The in vivo evaluation process described here was instrumental in the identification of SCH 66336 as a clinical candidate. Our lead FTI, SCH 66336, and several other FTIs are being evaluated in early-phase clinical trials to establish proof-of-principle for farnesyl transferase inhibition in human patients. The preclinical studies described here suggest that FTIs may have utility against a wide array of human cancers as a single agent and may, at least in some cases, lead to tumor regression. In addition, the results to date in combination with cytotoxic chemotherapeutic agents in animal models indicate that these combinations may enhance the clinical efficacy of FPT inhibitors. Further preclinical studies should help to guide the clinical development of this class of novel antitumor agents.

Inhibitors of farnesyltransferase (FTI) have been developed for cancer treatment for more than a decade. Aside from being a therapeutic target in tumor cells, little is known about the role of farnesyltransferase (FTase) in other physiological processes. In this study, we revealed the involvement of FTase in angiogenesis and showed that FTI inhibited angiogenesis by directly acting on endothelial cells. Inhibition of FTase interrupted cell migration in vitro and in vivo. In addition, we found that FTase was important for cell polarization, cell spreading and pseudopodia formation. We also found that FTase interacted with microtubule end binding protein 1 (EB1) and that this interaction was critical for the localization of EB1 to microtubule tips. Our findings thus offer novel insight into the functions of FTase in endothelial cells and provide valuable information for the use of FTI in cancer therapy.

Farnesyltransferase inhibitors (FTIs), developed as anti-cancer drugs, have the potential to modulate immune responses without causing nonspecific immune suppression. We have investigated the possibility that FTIs, by affecting T cell cytokine secretion, can attenuate alloreactive immune responses. The effects of FTIs on murine alloreactive T cells were determined both in vitro, by measuring cytokine secretion or cell proliferation in mixed lymphocyte cultures, and in vivo, by performing skin allografts from H-2(bm12) mice to MHC class II-disparate B6 mice. We found that two different FTIs, ABT-100 and L-744,832, blocked secretion of IFN-gamma, IL-2, IL-4, and TNF-alpha from naïve T cells in vitro. ABT-100 and L-744,832 blocked cytokine production from both CD4(+) and CD8(+) naïve T cells stimulated with CD3 and CD28 antibodies, but only if the cells were pretreated with the FTIs for 48 h. Proliferation of alloreactive T cells in mixed lymphocyte cultures was blocked by either FTI. We also found that the proliferation of enriched T cells stimulated with IL-2 was blocked by ABT-100 treatment. In mice with an MHC class II-disparate skin graft, rejection of primary allografts was significantly delayed by treatment with either ABT-100 or L-744,832. Secondary rejection in mice previously primed to the alloantigen was found to be unaffected by L-744,832 treatment. We have shown that FTIs can block T cell cytokine secretion and attenuate alloreactive immune responses. The ability of FTIs to block secretion of cytokines, including IFN-gamma and IL-4, from naïve T cells provides a likely biological mechanism for the specific suppression of class II MHC-mediated allorejection. These results demonstrate that FTIs may have useful immunomodulatory activity due to their ability to delay priming to alloantigens.

The targeting of molecular abnormalities in neoplasms may provide an opportunity to improve the selectivity of cancer therapy. Ras mutations are a common genetic event in human cancers. Other genetic changes in tumors can signal through ras-dependent pathways as well. The targeting of ras through the inhibition of Ras protein farnesylation is one new cancer treatment strategy under clinical evaluation. Several farnesyltransferase inhibitors (FTIs) have been evaluated in phase I trials. The toxicity and maximally tolerated doses of several FTIs have been determined, and clinical trials are underway to evaluate FTIs in combination with conventional cytotoxic chemotherapy agents. Also underway are attempts to develop assays to measure the biological effects of the FTI in patients. Inhibition of farnesylation of a number of surrogate markers are currently being investigated. These efforts may provide insight into the mechanism of action of these compounds and lead to improved patient selection for clinical trials.

