Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

Mitochondrial Dysfunction After Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug.

Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11 psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2 days post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared with its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated a mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. Although there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.

A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson's disease.

Dopaminergic neuronal cell loss in the substantia nigra is responsible for the motor symptoms that are the clinical hallmark of Parkinson's disease (PD). As of yet there are no treatments that slow or prevent the degeneration of dopaminergic neurons in PD patients. Here we tested the hypothesis that dopaminergic neurons can be protected by treatment with the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) and the novel DNP prodrug MP201. We found that mice treated with low doses of DNP and MP201 were protected against motor dysfunction and dopamine neuron loss in the 6-hydroxydopamine PD model, with MP201 being more efficacious than DNP. Amelioration of motor deficits and dopamine neuron loss by MP201 treatment was associated with reductions in microglial and astrocyte activation and neuroinflammation. These preclinical findings suggest the potential application of mitochondrial uncoupling agents such as MP201 as disease-modifying therapies for PD.

Disease modifying mitochondrial uncouplers, MP101, and a slow release ProDrug, MP201, in models of Multiple Sclerosis.

Mitochondrial dysfunction is thought to be involved in the pathogenesis of MS and here we tested if brain penetrant mitochondrial uncouplers, DNP (MP101) and a novel prodrug of DNP (MP201), have the pharmacology to suppress demyelination and axonal loss in two independent models of MS by modulating the entire organelle's physiology. First, the gold standard EAE mouse model for MS was evaluated by daily oral treatment Day 7-21 with either MP101 or MP201 post-immunization. Both MP101/MP201 significantly suppressed progression of paralysis with limited infiltration of inflammatory cells. Strikingly, although mitochondrial uncouplers do increase energy expenditure even at the low doses provided here, they paradoxically preserved body weight at all doses in comparison to wasting in advanced paralysis of the placebos. Second, the effects of the compounds on suppressing inflammation were also evaluated in the cuprizone model, independent of the immune system. MP101/MP201 had a striking effect preserving both myelination and protecting the axons, in comparison to the placebos where both were destroyed. Both MP101/MP201 induced a significant and sustained increase in neurotrophin, BDNF, in the spinal cords. Both MP101/MP201 suppressed the expression of inflammatory cytokines including IL-1ß, TNF-α and iNOS. Results indicate that MP101/MP201 may be a "disease modifying" treatment for MS by specifically modulating mitochondrial physiology. This would be a completely novel treatment for MS, targeting the mitochondria directly using a unique platform, mitochondrial uncouplers, that initially act non-genomically based upon biophysics, but cascades into cellular remodeling, neuroprotection and pro-survival. Clinical Phase I testing of MP101 in Normal Healthy Volunteers (NHV) is currently underway allowing for the potential to subsequently evaluate translation in MS patients and other insidious diseases, at expected weight neutral doses.

2,4 Dinitrophenol as Medicine.

In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950's to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and "morning sickness" anti-nausea medication targeting pregnant women in the 1950's. The "thalidomide babies" became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of "social responsibility" allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle's physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer's Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for "metabesity", an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP's induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80's years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).

PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats.

The increased hepatic gluconeogenesis in type 2 diabetes mellitus has often been ascribed to increased transcription of phosphoenolpyruvate carboxykinase 1, cystolic form (PEPCK1), although recent evidence has questioned this attribution. To assess the metabolic role of PEPCK1, we treated regular chow fed and high-fat fed (HFF) male Sprague-Dawley rats with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) against PEPCK1 and compared them with control ASO-treated rats. PEPCK1 ASO effectively decreased PEPCK1 expression in the liver and white adipose tissue. In chow fed rats, PEPCK1 ASO did not alter adiposity, plasma glucose, or insulin. In contrast, PEPCK1 ASO decreased the white adipose tissue mass in HFF rats but without altering basal rates of lipolysis, de novo lipogenesis, or glyceroneogenesis in vivo. Despite the protection from adiposity, hepatic insulin sensitivity was impaired in HFF PEPCK1 ASO-treated rats. PEPCK1 ASO worsened hepatic steatosis, although without additional impairments in hepatic insulin signaling or activation of inflammatory signals in the liver. Instead, the development of hepatic insulin resistance and the decrease in hepatic glycogen synthesis during a hyperglycemic clamp was attributed to a decrease in hepatic glucokinase (GCK) expression and decreased synthesis of glycogen via the direct pathway. The decrease in GCK expression was associated with increased expression of activating transcription factor 3, a negative regulator of GCK transcription. These studies have demonstrated that PEPCK1 is integral to coordinating cellular metabolism in the liver and adipose tissue, although it does not directly effect hepatic glucose production or adipose glyceroneogenesis.

Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice.

Traumatic brain injury (TBI) results in cognitive impairment, which can be long-lasting after moderate to severe TBI. Currently, there are no FDA-approved therapeutics to treat the devastating consequences of TBI and improve recovery. This study utilizes a prodrug of 2,4-dinitrophenol, MP201, a mitochondrial uncoupler with extended elimination time, that was administered after TBI to target mitochondrial dysfunction, a hallmark of TBI. Using a model of cortical impact in male C57/BL6 mice, MP201 (80 mg/kg) was provided via oral gavage 2-hr post-injury and daily afterwards. At 25-hr post-injury, mice were euthanized and the acute rescue of mitochondrial bioenergetics was assessed demonstrating a significant improvement in both the ipsilateral cortex and ipsilateral hippocampus after treatment with MP201. Additionally, oxidative markers, 4-hydroxyneneal and protein carbonyls, were reduced compared to vehicle animals after MP201 administration. At 2-weeks post-injury, mice treated with MP201 post-injury (80 mg/kg; q.d.) displayed significantly increased cortical sparing (p = .0059; 38% lesion spared) and improved cognitive outcome (p = .0133) compared to vehicle-treated mice. Additionally, vehicle-treated mice had significantly lower (p = .0019) CA3 neuron count compared to sham while MP201-treated mice were not significantly different from sham levels. These results suggest that acute mitochondrial dysfunction can be targeted to impart neuroprotection from reactive oxygen species, but chronic administration may have an added benefit in recovery. This study highlights the potential for safe, effective therapy by MP201 to alleviate negative outcomes of TBI.

Breast Cancer is Common in Women With Ovarian Malignant Mixed Mullerian Tumors.

BACKGROUND: Ovarian malignant mixed Mullerian tumors (MMMTs) are uncommon cancers. The purpose of the study was to determine the rate of metachronous or synchronous breast cancer as well as the rate of truncating germline BRCA1 and/or BRCA2 mutations in a series of women with these uncommon tumors. MATERIALS AND METHODS: Records were reviewed to identify all women with MMMTs treated by the gynecologic oncology service. The stage, grade, histology, survival, and rate of coexistent breast cancer were determined. Tumor and/or peripheral blood was tested for BRCA1 and BRCA2 truncating mutations. RESULTS: Twenty-four patients with MMMTs were found. Tumor and paired peripheral blood was available on 20 patients and 4 more patients had only peripheral blood available. Family pedigrees were available on all 24 patients. Fifteen of 24 (62.5%) patients were found to have metachronous or synchronous breast cancers with 9 of 15 (60%) having bilateral breast cancer. No BRCA1 or BRCA2 mutations were found (somatic or germline) in this cohort. CONCLUSIONS: Although an uncommon tumor, MMMTs are often found in women with breast cancer. Despite this finding, BRCA1 or BRCA2 germline mutations are not common in this population. PRECIS: Ovarian MMMTs are frequently found in women with cancer but are not frequently associated with defects in BRCA1 or BRCA2.

Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents.

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.

Mitochondrial Uncoupler Prodrug of 2,4-Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis.

The ability of novel mitochondrial uncoupler prodrug of 2,4-dinitrophenol (DNP), MP201, to prevent neuronal damage and preserve visual function in an experimental autoimmune encephalomyelitis (EAE) model of optic neuritis was evaluated. Optic nerve inflammation, demyelination, and axonal loss are prominent features of optic neuritis, an inflammatory optic neuropathy often associated with the central nervous system demyelinating disease multiple sclerosis. Currently, optic neuritis is frequently treated with high-dose corticosteroids, but treatment fails to prevent permanent neuronal damage and associated vision changes that occur as optic neuritis resolves, thus suggesting that additional therapies are required. MP201 administered orally, once per day, attenuated visual dysfunction, preserved retinal ganglion cells (RGCs), and reduced RGC axonal loss and demyelination in the optic nerves of EAE mice, with limited effects on inflammation. The prominent mild mitochondrial uncoupling properties of MP201, with slow elimination of DNP, may contribute to the neuroprotective effect by modulating the entire mitochondria's physiology directly. Results suggest that MP201 is a potential novel treatment for optic neuritis.

