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Alimentary leptin receptors are most abundant in the gallbladder
S12
Alimentary Tract I
topic tumors with local invasion, peritoneal and and mesenteric implants. Recombinant Thrombospondin Type I repeats (TSR), one of the antiangiogenic domains of TSP, was cloned and purified. One week after tumor implantation, mice were treated with 3TSR (n ⫽ 9, 0.3 mg/kg/day), gemcitabine (n ⫽ 6, 15 mg/kg, twice weekly) or the combination of the two drugs (n ⫽ 11) for 3 weeks. Subsequently, mouse weight, tumor size, number of metasteses were compared. Tumor volume was calculated using the formula 0.52 (width) 2 (length). Student’s t test (Mann-Whitney) was used for statistical comparison. RESULTS: Tumor bearing mice treated with TSR had a 65% reduction in tumor volume (371 ⫾ 97 vs 1064 ⫾ 375 mm3, p ⬍ 0.0001). Tumor volume was reduced 84% with gemcitabine alone (167 ⫾ 67 mm3 ) and 79% with gemcitabine plus TSR treatment (219.39 ⫾ 78.37 mm3 ) p ⬍ 0.001 when compared to control but p ⬎ 0.05 when compared to eachother. Mean vessel density was lowest in the TSR treated animals (3.74 ⫾ 1.2) and highest in the control group (7.96 ⫾ 6.7), p ⬍ 0.05. Proliferation and apoptosis rates were compared. CONCLUSIONS: Antiangiogenic therapy using TSR reduces tumor volume and vascular density in mice with orthotopic pancreatic tumors and can be used safely alone or in combination with gemcitabine.
Aerosolization of heparin and hyaluronan reduce peritoneal loco-regional tumour growth Nawar A Alkhamesi MD, FRCS, FRCSEd, David H Peck PhD, Ara W Darzi MD, FRCS, FRCSI, FACS Imperial College London London, United Kingdom INTRODUCTION: Loco-regional intraperitoneal recurrence remains a critical issue in the management of many abdominal malignancies and is associated with poor prognosis. Around 25% of patients that undergo curative surgery will develop peritoneal recurrence at some stage. Recently, we have shown that this can be inhibited successfully using both heparin and hyaluronan both in vitro and in vivo. The former via an ICAM-1 dependent mechanism while the latter functioned as a barrier. We used an aerosolization device to deliver our therapeutics during laparoscopic procedures. The design of the machine and the catheter enable the operator to cover the whole surface area of the peritoneum with the correct therapeutics’ dose and volume. METHODS: Thirty male WAG rats were divided into 3 groups of 10. After the introduction of 1x105 CC5135, synergistic rat colorectal cancer cells, either 100U/ml heparin, 0.25% hyaluronan or PBS (control) was introduced into the peritoneum using the peritoneal aerosilization technique. After a recovery period of 2 weeks, the animals were sacrificed and the tumor growth was assessed macroscopically and microscopically
J Am Coll Surg
RESULTS: Heparin completely blocked tumor growth with no obvious macroscopic or microscopic invasion detected (p ⬍ 0.05). Hyaluronic acid reduced tumor number and size in comparison to control but at a lower level then heparin CONCLUSIONS: Both modalities were capable of inhibiting tumor spread in vivo. The ability of heparin to abolish tumor development with no local or systemic complications indicates a possible therapeutic to prevent loco-regional recurrence and shows the efficacy of aerosolizarion within the peritoneum.
Alimentary leptin receptors are most abundant in the gallbladder Deborah A Swartz-Basile PhD, Carol Svatek BS, Shannon Graewin MD, James Kiely MD, Henry Pitt MD, FACS Medical College of Wisconsin Milwaukee, WI INTRODUCTION: We have demonstrated that leptin deficiency and leptin resistance are associated with abnormal motility in the gallbladder. In addition, we have shown that serum glucose and insulin are inversely correlated with biliary motility and that administration of leptin to deficient mice normalizes gallbladder function. Thus, leptin administration may be therapeutic for biliary dyskinesia. However, no data are available on biliary leptin receptor levels. Therefore, we hypothesized that leptin receptors would be abundant in the gallbladder. METHODS: 11 week old female lean control (C57Bl/6J, n ⫽ 12), leptin-deficient obese/diabetic (Lepob, n ⫽ 8), leptin-resistant obese/diabetic (Lepdb, n ⫽ 8) and non-obese, diabetic (NOD/LtJ, n ⫽ 8) mice were fasted overnight. The next day alimentary tissues including stomach, duodenum/jejunum, ileum, colon, gallbladder, liver and spleen were removed, and leptin receptor (Ob-Rb, long form) protein levels were determined by ELISA. Data were analyzed by Two-way and One-way ANOVA and by Student-Newman-Keuls for pair-wise multiple comparisons. RESULTS: Leptin receptors were similarly abundant in the gallbladder of each strain (p ⬍ 0.001) compared to spleen (6.8%), stomach (4.4%), jejunum (3.5%), colon (3.3%), ileum (2.8%), and liver (⬍1%). Leptin receptors (ng/mg protein) in the gallbladder by strain are presented in the table below. C57BI/6J
Lepob
Lepdb
NOD
Leptin receptors 22.6 ⫾ 4.9 23.8 ⫾ 3.5 24.6 ⫾ 4.0 35.5 ⫾ 8.3* *p ⬍ 0.001 vs other strains.
CONCLUSIONS: These data suggest that leptin receptors 1) are found most commonly in the gallbladder and 2) are increased in the gallbladder of non-obese diabetic mice. We conclude that alimentary leptin receptors are most abundant in the gallbladder and that leptin provides a link among obesity, diabetes, and gallstone formation.
Alimentary Tract I
topic tumors with local invasion, peritoneal and and mesenteric implants. Recombinant Thrombospondin Type I repeats (TSR), one of the antiangiogenic domains of TSP, was cloned and purified. One week after tumor implantation, mice were treated with 3TSR (n ⫽ 9, 0.3 mg/kg/day), gemcitabine (n ⫽ 6, 15 mg/kg, twice weekly) or the combination of the two drugs (n ⫽ 11) for 3 weeks. Subsequently, mouse weight, tumor size, number of metasteses were compared. Tumor volume was calculated using the formula 0.52 (width) 2 (length). Student’s t test (Mann-Whitney) was used for statistical comparison. RESULTS: Tumor bearing mice treated with TSR had a 65% reduction in tumor volume (371 ⫾ 97 vs 1064 ⫾ 375 mm3, p ⬍ 0.0001). Tumor volume was reduced 84% with gemcitabine alone (167 ⫾ 67 mm3 ) and 79% with gemcitabine plus TSR treatment (219.39 ⫾ 78.37 mm3 ) p ⬍ 0.001 when compared to control but p ⬎ 0.05 when compared to eachother. Mean vessel density was lowest in the TSR treated animals (3.74 ⫾ 1.2) and highest in the control group (7.96 ⫾ 6.7), p ⬍ 0.05. Proliferation and apoptosis rates were compared. CONCLUSIONS: Antiangiogenic therapy using TSR reduces tumor volume and vascular density in mice with orthotopic pancreatic tumors and can be used safely alone or in combination with gemcitabine.
Aerosolization of heparin and hyaluronan reduce peritoneal loco-regional tumour growth Nawar A Alkhamesi MD, FRCS, FRCSEd, David H Peck PhD, Ara W Darzi MD, FRCS, FRCSI, FACS Imperial College London London, United Kingdom INTRODUCTION: Loco-regional intraperitoneal recurrence remains a critical issue in the management of many abdominal malignancies and is associated with poor prognosis. Around 25% of patients that undergo curative surgery will develop peritoneal recurrence at some stage. Recently, we have shown that this can be inhibited successfully using both heparin and hyaluronan both in vitro and in vivo. The former via an ICAM-1 dependent mechanism while the latter functioned as a barrier. We used an aerosolization device to deliver our therapeutics during laparoscopic procedures. The design of the machine and the catheter enable the operator to cover the whole surface area of the peritoneum with the correct therapeutics’ dose and volume. METHODS: Thirty male WAG rats were divided into 3 groups of 10. After the introduction of 1x105 CC5135, synergistic rat colorectal cancer cells, either 100U/ml heparin, 0.25% hyaluronan or PBS (control) was introduced into the peritoneum using the peritoneal aerosilization technique. After a recovery period of 2 weeks, the animals were sacrificed and the tumor growth was assessed macroscopically and microscopically
J Am Coll Surg
RESULTS: Heparin completely blocked tumor growth with no obvious macroscopic or microscopic invasion detected (p ⬍ 0.05). Hyaluronic acid reduced tumor number and size in comparison to control but at a lower level then heparin CONCLUSIONS: Both modalities were capable of inhibiting tumor spread in vivo. The ability of heparin to abolish tumor development with no local or systemic complications indicates a possible therapeutic to prevent loco-regional recurrence and shows the efficacy of aerosolizarion within the peritoneum.
Alimentary leptin receptors are most abundant in the gallbladder Deborah A Swartz-Basile PhD, Carol Svatek BS, Shannon Graewin MD, James Kiely MD, Henry Pitt MD, FACS Medical College of Wisconsin Milwaukee, WI INTRODUCTION: We have demonstrated that leptin deficiency and leptin resistance are associated with abnormal motility in the gallbladder. In addition, we have shown that serum glucose and insulin are inversely correlated with biliary motility and that administration of leptin to deficient mice normalizes gallbladder function. Thus, leptin administration may be therapeutic for biliary dyskinesia. However, no data are available on biliary leptin receptor levels. Therefore, we hypothesized that leptin receptors would be abundant in the gallbladder. METHODS: 11 week old female lean control (C57Bl/6J, n ⫽ 12), leptin-deficient obese/diabetic (Lepob, n ⫽ 8), leptin-resistant obese/diabetic (Lepdb, n ⫽ 8) and non-obese, diabetic (NOD/LtJ, n ⫽ 8) mice were fasted overnight. The next day alimentary tissues including stomach, duodenum/jejunum, ileum, colon, gallbladder, liver and spleen were removed, and leptin receptor (Ob-Rb, long form) protein levels were determined by ELISA. Data were analyzed by Two-way and One-way ANOVA and by Student-Newman-Keuls for pair-wise multiple comparisons. RESULTS: Leptin receptors were similarly abundant in the gallbladder of each strain (p ⬍ 0.001) compared to spleen (6.8%), stomach (4.4%), jejunum (3.5%), colon (3.3%), ileum (2.8%), and liver (⬍1%). Leptin receptors (ng/mg protein) in the gallbladder by strain are presented in the table below. C57BI/6J
Lepob
Lepdb
NOD
Leptin receptors 22.6 ⫾ 4.9 23.8 ⫾ 3.5 24.6 ⫾ 4.0 35.5 ⫾ 8.3* *p ⬍ 0.001 vs other strains.
CONCLUSIONS: These data suggest that leptin receptors 1) are found most commonly in the gallbladder and 2) are increased in the gallbladder of non-obese diabetic mice. We conclude that alimentary leptin receptors are most abundant in the gallbladder and that leptin provides a link among obesity, diabetes, and gallstone formation.