Rats treated with the alkylating agent methylnitrosourea (MNU) develop multiple, hormonally dependent mammary tumors. Roughly 50% of the tumors have Ha-ras mutation, whereas 50% do not. The MNU-induced rat mammary tumor model was employed to examine the therapeutic efficacy of the farnesyltransferase inhibitor (FTI), R115777, and to examine the use of genomics in identifying susceptible tumors as well as identifying genes whose expression are modulated by FTI treatment. In animals bearing palpable mammary tumors (< 7 mm diameter), we performed a surgical biopsy, and 3 days following the biopsy, rats were treated with R115777 (50 mg/kg body wt/day) by gavage. Tumors with Ha-ras mutations underwent profound regression, with nearly 90% showing complete regressions within 4 weeks. In contrast, the non-Ha-ras mutation-bearing tumors yielded a more variable response, although roughly half of the non-Ha-ras mutation tumors underwent significant regression. These results show that although all tumors appear to respond to the FTI inhibitor the tumors with Ha-ras mutations were exquisitely sensitive. We employed a microarray approach to define potential targets and the mechanism of action of R115777 in Ha-ras mutant or wildtype tumors following treatment with FTI. In addition, we determined whether gene expression prior to FTI treatment can be used to differentiate highly sensitive tumors (Ha-ras mutant) and tumors with variable sensitivity (Ha-ras wildtype). Untreated or FTI-treated (4 days at 50 mg/kg body wt) tumors (Ha-ras mutant or wildtype) were examined using oligonucleotide arrays. A significant number of genes were differentially expressed in control rat mammary tumors with or without an activated Ha-ras mutation, suggesting that a microarray analysis might differentiate highly sensitive and variably sensitive tumors. Most of the genes whose expressions were modulated by FTI in tumors were independent of Ha-ras status and were presumably modulated by effects on farnesylation of proteins other than Ha-ras. However, treatment of Ha-ras-mutated mammary tumors with R155777 results in preferential modulation of genes involved in ras-MAP kinase signal transduction pathway and in decreased expression of many genes involved with cell proliferation. In contrast, several classes of genes are altered in rat mammary tumors without a mutated Ha-ras, suggesting that non-ras targets are involved. Ras pathway related genes, p53, WT1 and PCNA, were preferentially modulated in Ha-ras-mutated tumors, whereas modulation of genes in the G-protein pathway, various cytochrome p450s and RB1 are involved in Ha-ras wildtype tumors. Elucidation of gene expression changes in FTI-treated or control rat mammary adenocarcinomas will help in identifying potential pharmacodynamic markers of FTI treatment as well as potential molecular targets of R115777 and other FTIs.

The metabolic cost of force production, and therefore the demand for oxygen, increases with intensity and frequency of contraction. This study investigated the interaction between fatigue and oxygenation, as reflected by deoxymyoglobin (dMb), during slow and rapid rhythmic isometric contractions having the same duty cycles and relative force-time integrals (FTIs). We used 1H magnetic resonance spectroscopy and measures of dorsiflexor muscle force to compare dMb and fatigue (fall of maximal voluntary force, MVC) in 11 healthy adults (29 +/- 7 y) during 16 min of slow (4 s contraction, 6 s relaxation) and rapid (1.2 s, 1.8 s) incremental (10%-80% MVC) contractions. We tested the hypotheses that (i) the rate of Mb desaturation would be faster in rapid than in slow contractions and (ii) fatigue, Mb desaturation, and the fall in FTI would be greater, and PO2 (oxygen tension) lower, at the end of rapid contractions than at the end of slow contractions. Although dMb increased more quickly during rapid contractions (p = 0.05), it reached a plateau at a similar level in both protocols (approximately 42% max, p = 0.49), likely due to an inability to further increase force production and thus metabolic demand. Despite the similar dMb at the end of both protocols, fatigue was greater in rapid (56.6% +/- 2.7% baseline) than in slow (69.5% +/- 4.0%, p = 0.01) contractions. These results indicate that human skeletal muscle fatigue during incremental isometric contractions is in part a function of contraction frequency, possibly due to metabolic inhibition of the contractile process.

BACKGROUND

Caveolin-1 is an essential component of caveolae and its expression is known to be increased in human prostate cancer. The reduction of caveolin-1 expression has been reported to decrease the tumorigenic and metastatic potential of prostate cancer.

METHODS

Caveolin-1 expression was determined by real-time RT-PCR and Western blot analysis.

RESULTS

Incadronate, a third-generation bisphosphonate, was found to inhibit the caveolin-1 mRNA and protein expression in PC-3 prostate cells. The decrease in caveolin-1 mRNA expression by incadronate was prevented by co-incubation with geranylgeranyol, but not with farnesol. Moreover, treatment of GGTI-286, a geranylgeranyl transferase inhibitor, but not FTI-277, a farnesyl transferase inhibitor, also resulted in the inhibition of caveolin-1 mRNA expression.

CONCLUSIONS

These results indicate that the decrease in caveolin-1 expression elicited by incadronate is related to the inhibition of protein geranylgeranylation.

Nuclear lamins are the major components of the nuclear lamina at the periphery of the nucleus, supporting the nuclear envelope and participating in many nuclear processes, including DNA replication, transcription and chromatin organization. A group of diseases, the laminopathies, is associated with mutations in lamin genes. One of the most striking cases is Hutchinson-Gilford progeria syndrome (HGPS) which is the consequence of a lamin A dominant negative mutant named progerin. Due to the abnormal presence of a permanent C-terminal farnesyl tail, progerin gradually accumulates on the nuclear membrane, perturbing a diversity of signalings and transcriptional events. The accumulation of progerin has led to the speculation that progerin possesses higher stability than the wild type lamin A protein. However, the low solubility of lamin proteins renders traditional immunoprecipitation-dependent methods such as pulse-chase analysis ineffective for comparing the relative stabilities of mutant and wild type lamins. Here, we employ a novel platform for inferring differences in lamin stability, which is based on normalization to a co-translated reporter protein following porcine teschovirus-1 2A peptide-mediated co-translational cleavage. The results obtained using this method support the notion that progerin is more stable than lamin A. Moreover, treatment of FTI reduces progerin relative stability to the level of wild type lamin A.

BACKGROUND

Treatment of acute heart failure frequently requires positive-inotropic stimulation. However, there is still no inotropic agent available, which combines a favourable haemodynamic profile with low expenditure for energy metabolism. Pyruvate exhibits positive inotropic effects in vitro and in patients with heart failure. The effect on myocardial energy metabolism however remains unclear, but is meaningful in light of a clinical application.

OBJECTIVE

We investigated the influence of pyruvate on contractility and oxygen consumption in isolated isometric contracting rabbit myocardium compared to beta-adrenergic stimulation with isoproterenol.

RESULTS

Pyruvate (30 mM) increased developed force from 18.7+/-4.1 to 50.8+/-12.1 mN/mm2 (n=10, p<0.01). Force-time integral (FTI) increased by 329%, oxygen consumption assessed by diffusion-microelectrode technique increased from 2.86+/-0.30 mlO2/min*100 g to 6.28+/-1.28 mlO2/min*100 g (n=7, p<0.05). Economy of myocardial contraction calculated as the ratio of total FTI to oxygen consumption remained unchanged. In contrast, while isoproterenol (10 microM) produced a comparable increase in developed force from 21.4+/-8.3 to 67.3+/-15 mN/mm2 (n=7, p<0.01), FTI increased only by 260% and MVO2 increased from 2.96+/-0.43 to 6.12+/-1.01 mlO2/min*100 g (n=7, p<0.01); thus, economy decreased by 23% (n=7, p<0.05).

CONCLUSIONS

Pyruvate does not impair economy of myocardial contraction while isoproterenol decreases economy. Regarding energy expenditure, pyruvate appears superior to isoproterenol for the purpose of positive inotropic stimulation.

BACKGROUND

We have used a mouse model based on overexpression of c-Myc in B cells genetically engineered to be self-reactive to test the hypothesis that farnesyl transferase inhibitors (FTIs) can effectively treat mature B cell lymphomas. FTIs are undergoing clinical trials to treat both lymphoid and non-lymphoid malignancies and we wished to obtain evidence to support the inclusion of B cell lymphomas in future trials.

RESULTS

We report that two FTIs, L-744,832 and SCH66336, blocked the growth of mature B cell lymphoma cells in vitro and in vivo. The FTI treatment affected the proliferation and survival of the transformed B cells to a greater extent than naïve B cells stimulated with antigen. In syngeneic mice transplanted with the transgenic lymphoma cells, L-744,832 treatment prevented the growth of the tumor cells and the morbidity associated with the resulting lymphoma progression. Tumors that arose from transplantation of the lymphoma cells regressed with as little as three days of treatment with L-744,832 or SCH66336. Treatment of these established lymphomas with L-744,832 for seven days led to long-term remission of the disease in approximately 25% of animals.

CONCLUSIONS

FTI treatment can block the proliferation and survival of self-reactive transformed B cells that overexpress Myc. In mice transplanted with mature B cell lymphomas, we found that FTI treatment led to regression of disease. FTIs warrant further consideration as therapeutic agents for mature B cell lymphomas and other lymphoid tumors.

Ras CAAX (C = cysteine, A = aliphatic amino acid, and X = any amino acid) peptidomimetic inhibitors of farnesyl protein transferase suppress Ras-dependent cell transformation by preventing farnesylation of the Ras oncoprotein. These compounds are potential anticancer agents for tumors associated with Ras mutations. The peptidomimetic FTI-254 was tested for Ras1-inhibiting activity in whole animals by injection of activated Ras1val12 Drosophila larvae. FTI-254 decreased the ability of Ras1val12 to form supernumerary R7 photoreceptor cells in the compound eye of transformed flies. In contrast, it had no effect on the related supernumerary R7 phenotypes of flies transformed with either the activated sevenless receptor tyrosine kinase, Raf kinase, or a chimeric Ras1val12 protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1val12 signaling activity in a whole-animal model system.

OBJECTIVE

Evaluate which of two combinations of parameters based on ISRNM recommendations could better identify patients with Protein Energy Wasting (PEW) and to compare the relationship of these two combinations with other clinical and body composition parameters.

METHODS

This was a multicenter longitudinal study with 24 months of follow-up. The PEW patients were characterized by: Group A (GA ) - normalized Protein Catabolic Rate (nPCR) < 1.0 g/Kg/day, albumin < 3.8 g/dL and Body Cell Mass Index (BCMI) < 6.4 Kg/m2 (n=203); Group B (GB ) - nPCR < 1.0 g/Kg/day, albumin < 3.8 g/dL and Body Mass Index (BMI) <23 Kg/m2 (n=109). All the patients who did not meet these requirements were considered "well-nourished" (GA : n=1818; GB : n=3292).

RESULTS

When compared to the well-nourished patients, PEW patients in the GA presented higher age, Kt/V, C-reactive protein, relative overhydration, fat tissue index (FTI); lower creatinine, albumin, nPCR, PTH, hemoglobin, phosphorus, calcium X phosphorus product, potassium, dry weight, BMI, BCMI, lean tissue index, %IDWG . In the GB well-nourished patients FTI was significantly higher. In Cox analysis, the combination with BCMI was a strong independent predictor of mortality in these patients (HR: 1.48; CI: 1.00-2.19; p=0.048), even after adjustment. Although GB combination seemed to be also a predictor of death (HR: 2.67; CI: 1.92-3.71; p<0.001), when adjusted, the association remained no longer significant.

CONCLUSIONS

A new combination of parameters including protein intake, albumin and BCMI demonstrated significant associations with other nutrition and inflammation parameters as well as with mortality. This article is protected by copyright. All rights reserved.

Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

OBJECTIVE

Hypertension and hypervolemia relationship was proven among renal disease, although it is not known in normal population. Present study determines the fluid distribution defects in relation to blood pressure.

METHODS

In a population-based survey in Turkey demographics, height, weight, blood pressure, urine analysis, and serum creatinine measurements were recorded. Bioimpedance measured with the Body Composition Monitor.

RESULTS

Total 2034 population of 71.6% male, mean age 47 ± 12.6 (18-89) years, systolic blood pressure (SBP) 134.7 ± 20, diastolic blood pressure 77.9 ± 11.6 mmHg. Body mass index (BMI) was 28.5 ± 4.5 (15.8-50.6) kg/m(2); overhydration was 0.05 ± 1.05 L. There was a correlation between extracellular water (ECW)/height and SBP (r = 0.21, P < 0.001). Receiver operating characteristic (ROC) curve with the performance of 0.60 (P < 0.001) that showed cut-off value of ECW/height was 10.06 L/m, with the 69% sensitivity and 45% specificity for SBP: 140 mmHg values. Risk factors for high SBP were increase of ECW/Height, age, BMI and presence of diabetes. ECW/height, SBP, and fat tissue index (FTI) increased in BMI categories (low, normal, and obese) and in diabetics. SBP and FTI were lower in smokers.

CONCLUSIONS

High blood pressure may be accompanied by increased extracellular volume indices. In the future volume status assessment could be of use in evaluating the effectiveness of pharmacological intervention in the treatment of hypertension.

This study examined differences in the oxygenation kinetics and strength and endurance characteristics of boulderers and lead sport climbers. Using near infrared spectroscopy, 13-boulderers, 10-lead climbers, and 10-controls completed assessments of oxidative capacity index and muscle oxygen consumption (m⩒O2) in the flexor digitorum profundus (FDP), and extensor digitorum communis (EDC). Additionally, forearm strength (maximal volitional contraction MVC), endurance (force-time integral FTI at 40% MVC), and forearm volume (FAV and ΔFAV) was assessed. MVC was significantly greater in boulderers compared to lead climbers (mean difference = 9.6, 95% CI 5.2-14 kg). FDP and EDC oxidative capacity indexes were significantly greater (p = .041 and .013, respectively) in lead climbers and boulderers compared to controls (mean difference = -1.166, 95% CI (-3.264 to 0.931 s) and mean difference = -1.120, 95% CI (-3.316 to 1.075 s), respectively) with no differences between climbing disciplines. Climbers had a significantly greater FTI compared to controls (mean difference = 2205, 95% CI= 1114-3296 and mean difference = 1716, 95% CI = 553-2880, respectively) but not between disciplines. There were no significant group differences in ΔFAV or m⩒O2. The greater MVC in boulderers may be due to neural adaptation and not hypertrophy. A greater oxidative capacity index in both climbing groups suggests that irrespective of climbing discipline, trainers, coaches, and practitioners should consider forearm specific aerobic training to aid performance.

Aneuploidy caused by abnormal chromosome segregation during early embryo development leads to embryonic death or congenital malformation. Centromere protein F (CENPF) is a member of centromere protein family that regulates chromosome segregation during mitosis. However, its necessity in early embryo development has not been fully investigated. In this study, expression and function of CENPF was investigated in mouse early embryogenesis. Detection of CENPF expression and localization revealed a cytoplasm, spindle and nuclear membrane related dynamic pattern throughout mitotic progression. Farnesyltransferase inhibitor (FTI) was employed to inhibit CENPF farnesylation in zygotes. The results showed that CENPF degradation was inhibited and its specific localization on nuclear membranes in morula and blastocyst vanished after FTI treatment. Also, CAAX motif mutation leads to failure of CENPF-C630 localization in morula and blastocyst. These results indicate that farnesylation plays a key role during CENPF degradation and localization in early embryos. To further assess CENPF function in parthenogenetic or fertilized embryos development, morpholino (MO) and Trim-Away were used to disturb CENPF function. CENPF knockdown in Metaphase II (MII) oocytes, zygotes or embryos with MO approach resulted in failure to develop into morulae and blastocysts, revealing its indispensable role in both parthenogenetic and fertilized embryos. Disturbing of CENPF with Trim-Away approach in zygotes resulted in impaired development of 2-cell and 4-cell, but did not affect the morula and blastocyst formation because of the recovered expression of CENPF. Taken together, our data suggest CENPF plays an important role during early embryonic development in mice. Abbreviation: CENPF: centromere protein F; MO: morpholino; FTI: Farnesyltransferase inhibitor; CENPE: centromere protein E; IVF: in vitro fertilization; MII: metaphase II; SAC: spindle assembly checkpoint; Mad1: mitotic arrest deficient 1; BUB1: budding uninhibited by benzimidazole 1; BUBR1: BUB1 mitotic checkpoint serine/threonine kinase B; Cdc20: cell division cycle 20.

BACKGROUND

Climate change has contributed to increasing temperatures, earlier snowmelts and thinning ice packs in the Arctic, where crossing frozen bodies of water is essential for transportation and subsistence living. In some Arctic communities, anecdotal reports indicate a growing belief that falling-through-the-ice (FTI) are increasing. The objective of this study was to describe the morbidity and mortality associated with unintentional FTIs in Alaska.

METHODS

We searched newspaper reports to identify FTI events from 1990 to 2010. We also used data from a trauma registry, occupational health and law enforcement registries and vital statistics to supplement the newspaper reports. Morbidity and mortality rates were calculated for Alaska Native (AN) people and all Alaskans.

RESULTS

During the 21-year period, we identified 307 events, affecting at least 449 people. Events ranged from no morbidity to fatalities of five people. More than half of the events involved transportation by snow machine. Mortality rates were markedly higher for AN people than that for all Alaskans.