2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene huntingtin. There is no treatment to prevent or delay the disease course of HD currently. Oxidative stress and mitochondrial dysfunction have emerged as key determinants of the disease progression in HD. Therefore, counteracting mutant huntingtin (mHtt)-induced oxidative stress and mitochondrial dysfunction appears as a new approach to treat this devastating disease. Interestingly, mild mitochondrial uncoupling improves neuronal resistance to stress and facilitates neuronal survival. Mild mitochondrial uncoupling can be induced by the proper dose of 2,4-dinitrophenol (DNP), a proton ionophore that was previously used for weight loss. In this study, we evaluated the effects of chronic administration of DNP at three doses (0.5, 1, 5mg/kg/day) on mHtt-induced behavioral deficits and cellular abnormalities in the N171-82Q HD mouse model. DNP at a low dose (1mg/kg/day) significantly improved motor function and preserved medium spiny neuronal marker DARPP32 and postsynaptic protein PSD95 in the striatum of HD mice. Further mechanistic study suggests that DNP at this dose reduced oxidative stress in HD mice, which was indicated by reduced levels of F2-isoprostanes in the brain of HD mice treated with DNP. Our data indicated that DNP provided behavioral benefit and neuroprotective effect at a weight neutral dose in HD mice, suggesting that the potential value of repositioning DNP to HD treatment is warranted in well-controlled clinical trials in HD.

Assessment of False-negative Ascites Cytology in Epithelial Ovarian Carcinoma: A Study of 313 Patients.

OBJECTIVE: The objective was to determine how often peritoneal cytology is positive for malignancy in women with known ovarian cancer. Knowing this fact would help determine the usefulness of diagnostic paracentesis. METHODS: Records of all women diagnosed with invasive epithelial ovarian cancer from 2004 to 2012 were examined to correlate presence of ascites, cytologic, and pathologic findings. RESULTS: A total of 313 patients were included in analysis. A total of 210 of 313 patients (67.1%) with ascites had cytology positive for malignancy. This left 103 patients with ascites and cancer without malignant cells found in the ascites removed at the time of surgery. CONCLUSIONS: Except in a few cases, paracentesis is not recommended for the diagnosis of ovarian cancer because of the potential spreading of cancer. Furthermore, with only just over two thirds of cases of known cancer and ascites having cytology positive for malignancy, the value of paracentesis for diagnosis of ovarian cancer is minimal.

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya.

Recent findings have elucidated roles for mitochondrial uncoupling proteins (UCPs) in neuronal plasticity and resistance to metabolic and oxidative stress. UCPs are induced by bioenergetic challenges such as caloric restriction and exercise and may protect neurons against dysfunction and degeneration. The pharmacological uncoupler 2,4-dinitrophenol (DNP), which was once prescribed to >100,000 people as a treatment for obesity, stimulates several adaptive cellular stress-response signaling pathways in neurons including those involving the brain-derived neurotrophic factor (BDNF), the transcription factor cyclic AMP response element-binding protein (CREB), and autophagy. Preclinical data show that low doses of DNP can protect neurons and improve functional outcome in animal models of Alzheimer's and Parkinson's diseases, epilepsy, and cerebral ischemic stroke. Repurposing of DNP and the development of novel uncoupling agents with hormetic mechanisms of action provide opportunities for new breakthrough therapeutic interventions in a range of acute and chronic insidious neurodegenerative/neuromuscular conditions, all paradoxically at body weight-preserving doses.

Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

Is the routine use of bevacizumab in the treatment of women with advanced or recurrent cancer of the cervix sustainable?

BACKGROUND: New chemotherapy combinations are being tested for the treatment of women with advanced, persistent or recurrent cervical cancer. We sought to evaluate the cost effectiveness of some newer combination therapies in cervical cancer. PATIENTS AND METHODS: A cost effectiveness decision model was used to analyze Gynecologic Oncology Group 240. All regimens were modeled for seven cycles. The regimens studied are as follows: regimen 1, cisplatin/paclitaxel (CP); regimen 2, CP with bevacizumab (CP+B); regimen 3, paclitaxel/topotecan (PT); and regimen 4, PT with bevacizumab (PT+B). Overall survival, cost, and complications were studied. Sensitivity analyses were performed. RESULTS: Mean chemotherapy costs over mean total costs for seven cycles of each follows: CP $571/$32,966; CP+B $61,671/$96,842; PT $9,211/$71,620; and PT+B $70,312/$109,211. Incremental cost-effectiveness ratio (ICER) for CP+B was $133,559/quality adjusted life year (QALY). ICER for PT+B was $124,576/QALY. To achieve an incremental ICER for CP+B:CP of <$50,000/QALY gained, the mean overall survival has to increase from 1.1 years with CP to 3.5 years with CP+B. An ICER <$50,000/QALY for the other regimens would take a survival of >10 years for PT and 4.1 years for PT+B. Treating 1,000 women with cervical cancer with CP+B would cost almost double the cost of treating >18,000 women with ovarian cancer annually (carboplatin/paclitaxel). CONCLUSION: CP is the most cost effective regimen. A 12-month increase in overall survival will not even make the newer combinations cost effective. Currently, the use of bevacizumab is not sustainable at today's costs.

