated age-adjusted (to the 2000 US standard population) IRs per 100,000 persons using SEER*Stat version 8.4.0. We used Tiwari method to estimate IRRs with 95% CIs, comparing rates in 2006 and 2018 among Hispanic and non-Hispanic persons in rural and urban settings and Joinpoint software (v4.9.1.0) to evaluate annual percent change (APC). Results: Incidence rates of EOGC were significantly higher among Hispanic persons than non-Hispanic persons in both rural settings (1.44 vs 0.68 per 100,000 persons; IRR 2.12, 95% CI 1.64-2.73) and urban settings (1.75 vs 0.86 per 100,000 persons; IRR 2.04, 95% CI 1.91-2.16). Hispanic persons had higher incidences of EOGC in both rural and urban settings in every age group and stage (Table ). From 2006 to 2018 the APC was 1.40% for Hispanic persons living in rural census tracts compared to -10.
Introduction: Drug induced pancreatitis (DIP) is rare but potential cause of acute pancreatitis and accounts for 0.1-5.3% of all cases. In this case series, we report 2 cases of patients with doxycycline induced pancreatitis. Case Description/Methods: A 60-year-old woman with cervical osteomyelitis on iv ceftriaxone and doxycycline presented with 2-day history of severe nausea, vomiting, and epigastric pain. On exam, she had epigastric and right upper quadrant tenderness. Laboratory evaluation was significant for serum lipase 6,699 u/l , creatinine of 1.94 mg/dl. Liver function tests and lipid panel were within normal limits. Computerized tomography (CT) of the abdomen and pelvis confirmed acute interstitial pancreatitis (Figure). Triglyceride, IgG subclasses and calcium levels were normal. Thorough review of her medications revealed doxycycline induced pancreatitis was suspected. Her symptoms gradually improved and lipase returned to 85 u/l with discontinuation of doxycycline. A 91year-old woman with recent history of left elbow fracture complicated by wound dehiscence on doxycycline therapy, presented for hospital admission with several days of increased confusion, malaise, and generalized, severe abdominal pain. She appeared ill, with dry mucous membranes and diffuse abdominal tenderness. Laboratory test results were notable for blood urea nitrogen (BUN) 56 mg/dl, creatinine 2.35 mg/dl, ALP 223 u/l, total bilirubin 1.1 mg/dl, wbc count 26.7 k/ul, calcium 6.4 mg/dl, lipase 301 u/l, AST, ALT, triglycerides and IgG subclass levels were within normal limits. CT abdomen showed extensive intrapancreatic and peripancreatic edema, the patient was diagnosed with severe pancreatitis. With careful exclusion of other etiologies, she was diagnosed with doxycycline induced pancreatitis. Her symptoms improved with aggressive hydration and discontinuation of doxycycline. Discussion: Onset of symptoms with relation to starting the offending drug is key in identifying the causative agent of DIP. The severity, onset of symptoms, dosage of doxycycline and latency have been reported as variable as in our cases. Symptom onset was at 14 days of doxycycline therapy in the first vs 22 in the second case. Treatment includes cessation of doxycycline and aggressive IV fluid resuscitation. This case series emphasizes the importance of considering doxycycline as a cause of acute pancreatitis especially with its increased use in recent years.[1721] Figure 1. CT abdomen with extensive intrapancreatic and peripancreatic edema (second case presented).
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