CONCLUSIONS

We provide a numeric estimate of the importance of FTI events in Alaska. FTIs may represent an adverse health outcome related to climate changes in the Arctic, and may be particularly critical for vulnerable populations such as AN people.

OBJECTIVE

To determine the effects of metformin treatment on serum androgen levels ahead of and during the IVF cycle in infertile polycystic ovary syndrome (PCOS) women.

METHODS

A prospective, double-blind, placebo-controlled study.

METHODS

Single-center, university IVF clinic.

METHODS

Sixty-three PCOS women.

METHODS

Treatment with metformin 2,000 mg/day or identical placebo tablets for at least 14 weeks before and then during IVF treatment, ending on the day of hCG injection.

METHODS

Serum levels of dehydroepiandrosterone, dehydroepiandrosterone sulphate (DHEAS), androstenedione, free testosterone index (FTI), dihydrotestosterone, and the androgen metabolite 5alpha-androstane-3alpha, 17beta-diol-glucuronide were measured at five time points ending on the day of ovum collection.

RESULTS

During metformin pretreatment DHEAS increased, wheres other androgens were unaffected. During the IVF procedure androgens were unaffected by metformin treatment. Within 36 hours after the study medication was withdrawn the levels of androstenedione and FTI increased in the metformin group, whereas DHEAS decreased.

CONCLUSIONS

In infertile PCOS women metformin treatment increased DHEAS levels. During the IVF cycle androgen levels were unaffected by metformin, whereas there was a "rebound" effect when stopping metformin treatment.

BACKGROUND

Morphology and histology of filum terminale (FT) has a role in the pathophysiology of TCS.

OBJECTIVE

This research was implemented to investigate the morphometric parameters and histological structure of normal FT in adult human cadavers and MRI scans to correlate them with the pathophysiology of tethered cord syndrome (TCS).

METHODS

twenty five adult human cadavers (15 males &10 females) and 100 MR echo scans of lumbosacral region (50 males and 50 females), were used for this study. MRI patients were divided into 21-40 and 41-60 age groups. The cadavers were dissected at the prone position to explore their fila. The length of FT, filum terminale internum (FTI), filum terminale externum (FTE), vertebral level of beginning, dural piercing and termination of FT, and the initial, midpoint, and mid-FTE diameters were determined. Four segments were excised from lower conus, upper, middle, and lower thirds of FT. The specimens were processed for light microscopic examination. Statistical analysis was done for these parameters.

RESULTS

MRI morphometrical parameters of FT, except FTI length, revealed no age effect or sex differences, where length of FTI, FTE, initial diameter, level of conus medullaris termination (CMT) & dural sac termination (DST) were 174.1 ± 16.8, 75.8 ± 9.5, 1.6 ± 0.21, L1-2 & S2U in males and 166.9 ± 18.9, 74.1 ± 9.3, 1.53 ±0.25, L1-2 & S2M vertebrae in females respectively. However, non- significant sex difference was observed in morphometric parameters of cadaveric FT, where length of FTI & FTI, initial diameter, CMT & DST levels were 164.2 ± 11.6, 76.7 ± 8.1, 1.7 ± 0.14, L1L & S2U vertebrae in males and 159.2 ± 10.1, 71.02 ± 7.3, 1.6 ± 0.29, L1L & S2U in females respectively. Moreover, CMT below L2 vertebra was seen in 5% of MRI scans and 8% of cadavers. Also, the initial diameter of FT>> 2 mm was recorded in 7% of MRI and 8% of cadaveric cases. Histologically, the structure of FT showed gradual reduction in nervous, glial, & vascular tissues with converse increase in collagen content in FTE compared with those of FTI.

CONCLUSIONS

Morphometric parameters, histological structure, variants, and MR imaging of the filum terminale are necessary for clinicians who dealing with diagnosis or treatment of tethered cord syndrome.