Recurrent Pseudomembranous Colitis in an Ovarian Cancer Patient Undergoing Carboplatin Chemotherapy.

Background. Diarrhea is a common problem in ovarian cancer patients undergoing chemotherapy and Clostridium difficile infection has been identified as a cause. The proper diagnosis and treatment of diarrhea are critical to patient care, especially to prevent the serious complications from a severe Clostridium difficile infection (CDI). Case. We present a heavily pretreated ovarian cancer patient who developed recurrent pseudomembranous colitis while receiving carboplatin chemotherapy. Despite treatment with oral metronidazole for fourteen days, the patient's diarrhea relapsed and colonoscopy revealed extensive pseudomembranous colitis. The infection eventually resolved with the combination of oral vancomycin and metronidazole. Conclusions. Diarrhea is a common problem in patients undergoing chemotherapy for ovarian cancer. Management requires obtaining the proper diagnosis. Clostridium difficile associated pseudomembranous colitis must be part of the differential diagnosis. Treatment must be sufficient to prevent relapses of the Clostridium difficile infection to prevent serious consequences in an already vulnerable patient population.

Electrosurgical Settings and Vaginal Cuff Complications.

BACKGROUND AND OBJECTIVES: After being encouraged to change the technique for opening the vaginal cuff during robotic surgery, this study was performed to determine the correlation between vaginal cuff complications and electrosurgical techniques. METHODS: The study group consisted of patients who had their vaginal cuffs opened with a cutting current compared to the group of patients having their vaginal cuff opened with a coagulation current. Data were collected on 150 women who underwent robotic surgery for endometrial cancer. All patients received preoperative antibiotics. Data, including operative time, type of electrosurgery used, estimated blood loss, transfusion rate, and complications, were collected from the patients' records. RESULTS: Surgeries in 150 women and the associated complications were studied. The mean age of the patients was not significantly different between the groups (P = .63). The mean body mass index was 38 kg/m(2) in the coagulation arm and 36 kg/m(2) in the cutting arm (P = .03). Transfusion was not required. Estimated blood loss and operative time were not significantly different in the coagulation versus the cutting arms (P = .29 and .5; respectively). No patients in the cutting arm and 4 patients (with 5 complications) in the coagulation arm had cuff complications (P = .02). CONCLUSIONS: Complications involving the vaginal cuff appear to occur more frequently when the vagina is entered by using electrosurgery with coagulation versus cutting in this cohort of patients undergoing robot-assisted surgery for endometrial cancer..

The interaction of ifosfamide and aprepitant in gynecologic malignancies.

•Aprepitant combined with ifosfamide may lead to encephalopathy.•Aprepitant-ifosfamide induced encephalopathy was of short duration in these cases.

Treatment of advanced or recurrent cervical cancer with Cisplatin or Cisplatin containing regimens: a cost effective analysis.

BACKGROUND: Trials have demonstrated improvements in survival with adding paclitaxel (P) or topotecan (T) to cisplatin (C) for the treatment of advanced cervical cancer. We sought to evaluate the cost effectiveness of these regimens. METHODS: A decision model was developed based on Gynecologic Oncology Group (GOG) protocols 169 and 179. Arm 1 is 6 cycles of cisplatin. Arm 2 is 6 cycles of CP while arm 3 is 6 cycles of CT. Parameters include overall survival (OS), cost and complications. Sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) for C versus CP is $13,654/quality-adjusted life-year (QALY) gained. For CT compared to C, the ICER is $152,327/QALY. When compared simultaneously, CT is dominated. At a willingness to pay (WTP) threshold of $50,000/QALY, C is the preferred option but CP is acceptable. Sensitivity analyses suggest that CT would become the preferred option if it was to improve OS to 24 months (compared to 9.4 months). CONCLUSIONS: In this model, CP is an acceptable alternative to cisplatin for the treatment of these patients with an increase in cost of only $13,654/QALY. The addition of topotecan did not increase survival enough to justify the increased cost.

The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and -2.

Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with (13)C(3)-D(5)-glycerol or (13)C(18)-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that (13)C(3)-D(5)-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, (13)C(18)-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D(5)-glycerol to mice and measured plasma levels of D(5)-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D(5)-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered (13)C(18)-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol.