Low rate of intraperitoneal port placement in ovarian cancer patients, a population-based assessment.

INTRODUCTION: The National Comprehensive Cancer Network (NCCN) guidelines recommend intraperitoneal chemotherapy in optimally debulked stage III ovarian cancer patients. The objective of this investigation was to determine the rate of intraperitoneal port placement in patients undergoing surgery for ovarian cancer in a national database maintained by the American College of Surgeons. METHOD: We identified ovarian cancer patients in the National Surgical Quality Improvement Program database from 2006 to 2012. Demographics, comorbidities, operative outcomes, and postoperative complications were abstracted. Descriptive analyses were conducted using Wilcoxon rank-sum and Chi square tests, and multivariate regression models were used to analyze pre-operative and post-operative variables associated with intraperitoneal port placement. RESULTS: We identified 2659 ovarian cancer patients who underwent primary surgical management. Of these patients, only 128 (4.8%) had an intraperitoneal port placed at the time of surgery. In multivariable analyses, intraperitoneal ports were associated with body mass index ≤25, disseminated cancer, later portion of the study period (2009-2012), and operative time >200 min. Intraperitoneal port placement was not associated with any difference in surgical site infection, wound disruption, major postoperative complication, readmission within 30 days, or death within 30 days. DISCUSSION: Recent investigation of practice at NCCN institutions between 2003 and 2012 found only 35% of eligible ovarian cancer patients received intraperitoneal chemotherapy. Using intraperitoneal port placement as a surrogate for intraperitoneal chemotherapy administration, our investigation suggests an even lower rate (4.8%) nationally.

Structural selectivity of human SGLT inhibitors.

Human Na(+)-D-glucose cotransporter (hSGLT) inhibitors constitute the newest class of diabetes drugs, blocking up to 50% of renal glucose reabsorption in vivo. These drugs have potential for widespread use in the diabetes epidemic, but how they work at a molecular level is poorly understood. Here, we use electrophysiological methods to assess how they block Na(+)-D-glucose cotransporter SGLT1 and SGLT2 expressed in human embryonic kidney 293T (HEK-293T) cells and compared them to the classic SGLT inhibitor phlorizin. Dapagliflozin [(1S)-1,5,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol], two structural analogs, and the aglycones of phlorizin and dapagliflozin were investigated in detail. Dapagliflozin and fluoro-dapagliflozin [(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-4-F-4-deoxy-D-glucitol] blocked glucose transport and glucose-coupled currents with ≈100-fold specificity for hSGLT2 (K(i) = 6 nM) over hSGLT1 (K(i) = 400 nM). As galactose is a poor substrate for SGLT2, it was surprising that galacto-dapagliflozin [(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-galactitol] was a selective inhibitor of hSGLT2, but was less potent than dapagliflozin for both transporters (hSGLT2 K(i) = 25 nM, hSGLT1 K(i) = 25,000 nM). Phlorizin and galacto-dapagliflozin rapidly dissociated from SGLT2 [half-time off rate (t(1/2,Off)) ≈ 20-30 s], while dapagliflozin and fluoro-dapagliflozin dissociated from hSGLT2 at a rate 10-fold slower (t(1/2,Off) ≥ 180 s). Phlorizin was unable to exchange with dapagliflozin bound to hSGLT2. In contrast, dapagliflozin, fluoro-dapagliflozin, and galacto-dapagliflozin dissociated quickly from hSGLT1 (t(1/2,Off) = 1-2 s), and phlorizin readily exchanged with dapagliflozin bound to hSGLT1. The aglycones of phlorizin and dapagliflozin were poor inhibitors of both hSGLT2 and hSGLT1 with K(i) values > 100 µM. These results show that inhibitor binding to SGLTs is composed of two synergistic forces: sugar binding to the glucose site, which is not rigid, and so different sugars will change the orientation of the aglycone in the access vestibule; and the binding of the aglycone affects the binding affinity of the entire inhibitor. Therefore, the pharmacophore must include variations in both the structure of the sugar and the aglycone.

Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2.

The human Na(+)/D-glucose cotransporter 2 (hSGLT2) is believed to be responsible for the bulk of glucose reabsorption in the kidney proximal convoluted tubule. Since blocking reabsorption increases urinary glucose excretion, hSGLT2 has become a novel drug target for Type 2 diabetes treatment. Glucose transport by hSGLT2 was studied at 37°C in human embryonic kidney 293T cells using whole cell patch-clamp electrophysiology. We compared hSGLT2 with hSGLT1, the transporter in the straight proximal tubule (S3 segment). hSGLT2 transports with surprisingly similar glucose affinity and lower concentrative power than hSGLT1: Na(+)/D-glucose cotransport by hSGLT2 was electrogenic with apparent glucose and Na(+) affinities of 5 and 25 mM, and a Na(+):glucose coupling ratio of 1; hSGLT1 affinities were 2 and 70 mM and coupling ratio of 2. Both proteins showed voltage-dependent steady-state transport; however, unlike hSGLT1, hSGLT2 did not exhibit detectable pre-steady-state currents in response to rapid jumps in membrane voltage. D-Galactose was transported by both proteins, but with very low affinity by hSGLT2 (≥100 vs. 6 mM). ß-D-Glucopyranosides were either substrates or blockers. Phlorizin exhibited higher affinity with hSGLT2 (K(i) 11 vs. 140 nM) and a lower Off-rate (0.03 vs. 0.2 s⁻¹) compared with hSGLT1. These studies indicate that, in the early proximal tubule, hSGLT2 works at 50% capacity and becomes saturated only when glucose is ≥35 mM. Furthermore, results on hSGLT1 suggest it may play a significant role in the reabsorption of filtered glucose in the late proximal tubule. Our electrophysiological study provides groundwork for a molecular understanding of how hSGLT inhibitors affect renal glucose reabsorption.