We investigated the effects of the farnesyl transferase inhibitor (FTI) manumycin and the MEK inhibitor PD98059 on growth of human pancreatic cancer, with mutant (SUIT2) or wild-type (BxPC-3) K-ras, xenografted into nude mice. Tumor growth was not reduced by either of the agents at a dose of 3 mg/kg without irradiation. Growth of SUIT2 irradiated at 15 Gy or 30 Gy was reduced by manumycin and PD98059: at 15 Gy, tumor volume doubling time (TVDT) increased from 18.6+/-3.8 to 36.3+/-14.2 days with PD98059 (p<0.05); at 30 Gy, TVDT increased from 32.8+/-6.8 to 70.5+/-10.5 days and 70.7+/-1.5 days, respectively. Manumycin tended to reduce growth of BxPC-3, but the difference in TVDT was not statistically significant. PD98059 significantly increased the TVDT of BxPC-3 at 30 Gy from 34.4+/-18 to 62.6+/-9.8 at 30 Gy. The present results suggest that Ras signaling pathways are potential targets for manipulation of radiosensitivity, and that induction of an alternative pathway may enhance radiosensitivity of pancreatic cancer.

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed as farnesyltransferase (FTase) inhibitors (FTIs) by replacing AA with o-aryl or o-heteroaryl substituted p-hydroxy- or p-aminobenzoic acid, while maintaining the replacement of C with 1,4-benzodioxan-2-ylmethyl or 2-amino-4-thiazolylacetyl residue as in previous CAAX mimetics. Both FTase inhibition and antiproliferative effect were showed by two thiazole derivatives, namely those with 1-naphthyl (10 and 10a) or 3-furanyl (15 and 15a) in the central spacer, and by the benzodioxane derivative with 2-thienyl (6 and 6a) in the same position. Accumulation of unprenylated RAS was demonstrated in cells incubated with 15a. Consistently with FTIs literature, such results delineate the biaryl scaffold not only as a spacer but also as a sensible area of these mimetic molecules, where modifications at the branching aromatic ring are not indifferent and should be matter of further investigation.

Bioimpedance spectroscopy (BIS) is an easily applicable tool to assess body composition. The three compartment model BIS (3C BIS) conventionally expresses body composition as lean tissue index (LTI) (lean tissue mass [LTM]/height in meters squared) and fat tissue index (FTI) (adipose tissue mass/height in meters squared), and a virtual compartment reflecting fluid overload (FO). It has been studied extensively in relation to diagnosis and treatment guidance of fluid status disorders in patients with advanced-stage or end-stage renal disease. It is the aim of this article to provide a narrative review on the relevance of 3C BIS in the nutritional assessment in this population. At a population level, LTI decreases after the start of hemodialysis, whereas FTI increases. LTI below the 10th percentile is a consistent predictor of outcome whereas a low FTI is predominantly associated with outcome when combined with a low LTI. Recent research also showed the connection between low LTI, inflammation, and FO, which are cumulatively associated with an increased mortality risk. However, studies toward nutritional interventions based on BIS data are still lacking in this population. In conclusion, 3C BIS, by disentangling the components of body mass index, has contributed to our understanding of the relevance of abnormalities in different body compartments in chronic kidney disease patients, and appears to be a valuable prognostic tool, at least at a population level. Studies assessing the effect of BIS guided nutritional intervention could further support its use in the daily clinical care for renal patients.

Background: Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, affecting 5-20% of women worldwide. Hyperandrogenism, as the primary characteristic of PCOS, is not always present in every patient. The hyperandrogenic phenotype of PCOS patients is influenced by both hormonal and metabolic dysfunctions. Therefore, this study aims to determine the correlation between hormone profile, lipid profile, and clinical profile with free testosterone index in subjects with PCOS. Methods: This prospective cross-sectional study was conducted in the Dr. Cipto Mangunkusumo General Hospital between July 2014 and December 2016. The study involved 76 women with PCOS, who were classified into 2 subgroups: 39 subjects in the hyperandrogenism group and 37 subjects in the non-hyperandrogenism group. Each subject underwent physical examination, blood sample collection, and USG examination. Bivariate analysis was done using independent t-tests and Mann Whitney U-tests, while multivariate analysis was done using logistic regression. Results: Triglyceride and testosterone level showed weak (r = 0.232, p = 0.044) and moderate (r = 0.460, p ¡ 0.001) positive correlation with FTI, while SHBG level showed moderate negative correlation (r = -0.483, p ¡ 0.001). Triglyceride was also found to be determinant of hyperandrogenism condition in PCOS patient (OR 0.02, 95% CI 0.00-0.04, p = 0.013). However, there was no significant difference observed between FGS and hyperandrogenism (p = 0.43). Conclusions: Triglycerides, testosterone, and SHBG were associated with hyperandrogenism in PCOS patients, while FGS showed no such association.