Determination of coenzyme A levels in Pyrococcus furiosus and other Archaea: implications for a general role for coenzyme A in thermophiles.

Physiologically significant levels of intracellular coenzyme A were identified in Pyrococcus furiosus, Thermococcus litoralis, and Sulfolobus solfataricus, suggesting a role for CoA as an important low molecular mass thiol in the thermophilic Archaea. In P. furiosus, cells grown in the presence of sulfur showed significantly higher levels of oxidized CoA compared with those grown in the absence of S(0). T. litoralis showed strikingly similar CoA levels, although with low disulfide levels in both the presence and absence of S(0). S. solfataricus showed similarly high levels of CoA thiol, with correspondingly low levels of the CoA disulfide. These results are consistent with the identification of a coenzyme A disulfide reductase (CoADR) in P. furiosus and horikoshii as well as the presence of CoADR homologues in the genomes of S. solfataricus and T. kodakaraensis.

Rising leukemia rates in Thailand: the possible role of benzene and related compounds in cigarette smoke.

Epidemiological studies suggest that cigarette smoking is associated with an increased risk of leukemia and that benzene and related compounds in cigarette smoke may contribute to this elevated risk. This report presents new findings on selected components of cigarette smoke (including benzene and 1,3-butadiene) from major brands of cigarettes sold in Thailand, which represent about 80% of market share. Tested were also two major and popular brands of U.S. cigarettes sold in Thailand, representing about 100% of market share. The cigarettes tested were filter and non-filter, and with high and 'low' tar and nicotine levels. The observed range for benzene, toluene and 1,3-butadiene were found in the range of 25.5-63.7, 36.4-79.8 and 44.6-78.7 microg/cigarette, respectively. The amount of acrolein ranged from 79.9-181 microg/cigarette and for isoprene from 313-694 microg/cigarette. Yields of these substances showed no correlation with tar deliveries in mainstream smoke. Consumption of tobacco products increased in Thailand since 1970. This study also showed increases in leukemia mortality rates in Thailand, and in the relative frequency of leukemia among incident cancers diagnosed at a large hospital in Bangkok. Exposure to benzene and related compounds in cigarette smoke may have contributed to these trends. Analytic epidemiological studies are needed on the relationship between these compounds in smoke from tobacco products used in Thailand. These preliminary findings support the need for voluntary and/or government-regulated reduction in smoke yields of benzene and related compounds in tobacco products, and for expanded smoking prevention and cessation efforts, in Thailand.

Geographic distribution of liver and stomach cancers in Thailand in relation to estimated dietary intake of nitrate, nitrite, and nitrosodimethylamine.

It is our working hypothesis that the high rate of the liver and gastric cancers in North and Northeast Thailand is associated with increased daily dietary intake of nitrate, nitrite, and nitrosodimethylamine (NDMA). Samples of fresh and preserved Thai foods were systematically collected and analyzed from 1988 to 1996 and from 1998 to 2005. Consumption frequencies of various food items were determined on the basis of a dietary questionnaire given to 467 adults (212 males and 255 females) from 1998 to 2005. Food consumption data for the preceding and current year were collected and intakes (day, week, and month) of nitrate, nitrite, and NDMA were calculated. The trends in liver and stomach cancer age-standardized incidence rates (ASR) in four regions of Thailand were compared with the dietary intake of nitrate, nitrite, and NDMA in those same geographic regions. Mean daily intakes of nitrate of 155.7 mg/kg, of nitrite of 7.1 mg/kg, and of NDMA of 1.08 microg/kg per day were found. Significant differences in dietary nitrate, nitrite, and NDMA intakes were seen between various Thai regions (P < 0.0001), and these corresponded to the variations in liver and stomach cancer ASR values between the regions. Dietary factors are likely to play key roles in different stages of liver and stomach carcinogenesis in Thailand.

Borrelia burgdorferi bb0728 encodes a coenzyme A disulphide reductase whose function suggests a role in intracellular redox and the oxidative stress response.

The cellular responses of Borrelia burgdorferiTo reactive oxygen species (ROS) encountered during the different stages of its infective cycle are poorly understood. Few enzymes responsible for protecting proteins, DNA/RNA and lipids from damage by ROS have been identified and characterized. Data presented here suggest that bb0728 encodes an enzyme involved in this process. Biochemical analyses on purified recombinant BB0728 indicated that it functioned as a coenzyme A disulphide reductase (CoADR) (specific activity approximately 26 units per mg of protein). This enzyme was specific for coenzyme A (CoA) disulphide, required NADH and had no significant activity against other disulphides, such as oxidized glutathione or thioredoxin. The high intracellular concentration of reduced CoA (CoASH) in B. burgdorferi cells ( approximately 1 mM) and absence of glutathione suggest that CoA is the major low-molecular-weight thiol in this spirochete. Interestingly, CoASH was able to reduce H(2)O(2) and be regenerated by CoADR suggesting one role for the system may be to protect B. burgdorferi from ROS. Further, mobility-shift assays and transcriptional fusion data indicated that bb0728 was positively regulated by the Borrelia oxidative stress response regulator, BosR. Taken together, these data suggest a role for BB0728 in intracellular redox and the oxidative stress response in B. burgdorferi.